Cell Metabolism
Perspective
Diet and Aging
Matthew D.W. Piper1,* and Andrzej Bartke2
1UCL
Institute of Healthy Ageing, University College London, London, WC1E 6BT, UK
Illinois University School of Medicine, Springfield, IL 62794, USA
*Correspondence: m.piper@ucl.ac.uk
DOI 10.1016/j.cmet.2008.06.012
2Southern
Interventions that extend life span by moderately reduced nutrient intake are often referred to as dietary or
calorie restriction. Its efficacy in many species has led to the conclusion that a single, evolutionarily conserved, molecular mechanism operates in all cases to extend life. Here we discuss examples of diet/genotype
interactions that show a more complex mechanistic view is required and that mild dietary modifications can
dramatically change the interpretation of model organism aging studies.
Introduction
During the last 20 years, gerontological
research has produced impressive advances in the understanding of the genetic control of aging. This progress and
simultaneous demographic changes in
the industrialized countries stimulated
public interest in the study of aging and
in the real or imagined possibilities that
the symptoms and functional consequences of human aging can be delayed,
reduced, or perhaps eliminated. Since
reducing food intake is known to delay
aging and increase life span in many
species, there is also renewed interest in
the effects of diet on aging and longevity.
Recent studies in this area have greatly
strengthened the evidence that dietary restriction (DR) can dramatically influence
the aging process and uncovered intriguing interactions of diet with genes involved in the control of aging. The objectives of this brief commentary are (1) to
present the most widely used methods
of imposing DR in species commonly
used in aging research, (2) to discuss the
relative importance of the composition
as opposed to the amount of food consumed, and (3) to provide some examples
of interactions of the diet with the effects
of ‘‘longevity genes’’ and to alert the
reader to the complexities of selecting
optimal diet regimens in these types of
studies.
What is Dietary Restriction?
Diet Protocols Used in Rodent
Studies
Since the pioneering studies of McCay
and colleagues (1935) in rats, numerous
protocols have been developed to produce DR (also referred to as calorie re-
striction, or CR) in laboratory populations
of rats and mice. Commonly, the animals
serving as normal controls in these studies are given unrestricted (ad libitum, AL)
access to a standard laboratory diet,
and their daily food consumption is monitored. The ‘‘restricted’’ (DR, CR) animals
are fed daily an amount of food corresponding to some percentage (most often, 60% or 70%) of the amount of food
consumed during the preceding day by
AL controls of the same strain, sex, and
age. In practice, food consumption is often measured weekly and the results
used to calculate the daily food intake.
When food consumption of the AL controls begins to exhibit the expected decline at advanced age, the amount of
food given daily to the restricted group is
no longer coupled to the food intake of
the AL group but rather held constant for
the remainder of the study. Thus, the severity of CR is gradually reduced toward
the end of animal’s life as their appetite
naturally declines.
Another commonly used approach is to
determine the average daily food consumption of adult animals of a particular
strain and then feed the ‘‘restricted’’
group some predetermined fraction of
this amount, for example 60% throughout
their adult life. This protocol can be further
modified by not allowing the control animals unrestricted (AL) access to food
but giving them daily food allotments
empirically determined to prevent obesity
and maintain good health, typically an
amount that approximates 10% less
than the AL food intake (Anderson et al.,
2008). Finally, the very substantial labor
involved in these types of studies can be
reduced by feeding the animals double
their daily allotment on alternate days, or
double their daily allotment on Mondays
and Wednesdays and triple their daily
allotment on Fridays (Pugh et al., 1999).
Some investigators modify the DR protocols further by feeding the DR animals
with a diet fortified with vitamins and minerals in an attempt to prevent micronutrient deficiencies (Pugh et al., 1999).
