Chapter One - The Mitochondrial Free Radical Theory of Aging

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Abstract

The mitochondrial free radical theory of aging is reviewed. Only two parameters currently correlate with species longevity in the right sense: the mitochondrial rate of reactive oxygen species (mitROS) production and the degree of fatty acid unsaturation of tissue membranes. Both are low in long-lived animals. In addition, the best-known manipulation that extends longevity, dietary restriction, also decreases the rate of mitROS production and oxidative damage to mtDNA. The same occurs during protein restriction as well as during methionine restriction. These two manipulations also increase maximum longevity in rodents. The decrease in mitROS generation and oxidative stress that takes place in caloric restriction seems to be due to restriction of a single dietary substance: methionine. The information available supports a mitochondrial free radical theory of aging focused on low generation of endogenous damage and low sensitivity of membranes to oxidation in long-lived animals.

Introduction

Many different theories of aging have been proposed, but the mitochondrial free radical theory of aging (MFRTA)1 can still afford the best explanation for aging and longevity in mammals, birds, and multicellular animals in general. Any aging theory must explain why maximum longevity (referred here as “longevity”) varies so widely in animals: 30-fold from mice to men, 200-fold from shrews to the longest-living whales, or more than 5000-fold from perhaps a few days in some invertebrates to Arctica islandica mussels (longevity around 400 years). Such huge differences indicate that longevity is markedly regulated and flexible during species evolution. Copying only a small fraction of this natural capacity would make possible in the future to obtain negligible senescence in humans. It is known that mean life-span or the life expectancy at birth of the individuals of a population depends more on the environment than on the genes. On the contrary, longevity and its inverse—the species aging rate—depend more than 90% on the genotype, like in the case of any other species-specific trait. Longevity and aging rate are the main parameters that matter concerning the endogenous process of aging, which is situated at the main root of all the degenerative killer diseases. Presently, only two known factors correlate in the right sense with animal longevity in vertebrates including mammals and birds: (a) the rate of mitochondrial reactive oxygen species production (mtROSp)1, 2, 3, 4 and (b) the degree of fatty acid unsaturation of tissue cellular membranes including the mitochondrial ones.5, 6 The longer the longevity of a species, the smaller these two parameters are. The decrease in mtROSp in long-lived animal species lowers their generation of endogenous (free radical) damage at mitochondria. The decrease in the fatty acid double bond index (DBI) and peroxidizability index (PI) lowers the sensitivity of the cellular and mitochondrial membranes to free radical attack. No other theory of aging has parameters like these correlating in the right sense with longevity across species and offering plausible mechanistic explanations for the accumulation of damage from endogenous origin. The two known parameters appropriately correlating with animal longevity appertain to the MFRTA, not to any alternative theory. This is important since any theory trying to explain aging must explain why longevity varies so widely among different animal species. Species closely related by phylogeny can have very different longevities, indicating that evolution of longevity is a relatively flexible and fast process, and thus can be subjected to experimental manipulation.

Section snippets

Antioxidants and Longevity

Studies about MFRTA first focused in antioxidants, mainly because they could be measured with rather simple laboratory assays. In 1993, it was found that both enzymatic and nonenzymatic endogenous tissue antioxidants, including catalase, GSH-peroxidases, GSH-reductases, GSH, or ascorbate, correlated with longevity across vertebrates. However, and rather surprisingly, such correlation was negative7 instead of positive as it was then widely believed. That review on the relationship between

Mitochondrial ROS Production and Oxidative Damage in mtDNA

What is the reason why long-lived animals need less antioxidant levels in their vital organs? It was proposed10 that the rate of mtROSp could be negatively correlated with longevity and that this would be the critical factor for aging. Long-lived animals would not need to maintain high antioxidant enzyme levels, which is energetically expensive, because they would produce mtROS at a low pace (and they could transitorily induce them if needed). This was indeed experimentally corroborated both

Longevity and Membrane Fatty Acid Unsaturation

In addition to mtROSp, there is a second known parameter that also correlates with longevity in the right way, the fatty acid unsaturation degree of cellular (including mitochondrial) membranes. This is also firmly established since it has been studied many times and concordant results were always obtained. The degree of fatty acid unsaturation can be summarized as the DBI or alternatively as the PI. The longer the longevity of the species, the smaller the total number of fatty acid double

DR, mtROS Production, and Oxidative Damage in mtDNA

It is well known that standard (40%) DR increases not only mean but also maximum longevity (by around 40%) and decreases and delays the incidence of degenerative diseases in laboratory rodents, rotifers, flies, spiders, worms, fish, and other mammalian species.27 In rhesus monkeys, it was observed that 30%DR strongly decreases age-related mortality (from 37% to 13%), age-related diseases, and age-associated brain atrophy.28 Many mechanisms of action of DR on longevity have been proposed

Effect on longevity

It has been generally agreed for a long time that calorie intake per se would be exclusively responsible for the increase in life-span induced by DR in rodents. However, now many studies question this classical consensus. The results of many investigations are consistent with the possibility that part of the life-extending effects on DR is due to the decreased intake of particular components of the diet, such as proteins, and more specifically the amino acid methionine.37, 38, 39, 40, 41

Conclusions

An updated version of the MFRTA described above is schematized in Fig. 1.2. Long-lived mammals and birds have species-specific low mitochondrial ROS generation rates at complex I and low fatty acid unsaturation degrees in the cellular and mitochondrial membranes. These are the only two known traits correlating with animal longevity in the right sense concerning not only MFRTA but also all theories of aging in general. The close vicinity or even contact between the site of ROS generation and

Acknowledgments

Results obtained at the author laboratory described in this review have been supported by Grant No. BFU2011-23888 from the Ministry of Science and Innovation to G. Barja.

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