March 2023
[Read on Examine]
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Table of Contents
Editor's Picks
10 Studies
Muscle Gain & Exercise
Skin, Hair, & Nails
19 Studies
5 Studies
Mental Health
Vitamins & Minerals
8 Studies
7 Studies
Men’s Health
Herbal Supplements
11 Studies
8 Studies
Healthy Aging & Longevity
Joints & Bones
14 Studies
7 Studies
Women’s Health
Brain Health
12 Studies
10 Studies
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Editor's Picks
How does plant protein intake affect total protein intake,
quality, and cost, and nutrient intake?
This cross-sectional study suggests that as plant protein intake increases, total protein intake, protein
quality, protein cost, and intake of the vitamins B12 and D decrease, whereas fiber, folate, iron, and zinc
intake increase. These results should be interpreted with caution because protein research is complex,
and there is still plenty to unpack.
Background
Plant-based diets are rapidly gaining popularity for their environmental (e.g., less greenhouse-gas emissions
and land use) and health benefits (e.g., reduced cardiometabolic disease and mortality risk),[4] but plant
foods have their own limitations, such as low vitamin B12 content and poor iron bioavailability.[5] Plant
protein is also considered to be of “lower quality” than animal protein because it is often less digestible and
deficient in one or more indispensable amino acids (IAA), which are amino acids that can only be obtained
from the diet and cannot be made by the body.[6] Is plant protein intake associated with dietary nutrient
intake and protein quality and cost?
The study
This cross-sectional study evaluated data from three cycles of the National Health and Nutrition
Examination Survey (NHANES 2013–2014, 2015–2016, and 2017–2018) to assess protein and nutrient intake,
quality, and cost across quartiles of plant protein intake in 14,888 adults (19 and older). As a percentage of
total protein intake, the quartiles of plant protein intake were less than 28% (Q1), 28%–32% (Q2), 32%–36%
(Q3), and more than 36% (Q4).
Dietary intake data were collected by trained interviewers who conducted 24-hour dietary recalls per
survey set. Protein intakes from animal and plant sources were estimated using the United States
Department of Agriculture Food and Nutrient Database for Dietary Studies (FNDDS) and the Food Products
Equivalents Database. The FNDDS provides nutritional composition of all foods and food groups such as
“protein foods”, “grains”, or “vegetables”, and the Food Products Equivalents Database provides food group
composition of each food and beverage consumed. Amino acid intake was estimated according to the
FNDDS and the National Nutrient Database for Standard Reference. If amino acid contents were not
specified, they were estimated from matching similar foods/ingredients. Protein quality was estimated using
the protein digestibility-corrected amino acid score (PDCAAS).
3
Digging Deeper: How is protein quality assessed?
Although proteins can serve as a source of energy, they are also the main dietary source of nitrogen
and IAAs that play a crucial role in growth, function, and maintenance. Protein quality is defined by
the ability of a protein source to satisfy IAA needs for a specific population. It is characterized by
amino acid composition, digestibility (i.e., the proportion of ingested protein that is available for
absorption) of the IAAs, and the requirements of the target population. Generally, requirements for
growth and development decrease with age, and maintenance becomes the primary concern.[7]
There are two main methods that are used to determine protein quality based on the ratio of the
limiting IAA (i.e., the IAA with the lowest quantity) of a test protein compared to a digestibilitycorrected reference protein. The first method is the protein digestibility-corrected amino acid score
(PDCAAS) and the second method is the digestible indispensable amino acid score (DIAAS). Two
main differences are that the PDCAAS uses digestibility values determined at the protein level and at
the end of digestion (i.e., fecal level), where factors like nitrogen absorption and recycling and
microbial metabolism and metabolites can influence results and sometimes result in overestimation.
The DIAAS uses digestibility values determined at the individual amino acid level and at the end of
the small intestine (i.e., ileum), where most protein is absorbed. The choice to determine digestibility
at the end of digestion rather than at the end of the small intestine appears to account for most of
the variance between method scores.[7] Interestingly, neither of the methods properly account for
protein complimentarity, which is when protein sources with amino acid profiles that compensate for
limiting amino acids in each other are combined, such as in the case of grains and legumes or grains
and nuts/seeds. The PDCAAS has an upper limit of 100% for protein quality, and the DIAAS only uses
digestibility values for the limiting IAA.[7]
The PDCAAS is the current internationally approved method because there is a large amount of data
available for a large range of foods, it is easier to measure, and it has a longer history of use.
However, the PDCAAS has been criticized because the digestibility between amino acids can vary
widely[8] and protein is mainly digested and absorbed in the small intestine,[9] which can lead to
overestimates of protein quality of more than 10%.[7] In fact, the World Health Organization and Food
and Agriculture Organization of the United Nations recommends the use of DIAAS as the preferred
metric for protein quality assessment, but this requires amino acid digestibility data from
measurements at the end of the small intestine (i.e., ileum) that are extremely invasive and have
mostly only been collected in animals like pigs and rats.[7] This means that the current digestibility
values available for use with the DIAAS are only true for pigs and rats, and not necessarily humans.
Alternative methods (e.g., stable isotopes) developed for this reason have yielded promising results,
but they have not been rigorously validated,[10] and thus these data gaps limit the practical use of
DIAAS.[11]
The cost of protein (grams per U.S. dollar) were estimated using the 2001–2004 Center for Nutrient Policy
and Promotion’s National Food Prices Database and adjusted for inflation for the appropriate NHANES
year. Dietary modeling was conducted to evaluate the effects of plant protein complimentarity when amino
acids from grains were partially (25% or 50%) replaced by amino acids from higher quality plant protein
foods such as legumes (nonoil seeds, pulses such as beans and lentils, and oil-seed crops, such as peanuts
and soybeans).[12] Data and analyses were adjusted for the complex sample design of NHANES and
sociodemographics. In other words, the researchers used appropriate survey weights that estimate the
number of U.S. residents that each survey respondent represents.
The results
The usual protein intake was 82.6 grams per day, of which about 30% was plant protein. Plant protein
4
intake was positively associated with age, proportions of Hispanic and non-Hispanic Asian populations,
economic and education status, moderate physical activity, and not smoking. It was inversely associated
with proportions of male adults and non-Hispanic Black populations, vigorous physical activity, smoking,
and obesity.
Plant protein intake was inversely associated with total protein intake, protein quality, and protein cost.
Grains were the primary source of plant protein, despite not being considered a “protein food” (according
to the FNDDS), as well as the most economical source of protein (24–26 grams per dollar) from the FNDDS
food groups. Legumes were the most economical source of plant-based protein (28–38 grams per U.S.
dollar). Greater plant protein intake was associated with lower intakes of vitamins B12 and D, but with
higher intakes of fiber, folate, iron, and zinc.
Interestingly, even with a lower total protein intake at the highest quartile of plant protein intake, IAA intake
was sufficient (IAA score > 1.0), but protein quality was not adequate (PDCAAS = 0.80). It’s also worth
mentioning that protein from “snacks and sweets” and “grains” doubled and tripled, respectively, when
comparing people who consumed less than 28% of plant protein intake as a percentage of total protein
intake to people who consumed more than 36%, while mixed dishes (that could be optimized for protein
complementarity) increased by about 25%. Dietary modeling that replaced 50% of grain protein amino
acids with legumes suggested an improvement of protein quality of 10%.
Top 5 sources of protein according to quartiles of plant protein intake
Note
The results from the study should be interpreted with caution because the cross-sectional design prevents
the determination of cause and effect, the dietary intake data were self-reported and only collected for one
day, and there were several estimates based on many imperfect databases. For example, the amino acid
database was not complete and the authors used a conservative coefficient of 0.8 for the nitrogen
digestibility of most foods, which is likely an underestimation.
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The big picture
Globally, about 60% of dietary protein, providing about 20% of total global protein intake, comes from
plant sources and wheat, which is deficient in the two IAAs lysine and threonine.[13] In a 2021 systematic
review of 141 observational and intervention studies, protein intake was lower in people following plantbased diets, but well within recommended intake levels when compared to meat eaters.[14] In a 2021 analysis
of 6,498 Canadian adults that used data from the 2015 Canadian Community Health survey and was similar
to the study under review, protein content and quality (PDCAAS) decreased as plant protein intake
increased.[15] Most participants consumed 25%–50% of protein from plant foods, and grains represented the
majority of plant protein consumed.
Protein quality scores can give a relative reference for individual foods, but, in reality, several foods with
varying amino acid compositions are combined within a meal. Until a more accurate and inclusive
measurement method for protein quality becomes feasible (see sidebar and note above), overall dietary
protein intake for people who consume a greater proportion of plant protein can be improved with an
understanding of complementary proteins that optimize protein digestibility.[16][17] Because the body doesn’t
exactly have protein or IAA stores, it oxidizes excess amino acids that are not used within several hours,
meaning that protein complementarity must be considered on a meal basis. Generally, grains and legumes
or nuts and seeds complement each other, but because grains are more commonly consumed, an increase
in legume and nut and seed intake within each meal help, as modeled in the study under review.[18][19]
Moreover, legumes have a high level of protein and nutrient density per dollar.[20] Pulses, or edible seeds
from legumes such as beans, lentils and peas have been shown to improve nutrient density in the U.S.[19]
Beyond quality, quantity, and cost, food processing and nutrition content should be considered in the
context of plant protein intake. Food processing can influence protein digestibility and amino acid
composition. For example, dry heat reduces digestibility, while wet heat increases digestibility. In addition,
Maillard browning and heat can reduce lysine bioavailability. Digestibility of limiting IAAs in legumes ranges
from 75% to 101%, while that of grains ranges from 13% to 96%, often depending on processing.[7] A 2021
crossover randomized controlled trial suggested that a whole-grain diet promotes improved protein
turnover, net protein balance, and muscle function, when compared to a macronutrient-matched refinedgrain (i.e., more processed) diet.[21] Although plant protein sources can be deficient in vitamins B12, they
have relatively high levels of certain minerals and contain bioactive compounds such as fiber,
phytochemicals, and certain peptides (i.e., small proteins of two or more amino acids) with disease-fighting
properties like the ability to affect enzymes, hormone expression, and lipid metabolism. These properties
may give plant protein a different “edge” over animal protein.[22][23][24] In a 2020 prospective cohort study
that included 416,104 participants, greater plant protein intake was associated with small decreases in risk
of overall and cardiovascular disease mortality.[25] It appears that, with careful monitoring and
understanding of plant protein sources and processing and amino acid complementarity, plant protein may
be comparable to animal protein even when it comes to muscle protein synthesis and the protein needs of
older people.[6][26][27][13] However, further research is required to determine how more precise protein quality
measurements and the food matrix (interaction of nutrient and non-nutrient components) may influence
anabolic responses to protein intake.[16][28][7]
Do antioxidants interfere with muscular adaptations?
This randomized controlled trial found that supplementing with the antioxidant vitamins C and E had
negligible effects on resistance exercise-induced adaptations.
Background
Oxidative stress is an imbalance between the production of reactive oxygen and nitrogen species (RONS)
and the capacity of the body’s antioxidant defenses to neutralize them. Skeletal muscle contraction
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generates RONS, and if exercise is intense and prolonged, an excessive production of RONS can result. As
their name implies, RONS are highly reactive and can cause oxidative damage to cells, muscle fatigue, and
impairments in muscle force.[30] Thus, supplementing with antioxidants is of interest for minimizing the
adverse effects of RONS during and after exercise. However, evidence suggests that RONS are also
involved in regulating exercise-induced adaptations.[31] Does that mean supplementing with antioxidants
could impair such adaptations?
The study
In this 10-week randomized controlled trial, 23 recreationally resistance-trained men (ages 18 to 32)
performed resistance exercise 4 days per week and supplemented daily with either vitamins C (1,000 mg)
and E (235 mg) or a placebo every morning. All of the participants were instructed to follow a diet
conducive to building muscle (daily protein and carbohydrate intake of 2 and 4–7 grams per kilogram of
body weight, respectively, as well as a 300 kcal energy surplus on training days) and to avoid foods
containing high amounts of antioxidants.
The primary outcome was muscle mass, measured as total and segmental soft tissue fat-free mass using
dual-energy X-ray absorptiometry (DXA). The secondary outcomes were total and segmental fat mass,
handgrip strength, and 1-repetition maximum (1RM), maximum power, and maximum velocity in the bench
press and squat exercises performed on a Smith machine.
The results
There were no significant differences between groups for changes in fat-free mass, although dominant arm,
nondominant arm, and total upper body fat-free mass (which includes both arms and the trunk) increased
compared to baseline in the placebo group only.
Visceral adipose tissue increased in the placebo group compared to the vitamin group. There were no other
differences between groups for changes in fat mass, although gynoid fat (i.e., fat around the hips, chest,
and thighs) increased compared to baseline in the vitamin group only.
There were no significant differences between groups for performance-related outcomes, although
dominant-hand grip strength and maximal power and velocity dropoff (i.e., the amount of decrease in
velocity with an increase in load) in the bench press improved compared to baseline in the placebo group
only.
Note
A limitation of this study is that dietary intake was not assessed during the study, despite all the
participants being prescribed the same general muscle-building diet.
Additionally, the researchers calculated that 16 participants in each group were needed to detect
differences in muscle mass and strength between groups. Thus, the study was underpowered.
The big picture
Exercise promotes the activation of signaling pathways in skeletal muscle that, when repeatedly activated,
lead to gradual alterations in protein content and enzyme activities, yielding changes in muscle’s physical
properties and appearance.[32]
Although it’s compelling to try to counteract the negative effects of RONS with antioxidants, there’s
increasing evidence that the RONS produced during exercise contribute to the activation of the
aforementioned signaling pathways.[33] Thus, interventions that minimize the concentration of RONS in
muscle during exercise may prevent the physiological increase in RONS necessary to activate the signaling
pathways that facilitate muscular adaptations.
Indeed, studies that have used antioxidant supplements as a means to neutralize the effects of RONS have
reported a blunting of the molecular responses conducive to muscle hypertrophy.[31]
For instance, vitamin C blunted the increased phosphorylation of extracellular signal-regulated protein
kinases 1 and 2 and p70S6 kinase (all of which are positive regulators of muscle protein synthesis) induced
7
by resistance exercise in rats,[34] and this finding was also reported in humans supplementing with vitamins
C and E.[35]
Additionally, while excessive exposure to RONS during exercise causes fatigue and impairs muscle force
production, moderate amounts of RONS seem to be conducive to force production.[30] Thus, there seems to
be an optimal amount of RONS, where an increase or decrease in production results in suboptimal muscle
contractile function.[31]
The biphasic effect of ROS on skeletal muscle force production
Adapted from Powers * Jackson, 2008. [30]
Although there were no significant differences in fat-free mass (FFM) and muscle strength between groups
in the summarized study, the sample size was substantially less than what was calculated as necessary to
detect differences between groups. To help overcome this issue, the researchers calculated effect sizes for
each outcome to determine whether there may have been practically meaningful differences between
groups.
A small effect size was found for bench press 1RM (percent change of 12.40% vs. 18.30%) and maximal
force output (percent change of 10.54% vs. 14.13%) in favor of the placebo group. Additionally, a small
effect size was found for dominant arm FFM (percent change of 2.72% vs. 4.88%) in favor of the placebo
group. However, for many other outcomes, there were no clear differences between groups, and arguably,
some of them trended in favor of the vitamin group. All in all, the summarized study does not provide
convincing evidence that supplementing with vitamins C and E will limit muscular adaptations. Are other
studies on the topic in agreement?
When analyzing the available research in this area, it’s important to categorize studies based on the
population studied, namely, whether the participants were younger or older adults. (The reason for this is
discussed below.) Starting with younger adults, there are three main studies to consider.
One study found no differences between the vitamin and placebo groups for changes in upper arm, thigh,
or total lean mass,[36] and another found no difference between groups for the change in thigh muscle
thickness.[37] In the third study, which included three groups (vitamin, placebo, and a control group that did
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not perform exercise), there were no differences between groups for the change in total FFM, but the
percentage change in FFM was greater than the control group in the placebo group only.[38]
With respect to strength, one study reported that 1RM biceps curl increased in the placebo group compared
to the vitamin group, while there were no differences in 1RM triceps press, knee extension, or knee flexion
between groups.[36] In the other two studies, quadriceps peak torque did not differ between groups, and
estimated deadlift and dumbbell lunge strength did not differ between groups.[37][38]
A limitation of these studies is that they were all 10 weeks long. A longer intervention duration may be
required for the potential negative effects of supplementation with vitamins C and E to become more
apparent.
In adults at least 60 years old, evidence from two studies indicated that supplementing with vitamins C and
E may improve resistance exercise-induced gains in FFM,[39][40] while one study found no effect[41] and the
other reported a greater increase in lean mass in the placebo group.[42] For strength, there were no reported
differences between groups.[41][40][42]
Unlike the evidence in younger adults, which indicates that supplementation with vitamins C and E has a
neutral to slightly negative effect on resistance exercise-induced adaptations, there is some evidence in
older adults that supplementation with vitamins C and E may improve resistance exercise-induced
increases in FFM. A potential explanation for this is that aging results in increased levels of oxidative stress
and may blunt the adaptive increase in total antioxidant capacity in response to exercise.[43] Therefore,
supplementing with vitamins C and E may provide a beneficial effect in older adults by restoring the
balance between oxidants and antioxidants.
While the mechanistic basis for why vitamins C and E would dampen resistance exercise-induced
adaptations is sound, when it comes to direct outcomes of interest (i.e., changes in 1RM strength and FFM),
as opposed to indirect outcomes (i.e., changes in the activation of regulatory proteins), the available
evidence doesn’t clearly demonstrate that supplementing with vitamins C and E is cause for concern.[44] This
isn’t entirely surprising, as the physiological relevance of a blunted activation of one or two regulatory
proteins to functional endpoints is questionable.[45]
Further long-term randomized trials are needed to determine whether supplementing with vitamins C and E
impairs resistance exercise-induced adaptations in younger adults. The results of the available studies are
equivocal, but there is an absence of evidence to indicate any benefit of supplementation with vitamins C
and E for resistance exercise-induced adaptations in this population. Therefore, younger adults interested in
maximizing exercise-induced adaptations may find it prudent to avoid high-dose supplementation with
vitamins C and E, particularly in close proximity to resistance exercise sessions.
The health effects of saffron
In this meta-analysis of randomized controlled trials, supplementation with saffron extract had
beneficial effects on blood lipid levels, glycemic control, systolic blood pressure, and a marker of
inflammation. However, the certainty of evidence was very low for most outcomes.
Background
Crocus sativus, commonly known as saffron, is a flower traditionally used to make a spice of the same
name. Beyond its use as a culinary ingredient, saffron is a popular supplement, containing a variety of
compounds with suspected health-promoting effects, including crocin, crocetin, picrocrocetin, safranal, and
kaempferol. Saffron supplements have been repeatedly tested for their effects on markers of
cardiometabolic health, like blood lipid levels and glycemic control.
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Digging Deeper: The world's most expensive spice
Saffron is likely the most expensive spice in the world, with a by-weight cost similar to that of
precious metals like silver. Saffron’s extraordinary price tag is due to the labor-intensive nature of its
cultivation. Saffron spice consists only of the flower’s stigmas — small threads growing from the
center of the saffron flower itself. These threads are delicate, usually requiring careful harvesting by
hand. On top of that, saffron stigmas are very small, with over 100 flowers typically needed to make
about a single gram of dried saffron spice. This means that many hours of work are needed to
produce appreciable amounts of the spice.
Saffron supplements, however, aren’t always made of the stigmas, and often use the much more
readily available flower petals instead. Because the petals contain many of the same compounds as
the stigmas,[50] saffron supplements can be more affordable while maintaining some of the same
potential health benefits.
The study
This meta-analysis of 32 randomized controlled trials examined the effect of saffron supplementation on
various markers of health. The trials included a total of 1,674 participants (average ages of 27–58). The
trials ranged in duration from 1 to 12 weeks. The dosage of saffron ranged from 5 to 1,000 mg, provided as
either extract or isolated phytochemical.
The following outcomes were assessed:
Body weight
BMI
Waist circumference
Fat mass
Systolic blood pressure
Diastolic blood pressure
Fasting glucose
Fasting insulin
HbA1c
HOMA-IR, a marker of insulin resistance
Total cholesterol
LDL-C and HDL-C
Triglycerides
ApoB
The inflammatory markers C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α
The liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and alkaline
phosphatase (ASP)
Total antioxidant capacity (TAC) of serum
Malondialdehyde (MDA), a marker of oxidative stress
The studies were assessed for likelihood of bias using the Cochrane Collaboration tool. By this measure, 11
trials were rated as good, 12 trials were rated as fair, and 9 trials were rated as poor. The certainty of
evidence for each outcome was rated according to the GRADE criteria (Grading of Recommendations,
Assessment, Development and Evaluations), which is based on details like study blinding, consistency of
results, and signs of publication bias.
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The results
Supplementation with saffron decreased total cholesterol (−6.87 mg/dL), LDL-C (−6.71 mg/dL),
triglycerides (−8.81 mg/dL), fasting glucose (−7.59 mg/dL), HbA1c (−0.18%), HOMA-IR (−0.49), systolic
blood pressure (−3.42 mmHg), TNF-α (−2.54 pg/mL), waist circumference (−1.5 cm), MDA (−1.5 uM/L), ALT
(−2.16 U/L), and increased TAC.
The certainty of evidence for all these outcomes was rated as very low, with the exception of the decrease
in TNF-α, which was rated as low.
The big picture
Overall, the results of the current meta-analysis suggest that saffron supplementation might help improve
markers of cardiometabolic health, potentially reducing the risk and/or severity of conditions like diabetes
and cardiovascular disease. However, the evidence quality was considered to be low, so these possible
benefits need to be confirmed by future high-quality studies.
Saffron has also been investigated for its effect on a number of other health outcomes, most of which
relate to the brain. In particular, saffron has been repeatedly tested for its effect on depression, with
generally positive results found. In one meta-analysis of randomized controlled trials, saffron
supplementation (typically 30 mg of extract) reduced depression symptoms and increased depression
remission rates compared to a placebo.[51] However, this meta-analysis included a limited number of trials
included (6 with a placebo group), all lasting between 6 and 8 weeks, meaning that additional trials, ideally
with longer follow-ups, are needed.
Saffron has also been investigated for its effect on sleep, again with positive results. Examine previously
covered a meta-analysis of 8 randomized controlled trials, which found that saffron supplementation
improved sleep quality, with a possible dose-response relationship, meaning that higher doses of up to 100
mg per day seemed to increase the overall effect.[52] However, as with the studies on depression, the limited
number of trials reduces confidence in the finding.
Finally, a few studies have investigated whether saffron might be helpful for cognitive function and
dementia, with mixed results. One randomized controlled trial involving 46 participants with mild-tomoderate Alzheimer’s disease found that supplementation with saffron for 16 weeks improved two tests of
cognitive function compared to a placebo.[53] Another small RCT involving 25 people with mild cognitive
impairment also found that supplementation with saffron for 12 months improved performance on one test
of cognitive function, but it did not clearly improve performance on another.[54] Finally, a 12-week study on
37 people undergoing coronary artery bypass grafting found no clear benefit for cognitive function from a
saffron supplement.[55]
Saffron: Potential health benefits
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Low-carbohydrate vs. high-carbohydrate diets for type 2
diabetes
In this randomized controlled trial in people with type 2 diabetes, a low-carbohydrate, high-fat diet
improved HbA1c compared to a high-carbohydrate, low-fat diet at 6 months, but not at 9 months.
Background
Type 2 diabetes (T2D) is strongly associated with nonalcoholic fatty liver disease (NAFLD),[103] and glycemic
control and liver fat are both improved with weight loss.[104][105] As such, the consumption of a hypocaloric
diet is pivotal for disease treatment, but intentional caloric restriction can be difficult to sustain due to
increases in hunger. Therefore, it’s important to study whether certain types of diets can improve
cardiometabolic health without intentional caloric restriction.
The study
In this 6-month randomized controlled trial with an additional 3 months of follow-up, 165 participants
(average age of 65; average BMI of 34) with T2D, 88% of whom had NAFLD, were assigned to consume
one of two diets:
High-carbohydrate, low-fat (HCLF): 50%–60% of total daily energy intake from carbohydrate, 20%–
30% fat, 20%–25% protein.
Low-carbohydrate, high-fat (LCHF): no more than 20% of total daily energy intake from
carbohydrate, 50%–60% fat, 25%–30% protein.
12
In both groups, the participants were recommended to “eat the number of calories equal to their energy
expenditure.” Physical activity was tracked for 7 days at baseline and the end of the intervention using an
accelerometer, and dietary adherence was monitored monthly via food diaries that were evaluated by a
dietitian.
The primary outcome was HbA1c. The secondary outcomes were fasting blood glucose, blood lipids, blood
pressure, anthropometrics, insulin resistance (assessed via HOMA-IR), and NAFLD activity score (a sum of
the grades of liver fat, inflammation, and ballooning; assessed via liver biopsy).
The results
At 6 months, both groups improved HbA1c compared to baseline, but improvements were greater in LCHF
than HCLF (−0.88% vs. −0.29%). However, there was no difference between groups at 9 months.
For secondary outcomes, waist circumference was decreased at 6 months in both groups compared to
baseline, but the decrease was greater in LCHF than HCLF (−5.1 vs. −2.3 cm). Weight loss and
improvements in insulin resistance were also greater in LCHF compared to HCLF at 6 months. However,
there were no differences between groups for any of these outcomes at 9 months.
Blood lipid metrics were also affected. Low-density lipoprotein cholesterol (LDL-C) levels increased in
LCHF and decreased in HCLF compared to baseline, resulting in a significant difference between groups at
6 months (+8.9 vs. −5.8 mg/dL), which remained at 9 months. Triglycerides were decreased at 6 and 9
months in both groups compared to baseline, with no difference between groups. High-density lipoprotein
cholesterol levels increased to a greater extent in LCHF compared to HCLF at 9 months (+6.6 vs. +2.7
mg/dL).
NAFLD activity score improved in both groups at 6 months, with no difference between groups. This
outcome was not assessed at 9 months.
Note
More participants in LCHF reported nausea, fatigue, headache, and dizziness within the first 2 weeks of the
intervention, and more participants in LCHF reported constipation and diarrhea throughout the intervention.
Despite the inclusion of numerous outcomes, the researchers did not adjust for multiple comparisons, which
increases the risk of false-positive results.
The big picture
The results of the summarized study suggest that a LCHF diet may be superior to higher-carbohydrate
diets for people with T2D in the short term, but its advantage seems to fade over time.
The good news is that the LCHF diet facilitated greater improvements in HbA1c at 6 months. This result can
mostly be explained by the difference in weight loss between groups. At 6 months, there was a significant
5.5 kg weight loss in LCHF compared to baseline, while in HCLF, there was a nonsignificant weight loss of
1.7 kg. Previous evidence indicates that weight loss reduces HbA1c in a dose-dependent manner (i.e., the
greater the weight loss, the greater the reduction in HbA1c) in people with T2D and overweight or
obesity.[106]
Two meta-analyses have reported that greater carbohydrate restriction results in greater improvements in
glycemic control.[107][108] However, greater carbohydrate restriction was also associated with greater weight
loss,[107] precluding the ability to discern the isolated effects of carbohydrate restriction on glycemic control.
Although acute trials have shown that a LCHF can significantly improve markers of glycemic control with
minimal or no changes in body composition,[109][110][111][112] long-term randomized controlled trials featuring a
weight-maintaining LCHF diet intervention are needed to confirm whether these short-term benefits
translate into sustained improvements in blood glucose levels. Additionally, a limitation of many of these
acute studies is that the carbohydrate-restricted diet was also enriched in protein, a potent stimulator of
insulin secretion, which has a hypoglycemic effect.[113][114] As such, it’s unclear how much of the improvement
in glycemic control is due to carbohydrate restriction, specifically.
13
According to the self-reported dietary intake data, despite the recommendation to consume enough
calories to maintain body weight, participant calorie intake decreased by 98 and 211 kcal/day in the LCHF
and HCLF groups, respectively. Considering the difference in weight loss between groups, the LCHF group
evidently decreased calorie intake by much more than reported.
A decrease in free eating consumption during a LCHF diet has been reported in a number of other
studies.[110][115][116][117] This phenomenon may be explained by a modulation of hunger-related hormone levels
(i.e., ghrelin, leptin, cholecystokinin).[118] The omission of highly processed, carbohydrate-rich foods that are
energy dense and easy to overeat may explain reductions in ad libitum consumption with a LCHF diet.[119]
Now, on to the bad news. All of the benefits of the LCHF diet discussed above were lost at 9 months. In
agreement with the findings of the summarized study, meta-analyses have reported that while LCHF diets
tend to produce greater improvements in HbA1c in the short term (up to 6 months), this advantage
disappears in the long term.[120][108]
This disappearance seems to be largely a consequence of a drop-off in dietary adherence. Several studies
have observed a significant increase in reported carbohydrate intake in the LCHF diet group during followup.[121][122][123]
Prescribed vs. reported carbohydrate intake in LCHF diet trials
*Saslow results were reported at 3 and 12 months follow-up, respectively. ** Tay results were reported at 6, 12, and 24 months,
respectively. Adapted from Dyson, 2020. [124]
However, not all benefits are lost over time. One potential benefit of a LCHF diet that does not seem to
vanish over time is a reduction in antidiabetic medication use. Evidence suggests that despite similar
effects on HbA1c at 12 months, a LCHF diet reduces medication use to a greater extent than a highercarbohydrate diet at 12 months.[120][108]
In fact, it’s been argued that a greater reduction in medication use in the LCHF group may diminish the
effects of a LCHF diet on glycemic control. In other words, if medications had not been reduced to a
greater extent in the LCHF group, greater reductions in HbA1c would have been observed.[125] Further long-
14
term research is needed to understand the true effect of a LCHF diet on HbA1c independent of changes in
medication use.
Unfortunately, the LCHF diet also increased LDL-C levels, which is a causal risk factor for cardiovascular
disease.[126] Other studies have also reported a significant increase in LDL-C with the consumption of a
LCHF diet.[127][128]
However, an increase in LDL-C is not an inevitable consequence of consuming a LCHF diet, as LDL-C
changes depend on the composition of the diet.[118] In the summarized study, the percentage of daily energy
intake from saturated fat increased from about 13% at baseline to 21% in the LCHF group. A diet rich in
saturated fat is known to increase LDL-C[129][130] along with the risk of cardiovascular disease.[131] On the other
hand, a decrease in saturated fat intake and a corresponding increase in unsaturated fat or carbohydrate
intake decreases LDL-C.[132]
In sum, while a LCHF diet seems to improve HbA1c to a greater extent than higher-carbohydrate diets in
people with T2D, this effect typically disappears in studies longer than 6 months, mostly due to a drop-off
in dietary adherence. In addition, the greater improvements in HbA1c seem to be largely a consequence of
greater weight loss in the LCHF diet group. So while a LCHF diet may be a useful tool for people with T2D
— particularly for reducing antidiabetic medication use — the available evidence indicates that highercarbohydrate diets are similarly effective in the long term for improving HbA1c. Higher-carbohydrate diets
might also be just as effective over shorter time frames, if weight loss and protein intake is similar between
groups.
Alternate-day fasting and exercise for reducing liver fat
In this randomized controlled trial, combining alternate-day fasting (ADF) with aerobic exercise
decreased liver fat more than ADF or exercise alone in people with nonalcoholic fatty liver disease.
Background
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive liver fat and elevated
cardiometabolic risk factors. Lifestyle interventions involving dietary modifications and increased physical
activity, with the goal of inducing significant weight loss, are the cornerstone of NAFLD treatment.[105] A
variety of hypocaloric diets can be effective for this task, including alternate-day fasting (ADF). However, a
study had yet to directly quantify changes in liver fat from ADF or examine whether combining ADF with an
exercise intervention augments improvements in cardiometabolic risk factors.
The study
In this 3-month randomized controlled trial, 80 participants (81% women, mainly Hispanic or Black, ages
23–65) with NAFLD were assigned to one of four groups:
ADF: participants alternated days of free eating with modified fasting days in which they consumed
600 kcal (30% of energy from fat, 55% carbohydrate, 15% protein) between 5 p.m. and 8 p.m.
Exercise (EX): participants completed 60 minutes of moderate-intensity aerobic exercise (65%–80%
of maximum predicted heart rate) five times per week, which was supervised by the study staff.
ADF+exercise (COMBO): participants followed the ADF and EX interventions.
Control: participants were instructed to maintain current eating and exercise habits (no
intervention).
At baseline and the end of the study, dietary intake was assessed using a 24-hour dietary assessment tool,
and physical activity was monitored over 7 days using a pedometer.
The primary outcome was liver fat, measured using a specialized magnetic resonance imaging (MRI)
technique. The secondary outcomes were anthropometrics, blood lipids, markers of glycemic control
(fasting glucose, fasting insulin, HbA1c, insulin resistance assessed via HOMA-IR, and insulin sensitivity
15
assessed via QUICKI), blood pressure, liver enzymes (ALT and AST), liver fibrosis (estimated using the FIB-4
index), and hepatokines (proteins secreted from the liver that regulate metabolic processes; FGF-21,
selenoprotein P, fetuin-A).
The results
Compared to control and EX, liver fat decreased in COMBO. Additionally, liver fat nonsignificantly (p=0.05)
decreased in COMBO compared to ADF (−5.48% vs. −2.25%). Compared to control, serum levels of ALT
decreased in COMBO.
Compared to control and EX, body weight and fat mass decreased in COMBO. However, weight and fat
loss were not different between COMBO and ADF (−4.58% vs. −5.06%; −3.24 vs. −3.32 kg).
Compared to control, fasting insulin and insulin resistance decreased and insulin sensitivity increased in
COMBO. Additionally, insulin sensitivity nonsignificantly increased in COMBO compared to ADF (p=0.05)
and EX (p=0.07). There were no other differences between groups.
COMBO results
Note
The participants had a low risk of advanced fibrosis at baseline, according to the average FIB-4 score,
which may help explain the lack of effect of the interventions on fibrosis.
The researchers did not adjust for multiple comparisons, despite the inclusion of numerous outcomes,
which increases the risk of false-positive results. Therefore, the results for the secondary outcomes should
be interpreted with caution.
The big picture
The standout finding of this study was that, despite similar reductions in body weight and fat mass in
COMBO and ADF, reductions in liver fat were greater in COMBO, suggesting that just losing weight isn’t the
16
only important factor for reducing liver fat. To maximize these reductions, it may be pivotal to combine a
hypocaloric diet with exercise.
That said, this finding (i.e., a greater reduction in liver fat in COMBO compared to ADF) was technically
nonsignificant, so further trials utilizing a similar design are needed. In the meantime, other research can
shed light on the question of whether exercise reduces liver fat independent of changes in body weight. If
this is indeed the case, it’s possible that exercise truly had an additive effect in the summarized study.
Fortunately, this subject is quite well studied. Multiple trials have reported that exercise significantly
decreases liver fat independent of weight loss.[139][140][141] According to a 2018 meta-analysis, in the absence
of significant weight loss, exercise interventions reduce liver fat by 2.16%, on average, in people with
NAFLD.[142] However, the addition of significant weight loss still produced larger reductions in liver fat.
