Acid-base, diet, and
preventing “age-related”
dysfunction of bone,
muscle, kidney, and
cardiovascular system
Lynda Frassetto, MD
NASA 10-7-09
Hypothesis (1)
Some of the effects attributed to
“aging” are due to the body’s attempts
to mitigate the actions of a chronic,
low-grade metabolic acidosis
associated with acid-producing foods
in the diet and declining renal function
Take home points
™ Even small changes in acid levels can
have big effects
™ Only some acid regulatory factors are
modifiable, e.g., diet
™ Supplemental alkali buffering may help
™ “Acid-related” organ dysfunction w/
aging may be preventable
Stewart: predicts many factors alter [H+]
Acid-base balance: intake, buffering, excretion
44
r=0.37, p=0.002
Blood [H ] (neq/L)
Blood [H+ ] (neq/L)
Acid retention in healthy humans with
increasing age and declining renal function
42
40
+
38
36
Plasma [HCO 3- ] (meq/L)
28
26
3
Plasma [HCO- ] (meq/L)
34
24
22
20
r=-0.37, p=0.002
20
40
60
AGE (yrs)
80
r=0.36, p<0.001
44
42
40
38
36
34
n=64 subjects
28
26
24
22
r=0.46, p<0.001
20
18
80
100
120
140
160
CREATININE CLEARANCE (ml/min/70 kg)
Acid retention in healthy humans with increasing diet acid
load and salt intake
+
44
Blood [H+] @ RNAE=56
meq/d
Blood [H ] (neq/L)
48
r=0.34, p<0.005
42
40
38
36
34
r=0.22, p<0.05
44
40
36
28
r=-0.36, p<0.005
26
24
22
0
50
100
36
Plasma [HCO3-] @
RNAE=56 meq/d
Plasma [HCO-3 ] (meq/L)
32
150
Urine Acid (NAE, meq/24 hr/70 kg)
r=0.45,
p<0.001
32
28
24
20
16
0
50
100
150
Urine Chloride meq/day
200
250
Net Acid Balance In Normal Subjects
+NH4CL
+40
DIET ONLY
+20
+NaHCO3
ACID
RETENTION
0
BASE
RETENTION
y = 0.13x - 10.7
-20
r=0.88, p<0.001
-40
-200
d:\abcfigs\nabeapdz.drw
Acidogenic
diets
Basogenic
diets
0
+200
ENDOGENOUS ACID PRODUCTION, meq/day
+400
Recap 1
™ the higher the acid load and the older you are, the
worse your kidney function is and the higher the
body’s acid level is maintained
“TRADE-OFF” Hypothesis (2)
™ Renal responses to acidosis
Ï proximal and distal tubule secretion of H+ ions
Ï proximal reabsorption of HCO3- ions
Ï NH3 synthesis and excretion
™ Trade-offs in the response to acidosis
Ï proximal reabsorption of citrate and other organic
anions
Ð distal reabsorption of Ca
Bone responses to acid
Catabolism of protein from muscle (glutamate => NH3)
Hypertrophy, hyperplasia and ? progressive renal
dysfunction
From Alpern RJ KI 47:1205, 1995
Influence of pH
levels on bone
calcium (i.e. BASE)
BASE
efflux, independent
of other factors
Within the normal
human pH range
(7.35 to 7.45), is
SPECTRUM of effect
Bushinsky AJP 283: F1091-F1097, 2002
Extracellular pH and bone cell function
pH ≥ 7.4
BLOOD
pH ≈ 7.2
pH ≤ 7.0
NORMAL TISSSUES
BLOOD ACIDOSIS
TISSSUE
ACIDOSIS
osteoblasts
net bone formation
Ca2+ ↓
bone maintenance
PO43- ↓ OH- ↓
bone loss,
no mineralisation
Ca2+ ↑
PO43- ↑ OH- ↑
osteoclasts
pre-existing
bone
active
osteoblasts
mineralised
bone matrix
http://www.anat.ucl.ac.uk/research/arnett_lab/images/osteoclast_bfast_lunch_dinner.jpg
unmineralised
bone matrix
inactive osteoclast
active osteoclast
Effects of acidosis
on bone cells
Ï Osteoclast
activation &
osteoid area
Ð Osteoblast
activation &
bone
mineralization
Frick AJP 1998
Domrongkitchaiporn KI 2001
Pathophysiologic effects w/ aging
Decline in bone mass with age
Decline in muscle
mass with age
http://www.mrc-hnr.cam.ac.uk/research/bone_health/pbm.html
http://jn.nutrition.org/cgi/content/full/127/5/990S
Ï proteolysis due to activation of
ubiquitin-proteasome pathways =>
Ï renal excretion of NH4+
Pediatr Nephrol. 2008 April; 23(4): 527–535.