While this is a legitimate concern, particularly with the more severe protocols of DR,
it is probably not necessary, because
standard laboratory diets are rich in essential micronutrients. Moreover, in longterm studies, DR animals exhibit reduced
growth and body weight and, in comparison to AL controls, consume an equal or
greater amount of food per unit of body
weight. It thus seems appropriate not to
vary the micronutrient content of the DR
diet. It should be emphasized that each
of the methods of DR listed above was
shown to produce improvements in
health, delay and/or prevent cancer and
other age-related diseases, and significantly increase longevity.
Another approach to producing DR is
intermittent fasting, most often in the
form of every-other-day (EOD) feeding.
The animals in these studies have no
food for 24 hr and AL access to food during the next 24 hr. There is some uncertainty whether EOD feeding should be
considered primarily a mild form of DR
(since animals gorge when the food is
available and the food consumption per
week is usually only modestly reduced)
or as repeated periods of starvation,
with hunger and stress contributing to
the effects of this regimen. Regardless of
the mechanisms involved, EOD feeding
can protect laboratory rodents from
Cell Metabolism 8, August 6, 2008 ª2008 Elsevier Inc. 99
Cell Metabolism
Perspective
age-related pathology and functional decline and has been shown to significantly
extend life (Goodrick et al., 1990; Anson
et al., 2005).
Other methods of controlling food intake can also produce beneficial effects.
For example, alternating 3 week periods
of 50% DR with 3 weeks of AL refeeding
was reported to reduce development of
mammary tumors in mice (Cleary et al.,
2007). Defining optimal nutritional regimens for these animals is difficult since
standard husbandry practice involves
constant access to relatively high energy
food without need to expend any energy
to obtain it. These husbandry practices
were developed to support growth and
reproduction rather than longevity or
health in advanced age. Moreover, stocks
of mice and rats used in research have
been selected for hundreds of generations for thriving under these very artificial
conditions.
In the ongoing studies of DR effects in
rhesus monkeys, control animals are fed
according to a regular meal schedule
rather than having constant access to
food (Mattison et al., 2003; Weindruch,
2006). In the human, preventing obesity
by moderating food intake has been advocated for centuries as a means of improving health and extending life. Recent
studies of individuals practicing various
methods of long-term voluntary DR, as
well as participants in short-term (6
month) studies of strictly supervised reduction in calorie intake, demonstrated
significant improvements in blood pressure, serum lipids, and vascular function.
These findings are compatible with a
reduced rate of aging and increased life
expectancy (Holloszy and Fontana, 2007;
Redman et al., 2007).
Dietary Restriction in Drosophila
When performing DR experiments with
the fruitfly Drosophila melanogaster, two
major challenges are faced: (1) how to accurately restrict the diet of an animal that
only consumes up to 5 ml of food per 24 hr
(Ja et al., 2007) and, (2) in the absence
of established pathology for flies, how to
distinguish between life-span extension
due to DR from life-span rescue by restricting access to a toxic, life-shortening
diet. In answer to the former, DR is usually
performed by diluting the concentration of
the food medium, which is in vast excess
and to which the flies have AL access. Although this opens up the possibility that
DR flies could overcome the nutrient dilution by increasing their feeding behavior,
this appears not to be the case (Mair
et al., 2005; Carvalho et al., 2005; Min
and Tatar, 2006a). Second, to combat
the potentially toxic effects of a particular
diet, female fecundity can be measured
by monitoring egg deposition and used
to define the biologically appropriate
limits of dietary quality and quantity. As
food concentration increases, it is important that life-span shortening is accompanied by increased daily and lifetime fecundity. At the very least, this ensures that
life-span extension in response to DR is
correlated with a change in accessibility
to a biologically appropriate diet (reviewed in Partridge et al., 2005).
Although it is standard to restrict the
flies’ access to nutrients via dietary dilution, attempts have also been made to
implement practices that are more similar
to those used for rodents. Indeed, the first
DR experiment with Drosophila used
a protocol whereby flies had intermittent
access to excess food (similar to EOD
feeding) (Kopec, 1928). Elsewhere, daily
provision of a limited amount of food,
which could be completely consumed before the next meal, has also been attempted on medflies and houseflies (Carey
et al., 2002; Cooper et al., 2004). None
of these studies has reported positive results on life span, which has been interpreted as DR not being protective for flies.
