We propose 3 Specific Aims: #t) To feed old rats high doses of 8 B vitamins, which markedly raise coenzyme levels in humans, to ameliorate the mitochondrial decay of aging and thus improve motor, cognitive and neuromuscular functions, which will be tested to determine the Optimum dose. #2) To determine whether the mitochondrial dysfunction of age is in part restored by this feeding and whether coenzyme levels are indeed higher in the old rats. #3) To test the effect of feeding high-dose B vitamins with mitochondrial metabolites acetyl carnitine and lipoic acid, which we have shown delay mitochondrial decay. The rationale for this project is as follows. Mitochondria contain about 1,000 proteins and they host much cell metabolism. Mitochondrial decay, ? due to oxidant leakage from the electron transport chain, plays an important role in aging and age-associated neurodegenerative diseases. Oxidation of mitochondrial RNA/DNA, enzymes, and membrane lipid increases with age, despite constant mitochondrial turn over. Such oxidation deforms many mitochonddal enzymes during aging by direct protein oxidation, adduction of aldehydes from lipid peroxidation, and, in the case of membrane proteins, decrease in fluidity of oxidized membranes. These enzyme modifications cause a decrease in their affinity for their substrates or coenzymes. For example, carnitine acetyl transferase loses binding affinity for CoA as well as for acetyl carnitine. Many mitochondrial enzymes lose activity with age and feeding high levels of several mitochondrial metabolites may reverse some of the decay of aging. We have documented in detail in a recent review that feeding high-dose B vitamins to humans, markedly elevates the respective coenzyme levels, and thus stimulates the activity of defective human enzymes with decreased coenzyme-binding affinity. About 50 human genetic diseases due to defective enzymes, including 14 in mitochondria, can be remedied by the ingestion of high levels of the vitamin component of the corresponding coenzyme. Vitamin pills are sold containing 25, 50 or 100 mg of each of the B vitamins (i.e., 10 to 100 times the RDA), yet no convincing reason is available for using such high doses. We suggest that there may be a rational basis for using high-dose B vitamins. This proposal is scientifically plausible, novel, and could have a high pay-off: if old people require high doses of B vitamins to delay mitochondrial decay and the degenerative diseases of aging, there could be a major improvement in public health and a new research direction in nutrition. ? ?
| Long, Jiangang; Gao, Feng; Tong, Liqi et al. (2009) Mitochondrial decay in the brains of old rats: ameliorating effect of alpha-lipoic acid and acetyl-L-carnitine. Neurochem Res 34:755-63 |
| Mashiyama, Susan T; Hansen, Christine M; Roitman, Esther et al. (2008) An assay for uracil in human DNA at baseline: effect of marginal vitamin B6 deficiency. Anal Biochem 372:21-31 |
| Ames, Bruce N (2006) Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proc Natl Acad Sci U S A 103:17589-94 |
| Ames, Bruce N; Atamna, Hani; Killilea, David W (2005) Mineral and vitamin deficiencies can accelerate the mitochondrial decay of aging. Mol Aspects Med 26:363-78 |