Mitch JCI 1996
Effects of acidosis on
muscle structure
Normal thigh MRI
cross section
Courtesy of Kirsten Johansen
Renal failure thigh
MRI cross section
Effects of acidosis on muscle function
(actin filament contraction velocities)
Debold Am J Physiol Cell Physiol 295: C173-C179 2008
Recap 2
™ the higher the acid load and the older you are, the worse
your kidney function is and the higher the body’s acid
level is maintained
™ ‘trade-offs’ for maintaining acid-base balance include bone
dissolution to provide base and muscle breakdown to
increase renal H+ excretion
What factors can we change?
™ Avoid lung damage
™ Prevent age-related renal functional
decline?
™ Alter diet
™ Increase buffering capacity
The 4 known alterable factors that affect
renal function
™ Glomerular factors:
Proteinuria
™ Vascular (endothelial) factors:
Blood pressure
Hyperglycemia
™ Diet factors:
Metabolic acidosis (NaCl, SO4, etc)
Pathophysiologic effects w/ aging
Increase in % pts w/ hypertension
with increasing age & salt intake
AGE
NaCl
º
ºº
Development of low-grade
metabolic acidosis w/ increasing
NaCl intake => ↑ bone breakdown
o pH v(& HCO3) values decrease w/
increasing NaCl intake (p = 0.04),
and
o increase when NaCl intake was
again restricted (p = 0.04).
*p < 0.05, **p < 0.01
º
ººº
o bone resorption marker Ctelopeptide (CTX) excretion in 24-h
urine pools increased with
increasing NaCl intake (p = 0.013),
and
o decreased after the NaCl load
was reduced (p < 0.001)
*p < 0.05, ***p < 0.001
Heer J Bone Min Res 2008
SS rats have dose-dependent MA from È intracellular pH
Batlle D et al. JCI 1993
NO synthesis pathway
in endothelial cells
Metabolic Acidosis:
↓ insulin & IGF-1 =>
↓ PI3K =>
activation of
nuclear factors
&
↑ caspase-3 activity
=> ↑ protein
degradation
Dose-dependent decrease in eNOS activity in endothelial
cells with increasing [Na+]
BAEC
CHO-eNOS
BAEC
Li, J. et al. J. Nutr. 2009;139:447-451
a vs b vs c vs d; p<0.05
Clinical observation:
12 months of nitrate therapy is as effective as bisphosphonates
in increasing BMD in postmenopausal women (n=60)
Nabhan Intl J OBGYN 103:213, 2008
Modifiable factors: Diet alkali intake
™ The chronic low-grade metabolic acidosis and its
sequelae typical of present-day humans eating
contemporary diets reflects a mismatch between
the nutrient composition of our present diets and
the genetically determined nutrients we require for
optimal systemic acid-base status
™ Adopting an agricultural-based diet ~10,000 years
ago, Homo sapiens crossed the neutral zone,
zone
switching from systemic net base-production to
net acid-production
Change in dietary mineral and acid-base from
pre-agricultural times: less base & more acid
300
Then
Then
Now
300
K+
HCO3-
meq/day
Na+
200
200
100
100
K+
0
Na+
Now
0
Cl-
Cl-
HCO3-
Reduction in [K/Na] and [HCO3-/Cl-] ratio > 30
Transitioning to a net base producing diet: Substitute nongrain plant foods for energy dense, nutrient poor foods
EDNP foods
fruit
vegetables
Average
American diet
with grains &
EDNP foods
beans
nuts
grain
eggs
Total Daily Net Acid
Total
Daily
NEAP =
= +48
mEq/day
+48 meq/day
milk/yogurt
EDNP = energydense, nutrient
poor foods (e.g.,
donuts, pastries,
candy, cookies,
etc)
cheese
meat
X
EDNP foods
fruit
No grains or EDNP