However, an alternative interpretation is
that the protective effect of DR for flies is
simply different from that in rodents and
that protocols involving periods of fasting
are not effective. It remains to be seen
how deep, at the mechanistic level, these
differences run.
Dietary composition is also nonstandard in fly DR studies. Generally, fly life
span can be maximized on an agar-gelled
diet of sugar and lyophilized yeast, which
contains all the necessary lipids, vitamins,
proteins, and minerals. This diet reflects
our knowledge of the ecology of D. melanogaster that feed on rotting/fermenting
fruit from which they consume mainly
fungus, but also some of the fruit flesh
(Spieth, 1974). While lyophilized yeast is
nutritionally sufficient, some laboratories
substitute the yeast fraction with yeast extract or live yeast (summarized in Piper
and Partridge, 2007). In all cases a DR effect has been reported, which in part is
due to the smell of live yeast alone (Libert
100 Cell Metabolism 8, August 6, 2008 ª2008 Elsevier Inc.
et al., 2007). However, this robust effect is
not insensitive to small changes in diet.
During experiments to optimize our diets
for life-span studies, we found conditions
in which substitution of the yeast component with yeasts from different suppliers
could alter, or even eliminate the DR effect
(Bass et al., 2007). Thus, it is not sufficient
to assume that all dietary protocols have
equal effects on physiology in different
laboratories without first being optimized
to maximize fecundity and life span, as
outlined above.
Dietary Restriction in C. elegans
Similar to flies, reproductive vigor can be
used to frame the nutritional limits of DR
when using the nematode worm Caenorhabditis elegans. Although relatively little
is known about food availability and feeding levels of worms in the wild, it is thought
that their natural food source is exclusively bacterial (Caswell-Chen et al.,
2005). This is in agreement with the fact
that it is possible to maintain C. elegans
successfully in the laboratory on a bacterial lawn (usually OP50 Escherichia coli
[Brenner, 1974]) growing on agar plates
supplemented with minerals, cholesterol,
and peptone.
Several types of DR interventions can
extend worm life span. These involve either bacterial dilution, substituting bacteria with a defined or semidefined medium,
or introducing mutations that physically
limit food ingestion (summarized in Houthoofd and Vanfleteren, 2007). Within
these groupings, at least eight different
DR methods have been published for
worms (Greer et al., 2007). Bacterial dilution has been implemented in both liquid
medium and on plates. The latter method
has yielded the remarkable finding that
complete removal of bacteria has the
most pronounced life-span-extending effect (Kaeberlein et al., 2006; Lee et al.,
2006). Even longer life spans can be
achieved by using nutritionally defined
axenic liquid media (without bacteria),
which is somewhat counterintuitive, as
the media are theoretically nutritionally
abundant (Vanfleteren, 1980). Finally, mutations such as eat-2 that affect the neuronal and muscular functions controlling
pharyngeal pumping can also extend life
span in a nutrient-dependent manner
(Lakowski and Hekimi, 1998). It is thought
that eat-2 mutants and bacterial dilution
extend life span by a common mechanism
because eat-2 mutants are no longer lived
Cell Metabolism
Perspective
than wild-types upon bacterial deprivation on plates (Kaeberlein et al., 2006;
Lee et al., 2006). It is, however, uncertain
if the life-span extension of worms on
axenic media is also operating through
the same mechanism.
A complication of studying worm DR by
reduced bacterial ingestion is that proliferating E. coli is apparently slightly toxic
to worms and reduces their life span
(Gems and Riddle, 2000; Garigan et al.,
2002). Furthermore, substituting E. coli
with Bacillus subtilis has been shown to
extend worm life span by nearly 100% under certain conditions (Garsin et al., 2003).
