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
). 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 long-term 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
, and ·OH, which by further reactions can generate an array of additional reactive oxygen metabolites (ROMs) and cause extensive oxidative damage to biological macromolecules (5
). This damage manifests as the peroxidation of membrane polyunsaturated fatty acid chains, modification of DNA (including base alterations, single-strand breaks, sister chromatid exchanges, and DNA-protein cross-links), and carbonylation and loss of sulfhydryls in proteins, among other changes. Carbonyl modifications of proteins occur in certain amino acid residues present near transition metal–binding sites and have been shown convincingly to cause enzymatic inactivation and enhance the likelihood of proteolysis (2
There are several indications that the oxidant challenge to aerobic cells is not trivial. It is estimated that ~2 to 3% of the oxygen consumed by aerobic cells is diverted to the generation of
). A typical cell in the rat may undergo 100,000 ROM attacks on DNA per day (3
), and under steady-state conditions, ~10% of protein molecules may exhibit carbonyl modifications (2
). The presence of the products of ROM interactions with macromolecules under steady-state conditions has led to the concept that antioxidative defenses are not fully efficient, that cells are chronically under oxidative stress, and that aging is a consequence of oxidative damage.