Bruce N. Ames

About Dr. Ames

Dr. Ames is a Professor of Biochemistry and Molecular Biology, University of California, Berkeley, and a Senior Scientist at Children's Hospital Oakland Research Institute (CHORI).

He is a member of the National Academy of Sciences and he was on their Commission on Life Sciences. He was a member of the board of directors of the National Cancer Institute, the National Cancer Advisory Board, from 1976 to 1982. He was the recipient of the General Motors Cancer Research Foundation Prize (1983), the Tyler Environmental Prize (1985), the Gold Medal Award of the American Institute of Chemists (1991), the Glenn Foundation Award of the Gerontological Society of America (1992), the Lovelace Institutes Award for Excellence in Environmental Health Research (1995), the Honda Prize of the Honda Foundation, Japan (1996), the Japan Prize, (1997), the Kehoe Award, American College of Occup. and Environ. Med. (1997), the Medal of the City of Paris (1998), the U.S. National Medal of Science (1998), The Linus Pauling Institute Prize for Health Research (2001), and the American Society for Microbiology Lifetime Achievement Award (2001).

His over 450 publications have resulted in his being among the few hundred most-cited scientists (in all fields): 23rd most-cited (1973-1984). 

Research Interests

The research of the lab involves various aspects of tuning-up metabolism to optimize health.

Mitochondrial decay with age due to oxidation of RNA/DNA, proteins, and lipids, is a major contributor to aging and the degenerative diseases of aging. 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 (1-3). Feeding old rats the normal mitochondrial metabolites acetyl carnitine (ALC) and lipoic acid (LA) at high levels for a few weeks reverses much of this decay, the two complementing each other, in some cases synergistically, and restores the lost mitochondrial function to the level of young mitochondria (1-3). Ambulatory activity, cognition, heart, and immune function decline with age and feeding ALC and LA to the old rats also restores a good part of the lost function (1-4). Considerable progress has been made in understanding the mechanism of action of the two metabolites (1-3, 5, 6). LA is a mitochondrial coenzyme and is reduced in the mitochondria to a potent antioxidant, dihydrolipoic acid. LA is also an effective inducer of the phase-2 antioxidant enzymes, about 200 enzymes including those required for glutathione synthesis (5, 6).

Inadequate intakes of vitamins and minerals from food can lead to DNA damage, mitochondrial decay, and other pathologies (7). Intakes below the EAR, i.e. 2 standard deviations <RDA, are widespread (e.g. in the U.S.: 56% for magnesium; 12% for zinc; 16% menstruating women for iron; 16% of women for folate) (7). Intakes <EAR are particularly widespread among the poor, African-Americans, teenagers, the obese, and the elderly (7). Inadequate intake of folate, B12, or B6 leads to uracil incorporation into DNA and chromosome breaks ---a radiation mimic (8, 9). Inadequate zinc in human cells in culture causes release of oxidants, oxidative damage to DNA, and inactivation of p53 and other zinc enzymes involved in DNA damage repair (10, 11). Inadequate iron intake inactivates Complex IV in mitochondria, which causes oxidant release, mitochondrial decay, and DNA damage; in the brain complex IV inactivation mimics the neurodegeneration of aging (12, 13). Biotin inadequacy from food is present in 40% of pregnant women; biotin deficiency in human cells in culture leads to oxidant release, DNA damage, accelerated mitochondrial decay, and premature senescence (14). Magnesium deficiency in human cells in culture causes mtDNA- protein crosslinks, accelerated telemore shortening, and premature senescence (15). I suggest evolutionary allocation of scarce micronutrients by enzyme triage is an explanation of why DNA damage is commonly found on micronutrient deficiency (7). We are developing sensitive assays for measuring DNA damage in human blood (16) so as to determine what level of each micronutrient is optimum for keeping DNA damage to a minimum.

High dose B vitamins can counteract a poorer Km. As many as one-third of mutations in a gene result in the corresponding enzyme having an increased Km (decreased binding affinity) for a coenzyme, causing a lower rate of reaction (17, 18). About 50 different human genetic diseases due to a poorer binding affinity of the mutant enzyme for its coenzyme can be remedied by feeding high dose B vitamins, which raise levels of the corresponding coenzyme; many polymorphisms also result in a lowered affinity of enzyme for coenzyme (17) and thus may be in part remediable. We are exploring the effect of high dose B vitamins in delaying the mitochondrial decay of aging (18).