This indicates that dividing E. coli is not an
optimal food source for studying life span,
as any intervention that enhances longevity could be acting simply to reduce the
effects of E.coli-mediated killing. For DR,
however, this explanation cannot fully account for the extended longevity, as fooddeprived animals are still longer-lived than
those provided with UV-killed E.coli,
which is thought to be nonhazardous
(Kaeberlein et al., 2006).
Food Composition Versus Caloric
Intake
Early studies in laboratory rodents provided evidence that as long as malnutrition is avoided, the increased longevity
of DR animals is due to reduced total
food (caloric) intake rather than to reduced availability of any of the major
food components: carbohydrates, protein, or fat (Weindruch and Walford,
1988). However, a series of studies by
Orentreich et al. (1993) demonstrated
that depriving rats of one of the essential
amino acids—methionine—can mimic
many effects of DR, including increased
longevity. Miller et al. (2005) reported
that a methionine-deficient diet also extended longevity in mice and produced
many physiological changes strikingly resembling the effects of DR. Ayala et al.
(2007) reported that reducing intake of
protein but not carbohydrates or fat can
suppress mitochondrial production of reactive oxygen species (ROS) and reduce
oxidative damage, thus resembling the
effects of DR. These investigators suggested that the beneficial effects of
a low-protein diet are due to reducing
methionine intake (Ayala et al., 2007).
Because whole-food DR involves reduction of energy intake and produces
reductions in growth rate and body tem-
perature, it would seem reasonable to assume that it reduces metabolic rate. This
and the presumed associated reduction
in ROS generation has been considered
the mechanistic basis for how DR might
extend life span. However, results of careful around-the-clock studies in rats exposed to DR for several months (McCarter
et al., 1985) revealed no differences between DR and control animals in metabolic rate when expressed per unit of
lean body mass. This landmark study is
frequently cited as evidence that DR in
mammals does not prolong life by slowing
metabolic rate. Recent studies in rhesus
monkeys and in human subjects reopened this issue by showing that the resting energy expenditure adjusted for fatfree mass was reduced in monkeys after
11 years of DR (Blanc et al., 2003) and
that sedentary energy expenditure (adjusted for changes in body composition)
was decreased in overweight humans
who reduced their caloric intake by 25%
for a period of 6 months (Heilbronn et al.,
2006). Aside from differences in techniques for imposing DR, arriving at a
consensus as to the effects of DR on
metabolic rate in rodents, and the role
of DR-induced metabolic adaptations in
preventing disease and extending life
span is complicated by using different
methods to measure metabolic rate and
to express the results (Selman et al.,
2005). These considerations are not trivial, because long-term DR leads to major
changes in body weight and important
alterations in body composition (Rikke
et al., 2003). It thus remains unknown
what the relevance of the rate of metabolism is for the prolongation of life.
Drosophila
Although the data are as yet inconclusive,
there is increasing evidence that the protein component of the fly diet is critical for
the published effects of DR on life span.
Work by Mair et al. (2005) demonstrated
that the yeast component of the fly diet
could account for nearly the full lifespan response of flies to DR and that
this was independent of calorie intake.
This is supported by respiration rate
measurements that have shown for one
particular life-span-extending dietary
regime, the resting metabolic rate of
control flies is not more than those subject to DR (Hulbert et al., 2004). It should
be noted, however, that interpretation of
these metabolic data is limited by technical considerations as the measurements
were made on flies housed under conditions very different from those in which
life-span extension was observed and
the data were not adjusted for body composition, which is sensitive to dietary history. More recently, reports have identified a negative relationship between
protein ingestion and life span, thus developing the idea that energy metabolism
per se is not critical for DR under the conditions tested (Min and Tatar, 2006b; Lee
et al., 2008). If protein ingestion does play
a role in life span, it raises the attractive
possibility that diet and life span are connected via the amino-acid sensing TOR
signaling pathway, which can extend fly
life span when mutated (Kapahi et al.,
2004). However, it is impossible at this
stage to reach any definitive conclusions
on this topic as no experiments have
been performed to test genotype by diet
interactions using precise nutritional manipulations of physiologically appropriate
alterations to protein, lipids, vitamins and
minerals.
