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Research on Aging & Nutrition

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Oct 02, 2005 11:28 PDT

 

Research on Aging & Nutrition

 

Introduction

 

http://www.bruceames.org/n/research.php

Tuning-up human metabolism, which varies with genetic constitution

and

changes with age, is likely to be a major way to minimize DNA

damage,

improve health and prolong healthy lifespan. The decay of

mitochondria

with age due to oxidation of RNA/DNA, proteins, and lipids is a

major

interest; we are making progress in reversing some of this decay in

old

rats by feeding them normal mitochondrial metabolites at high levels

and

are extending the work to humans. Another major interest is

determining

optimum micronutrient intakes for minimizing human DNA damage, as an

aid

in the prevention of cancer, and other degenerative diseases

associated

with aging [1]. High levels of B vitamins raise the corresponding

coenzyme levels in humans and will be beneficial to that

considerable

fraction of the population who have a variant enzyme with a

suboptimal

binding affinity for its coenzyme [2].

 

Delaying the Mitochondrial Decay of Aging

Mitochondria decay with age due to oxidation of RNA/DNA, proteins,

and

lipids. Oxidative mitochondrial decay is a major contributor to

aging

[3-7]. We are making progress in reversing some of this decay in old

rats by feeding them normal mitochondrial metabolites (acetyl

carnitine

and lipoic acid) at high levels and are extending the work to

humans.

The principle behind this effect appears to be that with age

increased

oxidative damage to protein causes a deformation of structure of key

enzymes, with a consequent lessening of affinity (Km) for the enzyme

substrate [8]. The effect of age on the enzyme binding affinity can

be

mimicked by reacting it with malondialdehyde (a lipid peroxidation

product). Feeding the substrate (acetyl carnitine) with lipoic acid,

a

mitochondrial antioxidant, restores the velocity of the reaction, Km

for

acyl carnitine transferase, and mitochondrial function [8]. In old

rats

(vs. young rats) mitochondrial membrane potential, cardiolipin

level,

respiratory control ratio, and cellular O2 uptake are lower;

oxidants/02, neuron RNA oxidation, and mutagenic aldehydes from

lipid

peroxidation are higher [5, 8-10]. Ambulatory activity and cognition

declines with age [9, 10]. Feeding old rats acetyl carnitine and

lipoic

acid for a few weeks restores mitochondrial function; lowers

oxidants,

neuron RNA oxidation, and mutagenic aldehydes; and increases rat

ambulatory activity and cognition (as assayed with the Skinner box

and

Morris water maze) [8-15].

 

DNA Damage Increases with Age

Apurinic/apyrimidinic (AP) sites are common DNA lesions that arise

from

spontaneous depurination or by base excision repair (BER) of

modified

bases. A biotin-containing aldehyde-reactive probe (ARP) is used to

measure AP sites in living cells [16]. The assay was applied to

living

cells and nuclei. The number of AP sites in old human fibroblasts

(IMR90

cells) was about two to three times higher than that in young cells,

and

the number in human leukocytes from old donors was about seven times

that in young donors. The repair of AP sites was slower in senescent

compared with young IMR90 cells. An age-dependent decline is shown

in

the activity of the glycosylase that removes methylated bases in

IMR90

cells and in human leukocytes. The decline in excision of methylated

bases from DNA suggests an age-dependent decline in 3-methyladenine

DNA

glycosylase, a BER enzyme responsible for removing alkylated bases.

 

Micronutrients and DNA Damage

Approximately 40 micronutrients are required in the human diet.

Deficiency of vitamins B12, folic acid, B6, niacin, C, or E, or

iron, or

zinc, appears to mimic radiation in damaging DNA by causing single-

and

double-strand breaks, oxidative lesions, or both [1]. The percentage

of

the U.S. population that has a low intake (less than 50% of the RDA)

for

each of these eight micronutrients ranges from 2% to 20+%; half of

the

population may be deficient in at least one of these micronutrients

[1].