The evidence is pretty clear that exercise can reduce liver fat independent of weight loss, but how much
exercise is needed? The summarized study utilized a relatively demanding moderate-intensity aerobic
exercise protocol (300 minutes per week), which may be an unsustainable approach for many people. This
may have been why, although there were no dropouts in COMBO, 25% of the participants assigned to EX
dropped out.
After 3 months, the summarized study found a nearly 5.5% reduction in liver fat in the COMBO group, which
is on par with reductions yielded by other lifestyle intervention with considerably less exercise volume. In an
observational study that instructed participants (including 50 with NAFLD) to reduce their energy intake
and perform aerobic exercise that only moderately increased heart rate for at least 180 minutes per week,
participants reduced liver fat by 4.6% over 9 months.[143] Similarly, a randomized controlled trial in
participants with NAFLD reported that two to three sessions of supervised nordic walking per week
(performed at 60–75% of VO2max for 30–60 minutes) combined with a dietary intervention reduced liver
fat by 7.6%.[144] Finally, evidence from a couple of meta-analyses indicate that exercise interventions
(without dietary interventions in most studies) involving roughly three sessions of 30–60 minutes of aerobic
exercise per week for 12 weeks significantly reduced liver fat.[142][145] One of these meta-analyses reported an
average reduction in liver fat of 3.3%.[142]
In sum, less demanding exercise interventions than used in the summarized study seem to be able to
promote similar reductions in liver fat. At the moment, there doesn’t appear to be a clear relationship
between reductions in liver fat and the weekly frequency and volume of exercise in people with NAFLD.[146]
Exercise type may also play a role. The present study used prolonged moderate-intensity aerobic exercise,
which may not suit many people’s preferences.
A 2017 meta-analysis reported that aerobic and resistance exercise interventions produce similar
reductions in liver fat in people with NAFLD, even though energy expenditure tended to be lower in
resistance exercise interventions.[145]
Additionally, the following results have been reported in trials that performed head-to-head comparisons
between different exercise interventions in participants with NAFLD:
4 weeks of either moderate-intensity aerobic exercise (55% of VO2max) or high-intensity interval
aerobic exercise (repeated cycles of 4 minutes at 80% of VO2max followed by 3 minutes at 50% of
VO2max), which were matched for energy expenditure (about 400 kcal per session), produced
similar reductions in liver fat.[147]
6 months of either moderate-intensity aerobic exercise (45%–55% of maximum predicted heart rate
for 150 minutes per week) or vigorous aerobic exercise (65%–80% of maximum predicted heart rate
for 150 minutes per week) produced similar reductions in liver fat.[148]
4 months of either aerobic exercise (60%–65% of heart rate reserve for 180 minutes per week) or
resistance exercise (three full-body sessions per week consisting of 9 exercises performed for 3
sets of 10 repetitions using 70%–80% of 1-repetition maximum) produced similar reductions in liver
fat.[149]
17
3 months of either aerobic exercise (60%–75% of VO2max for 180 minutes per week) or resistance
exercise (three full-body sessions per week consisting of 10 exercises performed for 2 sets of 8–12
repetitions to fatigue each) produced similar reductions in liver fat.[150]
Although head-to-head comparisons are sparse, the available evidence indicates that different types of
exercise have similar effects on reducing liver fat. Further research is needed to clarify the most effective
form of exercise for reducing liver fat, as well as the ideal amount of exercise. Moreover, it remains unclear
whether combining aerobic and resistance exercise is superior to either mode of exercise alone for
reducing liver fat.[146]
However, as it stands, the available evidence indicates that various types of exercise interventions can be
used to reduce liver fat. Thus, the general recommendation to accumulate at least 150 minutes of
moderate-intensity or 75 minutes of high-intensity exercise per week is a suitable target for most people.[146]
Following this recommendation, the mode, frequency, and duration of exercise should be customized to the
individual’s preferences and goals to maximize adherence.
Investigating the relationship between animal foods and
neurocognitive disorders
This meta-analysis of prospective cohort studies looked at the association between different animal
foods and the risk of several neurocognitive disorders. Dairy intake was associated with a higher risk
of Parkinson’s disease and a lower risk of dementia, and fish intake was associated with a lower risk of
dementia.
Background
A number of neurodegenerative disorders can occur during aging, including the following:
Cognitive impairment: a worsening of cognitive function beyond what is expected based on age,
though not to the point of interfering with daily functioning.
Dementia: an impairment in cognitive functioning that interferes with a person’s ability to function in
daily life. A large number of diseases and health conditions can result in dementia.
Alzheimer’s disease: a specific type of dementia, representing about 60% of all cases.
Parkinson’s disease: a disease resulting from a specific type of neuronal damage. It can cause
motor disturbances (tremors) as well as cognitive issues like dementia.
Thankfully, there’s evidence to suggest that a healthy dietary pattern can reduce the risk of developing all
of these disorders.[81][187][188] Still, the effects of animal foods on the risk of these neurocognitive disorders is
complex and controversial. On one hand, animal foods tend to be a good source of various nutrients
important for brain health, like iron, vitamin B12, zinc, and in the case of fish, omega-3 fatty acids. On the
other hand, animal foods can also contain compounds suspected of adversely affecting brain health, like
saturated fat, iron (in excess), and in the case of fish, mercury.
What does the existing body of literature say about the relationship between animal foods and
neurocognitive disorders?
The study
This meta-analysis of prospective cohort studies examined the association between different animal foods
and the risk of several neurodegenerative disorders. A total of 33 studies with 1,199,730 participants were
included. Study follow-up times ranged from 3 to 30 years.
The animal foods investigated in the studies were total dairy product intake, milk, yogurt, cheese, total
meat intake, red meat, processed meat, poultry, fish, and eggs. The neurodegenerative diseases
investigated in the studies were Parkinson’s disease (8 studies), Alzheimer’s disease (9 studies), dementia
(12 studies), and cognitive impairment (11 studies).
18
The overall certainty of evidence for each outcome was rated using the GRADE (Grading of
Recommendations Assessment, Development and Evaluation) guidelines.
The results
The researchers determined the following associations through their main analysis:
Dairy: A higher intake of total dairy was associated with a 49% higher risk of Parkinson’s disease, a
65% lower risk of dementia, a 37% lower risk of Alzheimer’s disease, and an 11% lower risk of
cognitive impairment. A higher intake of milk was associated with a 40% higher risk of Parkinson’s
disease and a 65% lower risk of Alzheimer’s disease.
Total meat: A higher intake of meat was associated with a 28% lower risk of cognitive impairment.
Red meat: Although no outcomes were statistically significant in the main analysis, in doseresponse analyses, every 100-gram increase in red meat intake was associated with a 60% increase
in the risk of cognitive impairment and every 30-gram increase in red meat intake was associated
with a 5% higher risk of dementia and a 40% lower risk of Alzheimer’s disease.
Processed meat: A higher intake of processed meat was associated with a 49% lower risk of
Parkinson’s disease, a 13% higher risk of dementia, and a 30% higher risk of Alzheimer’s disease.
Poultry: A higher intake of poultry was associated with a 43% higher risk of dementia and an 18%
lower risk of cognitive impairment.
Fish: A higher intake of fish was associated with a 16% lower risk of dementia, a 25% lower risk of
Alzheimer’s disease, and a 15% lower risk of cognitive impairment.
Notable findings from the study
19
Note
There was no association between egg intake and any of the outcomes. One reason for this could be that
most people don’t eat many eggs, meaning that participants typically only needed to consume a few eggs
per week (a fraction of an egg per day, on average) to be categorized as a high egg eater. Whether eating
multiple eggs per day is positively or negatively associated with any of the examined disorders therefore
remains uncertain.
The big picture
The current study had a number of findings worth digging into. Of note, a higher intake of fish was
associated with a lower risk of cognitive decline, dementia, and Alzheimer’s disease. The lower risk of
dementia associated with fish consumption was considered “high quality” evidence and was the only finding
from the study to receive this rating.
Fish tends to be a good source of omega-3 fatty acids, which may help explain why eating fish is
associated with a lower risk of dementia and cognitive decline. However, omega-3 fatty acids may not
reduce the risk of Alzheimer’s disease specifically, which is the most common type of dementia. In several
cohort studies, supplementing with fish oil was associated with a lower risk of dementia, but not
Alzheimer’s disease.[189][190][191] This suggests that other factors could be responsible for the lower risk of
Alzheimer’s disease with greater fish consumption.
One such factor could be vitamin D, which is found in oily fish, including salmon, sardines, trout, pike, and
mackerel. Having low vitamin D levels (e.g., less than 20 ng/mL) is associated with a higher risk of
Alzheimer’s disease,[192] and while it’s possible this is the result of confounding, people with genetically
20
higher vitamin D levels are also less likely to develop Alzheimer’s disease, suggesting that the effect is
indeed causal.[193][194] Still, more research is needed to determine what factors might mediate the relationship
between fish intake and cognitive outcomes.
Another intriguing finding from this study was that a higher intake of total dairy was associated with an
increased risk of Parkinson’s disease. This is also supported by genetic evidence, in which people with
lactose tolerance, who therefore consume more dairy, have been found to be at a high risk of Parkinson’s
disease.[195] Various mediators of the link between dairy and Parkinson’s have been proposed, including
galactose (formed from the metabolism of lactose), dairy-derived microRNAs,[196], pesticide contaminants in
dairy products, and a uric acid-lowering effect of dairy (higher uric acid is associated with a lower risk of
Parkinson’s disease).[197] However, none of these theories are currently well supported by evidence.
Interestingly, available research tentatively suggests that only lower-fat dairy foods are associated with
Parkinson’s disease.[198] The reason for this is also unclear, but it could be attributable to yet unidentified
protective compounds in dairy fat (e.g., odd chain-fatty acids). Alternatively, other diet and/or lifestyle
factors may simply differ between lower-fat and higher-fat dairy consumers. These consumers may have
differences in smoking habits, alcohol intake, physical activity, and more, which would explain this
discrepancy.
In contrast to the increased risk of Parkinson’s disease, a higher intake of dairy was associated with a lower
risk of dementia. Although it’s not clear what explains this finding and, given the observational nature of the
evidence, whether it is indeed causal, various possible mediators have been suggested, including bioactive
peptides, fatty acids, and phospholipids found in dairy products. More broadly, the link could be explained
by the fact that consuming more dairy has been linked to a lower risk of type 2 diabetes,[199] a disease that
seems to increase the risk of dementia.[200][201]
Ultimately, some of these results seem consistent with existing dietary patterns (e.g., a Mediterranean-style
diet) that have been linked to a lower risk of neurocognitive disorders. These dietary patterns tend to
involve eating some fish and limiting red meat intake. Still, more research is needed to understand how
certain animal foods, like eggs, affect the risk of neurocognitive disorders. In addition, the role of dairy
could be described as complicated, as it offers both potential risks (e.g., a higher risk of Parkinson’s
disease) and benefits (e.g., a lower risk of dementia).
The effect of mycoprotein on markers of gut health
In this randomized controlled crossover trial, eating a diet high in mycoprotein-based foods improved
some markers of gut health compared to eating a diet high in red and processed meat.
Background
People who avoid meat and animal products often look for alternative foods that can supply similar
amounts of protein. This can take the form of plant-based options made from legumes, like soy and lentils.
Alternatively, consumers can opt for a food that isn’t technically a plant at all, like mycoprotein, a food
made from a fungus called Fusarium venenatum. Commercially available mycoprotein products are
formulated to taste like meat and are naturally high in both protein and fiber.
People may opt to eat mycoprotein to avoid red and processed meat, since a growing body of evidence
suggests these meats are associated with a higher risk of colorectal cancer (although the evidence appears
stronger for processed meat). Can replacing red and processed meat with mycoprotein improve markers of
gut health indicative of a lower risk of colorectal cancer?
The study
This randomized controlled crossover trial examined the effects of mycoprotein on markers of gut health
compared to red and processed meat. A total of 20 men (average age of 30, average BMI of 24) were
assigned to consume 240 grams per day of either mycoprotein food products (brand name QuornTM) or red
21
and processed meat for 2 weeks and then consume the other food after a 4-week washout period.
The red and processed meats were beef steak, pork sausage, cold cut ham, gammon steak, bacon, beef
mince, and hot dogs. Compared to the diet with meat, the diet with mycoprotein was higher in fiber (26.5
vs. 43.3 grams per day) and nonsignificantly higher in carbohydrates (244 grams vs. 298 grams per day;
p=0.06).
The primary outcome was fecal water genotoxicity, a test in which the liquid derived from participants’
feces is added to cultured cells, and the amount of DNA damage that occurs in response is measured. Fecal
water genotoxicity is a suspected marker of colon cancer risk. Secondary outcomes were fecal microbiome
composition assessed using stool analysis and fecal levels of short-chain fatty acids (SCFAs; acetate,
propionate, butyrate, valerate, and caproate), branched-chain fatty acids (BCFAs; isobutyrate and
isovalerate), and nitroso compounds (NOCs; many of which are carcinogens).
The results
Mycoprotein had the following effects compared to red and processed meat:
Reduced DNA damage via fecal water test
Lower levels of NOCs
Higher levels of valerate
Higher levels of isobutyrate and isovalerate (due primarily to a decrease with meat)
Higher levels of acetate, propionate, and caproate, although these findings were not statistically
significant (p=0.20, p=0.09, and p=0.17, respectively)
In addition, the mycoprotein diet resulted in higher levels of Roseburia and Akkermansia bacteria in the
fecal microbiome, and the meat diet resulted in higher levels of Oscillobacter bacteria.
Primary study outcome
*p=0.09 vs. baseline, p<0.05 vs. mycoprotein.
Note
Generally speaking, SCFAs are associated with health benefits, including a lower risk of colorectal
cancer,[202] although whether this relationship is causal is far from clear. The BCFAs isobutyrate and
isovalerate, however, have a far more nebulous effect on health.[203]
22
Most mycoprotein products are high in sodium. It’s important to note that because the two studied diets
included similar amounts of sodium, this study does not reflect what would happen if eating mycoprotein
products led to a higher sodium intake, which is a very real possibility.
The big picture
Some people may feel cautious about eating mycoprotein because it is a somewhat novel food with a
limited history of human consumption. Thankfully, the current study suggests that mycoprotein may be
beneficial for gut health and colorectal cancer risk, at least when compared to red and processed meat.
No studies have looked at the association between mycoprotein ingestion and actual cancer risk, although
eating mushrooms is associated with a lower risk of total cancer and no difference in the risk of colorectal
cancer.[204] However, it can’t be assumed mycoprotein will have the same health effects as most mushrooms.
Mycoprotein isn’t even a mushroom, though there are important similarities between the two that make the
known health effects of mushrooms reassuring for consumers of mycoprotein. For example, both
mushrooms and mycoprotein are composed of similar polysaccharides.
Beyond markers of colorectal cancer risk, several clinical trials have investigated the effect of mycoprotein
on some other health metrics.
Muscle protein synthesis
Since mycoprotein is high in high-quality protein,[205] it may help with muscle mass development. To
investigate this possibility, a few studies have looked at whether a diet high in mycoprotein supports
muscle protein synthesis (MPS).
In two short-term randomized controlled trials from the same research group — one in younger men
(average age of 22)[206] and one in older people (average age of 66)[207] — mycoprotein had similar effects
on MPS both at rest and in response to resistance exercise, relative to similar amounts of animal proteins.
Still, these studies were not able to look at actual muscle mass changes, which might not be perfectly
predicted by MPS. So while mycoprotein seems to support muscle growth, longer-term studies are needed
to confirm this effect.
Blood lipids
Mycoprotein contains a decent amount of fiber, particularly beta-glucans, a type of fiber that has been
widely studied and shown to reduce LDL-C when obtained from oats.[208] Likewise, in a few randomized
controlled trials, eating mycoprotein decreased LDL-C compared to eating meat[209][210] or when just added
to the diet.[211]
Blood glucose and insulin
Mycoprotein may be beneficial for people with glucose-related conditions and insulin excursions (e.g.,
people with type 2 diabetes) because it is high in protein and fiber and low in carbohydrates.
In one clinical trial, drinking a milkshake with added mycoprotein reduced blood glucose response
compared to a milkshake without mycoprotein.[212] Another randomized controlled trial compared the effect
of adding mycoprotein or chicken to a rice-based meal.[213] The two foods did not differ in their effect on
postprandial (postmeal) glucose levels, but the addition of mycoprotein did reduce the insulin response to
the meal.
Finally, a randomized controlled trial looked at the effect of eating a diet high in mycoprotein or meat and
fish for 7 days, ultimately finding no appreciable differences in glucose levels or insulin sensitivity between
the two foods.[209] Still, this study involved people who were young (average age of 24), lean (average BMI
of 23), and had no apparent health conditions, so this group was less likely to have disturbances in their
glycemic control or insulin sensitivity.
Uric acid
Purines are a group of compounds found abundantly in certain foods, including seafood, organ meats, and
23
legumes. The metabolism of ingested purines can increase uric acid levels, potentially precipitating gout
attacks or kidney stones in people prone to these conditions. Mycoprotein contains an appreciable amount
of purines, meaning that it may also increase uric acid levels.[214]
In one randomized controlled trial, young adults consumed mycoprotein for 7 days, with no appreciable
change in their fasting uric acid levels.[209] Another clinical trial investigated postprandial (postmeal) uric
acid levels and found that ingesting up to 18 grams of protein from mycoprotein did not increase uric acid,
but ingesting higher doses (27–36 gram of protein) did increase uric acid for a period of time after
consumption.[215] Based on this preliminary data, people prone to gout or kidney stones (specifically uric
acid-based kidney stones) may want to limit their consumption of mycoprotein.
The definition of whole-grain food needs standardization
This analysis of 8 sets of cross-sectional and nationally representative surveys suggests that different
whole-grain food definitions affected estimated intakes and trends of whole-grain food consumption in
U.S. adults from 2003 to 2018. Currently, consumption is well below recommended levels.
Background
A grain is characterized as “whole” when it contains all three parts of the original kernel:
The bran, a fibrous outer layer
The endosperm, a carbohydrate-rich middle layer
The germ, a nutrient-rich core
A refined grain generally only contains the carbohydrate-rich endosperm (e.g., flour). Greater whole-grain
intake has been recommended because of its benefits for health and the environment,[4] but several
organizations in the U.S. define whole-grain foods (WGFs, foods that contain whole grain as a predominant
ingredient) in different ways. This can confuse consumers,[216] members of the industry, and policymakers,[217]
and it may also affect estimated intake, trends, and sources of whole-grain foods.
Grain anatomy
The study
This analysis of 8 sets of cross-sectional and nationally representative National Health and Nutrition
Examination Surveys (NHANES, 2003–2018) included data from 39,755 U.S. adults (average age of 47) and
24
evaluated the influence of 5 different definitions (see summary table below) for WGFs on estimated intake,
trends, and sources of WGFs.
Dietary intake data were collected by trained interviewers who conducted 24-hour dietary recalls per
survey set. The United States Department of Agriculture Food and Nutrient Database for Dietary Studies
was used to estimate food and nutrient intake. The Food Patterns Equivalents Database and MyPyramid
Equivalents Database were used to estimate amounts of total grains, whole grains, and refined grains per
100 grams of each food. Foods that contain any flour or grain ingredients were classified into one of four
groups:
Flour-based noncombination foods
Grain-based noncombination foods
Flour-based mixed dishes
Grain-based mixed dishes
The primary outcome was mean WGF intake across total and socioeconomic population subgroups (age,
sex, race/ethnicity, education level, and ratio of family income to the federal poverty levels). The secondary
outcomes included the percentage of WGFs among total grain-containing or flour-containing foods
consumed and the mean intake of WGF subgroups, which were defined as breads, snack/meal bars, readyto-eat-cereals, cooked grains and cereals, savory snacks/crackers, and mixed dishes. Data and analyses
were adjusted for the complex sample design of NHANES (e.g., use of appropriate survey weights that
estimate the number of U.S. residents that each survey respondent represents) and socioeconomic factors,
respectively.
The results
Estimated WGF intakes ranged from 1.0 (AHA) to 0.5 (FDA) ounce equivalents (30–15 grams) per 2,000 kcal
per day. WGF intake increased between 3% (FDA) and 6% (AHA) over time (2003/04–2017/18), although
most of the change occurred between 2003 and 2012. No change was observed with the WGC definition.
Older, male, non-Hispanic white, college graduates and up, and people with higher income consumed higher
levels of WGFs.
Across all definitions and survey sets, WGF intake ranged from 6.26% to 18.4% as a percentage of total
grain-containing or flour-containing food intake. In 2017–2018, whole-grain breads contributed the largest
amount to WGFs consumed, and ready-to-eat cereals made up the largest proportion of all foods that were
defined as WGFs (43%–77%, depending on the definition).
Whole-grain food definitions, intake, trends, and sources
Organization
Definition
Dietary
Guidelines for
Americans (DGA)
≥50% of the
grain
component
from a whole
grain
Food and Drug
Administration
(FDA)
≥51% whole
grains by
weight per
RACC
American Heart
Association
(AHA)
# of WGFs
captured (#
uniquely
identified) in the
2017–2018
NHANES
Predominant
subgroups
captured in the
2017–2018
NHANES
% change
between
2003–2004
and 2017–
2018
581 (7)
Pizza, burgers
sandwiches and
“other mixed
dishes”
5.27
230 (0)
Cooked grains
and cereals and
“ready-to-eat
cereals”
2.92
Percentage by weight can be
affected by density, moisture,
or other ingredients.
Pizza, burgers,
sandwiches and
“other mixed
dishes”
6.45
Does not distinguish between
whole and refined grains for
total carbohydrate.
Carbohydrate
to fiber ratio 621 (230)
< 10:1
Limitations
25
Organization
American
Associations of
Cereal Chemists
International
(AACCI)
Whole Grain
Council (WGC)
Definition
# of WGFs
captured (#
uniquely
identified) in the
2017–2018
NHANES
≥ 8 grams of
whole grains
329 (2)
per 30 grams
of food
≥ 8 grams of
whole grains
per RACC
644 (44)
Predominant
subgroups
captured in the
2017–2018
NHANES
% change
between
2003–2004
and 2017–
2018
Limitations
“Ready-to-eat
cereals” and
cooked grains
and cereals
3.85
Proportion by weight can be
affected by density, moisture,
or other ingredients.
Pizza, burgers,
sandwiches and
“other mixed
dishes”
1.02 (95%
CI:−0.95,
2.99)
Too permissive; foods can
contain more calories and
added sugars than those not
meeting the definition.[218]
*RACC = reference amount customarily consumed ( serving); CI = confidence interval.
Note
The study results should be interpreted with caution because the cross-sectional design prevents the
determination of cause and effect, the dietary intake data were self-reported and only collected for one
day, and there were several estimates and categorizations based on many databases that may not be
perfect.
The big picture
The DGA recommends that at least half of grain intake should incorporate whole grains, which translates to
at least 3 ounces (about 90 grams) of equivalents per 2,000 kcal per day of whole grains. According to the
analysis under review, WGF intake levels in Western countries are still not even at half of recommended
levels and have increased trivially over the last two decades.[219] This is two decades after clear and
consistent recommendations for greater WGF intake, which was supported by the consistently
demonstrated health (e.g., reduced cardiometabolic disease and mortality risk) and environmental (e.g., less
greenhouse-gas emissions and land use) benefits.[4][220] The trend of poor WGF intake and policy
infrastructure appears to occur globally.[221][222][4] It seems that, regardless of the variation in how WGFs are
defined or their low cost and high nutrient density, consumers are not eating enough whole grains for
optimal environmental and human health.[223]
Beyond the carbohydrate content that makes whole grains a global staple, they are a good source of
protein, fiber, vitamins, minerals and phytochemicals.[23] The primary benefits of whole grains seem to be
attributed to their high fiber and phytochemical content, which promote microbial fermentation, microbial
diversity, and phytochemical bioavailability.[224] Unless they are fortified or enriched, refined grains will be
limited in the beneficial components that whole grains have (phytochemicals, fiber, vitamins, and minerals)
and even if these components are reintroduced, refined grains may still not be as beneficial due to the
interaction of nutritive and nonnutritive components. A 2021 randomized controlled crossover trial
suggested that a whole-grain diet (50 grams per 1,000 kcal) promotes improved protein turnover, net
protein balance, and muscle function, compared to a macronutrient-matched refined-grain diet.[21] It should
be noted that processing, not specifically for refined grain but for other purposes, can improve some
aspects of whole grains, such as protein digestibility and amino acid composition.[7]
There are several factors to consider when determining a standard definition for WGFs. A 2013 study
suggested that the total-carbohydrate-to-fiber ratio of no more than 10:1 (the AHA approach) was the best
approach to select the most healthful whole-grain products when compared to the WGC definition, which
identifies foods with higher calories and added sugars.[218] Although fiber content is a predominant
distinguishing factor of whole grain,[225] the AHA definition doesn’t distinguish between whole and refined
grains, potentially ignoring the other beneficial components of whole grains. However, definitions
characterized by a proportion of whole grain based on weight (FDA and AACCI) can be affected by
density, moisture, or other ingredients. A commentary on the study under review suggested a unified
26
definition for WGFs that might include the actual amount of whole grain along with the ratio of refined grain
or total carbohydrate to whole grain in a food product, which sounds similar to the DGA definition: at least
50% of the grain component is from a whole grain.[226] It also hinted that the definition should strike a
balance between intake for health, sufficient energy, taste, and convenience and that this balance may vary
across different populations.
If no definition is perfect, a focus on a core understanding of WGFs role in nutrition may be more important
than strict categorical thinking. Categorization of food may help identify “good” and “bad” foods on a
simple level, but foods are complex with many varying components, and how they fit into the context of an
overall diet amplifies the complexity of “good” and “bad” categorization to the point that it may not be
accurate and may lead to flawed heuristics (i.e., methods) and biases.[227][228] Still, some standards can be
more necessary than others. When 60 people were asked to select standard portion sizes, they revealed a
wide range of the perception of “standard”, such that the ranges selected for pasta and curry were 70%–
120% and 80%–160% of the reference portion.[229] Perceptions of portion size normality also predicted
intended food consumption, which could have broad implications. So, there may be a balance to strike
between educating consumers on the importance of understanding the complexity of nutrition and
oversimplifying definitions, such as what makes something a WGF.[230]
Exploring low-carb diets for high-intensity exercise
performance
In this 31-day study, a low-carbohydrate/high-fat diet led to equivalent performance, higher rates of fat
oxidation, and lower rates of carbohydrate oxidation during exercise and improved glycemic control
compared to a high-carbohydrate/low-fat diet.
Background
Athletes are typically advised to consume high-carbohydrate diets to maintain muscle glycogen stores and
support vigorous-intensity exercise, which is fueled almost exclusively by carbohydrates (glucose).
However, recent evidence suggests that low-carbohydrate/high-fat (LCHF) diets may promote greater fat
oxidation during exercise,[241] perhaps making them a suitable choice for athletes, despite some studies
noting performance impairments during an LCHF diet.[242]
Because LCHF diets also improve blood glucose control and cardiometabolic health, it’s worth exploring
whether this dietary pattern offers health and performance benefits compared to high-carbohydrate/low-
fat (HCLF) diets.
The study
In this randomized crossover study, 10 highly trained male athletes (average age of 40) completed two 31day dietary interventions separated by a 2-week washout period:
LCHF: less than 50 grams of carbohydrates, 75%–80% fat, 15%–20% protein
HCLF: 60%–65% carbohydrate, 20% fat, 15%–20% protein
The LCHF diet was also supplemented with 1–2 grams of sodium per day from bouillon cubes or homemade
broth and was designed to promote continuous nutritional ketosis throughout the 31-day intervention
period. Nutritional ketosis was verified by measures of blood ketones on days 3, 7, 14, 21, and 28.
The primary study outcomes included running performance (1-mile time trial and 6 x 800-meter repeated
sprint performance), carbohydrate and fat oxidation during exercise, body composition, continuous
glucose, and cardiometabolic biomarkers (HbA1C, total cholesterol, LDL cholesterol, very-low-density
lipoprotein cholesterol, HDL cholesterol, triglycerides, insulin, and high-sensitivity C-reactive protein (CRP)).
Outcomes were measured before and after each 31-day intervention.
The results
27
After the LCHF diet, average fat oxidation increased (+190%), and average carbohydrate oxidation
decreased (−20%) during the 1-mile time trial. During the repeated sprint test, average fat oxidation
increased (+92%) and average carbohydrate oxidation decreased (−54%). Performance on the 1-mile time
trial and repeated sprint test was no different before and after the LCHF diet.
There were no changes in carbohydrate oxidation, fat oxidation, or performance during the 1-mile time trial
or repeated sprint test after HCLF.
Average blood glucose was lower during LCHF than during HCLF on days 8, 13, 15–20, and 22 of the diet.
Total cholesterol, LDL cholesterol, and HDL cholesterol were higher after LCHF compared to HCLF. Body
weight and BMI decreased after both the LCHF and HCLF diets.
Note
While both diets were isocaloric (contained a similar amount of calories), they differed in their fat,
carbohydrate, protein, cholesterol, fiber, and sugar content. With the exception of protein intake, which was
31 grams higher on LCHF, all other nutrient differences were an expected outcome of the dietary
prescriptions.
The big picture
Dietary carbohydrates are used to maintain blood glucose and glycogen (glucose stored in the muscles and
liver), which can be used for energy during exercise. Muscle glycogen is the body’s preferred fuel source
during high-intensity and long-duration exercise. Indeed, consuming carbs during exercise delays and
reverses muscle fatigue, and though the practice is questionable, endurance athletes have long practiced
“carbohydrate loading” before big races to saturate their glycogen stores in hopes of improving
performance.
Why are carbs so essential for athletes? At rest and during low-intensity exercise, the body mainly burns fat
for energy. But at a certain intensity of exercise, the body begins to derive a larger percentage of its energy
from carbohydrates rather than fat. This is known as the “crossover point.”[243] As exercise intensity
increases above the crossover point, more glucose and less fat is used, until finally, at around 85% of
maximal aerobic capacity, fat’s contribution to energy is negligible, and the body is getting almost all of its
energy from glucose (carbs).
The “crossover concept” of exercise metabolism
28
At rest and during exercise below 60% of maximal oxygen uptake, fat is the main fuel source used to generate ATP. Above 75% of
maximal oxygen uptake, glucose and muscle glycogen become the dominant fuel sources. The crossover point refers to the
intersection of carbohydrate and fat metabolism, beyond which more energy is derived from carbohydrate (glucose) and less is
derived from fat.
The crossover effect explains why high-carb diets are promoted for performance and the general hesitancy
to adopt LCHF diets. However, there has lately been an increase in the interest in LCHF diets among
athletes.
The FASTER study was published in 2015. In that study, researchers characterized the metabolic profiles of
“keto-adapted” endurance athletes — those who had been eating a LCHF/ketogenic diet for several
years.[244] The study questioned some long-held beliefs about exercise metabolism.
The low-carb athletes had rates of peak fat oxidation that were more than two-fold higher than the highcarb athletes, and they hit their peak fat oxidation rate at around 70% of VO2 max, compared to 55% in the
high-carb group. Despite consuming less than 50 grams of carbohydrates per day, the low-carb athletes
also had similar levels of muscle glycogen at rest and after a 3-hour endurance run when compared to the
high-carb athletes. These results were some of the first to suggest that habituation to a low-carb diet can
shift the crossover point during exercise, allowing athletes to use more fat at a higher exercise intensity and
increase the exercise intensity where the crossover point occurs.
The results of the current study support these findings. Peak fat oxidation rates occurred at 85% of the
athletes’ VO2 max after just a month on a ketogenic diet. Interestingly, peak fat oxidation occurred at 80%
after the high-carb diet, though it was still nearly half of that observed after the low-carb diet. In addition,
some of the highest fat oxidation rates ever recorded were observed in these middle-aged athletes
following the LCHF diet, in excess of 1.85 grams/minute.
Altering diet composition definitely shifts energy metabolism during exercise. But athletes care about
29
performance. In this regard, previous studies haven’t been so supportive of LCHF diets.
Numerous studies published in the last few years have shown that keto adaptation could be costly. Athletes
who adopted a LCHF diet for 5–6 days[242], 3 weeks[245], and 25 days[246] displayed worse exercise economy
and impaired performance during simulated competition compared to when they consumed a highcarbohydrate diet. Six days of a LCHF diet also impaired high-intensity sprint performance but did not
affect 100-kilometer cycling performance in a group of cyclists.[241]
This study was designed to further test the hypothesis that high-intensity exercise performance is impaired
following a LCHF diet. This hypothesis that was not supported by the results. The athletes in this study
performed a 1-mile time trial and a series of 6 high-intensity 800-meter sprints — both of which are thought
to be primarily carbohydrate fueled. Nonetheless, performance on each test was equivalent following the
LCHF and HCLF diets — 367 seconds and 374 seconds (1-mile time trial) and 1,236 and 1,254 seconds
(total time for the 6 x 800-meter sprints) after the LCHF and HCLF diets, respectively.
Low-carb vs. high-carb for exercise performance and metabolism
It’s important to underscore the metabolic health benefits experienced by the participants during the LCHF
diet. Despite being healthy and fit athletes, 30% of the participants in this study had average glucose levels
during the HCLF diet that were greater than 100 mg/dL, putting them in the “prediabetic” range. Average
glucose and glycemic variability significantly improved in all participants during the LCHF intervention and
to a greater extent in the few participants with elevated glucose levels.
LCHF provided therapeutic benefits without compromising performance, suggesting that this dietary
pattern may be suitable for athletes who want to optimize their health and exercise routines. Though the
sample size was small (10 participants) and included only middle-aged men, which limits the generalizability
of the findings, the results of this study will certainly ignite some discussion.
Calorie restriction improves biological aging markers
In this randomized controlled trial, 2 years of calorie restriction slowed the pace of biological aging in
healthy adults.
Background
Calorie restriction (CR), defined as eating a diet that contains approximately 25% fewer calories than
30
normal, is one of the most reliable methods of extending lifespan and slowing aging in animals. Can CR also
affect the rate of aging in humans?
The study
In this randomized controlled trial called the Comprehensive Assessment of Long-term Effects of Reducing
Intake of Energy (CALERIE), 220 men and women (average age of 38, normal weight or slightly overweight
BMI) were prescribed a 25% reduction in calorie intake or a nonrestricted diet for 2 years.
The 25% CR was based on each participant’s individual energy requirements, which were estimated at the
beginning of the study.
The primary study outcomes were biological age and the rate of biological aging, which were estimated
using three different biological aging clocks: PhenoAge, GrimAge, and DunedinPACE. Biological aging
measures were assessed at baseline, 12 months, and 24 months.
The results
CR reduced the pace of biological aging by 2%–3%, as measured using DunedinPACE. Biological age
measured using PhenoAge and GrimAge was not affected by CR.