C. elegans
Due to difficulties in maintaining worms in
a fully defined synthetic medium, the effects of individual nutrient manipulations
on life span have not yet been reported.
However, similar to flies, it has been reported that the metabolic rate of worms
under DR imposed by eat mutation or
bacterial dilution is not lower than controls (Houthoofd et al., 2002). Interestingly, a number of mutations that cause
downregulation of general translation initiation have been shown to extend worm
life span (Pan et al., 2007; Hansen et al.,
2007; Henderson et al., 2006). Similar to
flies, these may implicate the protein
component of the diet as having a role
in life-span determination, especially
since RNAi against worm TOR, which
has a role in translation control, further
extends the life span of eat-2 mutants
(Hansen et al., 2007). Thus, dietary protein intake and TOR signaling may be
an evolutionarily conserved mechanism,
at least between flies and worms, by
which DR extends life span. However,
other data preclude this as an all-inclusive interpretation and indicate that the
mechanisms by which whole-diet manipulations affect worm life span are multifactorial.
Cell Metabolism 8, August 6, 2008 ª2008 Elsevier Inc. 101
Cell Metabolism
Perspective
Diet Can Modify Effects of LifeExtending Mutations on Longevity
Following the pioneering studies of
Johnson and colleagues (Johnson, 1990),
various spontaneous mutations as well
as targeted deletion of specific genes
have been shown to produce significant
increase in the longevity of yeast,
C.elegans, D. melanogaster, and mice
(reviewed in Tatar et al., 2003; Kenyon,
2005). The list of these life-extending mutations (aka ‘‘longevity genes’’) is rapidly
increasing.
In mice, effects of most of the life-extending natural or experimentally induced
mutations on longevity were examined
only under one set of dietary conditions,
typically AL access to a standard rodent
diet used in the laboratory conducting
these studies. In Prop1df (Ames dwarf)
and Ghr/bp / (Laron dwarf; GHRKO)
mice, longevity of mutant and normal (control) animals was compared using four different diets: standard laboratory diet, a casein diet without soy-derived components,
and two soy-based diets, one with a high
and one with a low soy isoflavone content
(Brown-Borg et al., 1996; Coschigano
et al., 2000; Bartke et al., 2004). On each
of these diets, mutant mice lived significantly longer than controls, but the relative
increase in average life span differed
widely, ranging from 35% to 69% in
Ames dwarf mice and from 23% to 51%
in GHRKO animals (Bartke et al., 2004).
Although these comparisons were based
on relatively small numbers of animals,
the results indicate that effects of longevity
genes on life span can be modified by differences in the composition of the diet.
This conclusion is consistent with results
of an earlier study in growth hormone
(GH) deficient Ghrhr-lit (‘‘Little’’) mice
(Flurkey et al., 2001) where life extension
depended on the use of a ‘‘maintenance
diet’’ (4% fat) as opposed to a ‘‘breeder
diet’’ (7% fat) diet.
Animals heterozygous for the deletion
of the insulin receptor substrate 2 (IRS2)
were recently reported to live longer than
normal controls (Taguchi et al., 2007),
while another laboratory reported no
effect of the same genetic modification
on the life span (Selman et al., 2007). We
suspect that use of different diets (9%
fat versus 4.5% fat) in these two studies
may have contributed to or perhaps accounted for the discrepancy between
the results.
Interactive Effects of LifeExtending Mutations and Diet
Restriction
Most of the long-lived mutant mice described to date have primary or secondary reduction of somatotropic (GH and
insulin-like growth factor 1, IGF-1) and/or
insulin signaling (Longo and Finch, 2003;
Bartke, 2006). It is well documented that
mutations affecting these or homologous
signaling pathways influence longevity in
an astoundingly wide range of organisms:
certainly from roundworms to mice and
likely from yeast to humans (Tatar et al.,
2003; Longo and Finch, 2003; Kenyon,
2005).