We have shown [17] that folate deficiency breaks chromosomes due to

massive incorporation of uracil in human DNA (4 million/cell) with

subsequent single strand breaks in DNA formed during base excision

repair: two nearby single strand breaks on opposite strands cause

the

chromosome to fall apart. The level of folate where we see high

uracil

and breaks was present in 10% of the U.S. population and close to

half

of poor urban minorities due to poor diets. Vitamin B12 (14%

elderly)

and B6 (10% of U.S.) deficiencies also cause high uracil in human

DNA

and chromosome breaks as indicated by our new evidence and as

expected

from mechanistic considerations. We are currently attempting to

determine the level of these three vitamins that minimizes both

nuclear

and mitochondrial DNA damage in humans. We have evidence that

inadequate

iron (19% of women of menstruating age in the U.S.) causes oxidative

damage to mtDNA in rats [18, 19] and that inadequate zinc intake

causes

DNA damage.

 

Micronutrient deficiency may explain, in good part, why the quarter

of

the population that eats the fewest fruits and vegetables (5

portions a

day is advised) has about double the cancer rate for most types of

cancer when compared to the quarter with the highest intake [1]. A

number of other degenerative diseases of aging are also associated

with

low fruit and vegetable intake. 80% of American children and

adolescents

and 68% of adults do not eat 5 portions a day [1]. Common

micronutrient

deficiencies are likely to damage DNA by the same mechanism as

radiation

and many chemicals, appear to be orders of magnitude more important,

and

should be compared for perspective [1, 20].

 

Micronutrients and Sperm.

We are investigating the effect of inadequate micronutrient intake

on

genetic damage to sperm [1]. We have shown that folic acid

deficiency

decreases the sperm count in the rat by 90%, and that uracil is

found in

the sperm DNA of men on low fruit and vegetable diets. Our recent

work

in humans [21] shows an inverse association between the level of the

non-methyl THF pool, but not the methyl-THF pool, with both sperm

count

and quality, consistent with a uracil misincorporation mechanism. We

had

previously shown that men with low vitamin C intake had more

oxidative

damage to their sperm DNA and that male smokers (smoking depletes

the

vitamin C level markedly) had more oxidative damage to their sperm

[1].

Recent epidemiology supports the notion that smoking males have more

offspring with childhood cancer.

 

SELECTED PUBLICATIONS

1. Ames, B.N., DNA Damage from micronutrient deficiencies is likely

to

be a major cause of cancer. Mutat. Res., 2001. 475: 7-20.

2. Ames, B.N., I. Elson-Schwab, and E. Silver, High-dose vitamins

stimulate variant enzymes with decreased coenzyme-binding affinity

(increased Km): relevance to genetic disease and polymorphisms. Am J

Clin Nutr, 2002. 75: April.

3. Shigenaga, M.K., T.M. Hagen, and B.N. Ames, Oxidative damage and

mitochondrial decay in aging. Proc. Natl. Acad. Sci. USA, 1994. 91:

10771-10778.

4. Beckman, K.B. and B.N. Ames, The free radical theory of aging

matures. Physiol. Rev., 1998. 78: 547-581.

5. Hagen, T.M., D.L. Yowe, J.C. Bartholomew, C.M. Wehr, K.L. Do, J.-

Y.

Park, and B.N. Ames, Mitochondrial decay in hepatocytes from old

rats:

Membrane potential declines, heterogeneity and oxidants increase.

Proc.

Natl. Acad. Sci. USA, 1997. 94: 3064-3069.

6. Helbock, H.J., K.B. Beckman, M.K. Shigenaga, P. Walter, A.A.

Woodall,

H.C. Yeo, and B.N. Ames, DNA oxidation matters: The HPLC-EC assay of

8-oxo-deoxyguanosine and 8-oxo-guanine. Proc. Natl. Acad. Sci. USA,

1998. 95: 288-293.

7. Beckman, K.B. and B.N. Ames, Mitochondrial aging: open questions.

Ann. N. Y. Acad. Sci., 1998. 854: 118-27.

8. Liu, J., D. Killilea, and B.N. Ames, Age-associated mitochondrial

oxidative decay: Improvement carnitine acetyltransferase substrate

binding affinity and activity in brain by feeding old rats

acetyl-L-carnitine and/or ®-alpha-lipoic acid. Proc Natl Acad Sci

U S

A, 2002. 99: 1876-1881.

9. Liu, J., E. Head, A.M. Gharib, W. Yuan, R.T. Ingersoll, T.M.

Hagen,

C.W. Cotman, and B.N. Ames, Memory loss in old rats is associated

with

brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by

feeding acetyl-L-carnitine and/or ®-alpha-lipoic acid. Proc Natl

Acad

Sci U S A, 2002. 99: 2356-2361.