γ-Tocopherol, the main form of vitamin E in the U.S. diet, unlike α-tocopherol, the main form of vitamin E in supplements, is an effective inhibitor of three different inflammatory pathways cyclooxygenase (COX), LTB4, and TNFα at physiological concentrations, both in human cells in culture and in rats (19). Previous work on γT had shown it is an effective nucleophile, unlike αT, and can inactivate lipid-soluble electrophilic mutagens such as nitrogen oxides. Epidemiological evidence supporting the importance of dietary γT has been reviewed (20). γT also is effective in inhibiting prostate and lung tumor cells by interrupting sphingolipid synthesis (21).

An optimum intake of micronutrients and metabolites, which varies with age and genetics, should tune up metabolism and markedly increase health at little cost, particularly for the poor, obese, and elderly (7).

1. Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc. Natl. Acad. Sci. USA 2002;99:1870-5.
2. Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl-L-carnitine and/or R-α-lipoic acid. Proc. Natl. Acad. Sci. USA 2002;99:2356-61.
3. Liu J, Killilea D, Ames BN. Age-associated mitochondrial oxidative decay: Improvement of carnitine acetyltransferase substrate binding affinity and activity in brain by feeding old rats acetyl-L-carnitine and/or R-α-lipoic acid. Proc. Natl. Acad. Sci. USA 2002;99:1876-81.
4. Hagen TM, Moreau R, Suh JH, Visioli F. Mitochondrial decay in the aging rat heart: Evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or lipoic acid. Ann. NY Acad. Sci. 2002;959:491-507.
5. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc. Natl. Acad. Sci. USA 2004;101:3381-6.
6. Suh JH, Wang H, Liu RM, Liu J, Hagen TM. (R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: Evidence for increased cysteine requirement for GSH synthesis. Arch. Biochem. Biophys. 2004;423:126-35.
7. Ames BN. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proc. Natl. Acad. Sci. U.S.A. 2006;103:17589-94.
8. Ames BN, Wakimoto P. Are vitamin and mineral deficiencies a major cancer risk? Nat. Rev. Cancer 2002;2:694-704.
9. Courtemanche C, Huang AC, Elson-Schwab I, Kerry N, Ng BY, Ames BN. Folate deficiency and ionizing radiation cause DNA breaks in primary human lymphocytes: A comparison. FASEB J. 2004;18:209-11.
10. Ho E, Ames BN. Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFκB, and AP1 DNA-binding, and affects DNA repair in a rat glioma cell line. Proc. Natl. Acad. Sci. USA 2002;99:16770-5.
11. Ho E, Courtemanche C, Ames BN. Zinc deficiency induces oxidative DNA damage and increases p53 expression in human lung fibroblasts. J. Nutr. 2003;133:2543-8.
12. Atamna H, Killilea DW, Killilea AN, Ames BN. Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. Proc. Natl. Acad. Sci. USA 2002;99:14807-12.
13. Walter PW, Knutson MD, Paler-Martinez A, Lee S, Xu Y, Viteri FE, Ames BN. Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats. Proc. Natl. Acad. Sci. USA 2002;99:2264-9.
14. Atamna H, Newberry J, Erlitzki E, Schultz CS, Ames BN. Biotin deficiency inhibits heme synthesis and impairs mitochondria in human lung fibroblasts. J. Nutr. 2006; in press.
15. Killilea DW and Ames BN. Magnesium deficiency accelerates cellular senescence in cultured human fibroblasts. Proc Natl Acad Sci USA 2008; 105:5768-73.
16. Offer T, Ho E, Traber MG, Bruno RS, Kuypers FA, Ames BN. A simple assay for frequency of chromosome breaks and loss (micronuclei) by flow cytometry of human reticulocytes. FASEB J. 2005;19:485-7.
17. Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulate variant enzymes with decreased coenzyme-binding affinity (increased Km): Relevance to genetic disease and polymorphisms. Am. J. Clin. Nutr. 2002;75:616-58.
18. Ames BN, Suh JH, Liu J. Enzymes lose binding affinity for coenzymes and substrates with age: A strategy for remediation. In: Nutrigenomics: Discovering the path to personalized nutrition. eds. JKR Rodriguez & J Kaput. Hoboken: John Wiley & Sons, Inc., 2006:277-93.
19. Jiang Q, Ames BN. γ-Tocopherol, but not α-tocopherol, decreases proinflammatory eicosanoids and inflammation damage in rats. FASEB J. 2003;17:816-22.
20. Jiang Q, Christen S, Shigenaga MK, Ames BN. γ-Tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am. J. Clin. Nutr. 2001;74:714-22.
21. Jiang Q, Wong J, Fyrst H, Saba JD, Ames BN. γ-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. Proc. Natl. Acad. Sci. USA 2004;101:17825-30.