Reduced IGF/insulin signaling is believed to be an important mechanism of
the action of DR on aging and longevity,
and many phenotypic characteristics of
long-lived hypopituitary and GH-resistant
mice overlap those of genetically normal
animals subjected to DR. These include
reduced body size, delayed puberty, reduced fertility, reduced plasma levels of
insulin, IGF1 and glucose, improved insulin sensitivity, and partial protection from
cancer (Bartke, 2006). However, major
differences in the phenotype and in the
profiles of gene expression also exist
(Miller et al., 2002; Tsuchiya et al., 2004).
Against this background, it was of interest to examine the interaction of murine
longevity genes with DR. Reduction in
food intake from AL to 70% starting (gradually) at approximately 2 months of age
produced further significant extension of
average and maximal longevity in Ames
dwarf (Prop1df) mice (Bartke et al.,
2001). Unexpectedly, an identical dietary
regimen had no effect on longevity of
GHRKO males and produced only a modest increase in maximal longevity without
affecting the median or the average life
span in GHRKO females (Bonkowski
et al., 2006). These results and the DRinduced alterations in insulin sensitivity
in these mutants were interpreted as evidence that the combined GH, thyrotropin,
and prolactin deficiency in Ames dwarfism influences longevity by mechanisms
different from those which affect longevity
of DR animals and that, in extremely insulin-sensitive animals, DR extends longevity only if it produces further enhancement
of insulin sensitivity (Bonkowski et al.,
2006). However, studies of interactions
of different intensities of DR with longevity
genes in Drosophila (details in the next
102 Cell Metabolism 8, August 6, 2008 ª2008 Elsevier Inc.
section) suggested that results obtained
using only one level of DR may not be generalizable to other nutritional interventions
(Clancy et al., 2002). While this question
remains to be systematically investigated,
data from our ongoing study of the effects
of EOD feeding in GHRKO mice suggest
that in this mutant, the failure of DR to affect male longevity is not limited to one
level of calorie restriction.
Drosophila
There are a number of studies on flies that
have tested the interaction of life-spanextending mutations with diet. Of these,
three have tested the effects of DR on
mutations in the insulin and insulin-like
growth factor signaling (IIS) pathway that
extend life span (Clancy et al., 2002; Min
et al., 2008; Giannakou et al., 2008). In
all three cases, the mutant line is longlived in a food concentration-dependent
manner such that food types can be found
for which the mutant is longer-lived, has
the same life span or is even shorter-lived
their control groups. Similar effects of
diet-dependent longevity have also been
reported for the long-lived mutants methuselah, rpd3 heterozygotes, SIR2 overexpressors, TSC2 overexpressors, and
neuronal expression of dominant-negative Drosophila p53 (Baldal et al., 2006;
Rogina et al., 2002; Rogina and Helfand,
2004; Kapahi et al., 2004; Bauer et al.,
2005).
These findings have generally been interpreted to indicate whether or not the
mutations extend life span through the
same mechanisms as DR. Currently, there
is evidence that all the above mutations,
except methuselah, are involved in the
DR response; however, this involves the
use of several different diets to implement
DR. Interestingly, for overexpression of
the IIS transcription factor FOXO, a qualitatively different response of life span to
food concentration was reported when
DR was implemented by reducing yeast
alone, or by reducing sugar and yeast together (Giannakou et al., 2008). This reveals a more complex interaction of the
mutation with diet and can explain how
different laboratories using a single, but
different, diet could find opposing effects
of a mutation on life span. It also shows
how a range of diets of different compositions could lead to varying interpretations
of how the two interact mechanistically to
extend life. Thus, it is not clear whether all
Cell Metabolism
Perspective
the above mutations operate in the same
pathway or that they operate to modify
the response of life span to dietary composition that varies across different DR
methods.