The big picture
There have been multiple studies published from the CALERIE trial in which CR has been reported to reduce
cholesterol, systolic and diastolic blood pressure, inflammation, and metabolic syndrome score and
increase insulin sensitivity.[262] Furthermore, CR resulted in an average weight loss of 7.5 kg, reductions in
waist circumference, and a preferential loss of visceral adipose tissue.[263][264] Thus, CR can improve risk
factors for cardiometabolic disease, even in a cohort of normal weight to slightly overweight, yet otherwise
healthy, middle-aged adults. These measurable changes in health outcomes are important to complement
and validate the changes in measures of biological aging reported in the current study. It’s another question
entirely whether the health improvements actually translate to reduced morbidity and mortality —
outcomes that take much longer to assess and won’t be realized for decades.
The “geroscience hypothesis” is the idea that interventions that slow or reverse molecular changes (i.e.,
DNA methylation) can delay or prevent the incidence of disease of aging and extend healthspan and
lifespan. CR has been at the forefront of investigations into the geroscience hypothesis, yet unfortunately,
most studies to date have been conducted in animal models. This is why CALERIE is such an important step
for longevity research. It’s the first study to rigorously investigate long-term CR in humans.
31
Digging Deeper: Biological aging clocks
DNA methylation (DNAm) is the process by which genes become methylated, an epigenetic
mechanism that alters DNA and gene transcription. Levels of DNAm increase with age. As such, the
accumulation of methylated DNA is proposed to be a biomarker of aging.
By measuring the amount of DNAm within certain sites in the genome, DNAm clocks, also known as
biological aging clocks, can be used to predict the age of an organism. Biological age is different
from chronological age — how old someone is in years — because it represents a person’s actual
age based on genomic factors. Biological age might be a better predictor of risk for death and
disease. For a quick example, consider someone who is 60 years old chronologically, but they eat
well, live an active lifestyle, and read Examine regularly. This person’s biological age might be 48 —
they are biologically younger than their chronological age.
Several DNAm clocks exist, but CALERIE used three specific clocks to measure the primary outcome
of biological aging:
PhenoAge and GrimAge: These clocks were developed to predict mortality risk based on biological
age. For example, if a 60-year-old person (chronologically) has a biological age of 48, then their
mortality risk is similar to that of a 48-year-old, not a 60-year-old, person.
DunedinPACE: This clock was developed to estimate the rate at which someone is aging. The
default rate of aging is 1 year per calendar year. A pace of aging less than 1 means someone is
biologically aging slower than this normal rate, and a pace of greater than 1 indicates accelerated
aging.
Based on the DunedinPACE clock, participants assigned to CR reduced their rate of biological aging at 12
months, a pattern that continued through 24 months. In other words, CR participants were aging slower
than their peers who were eating freely. The 2%–3% decline in the rate of aging is suggested by the authors
to correspond to as much as a 10%–15% reduction in mortality risk.
One of the main limitations of CALERIE was that participants assigned to CR didn’t achieve the prescribed
25% reduction in calories over the course of the 2-year intervention. The average reduction of
approximately 11.9% was less than half of the original goal and corresponds to about a 180 calorie per day
reduction, or about 2 tablespoons of peanut butter.
For this reason, the authors ran two additional analyses on the data. One of these involved separating
participants into those who achieved more than a 10% reduction in calories and those who achieved less
than a 10% reduction. This dose–response analysis revealed that the pace of biological aging
(DunedinPACE) slowed more in participants who achieved a greater level of CR, with no effect on the other
measures of biological age.
Effects of 2-year calorie restriction on biological age and the pace of aging
32
The second analysis was called a effect of treatment-on-the-treated (TOT) analysis, in which the expected
effects of achieving a 20% reduction in calories was investigated. In other words, what might have
happened if participants had achieved 20% CR? The effect size for DunedinPACE in the TOT analysis was
0.4, higher than the 0.25 from the original analysis. The other two measures of biological age were not
affected by CR in this analysis either.
Despite not achieving 25% CR, participants still experienced several health-related improvements
(mentioned above) and a slowing of biological age. That’s promising and suggests that CR interventions
need not be so “extreme” to benefit health — even a modest reduction in calories will do. However, the
failure of many participants to meet the CR goal underscores one of the downfalls of CR as a potential
longevity intervention. Specifically, adherence and sustainability may be difficult. CALERIE was only a 2year study, and even then, the participants’ ability to restrict calories waned at 12 months and continued to
decline at 24 months. Had the study been extended, it’s not clear whether any level of CR would have been
33
maintained. Longer-term studies, if possible, will be needed to determine the feasibility of sustaining CR
over years to decades.
34
Muscle Gain & Exercise
Can the antioxidant vitamins C and E prevent exerciseinduced muscle damage?
In this randomized controlled trial, supplementing with vitamins C and E before exercise had no effect
on markers of muscle damage or postexercise physical performance in male recreational runners.
Background
Prolonged and/or high-intensity exercise causes exercise-induced muscle damage, which is important for
long-term adaptation but briefly causes soreness, inflammation, and reduced muscular performance.[1] This
damage is thought to be due, in part, to oxidative stress; therefore, antioxidants may prevent or reduce
exercise-induced muscle damage, especially during strenuous exercise, such as running.
Vitamin C and vitamin E are two well-known dietary antioxidants, but their effects on muscle damage and
performance in runners required further investigation.
The study
In this randomized controlled trial, 18 male recreational runners (average age of 47) completed a single
session of moderate-intensity treadmill running 2 hours after receiving either (i) vitamin C + vitamin E
(1,000 mg of ascorbic acid + 235 mg of ɑ-tocopherol) or (ii) a placebo.
The primary study outcomes were muscle damage (measured by creatine kinase levels) and performance
(countermovement jump, squat jump, stiffness test). The secondary outcomes included lactate levels,
delayed onset muscle soreness (DOMS), and rating of perceived exertion (RPE), with the latter two
assessed using a 10-point scale. The outcomes were assessed before, immediately after, and 24 hours after
exercise.
The results
In both groups, creatine kinase levels increased 24 hours after exercise, and lactate levels increased
immediately after exercise, with no differences between groups. Countermovement jump and squat jump
height increased immediately after exercise in both groups, but squat jump height remained higher than
baseline levels at 24 hours after exercise in the vitamin C + vitamin E group only. Muscle stiffness
decreased (improved) from before exercise to 24 hours postexercise in the vitamin C + vitamin E group
only.
Ratings for DOMS and RPE were not different between the two groups.
Note
The exercise intensity used in this study — 75% of the participants’ maximum heart rate — and the
relatively short duration of exercise — around 16 minutes of total work — may not have been strenuous
enough to induce significant muscle damage, especially in a trained group of runners. Other studies
investigating similar outcomes have used higher-intensity or eccentric exercise for the purpose of inducing
muscle damage.
35
Can milk reduce inflammation postexercise?
This randomized crossover trial found that milk consumption after exercise reduced markers of
inflammation.
Background
After exercise, there is an inflammatory response, marked by elevations of cytokines. Given that there is
evidence that certain amino acids and the calcium in milk can reduce cytokines, what is milk’s impact on
inflammatory markers after a workout?
The study
This randomized crossover trial recruited 13 healthy women (average age of 20). After exercise, the
participants drank 19 ounces of skim milk (20 grams of protein, 29 grams of carbohydrates) and a
carbohydrate drink containing maltodextrin (52 grams of carbohydrates) in a randomized order; both
drinks contained the same number of calories. The participants consumed the drink 5–10 minutes after
exercise, and again at 1 hour after exercise. Blood samples were collected before exercise and then 15
minutes, 75 minutes, 24 hours, and 48 hours after exercise. After a minimum 2-week washout period, the
participants repeated the experimental protocol with the other drink.
The exercise was performed after an overnight fast and included high-intensity plyometric and resistance
training, with an emphasis on eccentric contractions.
The outcomes studied were levels of the cytokines interleukin-1 beta (IL-1β), IL-6, IL-10, and tumor necrosis
factor alpha.
The results
There were no differences between the groups in absolute levels of cytokines.
Note
At 24 and 48 hours, IL-10 decreased after drinking milk but increased after drinking the carbohydrate drink.
Although this result is interesting, the 20-gram difference in protein between the interventions may at least
partially explain it. It is unclear whether controlling for protein and amino acid composition would have
resulted in higher cytokine levels.
Do antioxidants interfere with muscular adaptations?
This randomized controlled trial found that supplementing with the antioxidant vitamins C and E had
negligible effects on resistance exercise-induced adaptations.
Background
Oxidative stress is an imbalance between the production of reactive oxygen and nitrogen species (RONS)
and the capacity of the body’s antioxidant defenses to neutralize them. Skeletal muscle contraction
generates RONS, and if exercise is intense and prolonged, an excessive production of RONS can result. As
their name implies, RONS are highly reactive and can cause oxidative damage to cells, muscle fatigue, and
impairments in muscle force.[30] Thus, supplementing with antioxidants is of interest for minimizing the
adverse effects of RONS during and after exercise. However, evidence suggests that RONS are also
involved in regulating exercise-induced adaptations.[31] Does that mean supplementing with antioxidants
could impair such adaptations?
The study
In this 10-week randomized controlled trial, 23 recreationally resistance-trained men (ages 18 to 32)
performed resistance exercise 4 days per week and supplemented daily with either vitamins C (1,000 mg)
and E (235 mg) or a placebo every morning. All of the participants were instructed to follow a diet
36
conducive to building muscle (daily protein and carbohydrate intake of 2 and 4–7 grams per kilogram of
body weight, respectively, as well as a 300 kcal energy surplus on training days) and to avoid foods
containing high amounts of antioxidants.
The primary outcome was muscle mass, measured as total and segmental soft tissue fat-free mass using
dual-energy X-ray absorptiometry (DXA). The secondary outcomes were total and segmental fat mass,
handgrip strength, and 1-repetition maximum (1RM), maximum power, and maximum velocity in the bench
press and squat exercises performed on a Smith machine.
The results
There were no significant differences between groups for changes in fat-free mass, although dominant arm,
nondominant arm, and total upper body fat-free mass (which includes both arms and the trunk) increased
compared to baseline in the placebo group only.
Visceral adipose tissue increased in the placebo group compared to the vitamin group. There were no other
differences between groups for changes in fat mass, although gynoid fat (i.e., fat around the hips, chest,
and thighs) increased compared to baseline in the vitamin group only.
There were no significant differences between groups for performance-related outcomes, although
dominant-hand grip strength and maximal power and velocity dropoff (i.e., the amount of decrease in
velocity with an increase in load) in the bench press improved compared to baseline in the placebo group
only.
Note
A limitation of this study is that dietary intake was not assessed during the study, despite all the
participants being prescribed the same general muscle-building diet.
Additionally, the researchers calculated that 16 participants in each group were needed to detect
differences in muscle mass and strength between groups. Thus, the study was underpowered.
The big picture
Exercise promotes the activation of signaling pathways in skeletal muscle that, when repeatedly activated,
lead to gradual alterations in protein content and enzyme activities, yielding changes in muscle’s physical
properties and appearance.[32]
Although it’s compelling to try to counteract the negative effects of RONS with antioxidants, there’s
increasing evidence that the RONS produced during exercise contribute to the activation of the
aforementioned signaling pathways.[33] Thus, interventions that minimize the concentration of RONS in
muscle during exercise may prevent the physiological increase in RONS necessary to activate the signaling
pathways that facilitate muscular adaptations.
Indeed, studies that have used antioxidant supplements as a means to neutralize the effects of RONS have
reported a blunting of the molecular responses conducive to muscle hypertrophy.[31]
For instance, vitamin C blunted the increased phosphorylation of extracellular signal-regulated protein
kinases 1 and 2 and p70S6 kinase (all of which are positive regulators of muscle protein synthesis) induced
by resistance exercise in rats,[34] and this finding was also reported in humans supplementing with vitamins
C and E.[35]
Additionally, while excessive exposure to RONS during exercise causes fatigue and impairs muscle force
production, moderate amounts of RONS seem to be conducive to force production.[30] Thus, there seems to
be an optimal amount of RONS, where an increase or decrease in production results in suboptimal muscle
contractile function.[31]
The biphasic effect of ROS on skeletal muscle force production
37
Adapted from Powers * Jackson, 2008. [30]
Although there were no significant differences in fat-free mass (FFM) and muscle strength between groups
in the summarized study, the sample size was substantially less than what was calculated as necessary to
detect differences between groups. To help overcome this issue, the researchers calculated effect sizes for
each outcome to determine whether there may have been practically meaningful differences between
groups.
A small effect size was found for bench press 1RM (percent change of 12.40% vs. 18.30%) and maximal
force output (percent change of 10.54% vs. 14.13%) in favor of the placebo group. Additionally, a small
effect size was found for dominant arm FFM (percent change of 2.72% vs. 4.88%) in favor of the placebo
group. However, for many other outcomes, there were no clear differences between groups, and arguably,
some of them trended in favor of the vitamin group. All in all, the summarized study does not provide
convincing evidence that supplementing with vitamins C and E will limit muscular adaptations. Are other
studies on the topic in agreement?
When analyzing the available research in this area, it’s important to categorize studies based on the
population studied, namely, whether the participants were younger or older adults. (The reason for this is
discussed below.) Starting with younger adults, there are three main studies to consider.
One study found no differences between the vitamin and placebo groups for changes in upper arm, thigh,
or total lean mass,[36] and another found no difference between groups for the change in thigh muscle
thickness.[37] In the third study, which included three groups (vitamin, placebo, and a control group that did
not perform exercise), there were no differences between groups for the change in total FFM, but the
percentage change in FFM was greater than the control group in the placebo group only.[38]
With respect to strength, one study reported that 1RM biceps curl increased in the placebo group compared
to the vitamin group, while there were no differences in 1RM triceps press, knee extension, or knee flexion
between groups.[36] In the other two studies, quadriceps peak torque did not differ between groups, and
estimated deadlift and dumbbell lunge strength did not differ between groups.[37][38]
A limitation of these studies is that they were all 10 weeks long. A longer intervention duration may be
required for the potential negative effects of supplementation with vitamins C and E to become more
38
apparent.
In adults at least 60 years old, evidence from two studies indicated that supplementing with vitamins C and
E may improve resistance exercise-induced gains in FFM,[39][40] while one study found no effect[41] and the
other reported a greater increase in lean mass in the placebo group.[42] For strength, there were no reported
differences between groups.[41][40][42]
Unlike the evidence in younger adults, which indicates that supplementation with vitamins C and E has a
neutral to slightly negative effect on resistance exercise-induced adaptations, there is some evidence in
older adults that supplementation with vitamins C and E may improve resistance exercise-induced
increases in FFM. A potential explanation for this is that aging results in increased levels of oxidative stress
and may blunt the adaptive increase in total antioxidant capacity in response to exercise.[43] Therefore,
supplementing with vitamins C and E may provide a beneficial effect in older adults by restoring the
balance between oxidants and antioxidants.
While the mechanistic basis for why vitamins C and E would dampen resistance exercise-induced
adaptations is sound, when it comes to direct outcomes of interest (i.e., changes in 1RM strength and FFM),
as opposed to indirect outcomes (i.e., changes in the activation of regulatory proteins), the available
evidence doesn’t clearly demonstrate that supplementing with vitamins C and E is cause for concern.[44] This
isn’t entirely surprising, as the physiological relevance of a blunted activation of one or two regulatory
proteins to functional endpoints is questionable.[45]
Further long-term randomized trials are needed to determine whether supplementing with vitamins C and E
impairs resistance exercise-induced adaptations in younger adults. The results of the available studies are
equivocal, but there is an absence of evidence to indicate any benefit of supplementation with vitamins C
and E for resistance exercise-induced adaptations in this population. Therefore, younger adults interested in
maximizing exercise-induced adaptations may find it prudent to avoid high-dose supplementation with
vitamins C and E, particularly in close proximity to resistance exercise sessions.
39
Is HIIT helpful for people with musculoskeletal disorders?
In this meta-analysis, high-intensity interval training reduced pain intensity and increased maximal
oxygen uptake (VO2max), in adults with musculoskeletal disorders, but it was not superior to other
exercise interventions.
Background
Musculoskeletal pain reduces a person’s quality of life and is a significant source of disability. Exercise has
pain-relieving effects, through the release of endorphins and endocannabinoids along with other
mechanisms.[46] High-intensity interval training (HIIT) is a popular form of exercise that may be superior to
other forms of exercise for improving fitness. Could HIIT represent an effective therapy for people with
musculoskeletal pain?
The study
This meta-analysis of 13 studies assessed the effectiveness of HIIT in participants with musculoskeletal
disorders.
The participants were diagnosed with chronic nonspecific low back pain (3 studies), osteoarthritis (2
studies), axial spondyloarthritis (2 studies), episodic migraines (1 study), fibromyalgia (1 study), and
subacromial pain syndrome (1 study). In most studies, HIIT was compared to another exercise intervention
or a nonexercise control intervention (i.e., standard/usual care). The interventions lasted between 6 and 12
weeks.
The primary outcomes were pain intensity, maximal oxygen uptake (VO2max), disability, and health-related
quality of life (QoL).
The results
HIIT reduced pain intensity and improved VO2max compared to nonexercise control interventions, but not
compared to other exercise interventions. HIIT did not affect disability or QoL compared to nonexercise
control interventions. Pain intensity was inversely associated with VO2max.
The quality of evidence was rated as low for pain intensity and QoL and moderate for VO2max and
disability.
40
Does training status modulate the effects of caffeine?
In this randomized controlled crossover trial, training status did not modulate the ergogenic effects of
caffeine.
Background
The ergogenic (performance-enhancing) effects of caffeine have been demonstrated in many studies in
various groups of participants, but most cohorts have been homogenous in terms of training status.
Therefore, research was needed to determine whether the ergogenic effects of caffeine are modulated by
training status.
The study
This randomized controlled crossover trial recruited 20 men (average age of 21) who were low habitual
caffeine consumers (<50 mg/day). Half of the participants were classified as trained, and the other half
were classified as recreationally active.
The trained participants had a minimum of 5 years of resistance training experience and were training three
or more times per week with the purpose of competing in a specific sport. The recreationally active
participants had less than 6 months of resistance training experience and engaged in 3 or fewer hours of
training per week.
In the crossover design, each participant completed all 3 testing conditions of caffeine, placebo, and
control (no intervention), and each participant’s testing sessions were conducted at least 72 hours apart.
Caffeine was administered via capsule at a dose of 6 milligrams per kilogram of body weight. The
participants were provided with a standardized preworkout snack and were asked to refrain from caffeine
ingestion prior to arrival at the laboratory.
The participants were tested in the bench press and squat exercises, including 1-repetition maximum
strength (1RM) and muscular endurance (i.e., the number of reps performed in a single set to muscular
failure using 70% of 1RM). Countermovement jump performance was also assessed along with the rating of
perceived exertion at the end of each testing session.
The results
An ergogenic effect of caffeine was noted compared to the placebo and control conditions, but there was
no significant interaction between training status and caffeine in any of the analyzed outcomes.
The authors of this study concluded that caffeine is ergogenic for muscular strength, endurance, and jump
height and that the effects are likely to be of similar magnitude in trained and recreationally active men.
The effects on skeletal muscle of supplementing with HMB
and vitamin D
In this randomized controlled trial in middle-aged women, supplementing with HMB and vitamin D had
beneficial effects on skeletal muscle size in sedentary conditions but did not affect changes in skeletal
muscle size when supplementation was combined with resistance exercise.
Background
Aging combined with a sedentary lifestyle results in reductions in skeletal muscle mass. It also unfavorably
changes the composition of muscle, as evidenced by an accumulation of intermuscular fat.
Although exercise is the gold-standard approach to remedy these issues, alternative approaches to
improve skeletal muscle health — either in the absence of exercise or through enhancing exercise-induced
adaptations — are worth exploring. Two potential candidates are hydroxymethylbutyrate (HMB), which has
41
been shown to have anticatabolic effects, and vitamin D because insufficient blood vitamin D levels are
often associated with lower muscle mass and strength.
The study
In this 12-week randomized controlled trial, 39 middle-aged women (average age of 53) were assigned to
one of four conditions:
Resistance exercise + supplementation with calcium HMB (3 grams) and vitamin D 3 (2,000 IU) daily
Resistance exercise + placebo
Sedentary + supplementation with calcium HMB and vitamin D 3
Sedentary + placebo
In the resistance exercise conditions, the participants performed three full-body workouts under supervision
each week. In the sedentary conditions, the participants were instructed to not change their physical
activity habits. Nutrition intake was assessed using 3-day food journals at baseline and the end of the
study.
The primary outcome was thigh skeletal muscle volume. The secondary outcomes were lean mass (whole
body, appendicular, leg, and arm), fat mass (whole body, trunk, leg, and arm), thigh intermuscular fat
volume, 1-repetition maximum strength (assessed for the leg press, leg extension, and leg curl), 10repetition maximum strength (assessed for the chest press, shoulder press, and seated row), and blood
vitamin D levels.
The results
In the sedentary conditions, thigh skeletal muscle volume increased and thigh intermuscular fat volume
decreased in the supplement group compared to the placebo group. In the resistance exercise conditions,
thigh intermuscular fat volume decreased in the supplement group compared to the placebo group, but
there was no difference between groups for thigh muscle volume.
In the sedentary conditions, arm lean mass was maintained in the supplement group, whereas it decreased
in the placebo group. In the resistance exercise conditions, there were no differences between groups for
changes in lean or fat mass.
There were no differences between groups in either condition for changes in performance-related
outcomes.
Exploratory analysis indicated that participants who had insufficient blood vitamin D levels at baseline and
sufficient levels by the end of the study experienced a reduction in thigh intermuscular fat volume, but
those who remained vitamin D insufficient did not.
Note
The researchers did not adjust for multiple comparisons, despite the inclusion of numerous outcomes,
which increases the risk of false-positive results. Also, the outcomes reported in the preregistered version
of the study differ in many ways from the actual study. Therefore, the results should be interpreted with
caution.
42
Citrulline for soccer performance
This randomized controlled trial reported that a single dose of citrulline malate did not benefit
performance or subjective fatigue during a soccer-specific test.
Background
The amino acid L-citrulline is an endogenous precursor of L-arginine, an amino acid that is the main
substrate for the production of nitric oxide, which plays a role in performance and recovery. Supplementing
with citrulline has been shown to enhance physical performance in some contexts, which seems to be due
to an improvement in ammonia metabolism and oxygen delivery via increased vasodilation. Does a single
dose of citrulline before a field test benefit soccer players?
The study
In this randomized controlled trial, 18 male soccer players (average age of 26) from the top divisions of
three European countries consumed 6 grams of citrulline malate, 3 grams of citrulline malate, or a placebo
45 minutes before a field-based, soccer-specific test.
The test involved two 9-minute periods, which were separated by a rest interval of 6 minutes. During each
period, the participants dribbled a ball through 5 cones placed 2 meters apart and then passed the ball to
another player. Each run was about 10 seconds, followed by a passive rest interval of 20 seconds.
The outcomes were average heart rate, maximum heart rate, heart rate recovery (assessed 1, 3, and 5
minutes after the test), and maximum and average speed during the test. Also measured were blood lactate
levels (assessed immediately before the test, 3 minutes after each 9-minute period, and 30 minutes after
the test); rating of perceived exertion (RPE; assessed 10 minutes after the test); and creatine kinase levels
(assessed at baseline and 18–20 hours after exercise).
The results
Heart rate recovery improved in the placebo group compared with the citrulline groups 3 minutes after the
test. This may have been a false-positive finding, because the researchers did not adjust for multiple
comparisons.
Also, creatine kinase levels were nonsignificantly lower in the 6-gram citrulline group compared with the
other groups after the test. There were no other differences between the groups.
Note
The main limitation of this study is a small sample size, which is a consequence of the inclusion of elite
soccer players only.
43
Should you take creatine before or after resistance training?
In this randomized controlled trial, taking creatine before or after resistance training had similar effects
on resistance training adaptations and body composition.
Background
Creatine is undoubtedly one of the best-researched supplements with a proven track record of enhancing
sports performance. However, there is limited research on creatine timing. Is there an optimal time of day
to supplement with creatine?
The study
This 8-week randomized controlled trial in 34 healthy college athletes (average age of 20; 18 men and 16
women) compared the effectiveness of preexercise vs. postexercise supplementation with creatine on
resistance training adaptations and body composition.
The participants consumed 5 grams of creatine monohydrate in the form of a protein-maltodextrin
beverage either 1 hour before or 1 hour after resistance training. The researchers examined the effects on
body composition, muscular strength (assessed via isometric mid-thigh pull and 1-repetition maximum on
the back squat and bench press), and muscular endurance (assessed via repetitions to fatigue at 80% of 1repetition maximum on the back squat and bench press) before and after the 8-week supplementation
period.
The results
The timing of supplemental creatine had no influence on resistance training adaptations and body
composition. Supplemental creatine plus resistance exercise increased fat-free mass, enhanced 1-repetition
maximum on back squat and bench press, and decreased fat mass and body weight equally well in both
groups.
Note
Although the researchers intended to control for diet quality, there was poor compliance with recording of
dietary intake, which is a crucial confounding factor. Thus, the limited information on diet quality is a
drawback for interpreting these findings. Future studies examining the role of creatine timing should more
tightly control the diet quality of the participants.
Alternate-day fasting and exercise for reducing liver fat
In this randomized controlled trial, combining alternate-day fasting (ADF) with aerobic exercise
decreased liver fat more than ADF or exercise alone in people with nonalcoholic fatty liver disease.
Background
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive liver fat and elevated
cardiometabolic risk factors. Lifestyle interventions involving dietary modifications and increased physical
activity, with the goal of inducing significant weight loss, are the cornerstone of NAFLD treatment.[105] A
variety of hypocaloric diets can be effective for this task, including alternate-day fasting (ADF). However, a
study had yet to directly quantify changes in liver fat from ADF or examine whether combining ADF with an
exercise intervention augments improvements in cardiometabolic risk factors.
The study
In this 3-month randomized controlled trial, 80 participants (81% women, mainly Hispanic or Black, ages
23–65) with NAFLD were assigned to one of four groups:
44
ADF: participants alternated days of free eating with modified fasting days in which they consumed
600 kcal (30% of energy from fat, 55% carbohydrate, 15% protein) between 5 p.m. and 8 p.m.
Exercise (EX): participants completed 60 minutes of moderate-intensity aerobic exercise (65%–80%
of maximum predicted heart rate) five times per week, which was supervised by the study staff.
ADF+exercise (COMBO): participants followed the ADF and EX interventions.
Control: participants were instructed to maintain current eating and exercise habits (no
intervention).
At baseline and the end of the study, dietary intake was assessed using a 24-hour dietary assessment tool,
and physical activity was monitored over 7 days using a pedometer.
The primary outcome was liver fat, measured using a specialized magnetic resonance imaging (MRI)
technique. The secondary outcomes were anthropometrics, blood lipids, markers of glycemic control
(fasting glucose, fasting insulin, HbA1c, insulin resistance assessed via HOMA-IR, and insulin sensitivity
assessed via QUICKI), blood pressure, liver enzymes (ALT and AST), liver fibrosis (estimated using the FIB-4
index), and hepatokines (proteins secreted from the liver that regulate metabolic processes; FGF-21,
selenoprotein P, fetuin-A).
The results
Compared to control and EX, liver fat decreased in COMBO. Additionally, liver fat nonsignificantly (p=0.05)
decreased in COMBO compared to ADF (−5.48% vs. −2.25%). Compared to control, serum levels of ALT
decreased in COMBO.
Compared to control and EX, body weight and fat mass decreased in COMBO. However, weight and fat
loss were not different between COMBO and ADF (−4.58% vs. −5.06%; −3.24 vs. −3.32 kg).
Compared to control, fasting insulin and insulin resistance decreased and insulin sensitivity increased in
COMBO. Additionally, insulin sensitivity nonsignificantly increased in COMBO compared to ADF (p=0.05)
and EX (p=0.07). There were no other differences between groups.
COMBO results
45
Note
The participants had a low risk of advanced fibrosis at baseline, according to the average FIB-4 score,
which may help explain the lack of effect of the interventions on fibrosis.
The researchers did not adjust for multiple comparisons, despite the inclusion of numerous outcomes,
which increases the risk of false-positive results. Therefore, the results for the secondary outcomes should
be interpreted with caution.
The big picture
The standout finding of this study was that, despite similar reductions in body weight and fat mass in
COMBO and ADF, reductions in liver fat were greater in COMBO, suggesting that just losing weight isn’t the
only important factor for reducing liver fat. To maximize these reductions, it may be pivotal to combine a
hypocaloric diet with exercise.
That said, this finding (i.e., a greater reduction in liver fat in COMBO compared to ADF) was technically
nonsignificant, so further trials utilizing a similar design are needed. In the meantime, other research can
shed light on the question of whether exercise reduces liver fat independent of changes in body weight. If
this is indeed the case, it’s possible that exercise truly had an additive effect in the summarized study.
Fortunately, this subject is quite well studied. Multiple trials have reported that exercise significantly
decreases liver fat independent of weight loss.[139][140][141] According to a 2018 meta-analysis, in the absence
of significant weight loss, exercise interventions reduce liver fat by 2.16%, on average, in people with
NAFLD.[142] However, the addition of significant weight loss still produced larger reductions in liver fat.
The evidence is pretty clear that exercise can reduce liver fat independent of weight loss, but how much
exercise is needed? The summarized study utilized a relatively demanding moderate-intensity aerobic
exercise protocol (300 minutes per week), which may be an unsustainable approach for many people. This
may have been why, although there were no dropouts in COMBO, 25% of the participants assigned to EX
dropped out.
46
After 3 months, the summarized study found a nearly 5.5% reduction in liver fat in the COMBO group, which
is on par with reductions yielded by other lifestyle intervention with considerably less exercise volume. In an
observational study that instructed participants (including 50 with NAFLD) to reduce their energy intake
and perform aerobic exercise that only moderately increased heart rate for at least 180 minutes per week,
participants reduced liver fat by 4.6% over 9 months.[143] Similarly, a randomized controlled trial in
participants with NAFLD reported that two to three sessions of supervised nordic walking per week
(performed at 60–75% of VO2max for 30–60 minutes) combined with a dietary intervention reduced liver
fat by 7.6%.[144] Finally, evidence from a couple of meta-analyses indicate that exercise interventions
(without dietary interventions in most studies) involving roughly three sessions of 30–60 minutes of aerobic
exercise per week for 12 weeks significantly reduced liver fat.[142][145] One of these meta-analyses reported an
average reduction in liver fat of 3.3%.[142]
In sum, less demanding exercise interventions than used in the summarized study seem to be able to
promote similar reductions in liver fat. At the moment, there doesn’t appear to be a clear relationship
between reductions in liver fat and the weekly frequency and volume of exercise in people with NAFLD.[146]
Exercise type may also play a role. The present study used prolonged moderate-intensity aerobic exercise,
which may not suit many people’s preferences.
A 2017 meta-analysis reported that aerobic and resistance exercise interventions produce similar
reductions in liver fat in people with NAFLD, even though energy expenditure tended to be lower in
resistance exercise interventions.[145]
Additionally, the following results have been reported in trials that performed head-to-head comparisons
between different exercise interventions in participants with NAFLD:
4 weeks of either moderate-intensity aerobic exercise (55% of VO2max) or high-intensity interval
aerobic exercise (repeated cycles of 4 minutes at 80% of VO2max followed by 3 minutes at 50% of
VO2max), which were matched for energy expenditure (about 400 kcal per session), produced
similar reductions in liver fat.[147]
6 months of either moderate-intensity aerobic exercise (45%–55% of maximum predicted heart rate
for 150 minutes per week) or vigorous aerobic exercise (65%–80% of maximum predicted heart rate
for 150 minutes per week) produced similar reductions in liver fat.[148]
4 months of either aerobic exercise (60%–65% of heart rate reserve for 180 minutes per week) or
resistance exercise (three full-body sessions per week consisting of 9 exercises performed for 3
sets of 10 repetitions using 70%–80% of 1-repetition maximum) produced similar reductions in liver
fat.[149]
3 months of either aerobic exercise (60%–75% of VO2max for 180 minutes per week) or resistance
exercise (three full-body sessions per week consisting of 10 exercises performed for 2 sets of 8–12
repetitions to fatigue each) produced similar reductions in liver fat.[150]
Although head-to-head comparisons are sparse, the available evidence indicates that different types of
exercise have similar effects on reducing liver fat. Further research is needed to clarify the most effective
form of exercise for reducing liver fat, as well as the ideal amount of exercise. Moreover, it remains unclear
whether combining aerobic and resistance exercise is superior to either mode of exercise alone for
reducing liver fat.[146]
However, as it stands, the available evidence indicates that various types of exercise interventions can be
used to reduce liver fat. Thus, the general recommendation to accumulate at least 150 minutes of
moderate-intensity or 75 minutes of high-intensity exercise per week is a suitable target for most people.[146]
Following this recommendation, the mode, frequency, and duration of exercise should be customized to the
individual’s preferences and goals to maximize adherence.
47
Does “extra” exercise improve bone health in children?
This meta-analysis found no evidence of beneficial effects from additional exercise interventions
(compared to standard exercise) on markers of bone health or the incidence of fractures in primary
school children.
Background
The effect of additional exercise — that is, beyond the exercise already provided to children — on markers
of bone health and the incidence of fractures was unclear and required investigation.
The study
This meta-analysis of 15 trials (14 randomized controlled trials and 1 nonrandomized controlled trial)
examined the effect of additional exercise interventions, compared to standard exercise, on markers of
bone health (primary outcomes) and the incidence of fractures (secondary outcome) in a total of 4,030
healthy primary school children (ages 6–12).
The trials were conducted in Europe (5 trials), the United States (4 trials), Canada (3 trials), Australia (2
trials), and South Africa (1 trial). In most trials, the additional exercise interventions involved exercises
specifically selected for stimulating bone adaptations, such as jumping exercises. The duration of additional
exercise interventions ranged from 20 weeks to 4 years.
The markers of bone health were the bone mineral content (BMC) of the whole body, BMC measured at the
femoral neck and at the lumbar spine, and the areal bone mineral density (aBMD) of the whole body, as well
as aBMD measured at the femoral neck and at the lumbar spine. These markers were measured at less than
15 months and at 24–48 months after the start of the exercise interventions. Other markers of bone health
included measurements of the cross-sectional area of the femoral neck and tibia and volume-related
measures of BMC and BMD in the tibia.
The results
Additional exercise interventions increased femoral neck BMC; however, this result became statistically
nonsignificant in the sensitivity analyses. No effects were observed on any of the other outcomes.
The certainty of evidence was very low for all outcomes.
48
Can beta-alanine improve adaptations to resistance
exercise?
In this randomized controlled trial, supplemental beta-alanine had no beneficial effects on muscle
strength and thickness.
Background
Supplemental beta-alanine can improve endurance performance by enhancing the buffering capacity of
muscles. Similarly, beta-alanine could increase muscular performance and recovery from resistance
exercise, but the evidence is still limited.
The study
This randomized controlled trial in 19 resistance-trained men (average age of 27) examined the effect of
supplementation with beta-alanine (6.4 grams per day) on muscle strength and thickness in response to 8
weeks of a resistance training program (4 sessions per week), compared to placebo.
To assess muscle strength, the participants performed 1-repetition maximum tests on the bench press and
back squat before and after the 8-week resistance training program. The researchers also measured and
compared the changes in muscle thickness of the biceps brachii, triceps brachii, and vastus lateralis (largest
of the quadriceps muscles) using ultrasonography.
