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 ,

The hypothesis that oxygen free radicals are causally involved in the aging process was tested by a study of the effects of simultaneous overexpression of copper-zinc superoxide dismutase and catalase. As compared to diploid controls, transgenic flies carrying three copies of each of these genes exhibited as much as a one-third extension of life-span, a longer mortality rate doubling time, a lower amount of protein oxidative damage, and a delayed loss in physical performance. Results provide direct support for the free radical hypothesis of aging.

No abstract

No abstract

The mechanisms that cause aging are not well understood. The oxidative stress hypothesis proposes that the changes associated with aging are a consequence of random oxidative damage to biomolecules. We hypothesized that oxidation of specific proteins is critical in controlling the rate of the aging process. Utilizing an immunochemical probe for oxidatively modified proteins, we show that mitochondrial aconitase, an enzyme in the citric acid cycle, is a specific target during aging of the housefly. The oxidative damage detected immunochemically was paralleled by a loss of catalytic activity of aconitase, an enzyme activity that is critical in energy metabolism. Experimental manipulations which decrease aconitase activity should therefore cause a decrease in life-span. This expected decrease was observed when flies were exposed to hyperoxia, which oxidizes aconitase, and when they were given fluoroacetate, an inhibitor of aconitase. The identification of a specific target of oxidative damage during aging allows for the assessment of the physiological age of a specific individual and provides a method for the evaluation of treatments designed to affect the aging process.