Review
Optimal micronutrients delay mitochondrial decay and age-associated diseases

https://doi.org/10.1016/j.mad.2010.04.005Get rights and content

Abstract

Three of our research efforts are reviewed, which suggest that optimizing metabolism will delay aging and the diseases of aging in humans. (1) Research on delay of the mitochondrial decay of aging by supplementing rats with lipoic acid and acetyl carnitine. (2) The triage theory, which posits that modest micronutrient deficiencies (common in much of the population) accelerate molecular aging, including mitochondrial decay, and supportive evidence, including an analysis in depth of vitamin K, that suggests the importance of achieving optimal micronutrient intake for longevity. (3) The finding that decreased enzyme binding constants (increased Km) for coenzymes (or substrates) can result from protein deformation and loss of function due to loss of membrane fluidity with age, or to polymorphisms or mutation. The loss of enzyme function can be ameliorated by high doses of a B vitamin, which raises coenzyme levels, and indicates the importance of understanding the effects of age, or polymorphisms, on micronutrient requirements.

Section snippets

Lipoic acid and acetyl carnitine supplements decrease the mitochondrial decay of aging

Mitochondrial decay appears to be a major contributor to aging and its associated degenerative diseases including cancer and neural decay (Shigenaga et al., 1994, Beckman and Ames, 1998). Mitochondria from old rats compared with those from young rats generate increased amounts of oxidant by-products (Hagen et al., 2002a), and have decreased membrane potential, respiratory control ratio, cellular oxygen consumption, and cardiolipin (a key lipid found in mitochondria). Oxidative damage to DNA,

Triage theory suggests a cause of much preventable aging-associated disease

The “triage theory” (Ames, 2006, Ames and McCann, 2009) provides a unifying rationale for a causal link between deficiency of a micronutrient (∼40 essential minerals, vitamins, amino acids and fatty acids) and the many degenerative diseases accompanying aging such as cancer, immune dysfunction, cognitive decline, cardiovascular disease, and stroke. These diseases might be delayed by an inexpensive micronutrient intervention (Ames and McCann, 2009).

Triage theory (Ames, 2006, Ames and McCann, 2009

Enzymes lose binding affinity (increased Km) for coenzymes and substrates with mutation or age: a strategy for remediation with high dose vitamins

A review (Ames et al., 2002) showed that about 50 human genetic diseases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme, which at least partially restores enzyme activity. Up to a quarter of mutations in a gene result in the corresponding enzyme having a decreased binding constant (increased Km) for a coenzyme resulting in a lower rate of reaction. The review points out that many of the B

Conclusion

The work on acetyl carnitine and lipoic acid in rodents and dogs suggests that decay of mitochondria leading to dementia and a variety of other diseases of aging in humans is not inevitable, but may be delayed by various interventions to improve metabolism. Understanding the mechanisms will suggest still other interventions. For example, if lipoic acid is effective because it induces the ∼200 enzymes in the phase-2 defense system against oxidants, as seems likely, then the whole area of

Conflict of interest

Dr. Ames is one of the founders of Juvenon (www.juvenon.com), a company that has licensed the University of California patent on acetyl carnitine + lipoic acid for rejuvenating old mitochondria (Ames and T. Hagen, inventors), sells acetyl carnitine + lipoic acid supplements, and does clinical trials on them. Ames founder's stock was put in a non-profit foundation at the founding in 1999. He is director of Juvenon's Scientific Advisory Board, but reimbursement for that from Juvenon is given to the

Acknowledgements

We are indebted to T. Hagen, D. Killilea, J. Liu, J. McCann, S. Shenvi, and J. Suh for helpful criticisms and to the many excellent students and colleagues who have contributed to this work.

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