C.elegans
Many studies also exist for worms that
test the effect of IIS mutations on lifespan extension by DR. The IIS-regulated
transcription factor DAF-16 (FOXO homolog) is required for the extended longevity
of IIS mutant worms (Kenyon et al., 1993).
It is thus revealing that the life span of
daf-16 mutants can be prolonged by DR
through bacterial dilution, eat-2 mutation,
or culture in axenic medium (Lakowski
and Hekimi, 1998; Houthoofd et al.,
2003; Kaeberlein et al., 2006; Lee et al.,
2006). The independence of IIS mutations
and DR in enhancing longevity is further
supported by the fact that mutants for
the insulin receptor homolog (daf-2) or
PI3K (age-1) can have their already long
life spans further extended by DR (reviewed in Houthoofd et al., 2005). In fact,
this IIS/DR interaction is so well described
for worms that it is now used as a diagnostic test of whether a particular dietary manipulation is classifiable as DR. However,
a recent report has described a different
dietary manipulation involving bacterial
dilution that is called DR, is also DAF-2
independent, but surprisingly is DAF-16
dependent (Greer et al., 2007). Thus, it is
possible to find DR interventions that
extend life span in an IIS-dependent as
well as an IIS-independent manner.
Other genes have also been reported
to mediate life-span extension by DR
in worms. These include AMPK (aak-2),
sir-2.1, TOR (let-363), Foxa (pha-4), skn-1,
clk-1, rab-10, sams-1, several autophagy
genes, as well as two genes of unknown
function (Hansen et al., 2008; Jia and Levine, 2007; Hansen et al., 2005) and references in Greer et al. (2007). For two of
these genes, reports have also appeared
that show they do not block DR-mediated
life-span extension (Henderson et al.,
2006; Kaeberlein et al., 2006). It is possible that experimental differences, such
as the concentration or composition of
the diet, could account for these apparent
contradictions. In fact, such differences
could also lead to alternate findings for
each of the other above mutations that
block the response of life span to DR.
Thus, for worms, more so than the other
model organisms, it appears that the vari-
ety of experimental techniques to implement DR means its use in one lab is unlikely to yield the same effects as in
another.
Summary and Conclusions
Nutritional factors, including the amount
and composition of food, can exert major
effects on aging and life expectancy and
interact in interesting ways with spontaneous and experimentally induced mutations that influence longevity. Complex
interactions between caloric intake, diet
composition, and genotype in the control
of longevity are difficult to study in mammals but can be more readily approached
in short-lived, simpler organisms. Practical suggestions for studies of dietary influences on life span include the following:
(1) optimization of DR protocols (lab-bylab; finding diets that maximize reproduction and life span) to properly frame data
interpretations, (2) studying a range of
DR options to extend knowledge of the
genotype/nutrient interaction, or (3) not
attempting to standardize dietary procedures, but instead providing a very carefully described method when publishing,
so the effect of nutrient interactions with
mutants can be qualified.
An underlying problem exists in the imprecision of the term ‘‘dietary restriction.’’
This is inevitable because of the very fact
that we don’t know how DR operates, so
a functional definition has to be very superficial (i.e., diet reduction that extends
life span without malnutrition).Therefore,
it would be advisable to avoid calling
something simply DR without qualifying
the exact protocol being used in the
study. This should also affect the way
data are discussed in the context of the
wider literature on the topic.
Finally, a more helpful perspective
might be to consider studies in this area
as an approach to elucidating a dietary
network interaction with mutations. This
may reveal a continuum of change in
life-span outcomes and physiological
state changes in response to dietary
manipulations.
ACKNOWLEDGMENTS
Studies in the authors’ laboratories were supported by grants from The Wellcome Trust, NIA,
and the Ellison Medical Foundation. We apologize
to those whose work pertinent to this topic was not
discussed or cited due to limitations of the format
or inadvertent omission.
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