Optimal micronutrients delay mitochondrial decay and age-associated diseases
Children's Hospital Oakland Research Institute, Nutrition and Metabolism Center, Oakland, CA 94609, USA. Mechanisms of ageing and development
(Impact Factor: 3.4).
07/2010; 131(7-8):473-9. DOI: 10.1016/j.mad.2010.04.005
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.
Available from: Ash Virmani
- "Further studies are needed to define in more detail the mechanism of acetylcarnitine action at the molecular level and to explore the translational aspects of acetylcarnitine treatment. Acetylcarnitine diminishes the aging defect in different tissues (Paradies et al., 1992, 1994, 1995; Hagen et al., 1998; Iossa et al., 2002; Virmani and Binienda, 2004; Virmani et al., 2004; Lesnefsky et al., 2006; Ames, 2010) and has been tested in Clinical Phase I, II, and III studies on humans with no side effects. Since orally administered acetylcarnitine was as effective in increasing the mitochondrial acetylation potential as was intraperitoneal injection, it provides a convenient, non-invasive, and safe way to treat and to prevent the adverse cardiac effects associated with aging. "
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ABSTRACT: Previously we showed that in vivo treatment of elderly Fisher 344 rats with acetylcarnitine abolished the age-associated defect in respiratory chain complex III in interfibrillar mitochondria and improved the functional recovery of the ischemic/reperfused heart. Herein, we explored mitochondrial protein acetylation as a possible mechanism for acetylcarnitine's effect. In vivo treatment of elderly rats with acetylcarnitine restored cardiac acetylcarnitine content and increased mitochondrial protein lysine acetylation and increased the number of lysine-acetylated proteins in cardiac subsarcolemmal and interfibrillar mitochondria. Enzymes of the tricarboxylic acid cycle, mitochondrial β-oxidation, and ATP synthase of the respiratory chain showed the greatest acetylation. Acetylation of isocitrate dehydrogenase, long-chain acyl-CoA dehydrogenase, complex V, and aspartate aminotransferase was accompanied by decreased catalytic activity. Several proteins were found to be acetylated only after treatment with acetylcarnitine, suggesting that exogenous acetylcarnitine served as the acetyl-donor. Two-dimensional fluorescence difference gel electrophoresis analysis revealed that acetylcarnitine treatment also induced changes in mitochondrial protein amount; a two-fold or greater increase/decrease in abundance was observed for thirty one proteins. Collectively, our data provide evidence for the first time that in the aged rat heart in vivo administration of acetylcarnitine provides acetyl groups for protein acetylation and affects the amount of mitochondrial proteins.
Copyright © 2015. Published by Elsevier Ireland Ltd.
Available from: Bruce Ames
- "The author is indebted to J. McCann, D. Killilea, S. Shenvi, and J. Suh for helpful criticisms and to the many excellent students and colleagues who have contributed to this work. This paper has been adapted in part from . "
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ABSTRACT: I review three of our research efforts which suggest that optimizing micronutrient intake will in turn optimize metabolism, resulting in decreased DNA damage and less cancer as well as other degenerative diseases of aging. (1) Research on delay of the mitochondrial decay of aging, including release of mutagenic oxidants, 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 DNA damage, mitochondrial decay, and supportive evidence for the theory, including an in-depth analysis 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 an age-related decline in membrane fluidity, or to polymorphisms or mutation. The loss of enzyme function can be compensated by a high dietary intake of any of the B vitamins, which increases the level of the vitamin-derived coenzyme. This dietary remediation illustrates the importance of understanding the effects of age and polymorphisms on optimal micronutrient requirements. Optimizing micronutrient intake could have a major effect on the prevention of cancer and other degenerative diseases of aging.
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ABSTRACT: An anti-mutagen is any substance that reduces the rate of spontaneous mutations or counteracts or reverses the action of a mutagen, or any technique that protects cells against the effects of mutagens. Studies as early as the 1940s reported on substances that delayed detection of radiation-induced mutations, or reduced the appearance of mutations induced by chemicals such as acridine orange. However, a far more sophisticated range of anti-mutagens is now being identified. Mutagen scavengers act through absorption onto a larger molecule that is readily excreted. Good examples are provided by dietary fibre sources, such as wheat bran, or the planar molecule, chlorophyll and its stabilised derivative, chlorophyllin. Mutagens may be actively extruded from human cells through the action of one or more of a series of ATP-binding cassette (ABC) drug transporter proteins, including the multidrug resistance proteins (P-glycoproteins), multidrug resistance-associated proteins (MRP1-7) and the breast cancer resistance protein (BCRP). These proteins can affect the absorption, distribution and excretion of mutagens and carcinogens, as well as of their metabolites and conjugates. Even if the undesirable compound enters the cells, there are several mechanisms by which it may be prevented from interaction with DNA. Detoxification mechanisms are of increasing interest, especially those where transcription is regulated through the antioxidant response element (ARE), whose own transcription factor, Nrf2, is repressed under basal conditions. While much of the early literature on mutagenesis and carcinogenesis implicated exogenous chemicals, it is increasingly realised that unrepaired oxidative DNA lesions are important mutational precursors, and anti-oxidants represent an important class of anti-mutagens. It is also recognised that deficiency of certain micronutrients may lead to cell mutation, and that restoring nutrient balance is an important mechanism of antimutagenesis. An increasing number of studies focus on DNA repair and stress responses as novel mechanisms of anti-mutagenesis.
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