Substitute other
plant groups
vegetables
beans
nuts
X
grain
eggs
X
milk/yogurt
Total Daily Net Acid
Total Daily NEAP =
= -53
mEq/day
-53 meq/day
cheese
meat
-80
-60
-40
-20
0
20
Contribution Of Each Food Group To NEAP
(Net Acid Production), mEq/day
Animal foods & grains
meq/1000 kj
Fruits, vegetables and nuts
160
50
140
40
120
30
100
20
80
10
60
0
40
-10
20
-20
0
-30
0
50
100
150
0
K meq/1000kj
H2S04 meq/1000kJ
5
10
15
20
K meq/1000kJ
p_meq/1000 kJ
unmeasured anions,
meq/1000 kJ
25
30
Decreasing net acid production by supplementing HCO3 improves
blood HCO3 levels and the pre-existing metabolic acidosis
KHCO3
Plasma [HCO3 ], meq/L
30
NEAP ~
Renal Net Acid Excretion
PRE-Rx
100
POST-Rx
28
26
24
KHCO3, 120
meq/day (n=6)
p=0.03
22
KHCO3, 60
meq/day (n=12)
80
p<0.001
60
40
20
0
meq/day
-20
-40
-10
0
10
Days
20
30
from Sebastian et al NEJM 330:17761781, 1994
Bicarbonate decreases urinary nitrogen
excretion & improves nitrogen balance
Papadoyannakis Am J Clin Nutr 1984
Frassetto JCEM 1997
n=3226
In postmenopausal women,
higher dietary alkali intake
correlates with higher BMD
p=0.01
n=1035
MacDonald AJCN 2005 Aberdeen
p=0.02
Sellmeyer AJCN 2001 SOF
1 mEq/Kg
Effects of bicarbonate
for 3 months in men &
women over 50 yrs old
0.8 mEq/Kg
Men
Number
Women
Control
Bicarbonate
35
36
P
Control
Bicarbonate
49
42
P
Leg power output
Knee extension (40% 1-RM, W) b
0.63 ± 3.70
0.42 ± 3.34
0.949
2.04 ± 1.76
4.46 ± 1.83
0.263
Knee extension (70% 1-RM, W) †
0.16 ± 2.94
−2.77 ± 2.66
0.268
0.52 ± 1.66
5.82 ± 1.79
0.014
Double leg press (40% 1-RM, W)
−1.72 ± 4.68
−2.71 ± 4.25
0.812
−5.20 ± 2.55
4.08 ± 2.82
0.006
Double leg press (70% 1-RM, W)
−1.94 ± 3.62
−5.47 ± 3.27
0.275
−1.86 ± 3.39
11.61 ± 3.74
0.003
Knee extension (240º/s, Nm)
6.55 ± 4.40
5.46 ± 3.98
0.780
−3.59 ± 3.20
5.12 ± 3.66
0.047
Knee flexion (240º/s, Nm)
7.48 ± 4.58
5.66 ± 4.15
0.658
−7.30 ± 3.09
0.76 ± 3.54
0.057
Grip strength (kgf)b
4.42 ± 2.05
2.83 ± 1.85
0.382
−1.13 ± 1.21
1.07 ± 1.38
0.178
Isokinetic leg endurance b
Dawson-Hughes Osteoporosis Int’l 2009
Higher HCO3 and lower NaCl intakes predispose towards
lower acid loads & lower blood pressures
NaCl
Ç BP
Ç NEAP
È BP
È NEAP
KHCO3
SHR: Increased blood
pressures, more tissue damage
& declining renal function with
increased chloride intake
+ chloride
Schmidlin HTN 2005
+ bicarbonate
Diet
Potassium
content
Breakfast
Ramp 1
125 mEq
Ramp 2
180 mEq
Ramp 3
259 mEq
Paleo Diet
339 mEq
Honey
Fresh pineapple
Scrambled eggs
Honey
Orange juice
Fresh pineapple
Pork tenderloin
Honey
Orange juice
Fresh pineapple
Pork tenderloin
Honey
Carrot Juice
Fresh pineapple
Pork tenderloin
Lettuce, cucumber,
celery and tomatoes
with oil & vinegar
dressing
Carrot juice
Celery, cucumber,
red peppers and
tomatoes with oil &
vinegar dressing
Low salt tomato
soup
Almonds
Stir-fried fresh
zucchini
Tuna salad (tuna,
radish, shallots,
mayo) on lettuce
Applesauce
Carrot juice
Carrot juice
Carrot juice
Tuna salad/mayo on
lettuce
Tuna salad/mayo on
lettuce
Tuna Salad (mayo,
radishes, shallots)
on lettuce
Low salt tomato
soup with chopped
tomatoes
HEALTHY VOLUNTEER
STUDY
AM Snack
Carrot juice
Lunch
Honey
Honey
Paleo diet composite analysis:
30% protein
30% fat (mainly unsaturated)
40% carbohydrate
Day Snack
Lettuce, carrot and
peppers with oil &