The results
Although the resistance training program was effective (all participants gained muscle mass and strength),
supplemental beta-alanine had no additional benefits compared to the placebo.
49
Is vigorous activity linked to mortality risk in older adults?
This retrospective cohort trial found that vigorous activity, as measured by a wearable device,
correlated with reduced cardiovascular, cancer, and all-cause mortality risk in older adults.
Background
Exercise guidelines commonly recommend half as much exercise if it is done vigorously. However, vigorous
activity can be challenging for wearable devices to capture, especially if done for brief periods. Does
intermittent vigorous activity, as tracked by wearable technology, result in reduced mortality risk?
The study
This retrospective cohort study examined the wearable accelerometer data from 25,241 nonexercising
participants (average age of 62) in the UK Biobank study. The participants wore a wrist accelerometer for 7
days to track their activity, which was classified as sedentary, light, moderate, or vigorous. The outcomes
examined were risk of cardiovascular, cancer, or all-cause mortality.
The results
The average amount of vigorous exercise performed by the participants (3 bouts of vigorous movement,
lasting 1–2 minutes each) was associated with a 38%–40% reduction in all-cause and cancer mortality risks
and a 48%–49% reduction in cardiovascular mortality risk. The trends were near linear for all three causes,
with steeper reductions in mortality at lower volumes of vigorous activity.
Note
Similar effects were seen in the nonexercising participants who performed intermittent vigorous movement
throughout the day, compared to the participants who engaged in vigorous exercise during their leisure
time. This suggests that people who do not perform structured exercise can still obtain the mortality
benefits of vigorous activity, even when it is broken up into several short bouts of movement throughout
the day.
50
Can curcumin reduce fatigue and muscle soreness?
In this nonrandomized prospective cohort study, supplemental curcumin was associated with less
muscle fatigue and soreness.
Background
Curcumin, the natural bioactive compound of turmeric, has anti-inflammatory and antioxidative properties.
Given these properties, it’s possible that curcumin could reduce muscle fatigue and soreness after
resistance exercise, which are caused in part by oxidative stress and inflammatory processes.
The study
This nonrandomized prospective cohort study in 28 middle school and high school students (average age
of 17; 75% male, 25% female) examined the effect of supplementation with curcumin (300 milligrams daily
for 12 weeks) on body composition, exercise performance, inflammatory markers, muscle fatigue, and
muscle soreness, with comparison to a control condition (no supplementation).
The results
The participants in the curcumin group experienced reduced muscle fatigue and soreness compared to the
control group.
In terms of exercise performance, the curcumin group also showed improved reaction times compared to
the control group.
However, curcumin had no effects on most inflammatory markers and body composition.
Note
Given the study design, small sample size, and the high number of outcomes, this study’s results should be
interpreted cautiously. For instance, instead of random assignment of participants to groups, the
participants chose their own groups.
More extensive and better-controlled studies are needed to confirm the effects of supplemental curcumin
for improving fatigue and muscle soreness.
51
Exercise vs. caloric restriction for reducing visceral fat
In this meta-analysis of randomized controlled trials, greater amounts of exercise corresponded with
greater reductions in visceral fat, which was not the case for caloric restriction.
Background
Visceral fat (the fat stored deep in the belly and surrounding the internal organs) is a strong predictor of
cardiometabolic risk and is a much better predictor than body mass index.[240] An increase in exercise and
caloric restriction are recommended to reduce body weight, but it’s unclear whether one is more impactful
than the other for reducing visceral fat.
The study
This meta-analysis of 40 randomized controlled trials examined the effects of exercise and caloric
restriction on visceral fat (measured using computed tomography or magnetic resonance imaging) in 2,190
participants with overweight or obesity.
Fifteen studies were conducted in the U.S., 11 in Asia, and 9 in Europe. Eight studies included participants
with comorbidities (e.g., type 2 diabetes, dyslipidemia, metabolic syndrome, nonalcoholic fatty liver
disease). The exercise interventions ranged from 4 weeks to 2 years, whereas the caloric restriction
interventions ranged from 12 weeks to 1 year.
The results
Compared to the control group, exercise reduced visceral fat to a small extent, and caloric restriction
reduced visceral fat to a moderate extent.
In dose-response analyses, greater amounts of exercise facilitated greater reductions in visceral fat.
However, this relationship was not found for caloric restriction.
In an analysis that compared exercise and caloric restriction and equated for the weekly energy deficit,
exercise had a superior dose-response effect on reducing visceral fat.
Note
These results do not necessarily indicate that exercise is more effective than caloric restriction for reducing
visceral fat at a given weekly energy deficit; rather, once a given weekly energy deficit is surpassed,
greater amounts of exercise will continue to facilitate reductions in visceral fat, but greater amounts of
caloric restriction will not.
Exploring low-carb diets for high-intensity exercise
performance
In this 31-day study, a low-carbohydrate/high-fat diet led to equivalent performance, higher rates of fat
oxidation, and lower rates of carbohydrate oxidation during exercise and improved glycemic control
compared to a high-carbohydrate/low-fat diet.
Background
Athletes are typically advised to consume high-carbohydrate diets to maintain muscle glycogen stores and
support vigorous-intensity exercise, which is fueled almost exclusively by carbohydrates (glucose).
However, recent evidence suggests that low-carbohydrate/high-fat (LCHF) diets may promote greater fat
oxidation during exercise,[241] perhaps making them a suitable choice for athletes, despite some studies
noting performance impairments during an LCHF diet.[242]
Because LCHF diets also improve blood glucose control and cardiometabolic health, it’s worth exploring
whether this dietary pattern offers health and performance benefits compared to high-carbohydrate/low-
52
fat (HCLF) diets.
The study
In this randomized crossover study, 10 highly trained male athletes (average age of 40) completed two 31day dietary interventions separated by a 2-week washout period:
LCHF: less than 50 grams of carbohydrates, 75%–80% fat, 15%–20% protein
HCLF: 60%–65% carbohydrate, 20% fat, 15%–20% protein
The LCHF diet was also supplemented with 1–2 grams of sodium per day from bouillon cubes or homemade
broth and was designed to promote continuous nutritional ketosis throughout the 31-day intervention
period. Nutritional ketosis was verified by measures of blood ketones on days 3, 7, 14, 21, and 28.
The primary study outcomes included running performance (1-mile time trial and 6 x 800-meter repeated
sprint performance), carbohydrate and fat oxidation during exercise, body composition, continuous
glucose, and cardiometabolic biomarkers (HbA1C, total cholesterol, LDL cholesterol, very-low-density
lipoprotein cholesterol, HDL cholesterol, triglycerides, insulin, and high-sensitivity C-reactive protein (CRP)).
Outcomes were measured before and after each 31-day intervention.
The results
After the LCHF diet, average fat oxidation increased (+190%), and average carbohydrate oxidation
decreased (−20%) during the 1-mile time trial. During the repeated sprint test, average fat oxidation
increased (+92%) and average carbohydrate oxidation decreased (−54%). Performance on the 1-mile time
trial and repeated sprint test was no different before and after the LCHF diet.
There were no changes in carbohydrate oxidation, fat oxidation, or performance during the 1-mile time trial
or repeated sprint test after HCLF.
Average blood glucose was lower during LCHF than during HCLF on days 8, 13, 15–20, and 22 of the diet.
Total cholesterol, LDL cholesterol, and HDL cholesterol were higher after LCHF compared to HCLF. Body
weight and BMI decreased after both the LCHF and HCLF diets.
Note
While both diets were isocaloric (contained a similar amount of calories), they differed in their fat,
carbohydrate, protein, cholesterol, fiber, and sugar content. With the exception of protein intake, which was
31 grams higher on LCHF, all other nutrient differences were an expected outcome of the dietary
prescriptions.
The big picture
Dietary carbohydrates are used to maintain blood glucose and glycogen (glucose stored in the muscles and
liver), which can be used for energy during exercise. Muscle glycogen is the body’s preferred fuel source
during high-intensity and long-duration exercise. Indeed, consuming carbs during exercise delays and
reverses muscle fatigue, and though the practice is questionable, endurance athletes have long practiced
“carbohydrate loading” before big races to saturate their glycogen stores in hopes of improving
performance.
Why are carbs so essential for athletes? At rest and during low-intensity exercise, the body mainly burns fat
for energy. But at a certain intensity of exercise, the body begins to derive a larger percentage of its energy
from carbohydrates rather than fat. This is known as the “crossover point.”[243] As exercise intensity
increases above the crossover point, more glucose and less fat is used, until finally, at around 85% of
maximal aerobic capacity, fat’s contribution to energy is negligible, and the body is getting almost all of its
energy from glucose (carbs).
The “crossover concept” of exercise metabolism
53
At rest and during exercise below 60% of maximal oxygen uptake, fat is the main fuel source used to generate ATP. Above 75% of
maximal oxygen uptake, glucose and muscle glycogen become the dominant fuel sources. The crossover point refers to the
intersection of carbohydrate and fat metabolism, beyond which more energy is derived from carbohydrate (glucose) and less is
derived from fat.
The crossover effect explains why high-carb diets are promoted for performance and the general hesitancy
to adopt LCHF diets. However, there has lately been an increase in the interest in LCHF diets among
athletes.
The FASTER study was published in 2015. In that study, researchers characterized the metabolic profiles of
“keto-adapted” endurance athletes — those who had been eating a LCHF/ketogenic diet for several
years.[244] The study questioned some long-held beliefs about exercise metabolism.
The low-carb athletes had rates of peak fat oxidation that were more than two-fold higher than the highcarb athletes, and they hit their peak fat oxidation rate at around 70% of VO2 max, compared to 55% in the
high-carb group. Despite consuming less than 50 grams of carbohydrates per day, the low-carb athletes
also had similar levels of muscle glycogen at rest and after a 3-hour endurance run when compared to the
high-carb athletes. These results were some of the first to suggest that habituation to a low-carb diet can
shift the crossover point during exercise, allowing athletes to use more fat at a higher exercise intensity and
increase the exercise intensity where the crossover point occurs.
The results of the current study support these findings. Peak fat oxidation rates occurred at 85% of the
athletes’ VO2 max after just a month on a ketogenic diet. Interestingly, peak fat oxidation occurred at 80%
after the high-carb diet, though it was still nearly half of that observed after the low-carb diet. In addition,
some of the highest fat oxidation rates ever recorded were observed in these middle-aged athletes
following the LCHF diet, in excess of 1.85 grams/minute.
Altering diet composition definitely shifts energy metabolism during exercise. But athletes care about
54
performance. In this regard, previous studies haven’t been so supportive of LCHF diets.
Numerous studies published in the last few years have shown that keto adaptation could be costly. Athletes
who adopted a LCHF diet for 5–6 days[242], 3 weeks[245], and 25 days[246] displayed worse exercise economy
and impaired performance during simulated competition compared to when they consumed a highcarbohydrate diet. Six days of a LCHF diet also impaired high-intensity sprint performance but did not
affect 100-kilometer cycling performance in a group of cyclists.[241]
This study was designed to further test the hypothesis that high-intensity exercise performance is impaired
following a LCHF diet. This hypothesis that was not supported by the results. The athletes in this study
performed a 1-mile time trial and a series of 6 high-intensity 800-meter sprints — both of which are thought
to be primarily carbohydrate fueled. Nonetheless, performance on each test was equivalent following the
LCHF and HCLF diets — 367 seconds and 374 seconds (1-mile time trial) and 1,236 and 1,254 seconds
(total time for the 6 x 800-meter sprints) after the LCHF and HCLF diets, respectively.
Low-carb vs. high-carb for exercise performance and metabolism
It’s important to underscore the metabolic health benefits experienced by the participants during the LCHF
diet. Despite being healthy and fit athletes, 30% of the participants in this study had average glucose levels
during the HCLF diet that were greater than 100 mg/dL, putting them in the “prediabetic” range. Average
glucose and glycemic variability significantly improved in all participants during the LCHF intervention and
to a greater extent in the few participants with elevated glucose levels.
LCHF provided therapeutic benefits without compromising performance, suggesting that this dietary
pattern may be suitable for athletes who want to optimize their health and exercise routines. Though the
sample size was small (10 participants) and included only middle-aged men, which limits the generalizability
of the findings, the results of this study will certainly ignite some discussion.
55
Does EGCG increase the fat burn during exercise?
In this randomized controlled crossover trial, ingesting epigallocatechin-3-gallate before exercise
reduced adrenaline and noradrenaline levels and decreased fat oxidation but did not affect
performance variables compared with placebo.
Background
Green tea contains high amounts of the polyphenol epigallocatechin-3-gallate (EGCG). Consuming tea with
EGCG in it has been shown to increase whole-body metabolism and fat oxidation, making it a promising
weight-loss and fat-loss supplement.[247] EGCG may also alter substrate metabolism during exercise by
impacting the activity of catecholamines (i.e., adrenaline and noradrenaline), but this hypothesis had yet to
be investigated.
The study
In this randomized controlled crossover trial, 8 men (average age of 22) completed an exercise test to
exhaustion 2 hours after ingesting EGCG and a placebo, given in random order. There was a 7-day washout
period separating the conditions.
The primary study outcomes were levels of adrenaline and noradrenaline, levels of metanephrine and
normetanephrine (which result from the breakdown of noradrenaline), and rates of fat and carbohydrate
oxidation during exercise. Other outcomes included total test performance time, power output, heart rate,
lactate threshold (an indicator of exercise intensity), peak oxygen consumption (VO2 peak), peak fat
oxidation (PFO), blood glucose (sugar) and lactate levels, and rating of perceived exertion (RPE).
The results
PFO and lactate threshold occurred at a similar exercise intensity in both conditions. Performance time,
power output, heart rate, RPE, and VO2 peak were similar in the EGCG and placebo conditions.
At the participants’ PFO, the rates of fat oxidation and carbohydrate oxidation were 32% lower and 49%
higher, respectively, in the EGCG condition compared with the placebo condition. Levels of adrenaline and
noradrenaline were lower in the EGCG condition during exercise at PFO, lactate threshold, and VO2 peak,
whereas levels of metanephrine and normetanephrine were no different between conditions during exercise.
Note
The reason that the results of this study seem to conflict with other findings — which showed that EGCG
increases fat oxidation — may have to do with the fact that other studies provided caffeine (from green tea
or green tea extract) along with the EGCG, whereas this study used a supplement containing pure EGCG
(minimum of 94% EGCG) and no caffeine.
56
Is greater physical activity associated with greater weight
loss?
In this secondary analysis of a 24-month randomized controlled trial, greater amounts of physical
activity were associated with greater weight loss.
Background
Evidence suggests that greater amounts of physical activity facilitate greater amounts of weight loss[248]
and are more effective for attenuating weight gain.[249] This study investigated whether these findings held
true in the context of a multi-component lifestyle intervention in an underserved population in Louisiana.
The study
This study was a secondary analysis of a 24-month randomized controlled trial that assigned participants
with obesity to either an intensive lifestyle intervention or usual care.[250] The participants in the intervention
group worked with coaches to develop plans for eating and physical activity; the plans were designed to
achieve a weight loss of at least 10% of initial body weight in the first 6 months, followed by weight
maintenance.
The researchers used data from 402 participants (average age of 50; 354 women, 48 men; 73% Black) in
the intervention group to examine the association between changes in physical activity and changes in
body weight. Physical activity was assessed at baseline and at 6, 12, and 24 months of follow-up using a
questionnaire.
The results
Greater amounts of physical activity were associated with greater reductions in body weight. Across
tertiles of changes in walking, moving from the group that did the least walking to the group that did the
most, the respective percent changes in body weight were −3.2%, −5.5%, and −7.3% at 24 months. Across
tertiles of changes in moderate-to-vigorous-intensity physical activity, the respective percent changes in
body weight were −4.3%, −5.0%, and −7.0% at 24 months. Across tertiles of changes in vigorous-intensity
physical activity, the respective percent changes in body weight were −4.2%, −5.1%, and −7.6%.
Note
The original randomized controlled trial was not designed to examine the association between changes in
physical activity and changes in body weight, so the results should be considered observational. The lack
of data on dietary intake and the method used to assess physical activity are both limitations.
57
Managing postprandial glucose levels: Is it better to exercise
before or after a meal?
This meta-analysis of randomized crossover trials found that exercising after a meal was better than
exercising before a meal for reducing postprandial (postmeal) glucose levels.
Background
Some evidence suggests that excessively elevated postprandial (postmeal) blood glucose (blood sugar)
levels increase the risk of type 2 diabetes (T2D) and cardiovascular disease.[254][255] Preventing large rises in
glucose levels after a meal is also important for preventing complications in people who already have T2D.
Exercise helps control postprandial glucose levels by increasing muscle glucose uptake and improving
insulin action,[256] but it’s unclear whether there’s an optimal time to engage in exercise around food intake
to maximize its effects on glucose control.
The study
This meta-analysis of 8 randomized crossover trials examined the effect of premeal and postmeal exercise
on postprandial glucose levels in 116 participants (47 diagnosed with T2D, 69 without T2D).
The exercise interventions included 46 minutes of resistance exercise, 7 or 20 minutes of bodyweight
resistance exercise, 20–60 minutes of treadmill walking at a moderate intensity, 60 minutes of treadmill
walking at a high intensity, or standing upright for 30 minutes. The time interval between meal ingestion and
exercise ranged from 0 to 60 minutes.
A subgroup analysis was conducted to determine whether the effects varied by T2D status. Further
analyses explored whether exercise intensity, type, and duration or the time interval between meal ingestion
and exercise influenced the results.
The results
Compared with an inactive control group, postmeal exercise decreased postprandial glucose levels, but
premeal exercise did not.
In addition, compared with premeal exercise, postmeal exercise decreased postprandial glucose levels
(small effect size). However, the subgroup analysis indicated a statistically significant effect only in people
without T2D.
Analyses of potential moderators indicated that postmeal exercise performed immediately after the meal
was more effective for decreasing postprandial glucose levels than when the exercise was delayed (i.e., 60
minutes after a meal).
Note
The small number of studies included and the widely varying protocols (e.g., differences in the time of meal
ingestion, type of meal consumed, type of exercise performed, and population studied) limit the strength of
the findings.
58
Can cold exposure improve recovery after exercise?
In this meta-analysis of randomized controlled trials, cold water immersion enhanced recovery after
exercise, as assessed by improved ratings of perceived exertion, delayed-onset muscle soreness, and
certain blood biomarkers associated with recovery.
Background
Cold exposure (such as in the form of cold water immersion) is a popular method for reducing fatigue and
improving recovery, but clinical studies have led to conflicting results regarding its usefulness. What does
the totality of the evidence say?
The study
This meta-analysis of 20 randomized controlled trials (including 419 healthy adults, average ages of 19–31)
examined the effects of cold water immersion on fatigue recovery at 0, 24, and 48 hours after highintensity exercise (rugby, football, swimming, jumping, or running) compared to a passive control condition
(e.g., resting in a room with a normal temperature).
The researchers measured ratings of perceived exertion, delayed-onset muscle soreness (DOMS), and
countermovement jump test results, as well as blood markers associated with recovery, including lactate,
lactate dehydrogenase, creatine kinase, C-reactive protein, and interleukin 6.
The researchers also assessed the quality of the evidence and performed subgroup analyses to determine
whether the body parts immersed in cold water (up to the umbilicus/navel or up to the shoulders) or the
water temperature (<10°C or ≥10°C) influenced the outcomes.
The results
Cold water immersion reduced DOMS at 0 hours and 24 hours after exercise, but not at 48 hours. Ratings
of perceived exertion and countermovement jump were improved at 0 hours (but not 24 and 48 hours)
after exercise.
Creatine kinase was improved (i.e., reduced) 24 hours after exercise, and lactate was improved (i.e.,
reduced) at 24 and 48 hours after exercise. Cold water immersion had no effects on other biomarkers
associated with recovery.
Subgroup analyses showed that a water temperature of <10°C was more effective than ≥10°C in improving
countermovement jump. However, there was no difference in the outcomes between immersing the body
up to the umbilicus vs. up to the shoulders.
Note
Because the researchers judged the quality of the available evidence as concerning, the results of this
meta-analysis should be interpreted with caution. Although cold water immersion showed short-term
improvements in recovery, more studies are needed to confirm these findings.
59
Skin, Hair, & Nails
Can Pycnogenol prevent hair loss in postmenopausal
women?
In this randomized controlled trial, supplementation with Pycnogenol increased hair density in
postmenopausal Chinese women.
Background
Reduced subcutaneous blood flow and decreased angiogenesis (the formation of new blood vessels) may
be implicated in the development of female pattern hair loss (FPHL) — the progressive diffuse thinning and
loss of hair, especially in the central areas of the scalp. Because Pycnogenol (a patented blend of
procyanidins extracted from pine bark) may improve microcirculation (the circulation of blood in the
smallest blood vessels), supplementation with Pycnogenol may be useful in the treatment of FPHL.
The study
In this 6-month randomized controlled trial, 63 postmenopausal women (ages 45–60) in China took
capsules containing either 150 mg of Pycnogenol or a placebo daily.
The outcomes were hair density (assessed using digital photography), resting flux of the scalp skin (a
marker of changes in microcirculation), skin hydration levels, and the degree of transepidermal water loss
(TEWL).
The results
After 6 months, hair density increased more in the Pycnogenol group (+23%) than in the placebo group
(+9%). The resting flux of the scalp skin decreased more in the Pycnogenol group (−44%) than in the
placebo group (−20%), which may indicate a greater improvement in microcirculation in the Pycnogenol
group.
Note
The study was funded by Horphag Research (Europe) Ltd, which is the exclusive worldwide supplier of
Pycnogenol. Also, one of the researchers was the director of product development at Horphag Research
during the time that the study was conducted.
60
Probiotics for eczema in children and adolescents
In this randomized controlled trial, supplementation with probiotics reduced the severity of eczema in
children and adolescents.
Background
A 2018 trial found that supplementation with probiotics in children and adolescents improved the
symptoms of atopic dermatitis (AD; also known as eczema) and reduced the use of topical steroids.[183] The
summarized trial was a replication study that used the same blend and dose of probiotics.
The study
In this 12-week randomized controlled trial, 62 children and adolescents (ages 4–17) with AD of moderate
severity took capsules containing either probiotics (1 billion colony-forming units of Bifidobacterium
animalis subsp. lactis CECT 8145, Bifidobacterium longum CECT 7347, and Lactobacillus casei CECT 9104)
or a placebo.
The primary outcome was disease severity measured with the SCORAD index (a clinical tool for assessing
AD; lower scores denote lesser severity). The secondary outcomes were the number of days of topical
corticosteroid use, the total dose of topical corticosteroids used, the number of participants with
improvement in disease severity measured with the 5-point Investigator Global Assessment (IGA) scale, and
the number of adverse effects.
The results
The SCORAD index improved (decreased) more in the probiotics group (from 33.6 to 13.5) than in the
placebo group (from 33.5 to 19).
More participants experienced an improvement of 1 point of more points on the IGA scale in the probiotics
group (91%) than in the placebo group (57%). There were no differences between treatments in the other
outcomes.
61
Fighting wrinkles with a cream containing 1monoeicosapentaenoin
In this exploratory trial, a face cream containing 1-monoeicosapentaenoin exhibited antiwrinkle
properties.
Background
1-monoeicosapentaenoin (1-MEST) — a compound isolated from the green algae genus Micractinium —
may have anti-wrinkle properties. This trial explored that possibility.
The study
In this 12-week randomized controlled trial, 24 healthy women (average age of 50 years) who started to
form or had already formed wrinkles applied a cream containing 0.1% of 1-MEST (test cream) to the area
around the eyes on one side of their faces and a cream without 1-MEST (placebo cream) on the other side
of their faces.
The primary outcomes were skin wrinkle parameters (skin roughness, maximum roughness, average
roughness, smoothness depth, and arithmetic average roughness). These outcomes were assessed at
baseline and on weeks 4, 8, and 12. The secondary outcomes were the appearance of skin wrinkles, as
assessed visually by the researchers, and the efficacy and usability of the creams, as assessed with
questionnaires completed by the participants.
The results
Skin roughness and maximum roughness improved more with the test cream than with the placebo cream
on weeks 4, 8, and 12. Average roughness and arithmetic average roughness improved more with the test
cream than with the placebo cream on weeks 8 and 12. Smoothness depth improved more with the test
cream than with the placebo cream on weeks 4 and 8.
The appearance of skin wrinkles (assessed visually by the researchers) improved more with the test cream
than with the placebo cream on weeks 8 and 12. There were no differences between creams in terms of
self-reported efficacy and usability.
Note
The researchers assessed multiple outcomes at several different time points without adjusting for multiple
comparisons, increasing the likelihood of obtaining false positive results.
62
Is a proinflammatory diet linked to psoriasis risk?
This cross-sectional study found no association between the inflammatory potential of the diet and the
incidence of psoriasis.
Background
Because different dietary components have proinflammatory and anti-inflammatory properties, it’s possible
that the overall inflammatory potential of the diet is associated with the incidence of psoriasis (an immunemediated inflammatory skin disease).
The study
In this cross-sectional study, the researchers used data from the 2003–2006 and 2009–2014 National
Health and Nutrition Examination Surveys (NHANES) to examine the association between the inflammatory
potential of the diet and the incidence of psoriasis in a total of 13,284 adults (average age of 49 years), of
whom 383 had psoriasis.
The inflammatory potential of the diet was estimated using the Dietary Inflammatory Index (DII), which was
calculated using data from 24-hour dietary recalls. Per the DII, examples of proinflammatory foods include
processed meats, full-fat dairy, refined grains, and sugar-sweetened beverages, whereas examples of antiinflammatory foods include fruits, vegetables, whole grains, and fish.
The researchers made statistical adjustments to account for the effect of potential confounding factors,
including sex, race, age, calorie intake, protein intake, BMI, smoking status, physical activity, hypertension,
and diabetes.
The results
The inflammatory potential of the diet was not associated with the incidence of psoriasis.
63
Collagen and omega-3s for the healing of major burns
In this randomized controlled trial, supplementing with hydrolyzed collagen improved wound healing
outcomes in adults with 2nd or 3rd degree burns.
Background
Burn injuries result in endocrine, metabolic, and immune responses that are a natural part of the healing
process. However, an exaggerated and prolonged response can interfere with healing.[259]
Preliminary research suggests that collagen hydrolysates and omega-3 fatty acids may be useful in the
healing of burns. However, direct evidence for the efficacy of these compounds in the treatment of major
burns, as well as evidence of their potential synergistic effects, was lacking.
The study
In this 4-week randomized controlled trial, 57 adults (average age of 35) with 2nd or 3rd degree burns to
20%–45% of their bodies were assigned to one of the following groups:
Collagen: The participants consumed a drink containing 40 grams of hydrolyzed collagen and 10
grams of sunflower oil daily.
Collagen + omega-3s: The participants consumed a drink containing 40 grams of hydrolyzed
collagen and 10 mL of fish oil daily, containing 1,800 mg of eicosapentaenoic acid (EPA) and 1,200
mg of docosahexaenoic acid (DHA).
Placebo: The participants consumed a carbohydrate-based drink daily.
All participants received standard treatment (such as medications, surgery, and wound dressings, as
required).
The outcomes included the serum levels of several biochemical parameters (measured on weeks 2 and 3),
including prealbumin (a biomarker of nutritional status), transforming growth factor-beta 1 (TGF-β1; a
protein associated with better wound healing), and the ratio of high-sensitivity C-reactive protein (hs-CRP;
an inflammatory biomarker) to prealbumin, as well as the rate of 95% wound healing (measured on weeks
2, 3, and 4), the time in days to 95% healing, the time in days to complete healing, the Vancouver Scar
Scale (VSS; assesses wound healing and scar quality) measured on week 4, and duration of hospital stay.
The researchers made statistical adjustments in their analyses to account for multiple comparisons and the
potential confounding effects of baseline values and protein intake on weeks 2 and 3.
The results
On week 3, the levels of prealbumin were higher (better) and the CRP/prealbumin ratio was lower (better) in
the collagen + omega-3s group compared to the placebo group.
The wound healing rate was higher with collagen + omega-3s and with collagen alone than with placebo.
The time to 95% wound healing and the time to complete wound healing were lower with collagen +
omega-3s and with collagen alone than with placebo.
VSS was lower (better) with collagen + omega-3s and with collagen alone than with placebo. Hospital stay
duration was shorter with collagen than with placebo.
There were no differences between the collagen + omega-3s group and the collagen alone group in any of
the outcomes.
64
Mental Health
Can psilocybin improve treatment-resistant depression?
In this randomized trial, a single dose of 25 mg of psilocybin reduced symptoms of major depression.
Background
Treatment-resistant depression is common. A large U.S. trial found that 63% of participants did not
experience remission of their depression after the first course of treatment with antidepressant
medications, and this proportion increased with repeated courses of treatment.[3]
Recently, psilocybin (commonly referred to as “magic mushrooms”) has attracted research interest as an
alternative treatment for certain mental health conditions. Could it help people with treatment-resistant
depression?
The study
This randomized trial recruited 79 participants (ages 18+) with a clinical diagnosis of a single or recurrent
episode of major depressive disorder without psychotic features. The participants took a single dose of
one of three psilocybin treatments: 1 mg (control), 10 mg, or 25 mg. The participants also had three therapy
sessions before and two sessions after the psilocybin dose.
The investigators assessed depression using the Montgomery–Åsperg Depression Rating Scale (MADRS; a
score of 0–6 indicates absence of symptoms, 7–19 indicates mild depression, 20–34 moderate depression,
and 35–60 severe depression) at baseline, day 2, and at weeks 1, 3, 6, 9, and 12.
The primary outcome was the change in the MADRS score from baseline to week 3. The secondary
outcomes were the rates of response (≥50% decrease in MADRS score from baseline) at week 3, remission
(MADRS score of ≤10) at week 3, and sustained response (a ≥50% decrease that was sustained from weeks
3 to 12) at 12 weeks.
The results
On average, the participants’ scores decreased from moderate depression to a borderline absence of
depression. The average MADRS scores at baseline were 32 to 33. The average changes from baseline to
week 3 were –5.4 for the 1 mg group, –7.9 for the 10 mg group, and –12.0 for the 25 mg group.
Compared to the control group, the depression score decreased significantly only in the 25 mg psilocybin
group and only at the 3-week mark. The 25 mg group showed response and remission at 3 weeks, but
these findings were not sustained at 12 weeks.
Adverse events occurred in 84%, 75%, and 72% of the 25 mg, 10 mg, and 1 mg groups, respectively. The
most common adverse event in the 25 mg group was headache (24% of participants). One person in the 25
mg group was given an antianxiety medication on the day of the psilocybin dose. There were more
participants with suicidal thoughts or self-harm in the 25 mg and 10 mg groups.
65
Psychological interventions for reducing anxiety in the
perinatal period
In this meta-analysis, psychological interventions reduced anxiety and symptoms of depression in
women during the perinatal period.
Background
Trials that investigated the effect of psychological interventions — such as mindfulness-based interventions
(MBIs) and cognitive behavioral therapy (CBT) — on anxiety in women during the perinatal period (during
pregnancy and up to 1 year after giving birth) have produced mixed results. What does the totality of the
available evidence say?
The study
This meta-analysis of 22 trials (17 randomized controlled trials and 5 quasi-randomized/nonrandomized
controlled trials) examined the effect of psychological interventions on anxiety in women with anxiety
during the perinatal period. The secondary outcome was symptoms of depression.
The vast majority of trials were conducted during pregnancy. The most commonly used psychological
interventions were MBIs or CBT. The number of therapeutic sessions ranged from 2 to 14.
The results
Psychological interventions reduced anxiety (large effect size) and symptoms of depression (large effect
size).
In influence analyses in which the researchers excluded outlier trials, the beneficial effects of psychological
interventions on anxiety and symptoms of depression remained statistically significant but were reduced to
moderate and small effect sizes, respectively.
66
Cognitive behavioral therapy for anxiety-related disorders
In this meta-analysis of randomized controlled trials, cognitive behavioral therapy had a small to very
small beneficial effect on the severity of disorder symptoms in adults with anxiety disorders and
anxiety-related disorders.
Background
Two previous meta-analyses (published in 2008 and 2018) found that, compared to placebo, cognitive
behavioral therapy (CBT) was effective for the treatment of anxiety disorders.[97][98] The summarized study
was an updated meta-analysis that included trials published since 2017 and excluded trials included in the
aforementioned meta-analyses.
The study
This meta-analysis of 10 randomized controlled trials examined the effect of CBT, compared to placebo, on
the severity of disorder symptoms and depressive symptoms in a total of 1,250 adults with anxiety
disorders or anxiety-related disorders.
The types of anxiety disorders and anxiety-related disorders were posttraumatic stress disorder (PTSD; 7
trials), acute stress disorder (ASD; 1 trial), generalized anxiety disorder (GAD; 1 trial), and social anxiety
disorder (SAD; 1 trial). All trials compared CBT to a psychological placebo, and the most frequently used
placebo was present-centered therapy (4 trials), followed by psychoeducation (3 trials) and other
psychological placebos (3 trials). CBT was delivered individually in 4 trials and in a group setting in 6 trials.
The number of CBT sessions ranged from 4 to 16.
The results
CBT improved disorder symptoms to a small degree. In a subgroup analysis of only PTSD trials, CBT
improved disorder symptoms to a very small degree. There was no effect of CBT on depressive symptoms.
Overall, the risk of bias of the trials included in the meta-analysis was low.
Note
ASD and PTSD are no longer classified as anxiety disorders. However, the researchers included trials
involving these disorders in the meta-analysis so as to be consistent with the aforementioned metaanalyses.
67
Mindfulness vs. cognitive behavioral therapy for depression
In this meta-analysis of randomized controlled trials, cognitive behavioral therapy and mindfulnessbased interventions were equally effective for reducing symptoms of depression in adults.
Background
Both cognitive behavioral therapy (CBT) and mindfulness-based interventions (MBIs) — which include
mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) — have been
found to be effective for the treatment of depression. However, their effectiveness had not been compared
in a meta-analysis.
The study
This meta-analysis of 30 randomized controlled trials looked at the comparative effectiveness of CBT and
MBIs for improving symptoms of depression postintervention and at follow-up in a total of 2,750 men and
women with symptoms of depression (average ages of 22–52).
The number of MBI and CBT sessions ranged from 2 to 12. The therapeutic sessions were delivered in group
settings (23 trials), individually (3 trials), or online (4 trials). The follow-up duration ranged from 1 to 24
months.
The results
CBT and MBIs were equally effective for reducing symptoms of depression both postintervention and at
follow-up.
There were no differences between the interventions in dropout rates, average number of sessions, or
average therapy duration.
The risk of bias was high in 15 trials, unclear in 11 trials, and low in 4 trials.
68
Can carbohydrates make you anxious?
In this prospective cohort study, total carbohydrate intake was associated with a higher risk of incident
and persistent anxiety.
Background
There is some evidence from cross-sectional studies that consuming carbohydrates is linked to an
increased risk of anxiety.[99] What role does the type and source of carbohydrate play in this relationship?
The study
This prospective cohort study in 15,602 adults (average age of 54) investigated the association between
carbohydrate intake and the occurrence, persistence, and disappearance of anxiety over a period of 5.4
years.
