Under normal physiological conditions, the use of oxygen by cells of aerobic organisms generates potentially deleterious reactive oxygen metabolites. A chronic state of oxidative stress exists in cells because of an imbalance between prooxidants and antioxidants. The amount of oxidative damage increases as an organism ages and is postulated to be a major causal factor of senescence. Support for this hypothesis includes the following observations: (i) Overexpression of antioxidative enzymes retards the age-related accrual of oxidative damage and extends the maximum life-span of transgenic Drosophila melanogaster. (ii) Variations in longevity among different species inversely correlate with the rates of mitochondrial generation of the superoxide anion radical and hydrogen peroxide, (iii) Restriction of caloric intake lowers steady-state levels of oxidative stress and damage, retards age-associated changes, and extends the maximum life-span in mammals.A common feature of the life cycle of virtually all multicellular organisms is the progressive decline in the efficiency of various physiological processes once the reproductive phase of life is over. A variety of strategies and models have been used to understand the nature of the mechanisms underlying the phenomenon of senescence. Frequently the purported explanations or hypotheses deal with the manifestations of aging, which are unlikely to be self-initiating, rather than with a more fundamental underlying cause accounting for the plethora of changes associated with senescence. To elucidate the mechanisms of aging, any causal hypothesis should explain the following three conditions: (i) why organisms undergo progressive and irreversible physiological decline in the latter part of life, (ii) why the life expectancy or rate of aging varies within and among species, and (iii) why experimental regimens such as caloric restriction delay the onset of a variety of age-associated physiological and pathological changes and extend the average and maximum life-span of animals. A mechanistic understanding of the effects of caloric restriction is important because of the efficacy of this regimen in the prolongation of the maximum life-span of mammals and because of its implications for human health.A hypothesis ascribing one cause for aging postulates that the senescence-associated loss of functional capacity is due to the accumulation of molecular oxidative damage (1-4). This hypothesis is based on the fact that oxygen is potentially a toxic substance, and its use by aerobes, although necessary for their immediate survival, also may be hazardous to their longterm existence. The phenomenon of oxygen toxicity, sometimes referred to as the "oxygen paradox," is inherent in the atomic structure of oxygen. Molecular oxygen is a biradical that upon single electron additions sequentially generates the partially reduced molecules ,

Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.

Caloric restriction (CR) without malnutrition delays aging and extends lifespan in diverse species; however, its effect on resistance to illness and mortality in primates is not clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported 50% of control fed animals survived compared with 80% survival of CR animals. Further, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.