vinegar dressing
Canned pears
Turkey/mayo in
lettuce wrap
Turkey/mayo with
lettuce wrap
Carrots and
tomatoes with oil &
vinegar dressing
Carrots and
tomatoes with oil &
vinegar dressing
Tomato juice
Honey
Turkey, guacamole
and tomato lettuce
roll-ups
Almonds
Na 72 mmol
Dinner
Chicken breast stirfry with broccoli and
garlic
Mandarin oranges
Chicken breast stirfry with fresh
spinach, garlic and
broccoli
Mandarin oranges
Chicken breast stirfry with fresh
spinach, broccoli
and garlic
Mandarin oranges
Honey
Tomato juice
Chicken breast stirfry with fresh
spinach, garlic and
broccoli
Roasted parsnips
and mushrooms with
thyme
Low salt tomato
soup
PM Snack
Turkey & tomatoes
with mayo in lettuce
wrap
Per 3000 kcal:
Cantaloupe
Cantaloupe
Cantaloupe
Carrot juice
Carrot juice
Honey
Carrot juice
Cl
95 mmol
K
305 mmol
PO4 87 mmol
Greater arterial compressibility and dilation on
‘Paleolithic-type’ (high potassium and alkali) diet
D a y s – 2 to 0
(p r e d ie t)
D a y s 1 5 -1 7
(P a le o d ie t)
p
v a lu e
B r a c h ia l a r te r y d ia m e te r a t b a s e lin e
(B A D ; m m )
3 .9 7 ± 0 .8 8
3 .9 8 ± 0 .8 5
0 .1 4
B r a c h ia l a r te r y d ia m e te r a fte r c u ff
o c c lu s io n (m m )
4 .1 1 ± 1 .0 7
4 .0 4 ± .0 .8 1
0 .0 7
P e a k b r a c h ia l a r te r y d ia m e te r
d u r in g h y p e r e m ia (p k F M D ; m m )
4 .2 5 ± 0 .8 3
4 .3 5 ± 0 .7 3
0 .0 5
0 .2 8 8 ± 0 .0 8 9
0 .3 7 1 ± 0 .1 5 8
0 .0 6
A b s o lu te d iffe r e n c e , p k F M D -B A D
(m m )
∗ p < 0.05
Treadmill exercise stage
0
I
II
III
IV
V
VI
4
∗
Δ from baseline
0
-4
-8
∗
-12
-16
-20
∗
∗
∗
dMAP, mmHg
dHR, beats/min
dCO, L/min
No significant change in VO2peak (-0.7±3.3 mL/kg/min) or RER (-0.004±0.068)
Frassetto LA et al. ACSM abst 5/07
Comparison of insulin & glucose data
PREMIER STUDY: 55 subjects, 6 months
™ DASH-type diet vs control
™ + weight loss ~15 lbs
™ + increased exercise
PREMIER diet
Paleo diet
baseline
post
%Δ
baseline
post
%Δ
Fasting insulin
16±8
14±9
9
10±9
3±1
68
Fasting glucose
102±10
98±10*
4
91±13
86±8
5
* p<0.05 compared to baseline
Ard et al., Diab Care 27:340, 2004
Recap 3
™ the higher the acid load and the older you are, the worse
your kidney function is and the higher the body’s acid
level is maintained
™ ‘trade-offs’ for maintaining acid-base balance include bone
dissolution to provide base and muscle breakdown to
increase renal H+ excretion
™ typical westernized diets are high in acid precursors
™ ameliorating the diet acid load, either with alkali
supplements or by increased dietary alkali intake, is
associated with higher bone mineral density, higher
lean body mass, and
™ possibly improves vascular reactivity, at rest & with exercise
Recap 4: Take home points
™ Even small changes in acid levels can
have big effects
™ Only some acid regulatory factors are
modifiable, e.g., diet
™ Supplemental alkali buffering may help
™ “Acid-related” organ dysfunction may be
preventable
Tie-ins with the space program?
Acknowledgements
UCSF
UK
Anthony Sebastian, M.D.
Susan Lanham-New, Ph.D
RHPNutr
R. Curtis Morris, Jr., M.D.
Debbie Sellmeyer, M.D.
Patricia Painter, Ph.D
Richard Gannon, Ph.D
Manuela Abbate
Joanne Krasnoff, Ph.D
Clinical Research Center
nurses & dieticians
Germany
Thomas Remer, Ph.D
Shoma Berkemeyer, Ph.D