The researchers distinguished among three types of anxiety: transient anxiety (anxiety at baseline but not
at follow-up), persistent anxiety (anxiety at baseline and at follow-up), and incident anxiety (anxiety at
follow-up but not at baseline).
Moreover, the researchers determined the effects on anxiety of different types and sources of
carbohydrates, including complex carbohydrates, fruit juices, and sugar-sweetened beverages.
The results
Compared to the quartile with the lowest carbohydrate intake, the odds of persistent anxiety were 10%
higher in the quartile with the highest carbohydrate intake.
With respect to carbohydrate type and source, the quartile with the highest intake of complex
carbohydrates was associated with 12% and 9% higher odds of incident anxiety and persistent anxiety,
respectively
Additionally, the quartile with the highest intake of sugar-sweetened beverages was associated with 11%
higher odds of transient anxiety. In contrast, the quartile with the highest intake of 100% fruit juice was
associated with 13% lower odds of persistent anxiety.
Note
There are two important limitations to this study.
First, given the observational study design, these results cannot establish a cause-effect relationship.
Second, even though this study used a validated questionnaire to assess anxiety, it does not correspond to
a clinical diagnosis.
Future studies are needed to confirm whether reducing the intake of carbohydrates can reduce anxiety risk.
Strikingly, a meta-analysis of randomized controlled trials found that a low-carbohydrate diet did not
improve anxiety.[100]
69
Cannabis therapy for treatment-resistant depression
This uncontrolled case series concluded that more research is warranted on the topic of cannabis
therapy for individuals with treatment-resistant depression.
Background
There is growing interest in the use of cannabis as a treatment for depression, but clinical evidence is
lacking. Case studies may provide preliminary evidence and guide future research on this topic.
The study
This uncontrolled case series included 129 participants from the UK Medical Cannabis Registry who were
diagnosed with treatment-resistant depression and were prescribed cannabis-based medicinal products.
The participants completed validated questionnaires related to depression, anxiety, sleep, and quality of life
at baseline, 1 month, 3 months, and 6 months into treatment with cannabis.
The results
Cannabis use was associated with reductions in depression severity at 1, 3, and 6 months.
Improvements were also noted in questionnaire-based measures related to anxiety, sleep, and quality of
life. Adverse events were reported by 14% of participants, with 87% of the events described as mild or
moderate.
Note
Although more research is warranted, this evidence is insufficient to establish a causal relationship.
70
Can supplementation with vitamin D reduce depression
symptoms?
In this meta-analysis of randomized controlled trials, supplementation with vitamin D decreased
symptoms of depression in adults with depression. However, the certainty of the evidence was very
low.
Background
Vitamin D deficiency has been associated with an increased risk of depression. However, experimental
research examining the effect of supplementation with vitamin D on symptoms of depression have
produced mixed results.[161][162][163]
The study
This meta-analysis of 18 randomized controlled trials examined the effect of supplementation with vitamin
D 3, compared to placebo, on symptoms of depression and dropout rates in a total of 1,980 participants
with depression.
The trials were conducted in Asia (11 trials), Europe (5 trials), the United States (1 trial), and Australia (1
trial). Of the 18 trials, 17 recruited adults/older adults and 1 recruited children and adolescents. Eight trials
included participants with comorbidities (such as end-stage kidney disease, osteoarthritis, and type 2
diabetes). In 7 trials, the participants had low vitamin D levels at baseline, whereas information on vitamin D
status was not reported in the remaining trials.
Vitamin D was taken orally in 17 trials and administered intramuscularly in 1 trial. The average daily
supplemental vitamin D intake ranged from 1,000 to 14,286 IU. In most trials, vitamin D supplements were
taken daily (7 trials) or in large boluses 1–2 times per week (6 trials). The intervention duration ranged from
1 to 33 months.
The results
Supplementation with vitamin D decreased symptoms of depression, with a small effect size and low
certainty of evidence. In subgroup analyses, the effect was statistically significant in adults (but not in older
adults or children/adolescents) and when vitamin D was taken in large boluses or administered
intramuscularly (but not when taken daily).
There were no differences in dropout rates between the vitamin D and placebo groups.
71
Is dietary fiber intake associated with the risk of depression?
In this meta-analysis, the intake of dietary fiber was associated with lower odds of depression in both
adults and children.
Background
In a 2018 meta-analysis, a higher intake of fruits and/or vegetables was associated with a lower risk of
depression.[253] Because fruits and vegetables are rich in fiber, the intake of dietary fiber may be associated
with depression risk. However, studies exploring this potential association have reported mixed results.
The study
This meta-analysis of 18 observational studies (12 cross-sectional, 5 cohort, and 1 case-control) examined
the association between the intake of dietary fiber and risk of depression in adults (15 studies) and children
(3 studies). The average ages of the participants ranged from 13 to 75 years.
The studies were conducted in Asia (9 studies), the United States (4 studies), Europe (3 studies), and
Australia (2 studies). One study recruited participants with suspected myocardial ischemia, and all other
studies recruited participants with no known health conditions. In the vast majority of studies, fiber intake
was assessed using food frequency questionnaires. Most studies made statistical adjustments to account
for the potential confounding effect of age, physical activity, calorie intake, and history of chronic diseases.
The researchers performed subgroup analyses based on the participant age group (adults or adolescents)
and source of dietary fiber (cereals, fruits, vegetables, soluble fiber, or insoluble fiber). They also performed
a dose-response analysis.
The results
The highest (compared to the lowest) intake of dietary fiber was associated with 14% lower odds of
depression. This association was statistically significant in both children (57% lower odds of depression)
and adults (10% lower odds of depression) and when the source of fiber intake was vegetables (27% lower
odds of depression) and soluble fiber (20% lower odds of depression).
In the linear dose-response analysis, each daily 5-gram increase in total dietary fiber intake was associated
with a 5% reduction in the odds of depression.
Of the 18 studies included in the meta-analysis, 14 were of high methodological quality.
72
Vitamins & Minerals
Are antioxidants effective against COVID-19?
This systematic review concluded that the antioxidant vitamins C and D and the antioxidant minerals
selenium and zinc may be beneficial for improving clinical outcomes in people with COVID-19.
Background
COVID-19, the disease caused by infection with the SARS-CoV-2 virus, affects the body’s respiratory and
cardiovascular systems. One of the main mechanisms involved in the development of COVID-19 is oxidative
stress, which weakens the immune system and contributes to the high levels of inflammation seen with this
disease.
Antioxidants are molecules that neutralize reactive oxygen species and prevent oxidative stress. Is there
evidence that antioxidants improve clinical outcomes in people with COVID-19?
The study
This systematic review compiled evidence from a total of 27 observational studies and 9 randomized
controlled trials to determine the impact of antioxidants on clinical outcomes among participants with
COVID-19.
Vitamin C, vitamin D, selenium, and zinc were analyzed in the included studies. The observational studies
determined levels of these antioxidants from dietary intake or biological samples, whereas the randomized
controlled trials compared supplementation with these antioxidants against a placebo intervention.
The primary outcomes included COVID-19 disease severity, disease manifestations and complications,
inflammatory biomarkers, hospitalization, and mortality. Given the time frame in which the studies were
conducted, the review covered the COVID-19 variants alpha, beta, gamma, delta, epsilon, zeta, iota, and
kappa.
The results
The authors reported the following results:
Vitamin C: Overall, vitamin C was reported to have beneficial effects on inflammatory status, mortality rate,
and clinical symptom improvement in participants with COVID-19.
Vitamin D: Higher levels of vitamin D were associated with reduced COVID-19 disease severity,
inflammatory biomarkers, ventilator requirements, hospitalization, and mortality. Supplementation may also
reduce intensive care unit (ICU) admission.
Selenium: Overall, higher levels of selenium were associated with an improved COVID-19 cure rate and
reduced mortality in participants with the disease.
Zinc: Supplementation with zinc was reported to reduce hospitalization, ventilator requirements, and ICU
admission, and higher zinc levels were associated with reduced inflammatory biomarkers, fewer bacterial
infections, and fewer disease complications in participants with COVID-19.
Note
None of the studies included in this review directly investigated the mechanisms by which antioxidants may
improve clinical outcomes in COVID-19. Furthermore, there was no available evidence for vitamins A and E
or alpha-lipoic acid.
73
Are B vitamins linked to gestational diabetes risk?
This prospective cohort trial found that increased blood levels of vitamins B1 and B6 were associated
with an increased risk of gestational diabetes.
Background
Gestational diabetes involves the impaired metabolism of carbohydrates, which results in elevated levels of
blood sugar and increased risk of short-term and long-term effects on both the mother and child. Several
different B vitamins are involved in glucose metabolism and have links to lower risk of type 2 diabetes.
Does higher blood levels of various B vitamins reduce risk of gestational diabetes?
The study
This prospective cohort trial recruited 1,265 Chinese women who were pregnant. Vitamin B1, vitamin B2,
vitamin B6, folate, and vitamin B12 blood levels were measured between weeks 8 and 15, and an oral
glucose tolerance test (OGTT) was performed (to determine development of gestational diabetes) between
weeks 24 and 28.
The participants were categorized into four groups according to B-vitamin blood levels, from lowest to
highest. Blood glucose readings were collected during the fasting state and at 1 hour and 2 hours after
consumption of 75 grams of glucose in the OGTT.
The results
Surprisingly, the group with the highest vitamin B1 levels had a 128% increased risk of gestational diabetes
compared to the lowest group. In addition, compared to the lowest group, the highest and second highest
groups of vitamin B6 levels had a 84% and 93% increased risk of developing diabetes, respectively.
In addition, higher vitamin B1 levels were correlated with higher fasting, 1-hour, and 2-hour blood sugar
readings.
Note
There was an overall trend of decreasing gestational diabetes risk with increasing vitamin B12 levels, but it
was not significant.
74
Are vitamin D levels associated with ankylosing spondylitis
disease activity?
In this meta-analysis, ankylosing spondylitis was associated with lower vitamin D levels and higher
concentrations of inflammatory biomarkers; higher vitamin D levels were associated with lower
ankylosing spondylitis disease activity and lower concentrations of inflammatory biomarkers.
Background
Because vitamin D plays an important role in the modulation of inflammation,[76] serum vitamin D levels may
be associated with disease activity in individuals with ankylosing spondylitis (AS; a type of spondyloarthritis
characterized by chronic inflammation of the spine and pelvis).
The study
This meta-analysis of 6 observational studies (5 case-control and 1 cross-sectional) was conducted in a
total of 901 participants (503 participants with AS, 398 control participants without AS; average ages of
36–41) and examined the following:
The serum vitamin D levels in participants with AS relative to control participants
The concentrations of the inflammatory biomarkers erythrocyte sedimentation rate (ESR) and Creactive protein (CRP) in participants with AS relative to control participants
The association between serum vitamin D levels and AS disease activity
The association between serum vitamin D levels and the concentrations of ESR and CRP.
The studies were conducted in Turkey (3 studies), Germany (1 study), China (1 study), and Morocco (1
study).
The results
Compared to control participants, participants with AS had lower serum vitamin D levels and higher ESR
and CRP levels. Higher serum vitamin D levels were associated with lower AS disease activity and with
lower concentrations of ESR and CRP.
75
Vitamin B12 levels and diabetic retinopathy
In this meta-analysis of observational studies, participants with diabetic retinopathy tended to have
lower vitamin B12 levels, but this relationship may have been confounded by age .
Background
Diabetic retinopathy is a condition in which the retina of the eye is damaged, often resulting in vision loss.
The condition seems to occur as a result of various pathological changes accompanying both type 1 and
type 2 diabetes. It’s been suggested that vitamin B12 might protect against diabetic retinopathy by
reducing oxidative stress.
The study
This meta-analysis of 15 observational studies (12 were case-control, 2 were cross-sectional, 1 cohort)
assessed whether participants with diabetic retinopathy had lower vitamin B12 levels. The studies included a
total of 959 participants with diabetic retinopathy and 1,093 participants with diabetes but without diabetic
retinopathy (control group).
The results
Vitamin B12 levels were lower in participants with diabetic retinopathy compared to the control participants.
This finding was seen in East Asian and South Asian populations, but the difference was not statistically
significant in Caucasian (term used by the study authors) populations.
In subgroup analysis, the association between lower vitamin B12 levels and diabetic retinopathy was only
seen in studies that did not adjust for differences in age.
Note
The association between diabetic retinopathy and lower vitamin B12 levels could be explained by older age
being a risk factor for both.[134][135]
76
Can supplementation with vitamin D reduce depression
symptoms?
In this meta-analysis of randomized controlled trials, supplementation with vitamin D decreased
symptoms of depression in adults with depression. However, the certainty of the evidence was very
low.
Background
Vitamin D deficiency has been associated with an increased risk of depression. However, experimental
research examining the effect of supplementation with vitamin D on symptoms of depression have
produced mixed results.[161][162][163]
The study
This meta-analysis of 18 randomized controlled trials examined the effect of supplementation with vitamin
D 3, compared to placebo, on symptoms of depression and dropout rates in a total of 1,980 participants
with depression.
The trials were conducted in Asia (11 trials), Europe (5 trials), the United States (1 trial), and Australia (1
trial). Of the 18 trials, 17 recruited adults/older adults and 1 recruited children and adolescents. Eight trials
included participants with comorbidities (such as end-stage kidney disease, osteoarthritis, and type 2
diabetes). In 7 trials, the participants had low vitamin D levels at baseline, whereas information on vitamin D
status was not reported in the remaining trials.
Vitamin D was taken orally in 17 trials and administered intramuscularly in 1 trial. The average daily
supplemental vitamin D intake ranged from 1,000 to 14,286 IU. In most trials, vitamin D supplements were
taken daily (7 trials) or in large boluses 1–2 times per week (6 trials). The intervention duration ranged from
1 to 33 months.
The results
Supplementation with vitamin D decreased symptoms of depression, with a small effect size and low
certainty of evidence. In subgroup analyses, the effect was statistically significant in adults (but not in older
adults or children/adolescents) and when vitamin D was taken in large boluses or administered
intramuscularly (but not when taken daily).
There were no differences in dropout rates between the vitamin D and placebo groups.
77
Are lower vitamin D levels causally linked to male infertility?
In this Mendelian randomization study, higher serum vitamin D levels reduced the odds of developing
male infertility.
Background
Although observational studies have reported that low serum vitamin D levels may be associated with a
higher risk of male infertility,[171][172] it’s difficult to infer causality from observational research due to the
potential for confounding (e.g., people with a chronic disease that contributes towards lower sperm quality
may go outside in the sunlight less often, which can result in them having lower serum vitamin D levels).
By using the measured variation in genes of a known function (in this case, genes associated with serum
vitamin D levels), the Mendelian randomization study design allows for the assessment of potential causal
relationships from observational data while reducing the risk of confounding.
The study
This two-sample Mendelian randomization study used data from the United Kingdom Biobank and FinnGen
cohorts to examine whether lower serum vitamin D levels are causally linked to male infertility.
Specifically, the researchers used data from 417,580 Europeans in the UK Biobank to determine which
single-nucleotide polymorphisms (SNPs; common genetic variants) were linked to higher serum vitamin D
levels and assessed the prevalence of these SNPs in another data set involving 86,547 participants (of
whom 825 had male infertility) from FinnGen.
The results
The analysis included 99 SNPs associated with serum vitamin D levels and showed that each 1-unit increase
(as measured on a log-transformed scale) in genetically predicted natural-log-transformed serum vitamin D
levels was associated with a 38% decrease in the odds of male infertility. These findings remained
materially unchanged in sensitivity analyses.
78
Vitamin D and male fertility
This systematic review found an association between low vitamin D levels and lower total and/or
progressive sperm motility and that supplementation with vitamin D may improve total and/or
progressive sperm motility.
Background
The expression of vitamin D receptors and metabolizing enzymes in the human testes, male reproductive
tract, and sperm suggests that vitamin D plays an important role in male reproductive health.[236] However,
research exploring the effect of vitamin D on components of male fertility has been inconclusive.
The study
This systematic review of 53 studies (36 observational and 17 interventional) examined the following:
The association between serum vitamin D levels and sperm quality parameters (23 studies) and
between serum vitamin D levels and sex hormone levels (22 studies)
The effect of supplementation with vitamin D on sperm quality parameters (9 studies) and sex
hormone levels (12 studies)
The sperm quality parameters assessed were sperm concentration, progressive sperm motility, total
motility, sperm morphology, and sperm DNA fragmentation. The sex hormones measured were total
testosterone, free testosterone, estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and
sex hormone binding globulin (SHBG).
The results
The findings were as follows:
Association between serum vitamin D levels and sperm quality parameters: Of the 23 studies, 16
found that low vitamin D levels were associated with lower total and/or progressive sperm motility.
Association between serum vitamin D levels and sex hormone levels: Most studies failed to find
an association between serum vitamin D levels and total or free testosterone levels. However,
although studies conducted in younger men did not find an association between serum vitamin D
levels and testosterone levels, the majority of studies conducted in older men found an association
between low serum vitamin D levels and low testosterone levels. Because this association
disappeared when adjusting for confounding factors (such as comorbidities), the authors
speculated that the relationship between serum vitamin D and testosterone may be influenced by
age-varying factors, including age-related comorbidities.
Effect of supplementation with vitamin D on sperm quality parameters: Supplementation with
vitamin D improved sperm total motility and/or progressive motility in 6 of the 9 studies. The
majority of the studies did not find an effect of supplementation with vitamin D on other sperm
quality parameters.
Effect of supplementation with vitamin D on sex hormone levels: Overall, supplementation with
vitamin D did not seem to affect sex hormone levels.
79
Men’s Health
Does obesity or vitamin D deficiency affect sperm quality in
healthy men?
In this cross-sectional study, obesity was associated with negative effects on sperm parameters.
Background
Obesity raises the risk of vitamin D deficiency and many chronic diseases. Sperm and the male reproductive
system in general have vitamin D receptors, and there is some research showing links between vitamin D
levels and sperm health.
Sperm health includes parameters such as DNA integrity (head size of the sperm, indicating a normal or
abnormal amount of genetic content), motility (how well the sperm move), morphology (normally or
abnormally formed sperm), count (number of sperm), and viability (intact sperm head membrane or not).
There is considerable variability in sperm health parameters, even in parameters considered to be normal.
For example, a common cut-off value for amount of normal sperm is ≥20x106 per mL, but samples from
men with normal sperm counts can have values in a wide range of 60–95x106 per mL.[80]
Does obesity or vitamin D deficiency correlate with the above measures of sperm health in otherwise
healthy men?
The study
This cross-sectional study examined 64 Iranian men (ages 25–55) with normal sperm parameters. Obesity
and vitamin D deficiency were analyzed for their correlations with sperm health parameters such as sperm
DNA integrity, motility, morphology, count, and viability.
The results
Although vitamin D levels were lower in men with obesity, they were not correlated with sperm parameters.
Men with obesity had worsened sperm motility, viability, and DNA integrity. No other significant differences
were seen.
Note
In the abstract and results section, DNA integrity was reported to be worse in men without obesity.
However, the bar graph of DNA integrity in the results section shows that men without obesity had better
DNA integrity (less DNA fragmentation).
In addition, this study included men with overweight who were sorted into the “obese” category, perhaps
making the findings less strong than comparing men with normal weights to men with overweight.
80
Trends in cannabis use among men with sexual dysfunction
In this cross-sectional study in men with sexual dysfunction, cannabis users were younger and had
fewer comorbidities than nonusers, but had higher alcohol and tobacco consumption.
Background
Very little evidence is available on the effects of cannabis on male sexual function. Because randomized
trials with cannabis are scarce, cross-sectional studies can be used to identify trends in cannabis use and
male sexual dysfunction.
The study
This cross-sectional study included 4,800 men who were attending an andrology outpatient clinic in Italy
for sexual dysfunction. The participants’ physical characteristics were evaluated, and hormonal and
metabolic parameters were measured. Lifestyle characteristics such as cannabis, alcohol, and tobacco use
were also recorded.
The results
Cannabis use was not common in this cohort, with only 2.1% of men reporting use. The authors of the study
cited research that found a cannabis use rate of 12% among children and young adults in the general Italian
population.
Compared with nonusers, cannabis users were younger and had a lower prevalence of comorbidities,
despite higher alcohol and tobacco consumption. After adjustment for confounders, cannabis use was
associated with greater instability in a couple’s relationship and a higher frequency of masturbation.
Prolactin levels were higher in participants who smoked 1–2 joints per week compared with nonusers, but
no difference in total testosterone levels was observed.
The authors of this study found that cannabis use was associated with a lower body mass index and a more
favorable lipid profile compared to nonuse. They also noted that the low rate of cannabis usage in this
cohort suggests that cannabis may have a less unfavorable impact on sexual health than commonly
thought.
Note
Cross-sectional evidence is not sufficient to establish causal relationships.
81
Is a healthy eating pattern associated with better sperm
quality?
In this cross-sectional study conducted in men with infertility, a healthier eating pattern was associated
with a lower risk of having abnormally low sperm concentration.
Background
Some components of healthy diets (such as dietary fiber, vitamin C, and lycopene) have been associated
with higher sperm quality,[167] whereas some components of unhealthy diets (such as saturated fats, trans
fats, and alcohol) have been associated with lower sperm quality.[168][169][170]
Is an overall healthy eating pattern as measured with the Healthy Eating Index (HEI) associated with higher
sperm quality?
The study
In this cross-sectional study, the researchers analyzed data from a total of 254 Iranian men (ages 18–55)
with infertility to examine the association between HEI scores and sperm quality parameters.
The participants’ dietary intake was assessed using food frequency questionnaires. The sperm quality
parameters examined were sperm concentration, volume, total motility, and normal morphology. HEI scores
were calculated using 9 healthy dietary components (whole fruit, total fruit, greens and beans, total
vegetables, total protein foods, seafood and plant proteins, whole grains, dairy, and fatty acids) and 4
unhealthy dietary components (refined grains, sodium, added sugars, and saturated fats).
The researchers made statistical adjustments to account for the potential confounding effect of age, caloric
intake, BMI, marriage time, education, physical activity, alcohol intake, and smoking history.
The results
Compared to the lowest tertile of HEI scores (the least healthy eating pattern), the highest tertile of HEI
scores (the most healthy eating pattern) was associated with 61% lower odds of having abnormally low
sperm concentration.
82
Are lower vitamin D levels causally linked to male infertility?
In this Mendelian randomization study, higher serum vitamin D levels reduced the odds of developing
male infertility.
Background
Although observational studies have reported that low serum vitamin D levels may be associated with a
higher risk of male infertility,[171][172] it’s difficult to infer causality from observational research due to the
potential for confounding (e.g., people with a chronic disease that contributes towards lower sperm quality
may go outside in the sunlight less often, which can result in them having lower serum vitamin D levels).
By using the measured variation in genes of a known function (in this case, genes associated with serum
vitamin D levels), the Mendelian randomization study design allows for the assessment of potential causal
relationships from observational data while reducing the risk of confounding.
The study
This two-sample Mendelian randomization study used data from the United Kingdom Biobank and FinnGen
cohorts to examine whether lower serum vitamin D levels are causally linked to male infertility.
Specifically, the researchers used data from 417,580 Europeans in the UK Biobank to determine which
single-nucleotide polymorphisms (SNPs; common genetic variants) were linked to higher serum vitamin D
levels and assessed the prevalence of these SNPs in another data set involving 86,547 participants (of
whom 825 had male infertility) from FinnGen.
The results
The analysis included 99 SNPs associated with serum vitamin D levels and showed that each 1-unit increase
(as measured on a log-transformed scale) in genetically predicted natural-log-transformed serum vitamin D
levels was associated with a 38% decrease in the odds of male infertility. These findings remained
materially unchanged in sensitivity analyses.
83
Chokeberries for improving sperm quality and blood lipids in
men with hypercholesterolemia
In this randomized controlled crossover trial, supplementation with chokeberry extract increased the
levels of glutathione S-transferase (an antioxidant enzyme) in men with moderately elevated total
cholesterol levels.
Background
Oxidative stress is involved in the development of inflammation, dyslipidemia, hypertension, and type 2
diabetes (all of which have been linked to an increased risk of cardiovascular disease),[173][174] as well as the
pathogenesis of male infertility.[175] Because of their potent antioxidant properties, chokeberries (also called
Aronia berries) may improve sperm quality parameters and the aforementioned risk factors for
cardiovascular disease.
The study
In this 90-day randomized crossover trial, 95 Danish men with moderately elevated total cholesterol levels
took capsules containing either chokeberry extract (ARO3:5®) or a placebo. The chokeberry extract
comprised 3 wild Aronia species and a cultivated Aronia hybrid and was standardized to provide 150 mg of
anthocyanins daily. After a 90-day washout period, the participants crossed over to the other intervention
and repeated the experiment.
The primary outcomes were sperm-quality parameters (total motile sperm count and total progressive
motile sperm count) and blood lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides).
The secondary outcomes were blood pressure, the phase II group of antioxidant enzymes (superoxide
dismutase, catalase, and glutathione S-transferase), isoprostane (a marker of oxidative stress), glycated
hemoglobin (HbA1c; a marker of glycemic control), high sensitivity [C-reactive protein[ (hs-CRP; a marker
of inflammation), DNA fragmentation index (DFI), testosterone, and pregnancy rates during the study or
within 3 months of the end of the study.
The results
Glutathione S-transferase levels increased more with supplemental chokeberry extract than with placebo.
No other differences were observed between treatments in the overall analyses.
Note
Although the researchers reported a number of statistically significant findings in the subgroup analyses,
the subgroup analyses were not preplanned and should therefore be viewed with caution.
It’s also worth noting that (i) the researchers tested a large number of outcomes without making
adjustments for multiple comparisons, which increases the risk of false-positive results; (ii) there were
significant discrepancies between the prespecified outcomes and the outcomes specified in the published
paper; and (iii) one of the researchers was the owner of ByrialApS (the manufacturer of ARO3:5®) at the
time that the trial was conducted.
84
Quisqualis indica for lower urinary tract symptoms
In this randomized controlled trial, supplementation with Quisqualis indica was found to improve lower
urinary tract symptoms in men.
Background
Quisqualis indica (Q. indica), otherwise known as Rangoon Creeper, is a plant common in India that contains
a variety of phytochemicals with medicinal properties. Q. indica extract was found to reduce intra-urethral
pressure in rats, which should improve lower urinary tract symptoms (LUTS). Is this effect observed in
humans?
The study
In this 12-week randomized controlled trial, 135 men (ages 40–75) with LUTS were assigned to supplement
with 1,000 mg of Q. indica extract (low dose), 2,000 mg of Q. indica extract (high dose), or a placebo.
The primary outcome was LUTS (assessed via the International Prostate Symptom Score). The secondary
outcomes were prostate specific antigen, testosterone, dihydrotestosterone (DHT), maximum urinary flow
rate, postvoid residual volume, and erectile function (assessed via questionnaire).
The results
Compared to placebo, total LUTS scores improved in the low-dose and high-dose groups. In the low-dose
group, all LUTS subscores improved compared to placebo. In the high-dose group, incomplete emptying,
frequency, intermittency, straining, and quality of life improved, but urgency, weak stream, and nocturia did
not.
Concerning secondary outcomes, although there was no difference in total erectile function scores between
groups, orgasmic function and overall satisfaction improved in the high-dose group compared to placebo.
There were no other differences between groups.
Note
A limitation of this study is that the researchers did not analyze differences between the low-dose and
high-dose groups.
The researchers did not adjust for multiple comparisons, despite the inclusion of numerous outcomes,
which increases the risk of false-positive results. Therefore, the results should be interpreted with caution.
85
Vitamin D supplementation for prostate health
In this randomized controlled trial, supplementation with vitamin D had beneficial effects on prostate
health in older men with vitamin D deficiency.
Background
Vitamin D receptors are expressed in different types of cells, including prostate cells. Studies have
identified an association between vitamin D deficiency and (i) benign prostatic hyperplasia (BPH) and (ii)
BPH-related lower urinary tract symptoms.[234][235] Does supplementation with vitamin D improve prostate
health outcomes in older men?
The study
In this 1-year randomized controlled trial, 57 men (average age of 64) with vitamin D deficiency (25(OH)D
levels <20 ng/mL) were assigned to supplement with vitamin D or nothing (the control). In the vitamin D
group, the participants received an initial intramuscular injection of 200,000 IU of vitamin D. After 3
months, the vitamin D group then supplemented with 25,000 IU of oral vitamin D every 2 weeks for 9
months.
The outcomes assessed were prostate volume, uroflowmetry maximal flow rate, postvoid residual urine
volume, testosterone level, BPH symptoms, symptoms of hypogonadism (low testosterone), prostate
specific antigen levels, and blood vitamin D levels.
The results
Compared to baseline, prostate volume increased in the control group, whereas there was no change in the
vitamin D group. On the other hand, compared to baseline, blood vitamin D levels increased (from 15.5 to
30.9 ng/mL), postvoid residual urine volume decreased (improved), psychological issues associated with
hypogonadism improved, and BPH symptoms improved in the vitamin D group only.
Note
When interpreting the results, it’s important to keep in mind that the participants were included solely on
the basis of low blood vitamin D levels. On average, they had normal testosterone levels and mild
symptoms of hypogonadism, and only 21% had BPH/lower urinary tract symptoms.
This study had a couple of limitations: (i) it did not compare differences between groups (only within each
group compared to baseline), and (ii) the researchers did not adjust for multiple comparisons, despite the
inclusion of numerous outcomes, which increases the risk of false-positive results.
86
Vitamin D and male fertility
This systematic review found an association between low vitamin D levels and lower total and/or
progressive sperm motility and that supplementation with vitamin D may improve total and/or
progressive sperm motility.
Background
The expression of vitamin D receptors and metabolizing enzymes in the human testes, male reproductive
tract, and sperm suggests that vitamin D plays an important role in male reproductive health.[236] However,
research exploring the effect of vitamin D on components of male fertility has been inconclusive.
The study
This systematic review of 53 studies (36 observational and 17 interventional) examined the following:
The association between serum vitamin D levels and sperm quality parameters (23 studies) and
between serum vitamin D levels and sex hormone levels (22 studies)
The effect of supplementation with vitamin D on sperm quality parameters (9 studies) and sex
hormone levels (12 studies)
The sperm quality parameters assessed were sperm concentration, progressive sperm motility, total
motility, sperm morphology, and sperm DNA fragmentation. The sex hormones measured were total
testosterone, free testosterone, estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and
sex hormone binding globulin (SHBG).
The results
The findings were as follows:
Association between serum vitamin D levels and sperm quality parameters: Of the 23 studies, 16
found that low vitamin D levels were associated with lower total and/or progressive sperm motility.
Association between serum vitamin D levels and sex hormone levels: Most studies failed to find
an association between serum vitamin D levels and total or free testosterone levels. However,
although studies conducted in younger men did not find an association between serum vitamin D
levels and testosterone levels, the majority of studies conducted in older men found an association
between low serum vitamin D levels and low testosterone levels. Because this association
disappeared when adjusting for confounding factors (such as comorbidities), the authors
speculated that the relationship between serum vitamin D and testosterone may be influenced by
age-varying factors, including age-related comorbidities.
Effect of supplementation with vitamin D on sperm quality parameters: Supplementation with
vitamin D improved sperm total motility and/or progressive motility in 6 of the 9 studies. The
majority of the studies did not find an effect of supplementation with vitamin D on other sperm
quality parameters.
Effect of supplementation with vitamin D on sex hormone levels: Overall, supplementation with
vitamin D did not seem to affect sex hormone levels.
87
The effects of testosterone replacement therapy on sexual
function
This meta-analysis of randomized controlled trials indicated that testosterone replacement therapy
may improve sexual function in older men.
Background
The frequency of sexual intercourse tends to decline with age, and a notable proportion of older men
report at least one sexual problem (e.g., erectile dysfunction),[237] which is thought to be partly related to
hormonal status, namely, lower testosterone levels. Does testosterone replacement therapy (TRT) improve
sexual function?
The study
This meta-analysis of 5 randomized controlled trials examined the effect of TRT on sexual function (as
assessed via different validated questionnaires) in 2,056 older men (average ages of 57–72). The TRT
formulations were delivered via testosterone patch, gel, intramuscular injection, and oral medication. The
duration of the intervention ranged from 3 to 12 months.
The results
Compared to placebo, TRT did not improve overall sexual function, although it did improve individual
outcomes of sexual function, including erection, erectile function, motivation, and performance (but not
desire or scores on the Aging Male Symptoms scale).
Subgroup analysis indicated that only intramuscular injection of 1,000 mg of testosterone improved sexual
function, but this finding was based on a single study.
Note
Because of the small number of studies included, the results should be interpreted with caution.
88
Risk factors associated with sperm DNA fragmentation
In this meta-analysis, a number of lifestyle, environmental, health-related, and other factors were
associated with increased rates of sperm DNA damage.
Background
Sperm DNA integrity is considered an important marker of the fertility potential of spermatozoa.[239]
However, the factors associated with the risk of sperm DNA fragmentation (SDF) had not been established.
The study
This meta-analysis of 142 cohort studies examined the association between a large number of lifestyle,
environmental, health-related, and other factors and the degree of SDF.
Some of the specific factors examined were the following:
Health conditions: diabetes, varicocele, bacterial infections, testicular tumor, non-Hodgkin’s
lymphoma, Hodgkin’s lymphoma, leukemia, sexually transmitted infections, lymphoma, chlamydia,
viral infections, and human papillomavirus
Lifestyle factors: heavy smoking, moderate smoking, heavy drinking, moderate drinking, obesity,
overweight, underweight, and sexual abstinence
Environmental factors: pesticide/insecticide exposure and pollutant exposure
Other factors: Age >50 years, age >45 years, age >40 years, age >35 years, age >30 years, and
the levels of reactive oxygen species (ROS)
The results
The results were as follows:
Health conditions: The rates of SDF were higher in men with diabetes (13.8%), varicocele (13.6%),
bacterial infections (9%), testicular tumor (6.4%), lymphoma (5.2%), and Hodgkin’s lymphoma
(3.7%).
Lifestyle factors: Compared to nonsmokers, the rates of SDF were higher only in heavy smokers
(3.8%).
Environmental factors: The rates of SDF were higher in men exposed to pesticides/insecticides
(6%) and pollutants (6%).
Other factors: The rates of SDF were higher in men aged >50 years (12.6%), >40 years (5.5%), >30
years (4.3%), >45 years (3.9%), and >35 years (3.4%) and in men with higher levels of ROS (4.7%).
89
Can a low-carbohydrate diet increase testosterone levels?
In this randomized controlled trial, a low-carbohydrate diet improved clinical outcomes in men with low
testosterone and metabolic syndrome.
Background
Excess body weight is associated with hypogonadism (low testosterone) in middle-aged and older men,[260]
and diet-induced weight loss can increase testosterone levels and improve symptoms of hypogonadism.[261]
Does a low-carbohydrate diet improve clinical outcomes in men with hypogonadism and metabolic
syndrome?
The study
In this 3-month randomized controlled trial, 18 men (average age of 58) with hypogonadism and metabolic
syndrome were assigned to consume either a low-carbohydrate diet or a control diet. The lowcarbohydrate group was instructed by a nutritionist to reduce their carbohydrate intake (≤ 25%–30% of
total energy intake, with a goal of 20–30 grams of carbohydrate per day) and increase their fat and protein
intake. The control group was instructed to continue eating normally but received guidance on healthy
eating patterns.