10. Hagen, T.M., J. Liu, J. Lykkesfeldt, C.M. Wehr, R.T. Ingersoll,

V.

Vinarsky, J.C. Bartholomew, and B.N. Ames, Feeding acetyl-L-

carnitine

and lipoic acid to old rats significantly improves metabolic

function

while decreasing oxidative stress. Proc Natl Acad Sci U S A, 2002.

99:

1870-1875.

11. Hagen, T.M., R.T. Ingersoll, C.M. Wehr, J. Lykkesfeldt, V.

Vinarsky,

J.C. Bartholomew, M.-H. Song, and B.N. Ames, Acetyl-L-carnitine fed

to

old rats partially restores mitochondrial function and ambulatory

activity. Proc. Natl. Acad. Sci. USA, 1998. 95: 9562-9566.

12. Lykkesfeldt, J., T.M. Hagen, V. Vinarsky, and B.N. Ames,

Age-associated decline in ascorbic acid concentration, recycling and

biosynthesis in rat hepatocytes - reversal with ®-alpha-Lipoic

acid

supplementation. FASEB J., 1998. 12: 1183-1189.

13. Hagen, T.M., R.T. Ingersoll, J. Liu, J. Lykkesfeldt, C.M. Wehr,

V.

Vinarsky, J.C. Bartholomew, and B.N. Ames, ®-alpha-Lipoic

acid-supplemented old rats have improved mitochondrial function,

decreased oxidative damage, and increased metabolic rate. FASEB J.,

1998. 13: 411-418.

14. Hagen, T.M., C.M. Wehr, and B.N. Ames, Mitochondrial decay in

aging.

Reversal through dietary supplementation of acetyl-L-carnitine and

N-tert-butyl-a-phenylnitrone. Ann. N. Y. Acad. Sci., 1998. 854: 214-

223.

 

15. Hagen, T.M., V. Vinarsky, C.M. Wehr, and B.N. Ames, ®-alpha-

lipoic

acid reverses the age-associated increase in susceptibility of

hepatocytes to tert-butylhydroperoxide both in vitro and in vivo.

Antiox. Redox Signal., 2000. 2: 473-483.

16. Atamna, H., I. Cheung, and B.N. Ames, A method for detecting

abasic

sites in living cells: age-dependent changes in base excision

repair.

Proc Natl Acad Sci U S A, 2000. 97(2): 686-91.

17. Blount, B.C., M.M. Mack, C. Wehr, J. MacGregor, R. Hiatt, G.

Wang,

S.N. Wickramasinghe, R.B. Everson, and B.N. Ames, Folate deficiency

causes uracil misincorporation into human DNA and chromosome

breakage:

Implications for cancer and neuronal damage. Proc. Natl. Acad. Sci.

USA,

1997. 94: 3290-3295.

18. Atamna, H., P.W. Walter, and B.N. Ames, The role of heme and

iron-sulfur clusters in mitochondrial biogenesis, maintenance, and

decay

with age. Arch. Biochem. Biophys., 2002. 397: 345-353.

19. Walter, P.W., M.D. Knutson, A. Paler-Martinez, S. Lee, Y. Xu,

F.E.

Viteri, and B.N. Ames, Iron deficiency and iron excess damage

mitochondria and mitochondrial DNA in rats. Proc Natl Acad Sci U S

A,

2002. 99: 2264-2269.

20. 20. Ames, B.N. and L.S. Gold, Paracelsus to parascience: the

environmental cancer distraction. Mutat Res, 2000. 447(1): 3-13.

21. Wallock, L.M., T. Tamura, C.A. Mayr, K.E. Johnston, B.N. Ames,

and

R.A. Jacob, Low seminal plasma folate concentrations are associated

with

low sperm density and count in male smokers and nonsmokers. Fertil.

&

Steril., 2001. 75: 252-259.

 

 

• CURRICULUM VITAE • RESEARCH • PUBLICATIONS •

 

Dr. Bruce Ames' Publications are available by request. Please

Include

Contact Information and most importantly a valid e-mail address.

Contact

Information

Mailing Address: Children's Hospital Oakland Research Institute

(CHORI),

5700 Martin Luther King Jr. Way, .

Phone: (510) 450-7625

CHORI E-mail: bam-

UCB E-mail: bna-

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