The primary outcome was the change in total serum testosterone levels. The secondary outcomes were
free testosterone levels, anthropometric (body) measurements, blood pressure, symptoms of
hypogonadism (assessed via two questionnaires), and erectile function (assessed via a questionnaire).
The results
Compared to baseline, total serum testosterone increased in the low-carbohydrate group only (+81.6 vs.
+9.5 ng/dL).
For the secondary outcomes, compared to baseline, there were improvements in symptoms of
hypogonadism (from moderate to mild, on average), free testosterone (+2.0 ng/dL), and systolic blood
pressure (−9.1 mmHg) in the low-carbohydrate group only. Also, there was a reduction in body weight in
both groups compared to baseline, but there was a larger reduction in the low-carbohydrate group (−4.6
vs. −1 kg).
Note
This study had a couple of limitations: (i) it did not compare differences in testosterone between groups
(only within each group compared to baseline), (ii) dietary intake was not assessed, and (iii) a sample size
of 44 participants per group was calculated for the primary outcome, so the study was statistically
underpowered.
90
Herbal Supplements
The health effects of saffron
In this meta-analysis of randomized controlled trials, supplementation with saffron extract had
beneficial effects on blood lipid levels, glycemic control, systolic blood pressure, and a marker of
inflammation. However, the certainty of evidence was very low for most outcomes.
Background
Crocus sativus, commonly known as saffron, is a flower traditionally used to make a spice of the same
name. Beyond its use as a culinary ingredient, saffron is a popular supplement, containing a variety of
compounds with suspected health-promoting effects, including crocin, crocetin, picrocrocetin, safranal, and
kaempferol. Saffron supplements have been repeatedly tested for their effects on markers of
cardiometabolic health, like blood lipid levels and glycemic control.
Digging Deeper: The world's most expensive spice
Saffron is likely the most expensive spice in the world, with a by-weight cost similar to that of
precious metals like silver. Saffron’s extraordinary price tag is due to the labor-intensive nature of its
cultivation. Saffron spice consists only of the flower’s stigmas — small threads growing from the
center of the saffron flower itself. These threads are delicate, usually requiring careful harvesting by
hand. On top of that, saffron stigmas are very small, with over 100 flowers typically needed to make
about a single gram of dried saffron spice. This means that many hours of work are needed to
produce appreciable amounts of the spice.
Saffron supplements, however, aren’t always made of the stigmas, and often use the much more
readily available flower petals instead. Because the petals contain many of the same compounds as
the stigmas,[50] saffron supplements can be more affordable while maintaining some of the same
potential health benefits.
The study
This meta-analysis of 32 randomized controlled trials examined the effect of saffron supplementation on
various markers of health. The trials included a total of 1,674 participants (average ages of 27–58). The
trials ranged in duration from 1 to 12 weeks. The dosage of saffron ranged from 5 to 1,000 mg, provided as
either extract or isolated phytochemical.
The following outcomes were assessed:
Body weight
BMI
Waist circumference
Fat mass
Systolic blood pressure
Diastolic blood pressure
Fasting glucose
Fasting insulin
HbA1c
91
HOMA-IR, a marker of insulin resistance
Total cholesterol
LDL-C and HDL-C
Triglycerides
ApoB
The inflammatory markers C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α
The liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and alkaline
phosphatase (ASP)
Total antioxidant capacity (TAC) of serum
Malondialdehyde (MDA), a marker of oxidative stress
The studies were assessed for likelihood of bias using the Cochrane Collaboration tool. By this measure, 11
trials were rated as good, 12 trials were rated as fair, and 9 trials were rated as poor. The certainty of
evidence for each outcome was rated according to the GRADE criteria (Grading of Recommendations,
Assessment, Development and Evaluations), which is based on details like study blinding, consistency of
results, and signs of publication bias.
The results
Supplementation with saffron decreased total cholesterol (−6.87 mg/dL), LDL-C (−6.71 mg/dL),
triglycerides (−8.81 mg/dL), fasting glucose (−7.59 mg/dL), HbA1c (−0.18%), HOMA-IR (−0.49), systolic
blood pressure (−3.42 mmHg), TNF-α (−2.54 pg/mL), waist circumference (−1.5 cm), MDA (−1.5 uM/L), ALT
(−2.16 U/L), and increased TAC.
The certainty of evidence for all these outcomes was rated as very low, with the exception of the decrease
in TNF-α, which was rated as low.
The big picture
Overall, the results of the current meta-analysis suggest that saffron supplementation might help improve
markers of cardiometabolic health, potentially reducing the risk and/or severity of conditions like diabetes
and cardiovascular disease. However, the evidence quality was considered to be low, so these possible
benefits need to be confirmed by future high-quality studies.
Saffron has also been investigated for its effect on a number of other health outcomes, most of which
relate to the brain. In particular, saffron has been repeatedly tested for its effect on depression, with
generally positive results found. In one meta-analysis of randomized controlled trials, saffron
supplementation (typically 30 mg of extract) reduced depression symptoms and increased depression
remission rates compared to a placebo.[51] However, this meta-analysis included a limited number of trials
included (6 with a placebo group), all lasting between 6 and 8 weeks, meaning that additional trials, ideally
with longer follow-ups, are needed.
Saffron has also been investigated for its effect on sleep, again with positive results. Examine previously
covered a meta-analysis of 8 randomized controlled trials, which found that saffron supplementation
improved sleep quality, with a possible dose-response relationship, meaning that higher doses of up to 100
mg per day seemed to increase the overall effect.[52] However, as with the studies on depression, the limited
number of trials reduces confidence in the finding.
Finally, a few studies have investigated whether saffron might be helpful for cognitive function and
dementia, with mixed results. One randomized controlled trial involving 46 participants with mild-tomoderate Alzheimer’s disease found that supplementation with saffron for 16 weeks improved two tests of
cognitive function compared to a placebo.[53] Another small RCT involving 25 people with mild cognitive
impairment also found that supplementation with saffron for 12 months improved performance on one test
of cognitive function, but it did not clearly improve performance on another.[54] Finally, a 12-week study on
37 people undergoing coronary artery bypass grafting found no clear benefit for cognitive function from a
saffron supplement.[55]
92
Saffron: Potential health benefits
93
Garlic extract for weight loss in women with obesity
In this randomized controlled trial in women with obesity, supplementation with garlic extract had no
effect on anthropometric or biochemical parameters or on the composition of the gut microbiota.
Background
Garlic (Allium sativum) contains prebiotic components and antibacterial compounds (such as allicin) that
could affect the composition of the gut microbiota.[64] Moreover, supplementation with garlic may have
beneficial effects on anthropometric indices.[65] That said, more trials were needed to elucidate the potential
effects of garlic on gut microbiota composition and anthropometric indices in different populations.
The study
In this 2-month randomized controlled trial, 32 women with obesity (average age of 36) took capsules
containing either 800 mg of garlic extract (equivalent to 2.2 mg of allicin) or a placebo daily.
All participants were given dietary guidance for reducing their caloric intake to 500 kcal below their daily
energy requirements. Also, all participants were advised to be physically active for at least 30 minutes per
day.
The outcomes included anthropometric parameters (weight, BMI, waist circumference, hip circumference,
and waist-to-hip ratio), markers of glycemic control, blood lipids, liver enzymes, and gut microbiota
composition.
The results
All anthropometric parameters except waist-to-hip ratio improved in both groups. However, no differences
between groups were observed in any of the outcomes.
94
Which herbs may help with cyclic breast pain?
In this meta-analysis, several herbs reduced cyclic breast pain, though many of the included studies
were of poor quality.
Background
Breast pain that varies with the menstrual cycle is known as cyclic mastalgia. This condition can cause
anxiety, interfere with daily activities, and result in various diagnostic procedures.
Although it remains unknown, the cause of cyclic breast pain may be associated with a disturbance in
estrogen, progesterone, and/or prolactin. Certain herbs contain compounds known as phytoestrogens,
which can mimic the effects of estrogen in the body. Other herbs have also been shown to improve cyclic
mastalgia, but studies report conflicting results.
The study
This systematic review and meta-analysis examined 20 randomized trials in which the participants reported
cyclic mastalgia. The intervention categories were defined as (i) herbal medicine overall (16 studies), (ii)
phytoestrogens overall (13 studies), and (iii) each individual herb (chaste tree, 5 studies; flaxseed, 2 studies;
St. John’s Wort, 2 studies; evening primrose, 5 studies; chamomile, 1 study; red clover extract, 1 study;
cinnamon, 1 study; black cumin, 1 study).
The trials were 1–6 months in length, and each recruited 12–478 participants. Pain intensity was most often
evaluated with a visual analogue scale.
The results
Overall, herbal medicine was found to moderately reduce breast pain, compared to a control (e.g., omega-3
fatty acids, or vitamin E) or placebo.
Compared to a control, phytoestrogens had a large effect on reducing breast pain. Individually, chaste tree,
flaxseed, and evening primrose had moderate effects on reducing breast pain. Although this analysis was
based on a smaller body of evidence, the herbs chamomile, red clover, cinnamon, and black cumin were
also found to reduce breast pain scores (by 31%, 54%, and 50%, respectively). Compared to medication,
evening primrose and chaste tree had similar effects. No effect was seen with St. John’s Wort. Overall,
study heterogeneity was noted to be high.
Note
Due to the high amount of heterogeneity between studies, caution should be taken in interpreting these
results, and further studies with better methodological quality should be conducted to confirm these
findings before they are used to guide clinical decision-making.
95
Pomegranate juice and sumac for the treatment of COVID-19
In this exploratory trial, supplementation with pomegranate juice and sumac improved a number of
COVID-19 symptoms.
Background
Because of their antioxidant, anti-inflammatory, and immunomodulatory properties, pomegranate and
sumac may be useful in the treatment of COVID-19.
The study
In this 4-week randomized controlled trial, 178 adults (ages <60 years) with COVID-19 (but who were not
hospitalized) were assigned to one of two groups:
Treatment: The participants in this group consumed 600 mL of pomegranate juice and 3 grams of
sumac daily and received standard care.
Control: The participants in this group received standard care.
The study outcomes were the frequency of respiratory symptoms (cough and shortness of breath),
frequency of pain (abdominal pain, muscle pain, chest pain, and headache), frequency of gastrointestinal
symptoms (anorexia, vomiting, and diarrhea), and frequency of general symptoms (sore throat, smell and
taste dysfunction, chills, weakness, and dizziness).
Because the two groups differed in terms of sex distribution, the researchers reported the outcomes for
each sex separately.
The results
At the end of the trial, the frequency of cough, shortness of breath, abdominal pain, muscle pain, chest pain,
anorexia, vomiting, diarrhea, and weakness was lower in the treatment group than in the control group in
both men and women, whereas the frequency of sore throat was lower in men (but not in women), and the
frequency of dizziness was lower in women (but not in men).
Note
The researchers tested a large number of outcomes without making adjustments for multiple comparisons,
which increases the risk of false-positive results. It’s also worth noting that only one outcome was
prespecified.
96
Black cumin vs. clobetasol propionate gel in oral lichen
planus
In this randomized controlled trial, a cream containing Nigella sativa was as effective as a gel
containing corticosteroids for reducing the burning sensation and the size of the lesions in participants
with oral lichen planus.
Background
Topical corticosteroids such as clobetasol propionate are the first-line treatment for oral lichen planus
(OLP), but their use is often accompanied by adverse effects. One potential alternative is Nigella sativa
(black cumin or black seed), a medicinal spice with anti-inflammatory, immunomodulatory, antimicrobial,
and pain-relieving properties.
The study
In this 45-day randomized controlled trial, 49 adults with OLP applied either 1 gram of a cream containing
75% Nigella sativa or 1 gram of a gel containing 0.05% clobetasol propionate to their lesions twice per day.
The outcomes were the severity of burning sensation and the size of the lesions.
The results
The severity of burning sensation and the size of the lesions improved in both groups over time, with no
differences between groups.
97
Can Pycnogenol prevent hair loss in postmenopausal
women?
In this randomized controlled trial, supplementation with Pycnogenol increased hair density in
postmenopausal Chinese women.
Background
Reduced subcutaneous blood flow and decreased angiogenesis (the formation of new blood vessels) may
be implicated in the development of female pattern hair loss (FPHL) — the progressive diffuse thinning and
loss of hair, especially in the central areas of the scalp. Because Pycnogenol (a patented blend of
procyanidins extracted from pine bark) may improve microcirculation (the circulation of blood in the
smallest blood vessels), supplementation with Pycnogenol may be useful in the treatment of FPHL.
The study
In this 6-month randomized controlled trial, 63 postmenopausal women (ages 45–60) in China took
capsules containing either 150 mg of Pycnogenol or a placebo daily.
The outcomes were hair density (assessed using digital photography), resting flux of the scalp skin (a
marker of changes in microcirculation), skin hydration levels, and the degree of transepidermal water loss
(TEWL).
The results
After 6 months, hair density increased more in the Pycnogenol group (+23%) than in the placebo group
(+9%). The resting flux of the scalp skin decreased more in the Pycnogenol group (−44%) than in the
placebo group (−20%), which may indicate a greater improvement in microcirculation in the Pycnogenol
group.
Note
The study was funded by Horphag Research (Europe) Ltd, which is the exclusive worldwide supplier of
Pycnogenol. Also, one of the researchers was the director of product development at Horphag Research
during the time that the study was conducted.
98
Chokeberries for improving sperm quality and blood lipids in
men with hypercholesterolemia
In this randomized controlled crossover trial, supplementation with chokeberry extract increased the
levels of glutathione S-transferase (an antioxidant enzyme) in men with moderately elevated total
cholesterol levels.
Background
Oxidative stress is involved in the development of inflammation, dyslipidemia, hypertension, and type 2
diabetes (all of which have been linked to an increased risk of cardiovascular disease),[173][174] as well as the
pathogenesis of male infertility.[175] Because of their potent antioxidant properties, chokeberries (also called
Aronia berries) may improve sperm quality parameters and the aforementioned risk factors for
cardiovascular disease.
The study
In this 90-day randomized crossover trial, 95 Danish men with moderately elevated total cholesterol levels
took capsules containing either chokeberry extract (ARO3:5®) or a placebo. The chokeberry extract
comprised 3 wild Aronia species and a cultivated Aronia hybrid and was standardized to provide 150 mg of
anthocyanins daily. After a 90-day washout period, the participants crossed over to the other intervention
and repeated the experiment.
The primary outcomes were sperm-quality parameters (total motile sperm count and total progressive
motile sperm count) and blood lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides).
The secondary outcomes were blood pressure, the phase II group of antioxidant enzymes (superoxide
dismutase, catalase, and glutathione S-transferase), isoprostane (a marker of oxidative stress), glycated
hemoglobin (HbA1c; a marker of glycemic control), high sensitivity [C-reactive protein[ (hs-CRP; a marker
of inflammation), DNA fragmentation index (DFI), testosterone, and pregnancy rates during the study or
within 3 months of the end of the study.
The results
Glutathione S-transferase levels increased more with supplemental chokeberry extract than with placebo.
No other differences were observed between treatments in the overall analyses.
Note
Although the researchers reported a number of statistically significant findings in the subgroup analyses,
the subgroup analyses were not preplanned and should therefore be viewed with caution.
It’s also worth noting that (i) the researchers tested a large number of outcomes without making
adjustments for multiple comparisons, which increases the risk of false-positive results; (ii) there were
significant discrepancies between the prespecified outcomes and the outcomes specified in the published
paper; and (iii) one of the researchers was the owner of ByrialApS (the manufacturer of ARO3:5®) at the
time that the trial was conducted.
Thunder god vine for the treatment of rheumatoid arthritis
In this meta-analysis of randomized controlled trials, treatment with Tripterygium wilfordii Hook F and
methotrexate was more effective than methotrexate alone for reducing the symptoms of rheumatoid
arthritis and the levels of inflammatory biomarkers.
Background
99
Caution: This supplement has the potential to harm your health
Thunder god vine (Tripterygium wilfordii) is used in Traditional Chinese Medicine to treat a wide
range of conditions. By decreasing the number of white blood cells, it reduces inflammation (and
thus pain) around the joints, but it also makes the body more susceptible to infection, which can lead
to sickness and potentially death.
Although Tripterygium wilfordii appears to be effective in treating rheumatoid arthritis, the effective
dose of this supplement is close to a harmful dose. It is not safe and should not be supplemented.
Adverse effects of thunder god vine
Tripterygium wilfordii Hook F (TwHF; also known as Thunder god vine and léi gōng téng) is a herb with
anti-inflammatory properties that is traditionally used in China for the treatment of rheumatoid arthritis
(RA). What is the efficacy of TwHF when used alongside methotrexate (a drug commonly used in RA)?
The study
100
This meta-analysis of 14 randomized controlled trials examined the effect of supplementation with TwHF +
methotrexate, compared to methotrexate alone, for the treatment of RA in a total of 1,446 participants with
RA (average ages of 39–69).
TwHF was administered as Tripterygium glycoside tablets in 12 trials (at a daily dose of 10–60 mg) and as
Tripterygium wilfordii tablets in 2 trials (at a daily dose of 10–60 mg). The weekly dose of methotrexate
ranged from 7.5 to 15 mg. The intervention duration ranged from 12 to 24 weeks.
The primary outcomes were the effective rate (>20% improvement in RA symptoms), partial remission rate
(>50% improvement in RA symptoms), and remission rate (>75% improvement in RA symptoms). The
secondary outcomes were clinical outcomes (duration of morning stiffness, swollen joint count, and tender
joint count), the levels of biomarkers of RA severity (rheumatoid factors and anticyclic citrullinated
peptide), the levels of biomarkers of inflammation (C-reactive protein, erythrocyte sedimentation rate,
interleukin 1, interleukin 6, and tumor necrosis factor-alpha), and adverse effects.
The results
Compared to methotrexate, TwHF + methotrexate improved the treatment effective rate, partial remission
rate, and remission rate by 15%, 27%, and 31%, respectively.
In the secondary outcomes, TwHF + methotrexate was more effective than methotrexate for improving all
clinical outcomes, biomarkers of inflammation, and rheumatoid factors (but not anticyclic citrullinated
peptide).
In terms of adverse effects, TwHF + methotrexate was associated with a lower risk of total adverse effects,
infections, and liver adverse effects, but it was not associated with the risk of gastrointestinal adverse
effects, skin and mucous adverse effects, blood-related adverse effects, or menstrual-related adverse
effects.
101
Healthy Aging & Longevity
Eating fish is associated with a lower risk of dementia
In this meta-analysis of prospective cohort studies, eating more fish was associated with a lower risk
of dementia.
Background
Fish tends to be a good source of docosahexaenoic acid (DHA) and vitamin B12 — nutrients necessary for
proper brain health — but is also a major source of mercury, which can have adverse effects on the brain.
This study analyzed high-quality observational studies to see if people who eat more fish are at lower risk
of dementia.
The study
In this meta-analysis of 7 prospective cohort studies, the investigators examined the association between
fish intake and risk of dementia. The studies included a total of 30,638 participants. Three studies were
conducted in Asia, 3 in Europe, and 1 in the United States. The follow-up times ranged from 5.4 to 11 years.
In all of the studies, fish intake was determined using a food frequency questionnaire.
The included studies adjusted for potential confounding factors, most often age and education (7 studies),
gender (6 studies), and BMI (5 studies); a few studies adjusted for specific lifestyle and health status
factors.
Investigators assessed the quality of each study using the Newcastle-Ottawa Scale. Based on this scale, all
of the studies were rated high quality.
The results
In the main analysis, a higher intake of fish was associated with a 17% lower risk of dementia.
In a subgroup analysis, eating an additional 67.5 grams of fish or more per day (roughly equal to at least 1
extra pound of fish per week) was associated with a 24% lower risk of dementia.
102
Supplementing with anthocyanins to improve cognitive
function
In this randomized controlled study in adults at risk for dementia, supplementing with anthocyanins for
24 weeks did not improve attention, memory, or cognitive speed compared to placebo.
Background
Dementia is a highly prevalent condition worldwide, and the risk of dementia increases in the presence of
cardiometabolic risk factors such as hypertension, hypercholesterolemia, inflammation, and oxidative
stress.
Dietary factors are important for dementia risk prevention. Anthocyanins — plant polyphenols found in dark
berries and other fruits — have antioxidant properties and are associated with improved cognition.[59] Could
supplementing with anthocyanins boost memory and cognitive function in adults at risk for dementia?
The study
In this 24-week randomized controlled study, 206 adults (median age of 69; 103 men, 103 women) with
mild cognitive impairment or cardiometabolic disease (i.e., cerebrovascular disease, cardiovascular disease,
diabetes, hypercholesterolemia, or overweight) took 320 mg of purified anthocyanins (from bilberry and
black currant) or a placebo daily.
The study outcomes included attention, memory, and cognitive speed, which were measured at baseline
and monthly thereafter using an online digital cognitive test battery.
The results
There were no differences in attention, memory, or cognitive speed between the anthocyanin and placebo
groups at 24 weeks.
Note
The results were similar when the participants were separated into those with and without mild cognitive
impairment, with and without cardiometabolic disease, with or without the APOE e4 genotype (a genetic
risk factor for Alzheimer’s disease), with low or normal levels of amyloid beta protein (a marker of
Alzheimer’s disease risk), and those who were younger or older than the median age of 69 years.
103
Reducing dementia risk with “Life’s Simple 7”
In this meta-analysis, maintaining an ideal cardiovascular health score on seven modifiable risk factors
of cardiovascular health known as Life’s Simple 7 was associated with a decreased risk of dementia.
Background
In 2010, the American Heart Association (AHA) defined ideal levels of seven modifiable risk factors of
cardiovascular health (CVH), known as Life’s Simple 7, consisting of diet, smoking, physical activity, body
mass index, fasting blood glucose, total cholesterol, and blood pressure factors.[61]
Maintaining ideal levels of the seven CVH metrics is recommended to prevent cardiovascular disease and
neurodegenerative disorders such as cognitive decline and dementia.
Although growing evidence has confirmed the preventative effects of these metrics on cardiovascular
disease, research exploring the impact on cognitive outcomes has been inconsistent.
The study
This meta-analysis of 14 longitudinal studies examined the association between CVH score and cognitive
outcomes in 311,654 middle-aged and older adults (average ages of 50–75). The follow-up periods ranged
from 7 to 30 years.
The researchers assessed the correlation between CVH score and the risk of incident dementia and
analyzed which of the seven modifiable risk factors contributed most to increased dementia risk.
The researchers also assessed the dose-response relationship between CVH score and dementia risk and
examined whether this relationship differed between middle-aged and older adults.
The results
An ideal CVH score was linked to a 6% decreased risk of incident dementia. Physical activity, total
cholesterol, and fasting plasma glucose contributed the most to this association.
The relationship between CVH score and dementia risk was linear in middle-aged adults and J-shaped in
older adults, indicating that middle-aged adults benefit more from an ideal CVH score than older adults.
Note
This study’s results suggest that following the AHA recommendations may not only protect against
cardiovascular disease but also may slow cognitive aging.
104
Can a multicomponent supplement benefit cognitive
function?
In this randomized controlled trial in middle-aged participants, a supplement containing B vitamins,
Bacopa monnieri, and Ginkgo biloba did not clearly improve cognitive function. However, the
supplement improved attention among participants who followed a healthier diet.
Background
Some evidence suggests that various nutrients (e.g., B vitamins) and herbs (e.g., Ginkgo biloba) can help
improve cognitive function, although the effect tends to be small and/or inconsistent. It’s possible that
these nutrients and herbs have only a small effect on their own but when combined could produce a larger,
additive effect on cognitive function. This study explored that possibility.
The study
In this randomized controlled trial, 141 participants (ages 40–65; average age of 53) were assigned to take
a multicomponent supplement or a placebo for 12 weeks. The supplement contained vitamin B1 (50 mg),
vitamin B2 (70 mg), vitamin B3 (nicotinamide; 40 mg), vitamin B5 (128 mg), vitamin B6 (41 mg), vitamin B12
(50 µg), Bacopa monnieri (extract of 7.5 grams of whole plant), and Ginkgo biloba (extract from 6 grams of
leaf).
The investigators examined the effect of the supplement on various aspects of cognitive function, with
memory and attention as the primary outcomes. Other outcomes included stress, mood disturbances,
depression, and anxiety.
Additionally, the investigators assessed the effect of the supplement based on whether the participants had
higher or lower adherence to a healthy diet (defined as a higher intake of fruits, vegetables, legumes, olive
oil, and nuts and a lower intake of processed foods).
The results
Overall, the supplement did not clearly impact any outcome compared to placebo.
Among the participants with higher adherence to a healthy diet, the supplement improved attention.
105
Can lemon balm help with cognitive decline?
In this randomized controlled trial, lemon balm did not clearly improve cognitive function in
participants with subjective cognitive decline or mild cognitive impairment.
Background
Melissa officinalis, commonly known as lemon balm, is a plant in the mint family with leaves that have a
long history of use as an herbal medicine. Lemon balm contains a variety of potentially bioactive
compounds, including rosmarinic acid. Drawing from research suggesting that rosmarinic acid might inhibit
Alzheimer’s disease pathology, this study tested whether taking lemon balm might be helpful for people
showing signs of cognitive decline.
The study
This 96-week randomized controlled trial examined whether lemon balm is helpful for cognitive decline. The
trial included a total of 323 participants (ages 35–73) with mild cognitive impairment or subjective
cognitive decline. The participants were assigned to take either lemon balm extract (supplying 500 mg of
rosmarinic acid) or a placebo daily.
The primary outcome was cognitive function, assessed using the Alzheimer’s Disease Assessment Scale–
Cognitive Subscale (ADAS-Cog). The other outcomes were three measures of cognitive function:
hippocampal volume and two secondary measures, namely, the Mini–Mental State Examination and the
Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB).
The results
Overall, lemon balm extract did not clearly improve any outcome when compared with placebo.
In subgroup analysis, lemon balm resulted in better cognitive function scores on the CDR-SOB.
Note
It seems highly likely that the improved cognitive function on the CDR-SOB test was a chance finding, given
that it was the only outcome out of 18 total subgroup analyses that was statistically significant.
106
The role of calcium and magnesium in dementia prevention
In this prospective cohort study, Chinese older adults with higher magnesium intakes (>267 mg/day)
had an increased risk of incident dementia. Moreover, the ratio of calcium intake to magnesium intake
played a key role in this association.
Background
Cross-sectional evidence suggests that dietary intakes of calcium and magnesium may affect the risk of
developing dementia at an older age.[93] However, long-term observational studies were needed to further
explore this relationship.
The study
This 5-year prospective cohort study in 1,565 Chinese older adults (average age of 71) examined the
association between calcium and magnesium intakes and the risk of incident dementia. Moreover, the
researchers analyzed whether the ratio of calcium intake to magnesium intake influenced this relationship.
The results were adjusted for potential confounders, including basic characteristics (sex, age, years of
education), lifestyle factors (smoking and obesity), disease status (stroke, diabetes, and hypertension), and
supplementation with calcium and magnesium.
The results
Although calcium intake showed no association, a higher magnesium intake (>267 mg/day) was linked to a
126% increased risk of dementia.
Similarly, in participants with a low calcium-to-magnesium ratio (≤1.7), a higher intake of magnesium (>267
mg/day) was linked to a 297% increased risk for dementia.
Note
The results of this observational study suggest that the total intake of magnesium and the proper balance
between calcium and magnesium may be critical in preventing dementia. However, more research is needed
to confirm these findings in other populations.
107
Are vitamin D and omega-3s “VITAL” for inflammation?
In this randomized controlled study, adults who supplemented with vitamin D reduced their levels of Creactive protein at 2 years. Supplementing with vitamin D or omega-3s had no effect on other
inflammatory biomarkers at 2 years or 4 years.
Background
Chronic inflammation is a risk factor for several conditions including autoimmune disease, cancer,
cardiovascular disease, and diabetes. Although some evidence indicates that vitamin D and omega-3 fatty
acids may reduce levels of inflammation, meta-analyses have failed to find a benefit of these nutrients.[94][95]
However, low-quality evidence on the anti-inflammatory effects of vitamin D and omega-3s signaled the
need for a well-controlled, large-scale study on their effects.
The study
This 4-year randomized controlled study examined data from 1,054 adults (49% women, 51% men, average
age of 65) who were part of the Vitamin D and Omega-3 Trial (VITAL).[96] The participants received vitamin
D (2,000 IU/day), marine omega-3 fatty acids (840 mg, including 460 mg of EPA and 380 mg of DHA), or a
placebo daily.
The primary study outcomes were the inflammatory biomarkers C-reactive protein (CRP), interleukin 6 (IL6), and tumor necrosis factor alpha (TNF-α), and the anti-inflammatory biomarker interleukin 10 (IL-10). The
outcomes were assessed at baseline, 2 years, and 4 years.
The results
CRP decreased by 19% in the vitamin D group at 2 years, but there were no differences in any other
biomarkers at the 2-year or 4-year time point for the vitamin D group.
There were no differences in inflammatory biomarkers at 2 years or 4 years in the omega-3 fatty acid
group.
Note
The results of the compliance-adjusted analyses from this study support the robustness of these findings.
When participants who took less than two-thirds of the study pills or who supplemented with additional
vitamin D or omega-3s were excluded, the results were similar to those of the original analysis.
108
Can nut consumption increase longevity?
In this cohort study in Chinese older adults, nut consumption was associated with a reduced 10-year
mortality risk.
Background
Nuts are rich in vitamins, minerals, polyphenols, and fiber. Given these characteristics, nut consumption may
lower mortality risk and increase lifespan. However, more research was needed to investigate this
association.
The study
This cohort study in 11,915 Chinese older adults (average age of 84) examined the association between nut
consumption and 10-year mortality risk. The participants were asked to report their frequency of nut
consumption, including peanuts, walnuts, chestnuts, and melon seeds.
The researchers also performed subgroup analyses by age group (<80 vs. ≥80 years), sex (male vs.
female), activities of daily living (normal vs. impaired), and physical exercise (exercising vs. nonexercising)
to examine whether this association differed across populations.
The analyses were adjusted for potential confounders, including age, sex, education, residence,
socioeconomic status, exercise, smoking, drinking, and diabetes.
The results
Compared to rarely or never consuming nuts, more frequent nut consumption was associated with an 8.8%
lower mortality risk.
This risk reduction was more pronounced in male participants, participants who were <80 years old, and
participants who did not engage in exercise or had an impaired ability to perform activities of daily living.
Note
Given limitations in the available data, the researchers could not analyze the associations of other nut
consumption variables, such as the amount of nuts consumed and the specific type of nuts. More research
is needed to determine an optimal amount of nut consumption and the particular type(s) of nuts that would
be most effective in reducing mortality risk.
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Drinking tea is associated with a reduced risk of cognitive
impairment
In this meta-analysis of observational studies, a higher intake of tea was associated with a lower risk of
cognitive impairment.
Background
Tea made from the Camellia sinensis plant, which includes green tea and black tea, may help fend off the
cognitive impairment that often accompanies older age. Various mechanisms have been proposed as
explanations of how tea might provide this benefit, including reducing oxidative stress in the brain,[155]
inhibiting microglia activity (which can slow neuron activity),[156] and impeding amyloid aggregation (which
contributes to the development of Alzheimer’s and other diseases).[157]
Still, ideas about why drinking tea can support brain health during aging are not very meaningful unless
there is evidence that tea actually does provide this benefit.
The study
This meta-analysis examined the association between tea consumption and the risk of cognitive
impairment. A total of 23 prospective cohort studies and 12 cross-sectional studies were included. The
cohort studies ranged in duration from 1 to 21 years.
Depending on the study, different outcomes were included under the umbrella of overall cognitive
impairment, i.e., cognitive decline, mild cognitive impairment (MCI), dementia, or Alzheimer’s disease.
The results
A higher intake of tea was associated with a lower risk of cognitive impairment in both the cross-sectional
studies and the prospective cohort studies. This finding was also seen with green tea or black only and
when the analyses were restricted to higher-quality studies.
In the prospective cohort studies specifically, a higher intake of tea was associated with a lower risk of
overall cognitive impairment (19%), cognitive decline (23%), MCI (34%), and Alzheimer’s disease (11%).
Note
In addition to the meta-analyses of observational studies discussed above, the investigators performed a
meta-analysis of randomized controlled trials (RCT) that looked at the effect of tea on cognitive function.
We chose not to cover this analysis due to the following issues with its source data:
One study did not have a control group, making it an uncontrolled trial, not an RCT.
One study was a subgroup analysis derived from the uncontrolled study.
One RCT included placebo data from the wrong time point (i.e., at baseline, rather than at the end
of the study).
One RCT’s data were reported incorrectly.
We could not locate the source data from two of the studies, raising doubts about their validity,
especially in light of the previous errors.
The extent of these issues seems concerning enough to question the validity of the paper as a whole. That
said, during a nonsystematic check, we did not identify any errors in the other meta-analyses.
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Which dietary patterns reduce which kinds of mortality?
In this prospective cohort study, all four diets examined were associated with reduced total,
cardiovascular, cancer, and respiratory mortality risks.
Background
Certain eating indices have been developed to grade a person’s diet based on the quantity of foods that
have associations with improved or worsened health outcomes. Two such examples are the Healthy Eating
Index (HEI) and Alternate Healthy Eating Index (AHEI). A major difference between the two is that the AHEI
assigns a positive rating to moderate alcohol consumption.[179]
Another example is the Alternate Mediterranean Diet (aMED). The aMED includes several modifications to a
standard Mediterranean diet such as removing potatoes from the vegetable group, separating fruit and nuts
into two groups, eliminating the dairy group, including whole grain products only in the grain group, and
including only red and processed meat in the meat group. [180]
This study compared the associations between the HEI, AHEI, aMED, and the Healthful Plant–based Diet
Index (HPDI) and different causes of mortality.
The study
This prospective cohort study included 119,315 participants from the Nurses’ Health Study (1984–2020) and
the Health Professionals Follow-up Study (1986–2020). Food frequency questionnaires were filled out every
2–4 years in both of these studies and were used to calculate the HEI, AHEI, aMED and HPDI scores in the
summarized study.
The results
Each index was associated with reduced cardiovascular, cancer, and respiratory mortality and had similar
risk reductions in all-cause mortality (14%–20%). THe AHEI and aMED were associated with reduced
neurodegenerative mortality. These associations were consistent across different ethnic groups.
Note
One similarity between the AHEI and aMED that could explain the effect on neurodegenerative mortality is
the emphasis on nuts and monounsaturated fat.
Because all of the participants were health professionals, the results of this study may not be generalizable
to other populations.
Investigating the relationship between animal foods and
neurocognitive disorders
This meta-analysis of prospective cohort studies looked at the association between different animal
foods and the risk of several neurocognitive disorders. Dairy intake was associated with a higher risk
of Parkinson’s disease and a lower risk of dementia, and fish intake was associated with a lower risk of
dementia.
Background
A number of neurodegenerative disorders can occur during aging, including the following:
Cognitive impairment: a worsening of cognitive function beyond what is expected based on age,
though not to the point of interfering with daily functioning.
Dementia: an impairment in cognitive functioning that interferes with a person’s ability to function in
daily life. A large number of diseases and health conditions can result in dementia.
Alzheimer’s disease: a specific type of dementia, representing about 60% of all cases.
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Parkinson’s disease: a disease resulting from a specific type of neuronal damage. It can cause
motor disturbances (tremors) as well as cognitive issues like dementia.
Thankfully, there’s evidence to suggest that a healthy dietary pattern can reduce the risk of developing all
of these disorders.[81][187][188] Still, the effects of animal foods on the risk of these neurocognitive disorders is
complex and controversial. On one hand, animal foods tend to be a good source of various nutrients
important for brain health, like iron, vitamin B12, zinc, and in the case of fish, omega-3 fatty acids. On the
other hand, animal foods can also contain compounds suspected of adversely affecting brain health, like
saturated fat, iron (in excess), and in the case of fish, mercury.
What does the existing body of literature say about the relationship between animal foods and
neurocognitive disorders?
The study
This meta-analysis of prospective cohort studies examined the association between different animal foods
and the risk of several neurodegenerative disorders. A total of 33 studies with 1,199,730 participants were
included. Study follow-up times ranged from 3 to 30 years.
The animal foods investigated in the studies were total dairy product intake, milk, yogurt, cheese, total
meat intake, red meat, processed meat, poultry, fish, and eggs. The neurodegenerative diseases
investigated in the studies were Parkinson’s disease (8 studies), Alzheimer’s disease (9 studies), dementia
(12 studies), and cognitive impairment (11 studies).
The overall certainty of evidence for each outcome was rated using the GRADE (Grading of
Recommendations Assessment, Development and Evaluation) guidelines.
The results
The researchers determined the following associations through their main analysis:
Dairy: A higher intake of total dairy was associated with a 49% higher risk of Parkinson’s disease, a
65% lower risk of dementia, a 37% lower risk of Alzheimer’s disease, and an 11% lower risk of
cognitive impairment. A higher intake of milk was associated with a 40% higher risk of Parkinson’s
disease and a 65% lower risk of Alzheimer’s disease.
Total meat: A higher intake of meat was associated with a 28% lower risk of cognitive impairment.
Red meat: Although no outcomes were statistically significant in the main analysis, in doseresponse analyses, every 100-gram increase in red meat intake was associated with a 60% increase
in the risk of cognitive impairment and every 30-gram increase in red meat intake was associated
with a 5% higher risk of dementia and a 40% lower risk of Alzheimer’s disease.
Processed meat: A higher intake of processed meat was associated with a 49% lower risk of
Parkinson’s disease, a 13% higher risk of dementia, and a 30% higher risk of Alzheimer’s disease.
Poultry: A higher intake of poultry was associated with a 43% higher risk of dementia and an 18%
lower risk of cognitive impairment.
Fish: A higher intake of fish was associated with a 16% lower risk of dementia, a 25% lower risk of
Alzheimer’s disease, and a 15% lower risk of cognitive impairment.
Notable findings from the study
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Note
There was no association between egg intake and any of the outcomes. One reason for this could be that
most people don’t eat many eggs, meaning that participants typically only needed to consume a few eggs
per week (a fraction of an egg per day, on average) to be categorized as a high egg eater. Whether eating
multiple eggs per day is positively or negatively associated with any of the examined disorders therefore
remains uncertain.
The big picture
The current study had a number of findings worth digging into. Of note, a higher intake of fish was
associated with a lower risk of cognitive decline, dementia, and Alzheimer’s disease. The lower risk of
dementia associated with fish consumption was considered “high quality” evidence and was the only finding
from the study to receive this rating.
Fish tends to be a good source of omega-3 fatty acids, which may help explain why eating fish is
associated with a lower risk of dementia and cognitive decline. However, omega-3 fatty acids may not
reduce the risk of Alzheimer’s disease specifically, which is the most common type of dementia. In several
cohort studies, supplementing with fish oil was associated with a lower risk of dementia, but not
Alzheimer’s disease.[189][190][191] This suggests that other factors could be responsible for the lower risk of
Alzheimer’s disease with greater fish consumption.
One such factor could be vitamin D, which is found in oily fish, including salmon, sardines, trout, pike, and
mackerel. Having low vitamin D levels (e.g., less than 20 ng/mL) is associated with a higher risk of
Alzheimer’s disease,[192] and while it’s possible this is the result of confounding, people with genetically
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higher vitamin D levels are also less likely to develop Alzheimer’s disease, suggesting that the effect is
indeed causal.[193][194] Still, more research is needed to determine what factors might mediate the relationship
between fish intake and cognitive outcomes.
Another intriguing finding from this study was that a higher intake of total dairy was associated with an
increased risk of Parkinson’s disease. This is also supported by genetic evidence, in which people with
lactose tolerance, who therefore consume more dairy, have been found to be at a high risk of Parkinson’s
disease.[195] Various mediators of the link between dairy and Parkinson’s have been proposed, including
galactose (formed from the metabolism of lactose), dairy-derived microRNAs,[196], pesticide contaminants in
dairy products, and a uric acid-lowering effect of dairy (higher uric acid is associated with a lower risk of
Parkinson’s disease).[197] However, none of these theories are currently well supported by evidence.
Interestingly, available research tentatively suggests that only lower-fat dairy foods are associated with
Parkinson’s disease.[198] The reason for this is also unclear, but it could be attributable to yet unidentified
protective compounds in dairy fat (e.g., odd chain-fatty acids). Alternatively, other diet and/or lifestyle
factors may simply differ between lower-fat and higher-fat dairy consumers. These consumers may have
differences in smoking habits, alcohol intake, physical activity, and more, which would explain this
discrepancy.
In contrast to the increased risk of Parkinson’s disease, a higher intake of dairy was associated with a lower
risk of dementia. Although it’s not clear what explains this finding and, given the observational nature of the
evidence, whether it is indeed causal, various possible mediators have been suggested, including bioactive
peptides, fatty acids, and phospholipids found in dairy products. More broadly, the link could be explained
by the fact that consuming more dairy has been linked to a lower risk of type 2 diabetes,[199] a disease that
seems to increase the risk of dementia.[200][201]
Ultimately, some of these results seem consistent with existing dietary patterns (e.g., a Mediterranean-style
diet) that have been linked to a lower risk of neurocognitive disorders. These dietary patterns tend to
involve eating some fish and limiting red meat intake. Still, more research is needed to understand how
certain animal foods, like eggs, affect the risk of neurocognitive disorders. In addition, the role of dairy
could be described as complicated, as it offers both potential risks (e.g., a higher risk of Parkinson’s
disease) and benefits (e.g., a lower risk of dementia).
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Is vigorous activity linked to mortality risk in older adults?
This retrospective cohort trial found that vigorous activity, as measured by a wearable device,
correlated with reduced cardiovascular, cancer, and all-cause mortality risk in older adults.
Background
Exercise guidelines commonly recommend half as much exercise if it is done vigorously. However, vigorous
activity can be challenging for wearable devices to capture, especially if done for brief periods. Does
intermittent vigorous activity, as tracked by wearable technology, result in reduced mortality risk?
The study
This retrospective cohort study examined the wearable accelerometer data from 25,241 nonexercising
participants (average age of 62) in the UK Biobank study. The participants wore a wrist accelerometer for 7
days to track their activity, which was classified as sedentary, light, moderate, or vigorous. The outcomes
examined were risk of cardiovascular, cancer, or all-cause mortality.
The results
The average amount of vigorous exercise performed by the participants (3 bouts of vigorous movement,
lasting 1–2 minutes each) was associated with a 38%–40% reduction in all-cause and cancer mortality risks
and a 48%–49% reduction in cardiovascular mortality risk. The trends were near linear for all three causes,
with steeper reductions in mortality at lower volumes of vigorous activity.
Note
Similar effects were seen in the nonexercising participants who performed intermittent vigorous movement
throughout the day, compared to the participants who engaged in vigorous exercise during their leisure
time. This suggests that people who do not perform structured exercise can still obtain the mortality
benefits of vigorous activity, even when it is broken up into several short bouts of movement throughout
the day.
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A cannabidiol-rich cannabis extract for Parkinson’s disease?
In this randomized controlled trial, cannabis extract did not reduce Parkinson’s disease severity, but it
was associated with positive changes in metabolic markers related to kidney and liver health.
Background
Research suggests that cannabidiol (CBD; a component of cannabis) can reduce neurological excitotoxicity
and may have applications in the management of Parkinson’s disease. Placebo-controlled trials were
needed to determine whether CBD improves outcomes for individuals with Parkinson’s disease.
The study
This 8-week randomized controlled trial initially enrolled 40 participants with Parkinson’s disease, with 36
included in the final analysis. In addition to standard care, the participants received either a placebo or
CBD-rich cannabis extract, to be administered sublingually.
Cannabinoids were extracted from the Charlotte’s Angel strain of cannabis using ethanol and were then
dissolved in olive oil. The final cannabis extract contained 100 mg of CBD per mL and 3.9 mg of
tetrahydrocannabinol (THC) per mL. The placebo contained olive oil with a small amount of green
vegetable matter to mimic the appearance of the cannabis extraction.
All participants were prescribed a low initial dose, with gradual titration over 2 weeks based on individual
response and tolerance. Dosing was then maintained for 6 weeks. The mean cannabidiol dosage in the
treatment group was 15.6 mg per day.
The primary outcome of interest was changes in the Unified Parkinson’s Disease Rating Scale (UPDRS). The
secondary outcomes included changes in quality of life, functional performance, anxiety, and depression.
Markers of kidney and liver function were also tracked, along with the occurrence of adverse events.
The results
CBD-rich cannabis extract did not reduce disease severity, anxiety, or depression in participants with
Parkinson's disease, and functional performance was not improved.
However, the extract appeared to be safe and was associated with improvements in blood urea nitrogen
levels, serum albumin, serum globulin, and the albumin/globulin ratio. The study authors suggested that
these changes may reflect increased appetite and/or reduced inflammation in the CBD group.
Note
The authors of this study observed that quality of life was improved in the placebo group compared to the
CBD group. They suggested that confounders such as disease background or previous treatments may
have varied between groups or that the CBD group may have experienced an adverse effect that was not
adequately defined or recorded.
They advised that future studies should collect detailed data on adverse events and consider a higher
dosage of CBD to better determine the efficacy of this treatment.
Calorie restriction improves biological aging markers
In this randomized controlled trial, 2 years of calorie restriction slowed the pace of biological aging in
healthy adults.
Background
Calorie restriction (CR), defined as eating a diet that contains approximately 25% fewer calories than
normal, is one of the most reliable methods of extending lifespan and slowing aging in animals. Can CR also
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affect the rate of aging in humans?
The study
In this randomized controlled trial called the Comprehensive Assessment of Long-term Effects of Reducing
Intake of Energy (CALERIE), 220 men and women (average age of 38, normal weight or slightly overweight
BMI) were prescribed a 25% reduction in calorie intake or a nonrestricted diet for 2 years.
The 25% CR was based on each participant’s individual energy requirements, which were estimated at the
beginning of the study.
The primary study outcomes were biological age and the rate of biological aging, which were estimated
using three different biological aging clocks: PhenoAge, GrimAge, and DunedinPACE. Biological aging
measures were assessed at baseline, 12 months, and 24 months.
The results
CR reduced the pace of biological aging by 2%–3%, as measured using DunedinPACE. Biological age
measured using PhenoAge and GrimAge was not affected by CR.
The big picture
There have been multiple studies published from the CALERIE trial in which CR has been reported to reduce
cholesterol, systolic and diastolic blood pressure, inflammation, and metabolic syndrome score and
increase insulin sensitivity.[262] Furthermore, CR resulted in an average weight loss of 7.5 kg, reductions in
waist circumference, and a preferential loss of visceral adipose tissue.[263][264] Thus, CR can improve risk
factors for cardiometabolic disease, even in a cohort of normal weight to slightly overweight, yet otherwise
healthy, middle-aged adults. These measurable changes in health outcomes are important to complement
and validate the changes in measures of biological aging reported in the current study. It’s another question
entirely whether the health improvements actually translate to reduced morbidity and mortality —
outcomes that take much longer to assess and won’t be realized for decades.
The “geroscience hypothesis” is the idea that interventions that slow or reverse molecular changes (i.e.,
DNA methylation) can delay or prevent the incidence of disease of aging and extend healthspan and
lifespan. CR has been at the forefront of investigations into the geroscience hypothesis, yet unfortunately,
most studies to date have been conducted in animal models. This is why CALERIE is such an important step
for longevity research. It’s the first study to rigorously investigate long-term CR in humans.
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Digging Deeper: Biological aging clocks
DNA methylation (DNAm) is the process by which genes become methylated, an epigenetic
mechanism that alters DNA and gene transcription. Levels of DNAm increase with age. As such, the
accumulation of methylated DNA is proposed to be a biomarker of aging.
By measuring the amount of DNAm within certain sites in the genome, DNAm clocks, also known as
biological aging clocks, can be used to predict the age of an organism. Biological age is different
from chronological age — how old someone is in years — because it represents a person’s actual
age based on genomic factors. Biological age might be a better predictor of risk for death and
disease. For a quick example, consider someone who is 60 years old chronologically, but they eat
well, live an active lifestyle, and read Examine regularly. This person’s biological age might be 48 —
they are biologically younger than their chronological age.
Several DNAm clocks exist, but CALERIE used three specific clocks to measure the primary outcome
of biological aging:
PhenoAge and GrimAge: These clocks were developed to predict mortality risk based on biological
age. For example, if a 60-year-old person (chronologically) has a biological age of 48, then their
mortality risk is similar to that of a 48-year-old, not a 60-year-old, person.
DunedinPACE: This clock was developed to estimate the rate at which someone is aging. The
default rate of aging is 1 year per calendar year. A pace of aging less than 1 means someone is
biologically aging slower than this normal rate, and a pace of greater than 1 indicates accelerated
aging.
Based on the DunedinPACE clock, participants assigned to CR reduced their rate of biological aging at 12
months, a pattern that continued through 24 months. In other words, CR participants were aging slower
than their peers who were eating freely. The 2%–3% decline in the rate of aging is suggested by the authors
to correspond to as much as a 10%–15% reduction in mortality risk.
One of the main limitations of CALERIE was that participants assigned to CR didn’t achieve the prescribed
25% reduction in calories over the course of the 2-year intervention. The average reduction of
approximately 11.9% was less than half of the original goal and corresponds to about a 180 calorie per day
reduction, or about 2 tablespoons of peanut butter.
For this reason, the authors ran two additional analyses on the data. One of these involved separating
participants into those who achieved more than a 10% reduction in calories and those who achieved less
than a 10% reduction. This dose–response analysis revealed that the pace of biological aging
(DunedinPACE) slowed more in participants who achieved a greater level of CR, with no effect on the other
measures of biological age.
Effects of 2-year calorie restriction on biological age and the pace of aging
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The second analysis was called a effect of treatment-on-the-treated (TOT) analysis, in which the expected
effects of achieving a 20% reduction in calories was investigated. In other words, what might have
happened if participants had achieved 20% CR? The effect size for DunedinPACE in the TOT analysis was
0.4, higher than the 0.25 from the original analysis. The other two measures of biological age were not
affected by CR in this analysis either.
Despite not achieving 25% CR, participants still experienced several health-related improvements
(mentioned above) and a slowing of biological age. That’s promising and suggests that CR interventions
need not be so “extreme” to benefit health — even a modest reduction in calories will do. However, the
failure of many participants to meet the CR goal underscores one of the downfalls of CR as a potential
longevity intervention. Specifically, adherence and sustainability may be difficult. CALERIE was only a 2year study, and even then, the participants’ ability to restrict calories waned at 12 months and continued to
decline at 24 months. Had the study been extended, it’s not clear whether any level of CR would have been
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maintained. Longer-term studies, if possible, will be needed to determine the feasibility of sustaining CR
over years to decades.
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Joints & Bones
Are there additive effects of exercise and vitamin D for type 2
diabetes?
In this randomized controlled trial of adults with type 2 diabetes, supplementation with vitamin D
maintained bone health, while exercise decreased body fat, but combining the two had no additive
effects on these outcomes.
Background
People with type 2 diabetes are at high risk for low bone mineral density and reduced muscle mass and
strength, increasing their chances of physical disabilities and a lower quality of life.[2]
Exercise reliably improves health and physical function in individuals with diabetes. Vitamin D also plays an
important role in maintaining bone and musculoskeletal health. Could a combination of vitamin D and
exercise have additive effects for people with diabetes?
The study
In this 12-week randomized controlled trial, 61 adults with type 2 diabetes (average age of 50) were
assigned to one of the following groups:
Vitamin D supplementation (1,000 IU per day)
Exercise training (cycling 2×/week for 60 minutes at 60%–80% of maximum heart rate)
Vitamin D + exercise
Control
The primary study outcomes were body and trunk muscle mass, total and trunk body fat percentages, bone
mineral content and density, grip strength, reaction time, single-leg balance, vital capacity (the maximum
amount of air someone can exhale), and vitamin D (25-OH) levels.
The results
Vitamin D levels increased in the vitamin D (from 19.0 to 26.3 nanograms per milliliter; ng/mL) and Vitamin
D + exercise (from 17.7 to 27.5 ng/mL) groups. Furthermore, the rate of vitamin D deficiency decreased
(from 66.7% to 20%) in the vitamin D groups but increased (from 65.5% to 72.4%) in the groups without
supplemental vitamin D.
Supplementing with vitamin D maintained total and trunk bone mineral content and spine bone mineral
density, whereas these outcomes decreased in the groups without supplemental vitamin D. Exercise
decreased the total and trunk body fat percentages. Physical performance outcomes didn’t change in any
of the groups, and there were no additive effects of vitamin D + exercise for any of the outcomes.
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Green-lipped mussel extract for cartilage protection in
women with knee pain/discomfort
In this randomized controlled trial, supplementation with New Zealand green-lipped mussel extract
reduced knee pain in postmenopausal women with knee pain/discomfort.
Background
In research conducted in rodents with osteoarthritis, greenshell mussel™ (GSM) — an extract from the New
Zealand green-lipped mussels (Perna canaliculus) — has been found to protect against cartilage
degradation.[138] However, trials exploring the effect of GSM on markers of cartilage metabolism in humans
were lacking.
The study
In this 12-week randomized controlled trial, 49 postmenopausal women (ages 55–75) with
overweight/obesity and self-reported knee pain/discomfort (but without a diagnosis of arthritis) took
capsules containing 3 grams of either GSM powder (equivalent to 1–2 mussels) or sunflower seed protein
(placebo) daily. The daily 3-gram dose of GSM powder contained 1.2 grams of protein, 0.9 grams of
carbohydrate, 0.6 grams of eicosapentaenoic acid (EPA), and 0.2 grams of docosahexaenoic acid (DHA).
The primary outcomes were biomarkers of cartilage metabolism (urinary C-telopeptide of type II collagen
and serum cartilage oligomeric matrix protein). The secondary outcomes were knee pain measured with a
visual analogue scale, knee-related problems measured with the Knee Injury and Osteoarthritis Outcome
(KOOS) score, and levels of inflammatory cytokines. All outcomes were measured on weeks 6 and 12.
The results
Knee pain decreased more with GSM powder than with placebo. No other differences between groups were
observed in the main analyses.
Note
The researchers examined multiple outcomes at multiple time points without adjusting for multiple
comparisons, which increases the risk of false-positive results.
It’s also worth noting that the trial was partly funded by Sanford Ltd (the manufacturer of GSM) and that
one of the researchers was employed by Sanford Ltd at the time the trial was conducted.
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Is outdoor air pollution exposure linked to worse bone
health?
In this meta-analysis, exposure to certain air pollutants was associated with worse osteoporosisrelated outcomes. However, the certainty of the evidence was mostly low or very low.
Background
Observational studies examining the potential association between exposure to air pollutants (both gaseous
and particulate) and the risk of osteoporosis-related outcomes have reported mixed results. What does the
totality of the available observational evidence say?
The study
This meta-analysis of 19 observational studies (11 cross-sectional, 7 cohort, and 1 case-control) examined
the association between exposure to gaseous and particulate air pollutants and osteoporosis-related
outcomes in almost 10 million adults.
The outcomes were bone mineral density (BMD; 10 studies), osteoporotic fractures (7 studies), and
osteoporosis (6 studies). The air pollutants examined were particulate matter with an aerodynamic diameter
of less than 2.5 micrometers (PM2.5), PM10, PM1, coarse PM, nitrogen dioxide, ozone, sulfur dioxide,
carbon monoxide, black carbon, and nitrogen oxides. Most studies reported outcomes for the total
body/combined bone sites or for the hip.
The results
Exposure to nitrogen dioxide was associated with lower BMD, whereas exposure to ozone was associated
with higher BMD. Exposure to PM2.5 was associated with a higher risk of osteoporotic fractures. Exposure
to PM10 or PM2.5 was associated with a higher risk of osteoporosis.
The certainty of the evidence for most of the associations was low or very low.
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Does “extra” exercise improve bone health in children?
This meta-analysis found no evidence of beneficial effects from additional exercise interventions
(compared to standard exercise) on markers of bone health or the incidence of fractures in primary
school children.
Background
The effect of additional exercise — that is, beyond the exercise already provided to children — on markers
of bone health and the incidence of fractures was unclear and required investigation.
The study
This meta-analysis of 15 trials (14 randomized controlled trials and 1 nonrandomized controlled trial)
examined the effect of additional exercise interventions, compared to standard exercise, on markers of
bone health (primary outcomes) and the incidence of fractures (secondary outcome) in a total of 4,030
healthy primary school children (ages 6–12).
The trials were conducted in Europe (5 trials), the United States (4 trials), Canada (3 trials), Australia (2
trials), and South Africa (1 trial). In most trials, the additional exercise interventions involved exercises
specifically selected for stimulating bone adaptations, such as jumping exercises. The duration of additional
exercise interventions ranged from 20 weeks to 4 years.
The markers of bone health were the bone mineral content (BMC) of the whole body, BMC measured at the
femoral neck and at the lumbar spine, and the areal bone mineral density (aBMD) of the whole body, as well
as aBMD measured at the femoral neck and at the lumbar spine. These markers were measured at less than
15 months and at 24–48 months after the start of the exercise interventions. Other markers of bone health
included measurements of the cross-sectional area of the femoral neck and tibia and volume-related
measures of BMC and BMD in the tibia.
The results
Additional exercise interventions increased femoral neck BMC; however, this result became statistically
nonsignificant in the sensitivity analyses. No effects were observed on any of the other outcomes.
The certainty of evidence was very low for all outcomes.
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Continuous vs. traditional cryotherapy after knee
replacement surgery
In this meta-analysis of randomized controlled trials, there were no differences between continuous
and traditional cryotherapy after knee replacement surgery in terms of efficacy or safety.
Background
After total knee arthroplasty (commonly known as knee replacement surgery), local cryotherapy is often
used to reduce knee pain and swelling. Traditional cryotherapy involves the use of cold materials (such as
ice or gel packs) that deliver discontinuous and unregulated cold temperatures. In contrast, continuous
cryotherapy devices deliver a steady cooling temperature over a prolonged period of time. Is continuous
cryotherapy superior to traditional cryotherapy after knee replacement surgery?
The study
This meta-analysis of 7 randomized controlled trials compared the efficacy and safety of continuous
cryotherapy and traditional cryotherapy in a total of 519 participants who had undergone knee replacement
surgery.
The primary outcomes were pain intensity, consumption of analgesics (pain relievers), postoperative range
of motion, and swelling of the knee joint. The secondary outcomes were adverse events and the length of
hospital stay.
The trials were conducted in Europe (4 trials), the United States (1 trial), Canada (1 trial), and Turkey (1
trial). In all trials, traditional cryotherapy was applied via ice/gel packs. The application protocols differed
significantly with respect to the applied time and intervals both between treatments within the same trial
and within the same treatment between different trials.
The results
No differences were found between treatments for any of the primary or secondary outcomes.
The risk of bias was high in 3 trials and unclear in 4 trials.
Thunder god vine for the treatment of rheumatoid arthritis
In this meta-analysis of randomized controlled trials, treatment with Tripterygium wilfordii Hook F and
methotrexate was more effective than methotrexate alone for reducing the symptoms of rheumatoid
arthritis and the levels of inflammatory biomarkers.
Background
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Caution: This supplement has the potential to harm your health
Thunder god vine (Tripterygium wilfordii) is used in Traditional Chinese Medicine to treat a wide
range of conditions. By decreasing the number of white blood cells, it reduces inflammation (and
thus pain) around the joints, but it also makes the body more susceptible to infection, which can lead
to sickness and potentially death.
Although Tripterygium wilfordii appears to be effective in treating rheumatoid arthritis, the effective
dose of this supplement is close to a harmful dose. It is not safe and should not be supplemented.
Adverse effects of thunder god vine
Tripterygium wilfordii Hook F (TwHF; also known as Thunder god vine and léi gōng téng) is a herb with
anti-inflammatory properties that is traditionally used in China for the treatment of rheumatoid arthritis
(RA). What is the efficacy of TwHF when used alongside methotrexate (a drug commonly used in RA)?
The study
126
This meta-analysis of 14 randomized controlled trials examined the effect of supplementation with TwHF +
methotrexate, compared to methotrexate alone, for the treatment of RA in a total of 1,446 participants with
RA (average ages of 39–69).
TwHF was administered as Tripterygium glycoside tablets in 12 trials (at a daily dose of 10–60 mg) and as
Tripterygium wilfordii tablets in 2 trials (at a daily dose of 10–60 mg). The weekly dose of methotrexate
ranged from 7.5 to 15 mg. The intervention duration ranged from 12 to 24 weeks.
The primary outcomes were the effective rate (>20% improvement in RA symptoms), partial remission rate
(>50% improvement in RA symptoms), and remission rate (>75% improvement in RA symptoms). The
secondary outcomes were clinical outcomes (duration of morning stiffness, swollen joint count, and tender
joint count), the levels of biomarkers of RA severity (rheumatoid factors and anticyclic citrullinated
peptide), the levels of biomarkers of inflammation (C-reactive protein, erythrocyte sedimentation rate,
interleukin 1, interleukin 6, and tumor necrosis factor-alpha), and adverse effects.
The results
Compared to methotrexate, TwHF + methotrexate improved the treatment effective rate, partial remission
rate, and remission rate by 15%, 27%, and 31%, respectively.
In the secondary outcomes, TwHF + methotrexate was more effective than methotrexate for improving all
clinical outcomes, biomarkers of inflammation, and rheumatoid factors (but not anticyclic citrullinated
peptide).
In terms of adverse effects, TwHF + methotrexate was associated with a lower risk of total adverse effects,
infections, and liver adverse effects, but it was not associated with the risk of gastrointestinal adverse
effects, skin and mucous adverse effects, blood-related adverse effects, or menstrual-related adverse
effects.
127
Can omega-3s reduce quadriceps weakness after knee
replacement surgery?
In this randomized trial, supplementation with omega-3 fatty acids reduced weakness of the
quadriceps muscles after total knee arthroplasty for severe osteoarthritis.
Background
Total knee arthroplasty is a surgery performed to resurface the knee joint with metal and/or plastic for the
purpose of improving knee function. Postsurgery, weakness in a main muscle of the knee joint — the
quadriceps — can impair movement and recovery. Inflammation, swelling, and pain can affect quadriceps
strength. Because omega-3 fatty acids may reduce inflammation, can supplementing with omega-3 fatty
acids reduce quadriceps weakness after knee replacement surgery?
The study
This 34-day randomized trial examined 20 Japanese participants (ages 60–79) who were scheduled to
undergo replacement of one knee joint. The treatment group was given 645 mg of eicosapentaenoic acid
(EPA) and 215 mg of docosahexaenoic acid (DHA) daily for 30 days before the operation, and the control
group received no EPA/DHA.
The primary outcome was quadriceps weakness, as measured by a dynamometer during maximal
contractions of the quadriceps. The secondary outcomes were changes in oxidative stress (as measured by
derivatives of oxygen metabolites in blood samples), knee and thigh swelling, and knee pain (measured on
a numeric scale of 1–10). The outcomes were measured 30 days before surgery and 4 days after surgery.
The results
The treatment group had a lower increase in quadriceps weakness after surgery than the placebo group,
and the effect size was noted to be large.
Note
This study failed to recruit the required number of participants for statistical soundness; only 20
participants were recruited, and 23 were needed. Additionally, the participants, care providers, and
outcome assessors were not blinded to treatment versus control in this trial.
128
Women’s Health
Which lifestyle changes impact pregnancy outcomes in
women with overweight or obesity?
In this meta-analysis of randomized controlled trials conducted in pregnant women with
overweight/obesity, exercise reduced the risk of disorders related to hypertension by 48%.
Background
Maternal overweight and obesity raises the risk of short-term and long-term health consequences in both
the mother and the child. For example, maternal gestational diabetes raises the risk of high infant birth
weight and the maternal and infant long-term risks of type 2 diabetes.
What effect do lifestyle interventions, such as dietary and physical activity-based changes, have on the risk
of health outcomes in pregnant individuals with overweight or obesity?
The study
This systematic review and meta-analysis of 28 randomized trials included 11,416 pregnant participants
from high-income or middle-income countries. The interventions examined were dietary, exercise-based,
diet/exercise combined, and/or included behavioral therapy. Though it was not defined, it appears that the
“behavioral therapy” was not cognitive behavioral therapy, but was one-on-one sessions of some kind
delivered by either a clinician or a smartphone app.
The primary outcomes were hypertensive disorders in pregnancy, gestational diabetes, perinatal mortality,
and admission to the neonatal intensive care unit. The secondary outcomes were gestational weight gain
(GWG), excessive GWG (defined as exceeding the Institute of Medicine’s GWG recommendations), and
infant birth weight.
The results
Exercise reduced the risk of hypertensive disorders by 48%, and the related data had moderate to high
heterogeneity. Exercise and combined interventions reduced GWG and excessive GWG, with high data
heterogeneity. Behavioral therapy strengthened both GWG-related effects. When behavioral therapy
supported combined interventions, it reduced infant birth weight.
Note
Combined interventions plus behavioral therapy reduced infant birth weight, though it did not increase
weights that were small for gestational age or large for gestational age (defined as a birth weight ≤10th
percentile and ≥90th percentile of the referred population, respectively).
129
What level of alcohol consumption increases the risk of
endometriosis?
In this meta-analysis, moderate (but not other levels of) alcohol consumption was associated with
increased risk of endometriosis.
Background
Endometriosis is a common inflammatory, gynecologic condition that includes the growth of uterine tissue
outside of the uterus. It is associated with pelvic pain and subfertility and can severely compromise quality
of life.[57]
A previous meta-analysis from 2013, by the same group of authors as the summarized study, identified
alcohol intake as an important modifiable lifestyle factor that may increase endometriosis risk.[58] The
current study was conducted to update and solidify the relationship between alcohol and endometriosis.
The study
This systematic review and meta-analysis of 23 studies (cross-sectional, cohort, and case-control designs,
mostly conducted in North America and Europe) examined the association between alcohol intake and
endometriosis.
The presence of endometriosis was based on clinical or surgery-based diagnosis. Alcohol intake was
classified as infrequent, moderate, and heavy; the classification definitions varied, though some studies
defined them as <4 drinks per month, ≤7 drinks per week, and >7 drinks per week, respectively.
The results
Moderate alcohol intake was associated with a 22% increase in the risk of endometriosis.
Note
There was a borderline trend for any alcohol intake increasing the risk of endometriosis by 14%. This result
is in contrast to a nonborderline finding of 24% from the 2013 meta-analysis.[58]
The observational studies examined make it difficult to determine whether alcohol is a cause or result of
endometriosis; alcohol could cause endometriosis, or it is possible that the increased physical and
psychological pain that people with endometriosis tend to experience is a reason that some may start to
self-medicate after the condition has started and been diagnosed.
130
Can supplemental fiber improve gestational diabetes?
In this meta-analysis of randomized controlled trials, supplemental dietary fiber improved blood sugar
levels, blood lipids, and pregnancy outcomes in women with gestational diabetes.
Background
Gestational diabetes is characterized by the worsened tolerance of carbohydrates during pregnancy,
resulting in elevated levels of blood sugar. This condition increases the risk of short-term and long-term
health consequences for mother and child.
Dietary fiber can improve certain aspects of gestational diabetes. Does supplemental dietary fiber improve
outcomes of gestational diabetes?
The study
This systematic review and meta-analysis of 8 randomized controlled trials examined the effects of
supplemental dietary fiber on clinical outcomes in pregnant women with gestational diabetes. The trials
included 36 to 120 participants and were 2 to 12 weeks in duration.
The outcomes assessed were fasting glucose, 2-hour postprandial glucose (blood sugar at 2 hours after
drinking a standardized amount of sugar), HbA1c (a measure of average blood sugar control over the past
3 months), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol, low-density
lipoprotein cholesterol (LDL-C), and pregnancy outcomes (preterm delivery, cesarean delivery, fetal
distress, and neonatal weight).
Subgroup analyses were performed for the type of fiber (soluble, insoluble, or complex) and the amount of
fiber (<12 g/day or ≥12 g/day; 12 g/day is an average fiber dietary intake).
The results
Supplemental dietary fiber improved 2-hour postprandial glucose, with large effect sizes; improved
glycated hemoglobin, TC, LDL-C, preterm delivery, and cesarean delivery, with medium effect sizes; and
improved fasting glucose, TG, and neonatal weight, with small effect sizes.
In the subgroup analyses, soluble fiber and ≥12 g/day of fiber had a medium effect on improving fasting
glucose.
131
Garlic extract for weight loss in women with obesity
In this randomized controlled trial in women with obesity, supplementation with garlic extract had no
effect on anthropometric or biochemical parameters or on the composition of the gut microbiota.
Background
Garlic (Allium sativum) contains prebiotic components and antibacterial compounds (such as allicin) that
could affect the composition of the gut microbiota.[64] Moreover, supplementation with garlic may have
beneficial effects on anthropometric indices.[65] That said, more trials were needed to elucidate the potential
effects of garlic on gut microbiota composition and anthropometric indices in different populations.
The study
In this 2-month randomized controlled trial, 32 women with obesity (average age of 36) took capsules
containing either 800 mg of garlic extract (equivalent to 2.2 mg of allicin) or a placebo daily.
All participants were given dietary guidance for reducing their caloric intake to 500 kcal below their daily
energy requirements. Also, all participants were advised to be physically active for at least 30 minutes per
day.
The outcomes included anthropometric parameters (weight, BMI, waist circumference, hip circumference,
and waist-to-hip ratio), markers of glycemic control, blood lipids, liver enzymes, and gut microbiota
composition.
The results
All anthropometric parameters except waist-to-hip ratio improved in both groups. However, no differences
between groups were observed in any of the outcomes.
132
Are B vitamins linked to gestational diabetes risk?
This prospective cohort trial found that increased blood levels of vitamins B1 and B6 were associated
with an increased risk of gestational diabetes.
Background
Gestational diabetes involves the impaired metabolism of carbohydrates, which results in elevated levels of
blood sugar and increased risk of short-term and long-term effects on both the mother and child. Several
different B vitamins are involved in glucose metabolism and have links to lower risk of type 2 diabetes.
Does higher blood levels of various B vitamins reduce risk of gestational diabetes?
The study
This prospective cohort trial recruited 1,265 Chinese women who were pregnant. Vitamin B1, vitamin B2,
vitamin B6, folate, and vitamin B12 blood levels were measured between weeks 8 and 15, and an oral
glucose tolerance test (OGTT) was performed (to determine development of gestational diabetes) between
weeks 24 and 28.
The participants were categorized into four groups according to B-vitamin blood levels, from lowest to
highest. Blood glucose readings were collected during the fasting state and at 1 hour and 2 hours after
consumption of 75 grams of glucose in the OGTT.
The results
Surprisingly, the group with the highest vitamin B1 levels had a 128% increased risk of gestational diabetes
compared to the lowest group. In addition, compared to the lowest group, the highest and second highest
groups of vitamin B6 levels had a 84% and 93% increased risk of developing diabetes, respectively.
In addition, higher vitamin B1 levels were correlated with higher fasting, 1-hour, and 2-hour blood sugar
readings.
Note
There was an overall trend of decreasing gestational diabetes risk with increasing vitamin B12 levels, but it
was not significant.
133
Can black cumin and fennel improve polycystic ovary
syndrome?
In this randomized controlled trial, supplemental black cumin and fennel worsened one outcome of
polycystic ovary syndrome.
Background
Polycystic ovary syndrome (PCOS) is a health condition defined by at least two of three signs: irregular or
absent menstrual cycle, heightened levels of testosterones, and polycystic ovaries (too many follicles/cysts
in the ovary or an overly large ovary). PCOS can cause infertility and psychological distress.
Fennel (Foeniculum vulgare) is a herb that contains molecules similar to the estrogen molecule
(phytoestrogens) and has shown some promise for the treatment of dysregulated menstrual cycles. Black
cumin (Bunium persicum), and its active ingredient thymoquinone, has some evidence supporting its use in
improving reproductive disorders.[77] Can supplemental black cumin and fennel improve outcomes in PCOS?
The study
This 4-month randomized controlled trial recruited 70 Iranian women with PCOS who were referred to
infertility clinics. The participants took a capsule containing 60 mg of black cumin and 25 mg of fennel or a
placebo capsule containing starch twice daily.
Before and after the interventions, blood levels of luteinizing hormone, follicle-stimulating hormone,
progesterone, prolactin, testosterone, and DHEAS were measured. In addition, vaginal endometrial
thickness and follicle count were measured via ultrasound, and hirsutism (i.e., excessive hair growth) score
and menstrual pattern were recorded.
The results
The number of follicles in the ovaries worsened in the treatment group, compared to the placebo group.
There were no other significant effects in the other outcomes.
Note
Before the intervention, 5.7% of both groups had a menstrual pattern classified as normal. After the
intervention, this proportion increased to 31.4% and 25.7% in the treatment and placebo groups,
respectively. However, the study did not report whether the change in the intervention group was
significantly different from the change in the placebo group.
134
Can supplemental date palm pollen improve female sexual
function?
In this randomized controlled clinical trial, supplementing with date palm pollen improved desire,
lubrication, and overall sexual function score in nonmenopausal women.
Background
Female sexual dysfunction (FSD) is defined as a clinically significant disturbance in a person’s ability to
respond sexually or to experience sexual pleasure.
Studies in male rats have found that date palm pollen (DPP; pollen from Phoenix dactylifera L.) increases
follicle-stimulating hormone, luteinizing hormone, and sexual behavior. This study investigated whether DPP
can help to improve sexual function in women.
The study
This 35-day randomized controlled clinical trial recruited 68 Iranian women (ages 30–45) who took 300 mg
of DPP or a placebo daily.
The primary outcome was female sexual function, as measured by the Female Sexual Function Index (FSFI);
this questionnaire quantifies sexual function in the domains of desire, arousal, lubrication, orgasm,
satisfaction, and pain. The secondary outcome was the association between frequency of sexual
intercourse and preintervention FSFI scores in each domain and overall score. The FSFI scores were
assessed at the beginning and end of the trial.
The results
Compared to the placebo group, the DPP group experienced increases in the FSFI desire and lubrication
domains and in overall score.
For the secondary outcome, the baseline frequency of sexual intercourse was correlated with all FSFI
domains except pain and with the overall score.
Note
The exact definition of the secondary outcome is somewhat unclear. According to the researchers, “The
secondary outcome is the association between the coitus and preintervention FSFI domains scores and
overall score”. We assumed that they meant the baseline frequency of sexual intercourse and its relation to
FSFI domains and overall score before the intervention.
135
Which herbs may help with cyclic breast pain?
In this meta-analysis, several herbs reduced cyclic breast pain, though many of the included studies
were of poor quality.
Background
Breast pain that varies with the menstrual cycle is known as cyclic mastalgia. This condition can cause
anxiety, interfere with daily activities, and result in various diagnostic procedures.
Although it remains unknown, the cause of cyclic breast pain may be associated with a disturbance in
estrogen, progesterone, and/or prolactin. Certain herbs contain compounds known as phytoestrogens,
which can mimic the effects of estrogen in the body. Other herbs have also been shown to improve cyclic
mastalgia, but studies report conflicting results.
The study
This systematic review and meta-analysis examined 20 randomized trials in which the participants reported
cyclic mastalgia. The intervention categories were defined as (i) herbal medicine overall (16 studies), (ii)
phytoestrogens overall (13 studies), and (iii) each individual herb (chaste tree, 5 studies; flaxseed, 2 studies;
St. John’s Wort, 2 studies; evening primrose, 5 studies; chamomile, 1 study; red clover extract, 1 study;
cinnamon, 1 study; black cumin, 1 study).
The trials were 1–6 months in length, and each recruited 12–478 participants. Pain intensity was most often
evaluated with a visual analogue scale.
The results
Overall, herbal medicine was found to moderately reduce breast pain, compared to a control (e.g., omega-3
fatty acids, or vitamin E) or placebo.
Compared to a control, phytoestrogens had a large effect on reducing breast pain. Individually, chaste tree,
flaxseed, and evening primrose had moderate effects on reducing breast pain. Although this analysis was
based on a smaller body of evidence, the herbs chamomile, red clover, cinnamon, and black cumin were
also found to reduce breast pain scores (by 31%, 54%, and 50%, respectively). Compared to medication,
evening primrose and chaste tree had similar effects. No effect was seen with St. John’s Wort. Overall,
study heterogeneity was noted to be high.
Note
Due to the high amount of heterogeneity between studies, caution should be taken in interpreting these
results, and further studies with better methodological quality should be conducted to confirm these
findings before they are used to guide clinical decision-making.
136
Psychological interventions for reducing anxiety in the
perinatal period
In this meta-analysis, psychological interventions reduced anxiety and symptoms of depression in
women during the perinatal period.
Background
Trials that investigated the effect of psychological interventions — such as mindfulness-based interventions
(MBIs) and cognitive behavioral therapy (CBT) — on anxiety in women during the perinatal period (during
pregnancy and up to 1 year after giving birth) have produced mixed results. What does the totality of the
available evidence say?
The study
This meta-analysis of 22 trials (17 randomized controlled trials and 5 quasi-randomized/nonrandomized
controlled trials) examined the effect of psychological interventions on anxiety in women with anxiety
during the perinatal period. The secondary outcome was symptoms of depression.
The vast majority of trials were conducted during pregnancy. The most commonly used psychological
interventions were MBIs or CBT. The number of therapeutic sessions ranged from 2 to 14.
The results
Psychological interventions reduced anxiety (large effect size) and symptoms of depression (large effect
size).
In influence analyses in which the researchers excluded outlier trials, the beneficial effects of psychological
interventions on anxiety and symptoms of depression remained statistically significant but were reduced to
moderate and small effect sizes, respectively.
137
Cranberry, D-mannose, and NSAIDs, oh my! Are any useful
for UTI?
This meta-analysis reported that supplementing with D-mannose might help prevent recurrent urinary
tract infections, while the evidence was mixed for cranberry. One NSAID (aceclofenac) resolved
symptoms faster than an antibiotic alone.
Background
The most common cause of an uncomplicated urinary tract infection or cystitis (i.e., inflammation localized
to the bladder) is Escherichia coli bacteria. Antibiotics are the primary treatment, but due to rising rates of
antibiotic resistance, it’s worth investigating whether nonantibiotic treatments are similarly effective.
The study
This systematic review of 21 clinical trials investigated the effects of cranberry (12 studies), D-mannose (2
studies), cranberry + D-mannose (2 studies), and nonsteroidal anti-inflammatory drugs (NSAIDs; 5 studies)
in women (average age of 21–53) with uncomplicated UTIs.
Most of the trials (16) focused on the prevention of recurrent UTIs, while the rest focused on treatment.
Cranberry and/or D-mannose were used for prevention, while NSAIDs were used for treatment.
The participants in the cranberry trials supplemented with a capsule or juice, with a proanthocyanidin (the
primary active ingredient in cranberries) content that ranged from 2 to 112 mg. In 3 of the cranberry trials, it
was combined with other substances, such as propolis and zinc, lingonberry juice, or lactobacilli. The
comparator was a placebo, with the exception of 4 studies, which used antibiotics (2 studies), a
lactobacillus drink (1 study), or a lower dose of cranberry (1 study).
In the D-mannose trials, the participants supplemented with 2–3 grams of D-mannose. Both of the Dmannose trials used antibiotics as the comparator.
In the cranberry + D-mannose trials, other substances were added to the supplements, which may have
influenced the results.
In the NSAID trials, 4 used ibuprofen (3 used a dose of 1.2 grams, and 1 used 1.8 grams). The comparator
was antibiotics in 3 of the studies; the fourth used uva ursi, which is used to treat UTIs. One study tested
the effect of an antibiotic combined with aceclofenac (an NSAID) versus the same antibiotic alone.
The results
Half of the cranberry trials reported a statistically significant reduction in the number of UTIs during the
study period. Of the 5 trials that assessed time to first UTI, 3 reported a significant difference between the
groups, in favor of the cranberry group.
Both of the D-mannose trials found that D-mannose reduced the number of UTIs during the study period
and reduced the time to first UTI.
Both of the cranberry + D-mannose trials found that the supplements reduced the number of UTIs during
the study period.
Ibuprofen was not superior to the comparator in any of the trials. Combining an antibiotic with aceclofenac
resulted in faster UTI symptom resolution.
Note
The diagnostic criteria for UTI differed between the studies, and the trials did not report the participants’
fluid intake, which can influence the risk of recurrent UTIs.[133] These issues reduce our confidence in the
results.
138
Supplemental magnesium for polycystic ovary syndrome
In this randomized controlled trial, supplementation with magnesium did not benefit women with
polycystic ovary syndrome.
Background
Research has suggested that people with polycystic ovary syndrome (PCOS) tend to have lower
magnesium levels than those without PCOS.[165]
In addition, researchers have found an inverse association between serum magnesium and testosterone
concentrations among people with PCOS, which suggests that supplementation with magnesium might
reduce the hyperandrogenism (higher-than-normal levels of so-called “male hormones”) associated with
PCOS.
Additionally, a 2019 trial found that supplementation with magnesium and vitamin E reduced hirsutism
(abnormal hair growth) among women with PCOS.[166] Magnesium has also been studied for its effect on
sleep disorders, which are a common symptom of PCOS.
Can supplemental magnesium help treat PCOS symptoms?
The study
This 10-week randomized controlled trial recruited 64 women with PCOS. The participants took tablets
containing 250 mg of magnesium oxide or a placebo daily. Hyperandrogenism was assessed with a blood
test, and hirsutism and sleep quality were measured with validated questionnaires at baseline and after 10
weeks.
The results
Supplemental magnesium had no effect on hyperandrogenism, hirsutism, or sleep quality.
Note
The authors of this study noted that more research is needed and suggested that previous studies that
used combined supplements may have observed synergistic effects that are not present when only
magnesium is taken.
139
Can Pycnogenol prevent hair loss in postmenopausal
women?
In this randomized controlled trial, supplementation with Pycnogenol increased hair density in
postmenopausal Chinese women.
Background
Reduced subcutaneous blood flow and decreased angiogenesis (the formation of new blood vessels) may
be implicated in the development of female pattern hair loss (FPHL) — the progressive diffuse thinning and
loss of hair, especially in the central areas of the scalp. Because Pycnogenol (a patented blend of
procyanidins extracted from pine bark) may improve microcirculation (the circulation of blood in the
smallest blood vessels), supplementation with Pycnogenol may be useful in the treatment of FPHL.
The study
In this 6-month randomized controlled trial, 63 postmenopausal women (ages 45–60) in China took
capsules containing either 150 mg of Pycnogenol or a placebo daily.
The outcomes were hair density (assessed using digital photography), resting flux of the scalp skin (a
marker of changes in microcirculation), skin hydration levels, and the degree of transepidermal water loss
(TEWL).
The results
After 6 months, hair density increased more in the Pycnogenol group (+23%) than in the placebo group
(+9%). The resting flux of the scalp skin decreased more in the Pycnogenol group (−44%) than in the
placebo group (−20%), which may indicate a greater improvement in microcirculation in the Pycnogenol
group.
Note
The study was funded by Horphag Research (Europe) Ltd, which is the exclusive worldwide supplier of
Pycnogenol. Also, one of the researchers was the director of product development at Horphag Research
during the time that the study was conducted.
140
Brain Health
Eating fish is associated with a lower risk of dementia
In this meta-analysis of prospective cohort studies, eating more fish was associated with a lower risk
of dementia.
Background
Fish tends to be a good source of docosahexaenoic acid (DHA) and vitamin B12 — nutrients necessary for
proper brain health — but is also a major source of mercury, which can have adverse effects on the brain.
This study analyzed high-quality observational studies to see if people who eat more fish are at lower risk
of dementia.
The study
In this meta-analysis of 7 prospective cohort studies, the investigators examined the association between
fish intake and risk of dementia. The studies included a total of 30,638 participants. Three studies were
conducted in Asia, 3 in Europe, and 1 in the United States. The follow-up times ranged from 5.4 to 11 years.
In all of the studies, fish intake was determined using a food frequency questionnaire.
The included studies adjusted for potential confounding factors, most often age and education (7 studies),
gender (6 studies), and BMI (5 studies); a few studies adjusted for specific lifestyle and health status
factors.
Investigators assessed the quality of each study using the Newcastle-Ottawa Scale. Based on this scale, all
of the studies were rated high quality.
The results
In the main analysis, a higher intake of fish was associated with a 17% lower risk of dementia.
In a subgroup analysis, eating an additional 67.5 grams of fish or more per day (roughly equal to at least 1
extra pound of fish per week) was associated with a 24% lower risk of dementia.
141
Supplementing with anthocyanins to improve cognitive
function
In this randomized controlled study in adults at risk for dementia, supplementing with anthocyanins for
24 weeks did not improve attention, memory, or cognitive speed compared to placebo.
Background
Dementia is a highly prevalent condition worldwide, and the risk of dementia increases in the presence of
cardiometabolic risk factors such as hypertension, hypercholesterolemia, inflammation, and oxidative
stress.
Dietary factors are important for dementia risk prevention. Anthocyanins — plant polyphenols found in dark
berries and other fruits — have antioxidant properties and are associated with improved cognition.[59] Could
supplementing with anthocyanins boost memory and cognitive function in adults at risk for dementia?
The study
In this 24-week randomized controlled study, 206 adults (median age of 69; 103 men, 103 women) with
mild cognitive impairment or cardiometabolic disease (i.e., cerebrovascular disease, cardiovascular disease,
diabetes, hypercholesterolemia, or overweight) took 320 mg of purified anthocyanins (from bilberry and
black currant) or a placebo daily.
The study outcomes included attention, memory, and cognitive speed, which were measured at baseline
and monthly thereafter using an online digital cognitive test battery.
The results
There were no differences in attention, memory, or cognitive speed between the anthocyanin and placebo
groups at 24 weeks.
Note
The results were similar when the participants were separated into those with and without mild cognitive
impairment, with and without cardiometabolic disease, with or without the APOE e4 genotype (a genetic
risk factor for Alzheimer’s disease), with low or normal levels of amyloid beta protein (a marker of
Alzheimer’s disease risk), and those who were younger or older than the median age of 69 years.
142
Reducing dementia risk with “Life’s Simple 7”
In this meta-analysis, maintaining an ideal cardiovascular health score on seven modifiable risk factors
of cardiovascular health known as Life’s Simple 7 was associated with a decreased risk of dementia.
Background
In 2010, the American Heart Association (AHA) defined ideal levels of seven modifiable risk factors of
cardiovascular health (CVH), known as Life’s Simple 7, consisting of diet, smoking, physical activity, body
mass index, fasting blood glucose, total cholesterol, and blood pressure factors.[61]
Maintaining ideal levels of the seven CVH metrics is recommended to prevent cardiovascular disease and
neurodegenerative disorders such as cognitive decline and dementia.
Although growing evidence has confirmed the preventative effects of these metrics on cardiovascular
disease, research exploring the impact on cognitive outcomes has been inconsistent.
The study
This meta-analysis of 14 longitudinal studies examined the association between CVH score and cognitive
outcomes in 311,654 middle-aged and older adults (average ages of 50–75). The follow-up periods ranged
from 7 to 30 years.
The researchers assessed the correlation between CVH score and the risk of incident dementia and
analyzed which of the seven modifiable risk factors contributed most to increased dementia risk.
The researchers also assessed the dose-response relationship between CVH score and dementia risk and
examined whether this relationship differed between middle-aged and older adults.
The results
An ideal CVH score was linked to a 6% decreased risk of incident dementia. Physical activity, total
cholesterol, and fasting plasma glucose contributed the most to this association.
The relationship between CVH score and dementia risk was linear in middle-aged adults and J-shaped in
older adults, indicating that middle-aged adults benefit more from an ideal CVH score than older adults.
Note
This study’s results suggest that following the AHA recommendations may not only protect against
cardiovascular disease but also may slow cognitive aging.
143
Eating whole grains is associated with a lower risk of
dementia
In this prospective cohort study, eating more whole grains was associated with a lower risk of
developing dementia, including Alzheimer’s disease.
Background
Certain healthful dietary patterns are associated with a lower risk of dementia.[81] However, more research is
needed to determine which specific foods help explain that link. This study examined whether eating whole
grains is associated with a lower risk of dementia.
The study
This prospective cohort study examined the association between whole-grain intake and dementia risk. The
study included a total of 2,958 participants (average age of 61). The participants’ whole-grain intakes were
determined via a food frequency questionnaire.
The investigators examined the participants’ risk of dementia (including Alzheimer’s disease, which is the
most common type of dementia) according to their level of whole-grain intake over an average follow-up
period of 12.6 years.
The analyses were adjusted for potential confounders, including age, education, cognitive function at
baseline, calorie intake, depression, and a number of cardiovascular disease risk factors.
The results
Compared with the participants who ate the least amount of whole grains (<0.48 servings per day), the
participants who ate the most whole grains (≥1.35 servings per day) had a 34% lower risk of dementia and
a 40% lower risk of Alzheimer’s disease specifically.
Each of the following whole-grain foods was associated with a lower risk of dementia: whole-grain
breakfast cereal, cooked oatmeal, brown rice, and dark bread, as well as bran and germ added to foods.
Popcorn was not associated with a lower risk of dementia.
144
Can a multicomponent supplement benefit cognitive
function?
In this randomized controlled trial in middle-aged participants, a supplement containing B vitamins,
Bacopa monnieri, and Ginkgo biloba did not clearly improve cognitive function. However, the
supplement improved attention among participants who followed a healthier diet.
Background
Some evidence suggests that various nutrients (e.g., B vitamins) and herbs (e.g., Ginkgo biloba) can help
improve cognitive function, although the effect tends to be small and/or inconsistent. It’s possible that
these nutrients and herbs have only a small effect on their own but when combined could produce a larger,
additive effect on cognitive function. This study explored that possibility.
The study
In this randomized controlled trial, 141 participants (ages 40–65; average age of 53) were assigned to take
a multicomponent supplement or a placebo for 12 weeks. The supplement contained vitamin B1 (50 mg),
vitamin B2 (70 mg), vitamin B3 (nicotinamide; 40 mg), vitamin B5 (128 mg), vitamin B6 (41 mg), vitamin B12
(50 µg), Bacopa monnieri (extract of 7.5 grams of whole plant), and Ginkgo biloba (extract from 6 grams of
leaf).
The investigators examined the effect of the supplement on various aspects of cognitive function, with
memory and attention as the primary outcomes. Other outcomes included stress, mood disturbances,
depression, and anxiety.
Additionally, the investigators assessed the effect of the supplement based on whether the participants had
higher or lower adherence to a healthy diet (defined as a higher intake of fruits, vegetables, legumes, olive
oil, and nuts and a lower intake of processed foods).
The results
Overall, the supplement did not clearly impact any outcome compared to placebo.
Among the participants with higher adherence to a healthy diet, the supplement improved attention.
145
Can lemon balm help with cognitive decline?
In this randomized controlled trial, lemon balm did not clearly improve cognitive function in
participants with subjective cognitive decline or mild cognitive impairment.
Background
Melissa officinalis, commonly known as lemon balm, is a plant in the mint family with leaves that have a
long history of use as an herbal medicine. Lemon balm contains a variety of potentially bioactive
compounds, including rosmarinic acid. Drawing from research suggesting that rosmarinic acid might inhibit
Alzheimer’s disease pathology, this study tested whether taking lemon balm might be helpful for people
showing signs of cognitive decline.
The study
This 96-week randomized controlled trial examined whether lemon balm is helpful for cognitive decline. The
trial included a total of 323 participants (ages 35–73) with mild cognitive impairment or subjective
cognitive decline. The participants were assigned to take either lemon balm extract (supplying 500 mg of
rosmarinic acid) or a placebo daily.
The primary outcome was cognitive function, assessed using the Alzheimer’s Disease Assessment Scale–
Cognitive Subscale (ADAS-Cog). The other outcomes were three measures of cognitive function:
hippocampal volume and two secondary measures, namely, the Mini–Mental State Examination and the
Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB).
The results
Overall, lemon balm extract did not clearly improve any outcome when compared with placebo.
In subgroup analysis, lemon balm resulted in better cognitive function scores on the CDR-SOB.
Note
It seems highly likely that the improved cognitive function on the CDR-SOB test was a chance finding, given
that it was the only outcome out of 18 total subgroup analyses that was statistically significant.
146
The role of calcium and magnesium in dementia prevention
In this prospective cohort study, Chinese older adults with higher magnesium intakes (>267 mg/day)
had an increased risk of incident dementia. Moreover, the ratio of calcium intake to magnesium intake
played a key role in this association.
Background
Cross-sectional evidence suggests that dietary intakes of calcium and magnesium may affect the risk of
developing dementia at an older age.[93] However, long-term observational studies were needed to further
explore this relationship.
The study
This 5-year prospective cohort study in 1,565 Chinese older adults (average age of 71) examined the
association between calcium and magnesium intakes and the risk of incident dementia. Moreover, the
researchers analyzed whether the ratio of calcium intake to magnesium intake influenced this relationship.
The results were adjusted for potential confounders, including basic characteristics (sex, age, years of
education), lifestyle factors (smoking and obesity), disease status (stroke, diabetes, and hypertension), and
supplementation with calcium and magnesium.
The results
Although calcium intake showed no association, a higher magnesium intake (>267 mg/day) was linked to a
126% increased risk of dementia.
Similarly, in participants with a low calcium-to-magnesium ratio (≤1.7), a higher intake of magnesium (>267
mg/day) was linked to a 297% increased risk for dementia.
Note
The results of this observational study suggest that the total intake of magnesium and the proper balance
between calcium and magnesium may be critical in preventing dementia. However, more research is needed
to confirm these findings in other populations.
147
Drinking tea is associated with a reduced risk of cognitive
impairment
In this meta-analysis of observational studies, a higher intake of tea was associated with a lower risk of
cognitive impairment.
Background
Tea made from the Camellia sinensis plant, which includes green tea and black tea, may help fend off the
cognitive impairment that often accompanies older age. Various mechanisms have been proposed as
explanations of how tea might provide this benefit, including reducing oxidative stress in the brain,[155]
inhibiting microglia activity (which can slow neuron activity),[156] and impeding amyloid aggregation (which
contributes to the development of Alzheimer’s and other diseases).[157]
Still, ideas about why drinking tea can support brain health during aging are not very meaningful unless
there is evidence that tea actually does provide this benefit.
The study
This meta-analysis examined the association between tea consumption and the risk of cognitive
impairment. A total of 23 prospective cohort studies and 12 cross-sectional studies were included. The
cohort studies ranged in duration from 1 to 21 years.
Depending on the study, different outcomes were included under the umbrella of overall cognitive
impairment, i.e., cognitive decline, mild cognitive impairment (MCI), dementia, or Alzheimer’s disease.
The results
A higher intake of tea was associated with a lower risk of cognitive impairment in both the cross-sectional
studies and the prospective cohort studies. This finding was also seen with green tea or black only and
when the analyses were restricted to higher-quality studies.
In the prospective cohort studies specifically, a higher intake of tea was associated with a lower risk of
overall cognitive impairment (19%), cognitive decline (23%), MCI (34%), and Alzheimer’s disease (11%).
Note
In addition to the meta-analyses of observational studies discussed above, the investigators performed a
meta-analysis of randomized controlled trials (RCT) that looked at the effect of tea on cognitive function.
We chose not to cover this analysis due to the following issues with its source data:
One study did not have a control group, making it an uncontrolled trial, not an RCT.
One study was a subgroup analysis derived from the uncontrolled study.
One RCT included placebo data from the wrong time point (i.e., at baseline, rather than at the end
of the study).
One RCT’s data were reported incorrectly.
We could not locate the source data from two of the studies, raising doubts about their validity,
especially in light of the previous errors.
The extent of these issues seems concerning enough to question the validity of the paper as a whole. That
said, during a nonsystematic check, we did not identify any errors in the other meta-analyses.
Investigating the relationship between animal foods and
neurocognitive disorders
This meta-analysis of prospective cohort studies looked at the association between different animal
foods and the risk of several neurocognitive disorders. Dairy intake was associated with a higher risk
148
of Parkinson’s disease and a lower risk of dementia, and fish intake was associated with a lower risk of
dementia.
Background
A number of neurodegenerative disorders can occur during aging, including the following:
Cognitive impairment: a worsening of cognitive function beyond what is expected based on age,
though not to the point of interfering with daily functioning.
Dementia: an impairment in cognitive functioning that interferes with a person’s ability to function in
daily life. A large number of diseases and health conditions can result in dementia.
Alzheimer’s disease: a specific type of dementia, representing about 60% of all cases.
Parkinson’s disease: a disease resulting from a specific type of neuronal damage. It can cause
motor disturbances (tremors) as well as cognitive issues like dementia.
Thankfully, there’s evidence to suggest that a healthy dietary pattern can reduce the risk of developing all
of these disorders.[81][187][188] Still, the effects of animal foods on the risk of these neurocognitive disorders is
complex and controversial. On one hand, animal foods tend to be a good source of various nutrients
important for brain health, like iron, vitamin B12, zinc, and in the case of fish, omega-3 fatty acids. On the
other hand, animal foods can also contain compounds suspected of adversely affecting brain health, like
saturated fat, iron (in excess), and in the case of fish, mercury.
What does the existing body of literature say about the relationship between animal foods and
neurocognitive disorders?
The study
This meta-analysis of prospective cohort studies examined the association between different animal foods
and the risk of several neurodegenerative disorders. A total of 33 studies with 1,199,730 participants were
included. Study follow-up times ranged from 3 to 30 years.
The animal foods investigated in the studies were total dairy product intake, milk, yogurt, cheese, total
meat intake, red meat, processed meat, poultry, fish, and eggs. The neurodegenerative diseases
investigated in the studies were Parkinson’s disease (8 studies), Alzheimer’s disease (9 studies), dementia
(12 studies), and cognitive impairment (11 studies).
The overall certainty of evidence for each outcome was rated using the GRADE (Grading of
Recommendations Assessment, Development and Evaluation) guidelines.
The results
The researchers determined the following associations through their main analysis:
Dairy: A higher intake of total dairy was associated with a 49% higher risk of Parkinson’s disease, a
65% lower risk of dementia, a 37% lower risk of Alzheimer’s disease, and an 11% lower risk of
cognitive impairment. A higher intake of milk was associated with a 40% higher risk of Parkinson’s
disease and a 65% lower risk of Alzheimer’s disease.
Total meat: A higher intake of meat was associated with a 28% lower risk of cognitive impairment.
Red meat: Although no outcomes were statistically significant in the main analysis, in doseresponse analyses, every 100-gram increase in red meat intake was associated with a 60% increase
in the risk of cognitive impairment and every 30-gram increase in red meat intake was associated
with a 5% higher risk of dementia and a 40% lower risk of Alzheimer’s disease.
Processed meat: A higher intake of processed meat was associated with a 49% lower risk of
Parkinson’s disease, a 13% higher risk of dementia, and a 30% higher risk of Alzheimer’s disease.
Poultry: A higher intake of poultry was associated with a 43% higher risk of dementia and an 18%
lower risk of cognitive impairment.
149
Fish: A higher intake of fish was associated with a 16% lower risk of dementia, a 25% lower risk of
Alzheimer’s disease, and a 15% lower risk of cognitive impairment.
Notable findings from the study
Note
There was no association between egg intake and any of the outcomes. One reason for this could be that
most people don’t eat many eggs, meaning that participants typically only needed to consume a few eggs
per week (a fraction of an egg per day, on average) to be categorized as a high egg eater. Whether eating
multiple eggs per day is positively or negatively associated with any of the examined disorders therefore
remains uncertain.
The big picture
The current study had a number of findings worth digging into. Of note, a higher intake of fish was
associated with a lower risk of cognitive decline, dementia, and Alzheimer’s disease. The lower risk of
dementia associated with fish consumption was considered “high quality” evidence and was the only finding
from the study to receive this rating.
Fish tends to be a good source of omega-3 fatty acids, which may help explain why eating fish is
associated with a lower risk of dementia and cognitive decline. However, omega-3 fatty acids may not
reduce the risk of Alzheimer’s disease specifically, which is the most common type of dementia. In several
cohort studies, supplementing with fish oil was associated with a lower risk of dementia, but not
Alzheimer’s disease.[189][190][191] This suggests that other factors could be responsible for the lower risk of
150
Alzheimer’s disease with greater fish consumption.
One such factor could be vitamin D, which is found in oily fish, including salmon, sardines, trout, pike, and
mackerel. Having low vitamin D levels (e.g., less than 20 ng/mL) is associated with a higher risk of
Alzheimer’s disease,[192] and while it’s possible this is the result of confounding, people with genetically
higher vitamin D levels are also less likely to develop Alzheimer’s disease, suggesting that the effect is
indeed causal.[193][194] Still, more research is needed to determine what factors might mediate the relationship
between fish intake and cognitive outcomes.
Another intriguing finding from this study was that a higher intake of total dairy was associated with an
increased risk of Parkinson’s disease. This is also supported by genetic evidence, in which people with
lactose tolerance, who therefore consume more dairy, have been found to be at a high risk of Parkinson’s
disease.[195] Various mediators of the link between dairy and Parkinson’s have been proposed, including
galactose (formed from the metabolism of lactose), dairy-derived microRNAs,[196], pesticide contaminants in
dairy products, and a uric acid-lowering effect of dairy (higher uric acid is associated with a lower risk of
Parkinson’s disease).[197] However, none of these theories are currently well supported by evidence.
Interestingly, available research tentatively suggests that only lower-fat dairy foods are associated with
Parkinson’s disease.[198] The reason for this is also unclear, but it could be attributable to yet unidentified
protective compounds in dairy fat (e.g., odd chain-fatty acids). Alternatively, other diet and/or lifestyle
factors may simply differ between lower-fat and higher-fat dairy consumers. These consumers may have
differences in smoking habits, alcohol intake, physical activity, and more, which would explain this
discrepancy.
In contrast to the increased risk of Parkinson’s disease, a higher intake of dairy was associated with a lower
risk of dementia. Although it’s not clear what explains this finding and, given the observational nature of the
evidence, whether it is indeed causal, various possible mediators have been suggested, including bioactive
peptides, fatty acids, and phospholipids found in dairy products. More broadly, the link could be explained
by the fact that consuming more dairy has been linked to a lower risk of type 2 diabetes,[199] a disease that
seems to increase the risk of dementia.[200][201]
Ultimately, some of these results seem consistent with existing dietary patterns (e.g., a Mediterranean-style
diet) that have been linked to a lower risk of neurocognitive disorders. These dietary patterns tend to
involve eating some fish and limiting red meat intake. Still, more research is needed to understand how
certain animal foods, like eggs, affect the risk of neurocognitive disorders. In addition, the role of dairy
could be described as complicated, as it offers both potential risks (e.g., a higher risk of Parkinson’s
disease) and benefits (e.g., a lower risk of dementia).
151
A cannabidiol-rich cannabis extract for Parkinson’s disease?
In this randomized controlled trial, cannabis extract did not reduce Parkinson’s disease severity, but it
was associated with positive changes in metabolic markers related to kidney and liver health.
Background
Research suggests that cannabidiol (CBD; a component of cannabis) can reduce neurological excitotoxicity
and may have applications in the management of Parkinson’s disease. Placebo-controlled trials were
needed to determine whether CBD improves outcomes for individuals with Parkinson’s disease.
The study
This 8-week randomized controlled trial initially enrolled 40 participants with Parkinson’s disease, with 36
included in the final analysis. In addition to standard care, the participants received either a placebo or
CBD-rich cannabis extract, to be administered sublingually.
Cannabinoids were extracted from the Charlotte’s Angel strain of cannabis using ethanol and were then
dissolved in olive oil. The final cannabis extract contained 100 mg of CBD per mL and 3.9 mg of
tetrahydrocannabinol (THC) per mL. The placebo contained olive oil with a small amount of green
vegetable matter to mimic the appearance of the cannabis extraction.
All participants were prescribed a low initial dose, with gradual titration over 2 weeks based on individual
response and tolerance. Dosing was then maintained for 6 weeks. The mean cannabidiol dosage in the
treatment group was 15.6 mg per day.
The primary outcome of interest was changes in the Unified Parkinson’s Disease Rating Scale (UPDRS). The
secondary outcomes included changes in quality of life, functional performance, anxiety, and depression.
Markers of kidney and liver function were also tracked, along with the occurrence of adverse events.
The results
CBD-rich cannabis extract did not reduce disease severity, anxiety, or depression in participants with
Parkinson's disease, and functional performance was not improved.
However, the extract appeared to be safe and was associated with improvements in blood urea nitrogen
levels, serum albumin, serum globulin, and the albumin/globulin ratio. The study authors suggested that
these changes may reflect increased appetite and/or reduced inflammation in the CBD group.
Note
The authors of this study observed that quality of life was improved in the placebo group compared to the
CBD group. They suggested that confounders such as disease background or previous treatments may
have varied between groups or that the CBD group may have experienced an adverse effect that was not
adequately defined or recorded.
They advised that future studies should collect detailed data on adverse events and consider a higher
dosage of CBD to better determine the efficacy of this treatment.
152
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