Rate Of Aging
Aging is a complex process and is unlikely to result from a single cause or a single gene. Conditions that slow or accelerate aging and genes that control the rate of aging provide clues about what causes aging. Although aging is not equal to life span, genes that regulate life span are often important in resistance to stress and may be able to slow aging: superoxide dismutase prevents the accumulation of free radicals, and nucleotide excision repair enzymes repair DNA. Furthermore, cell stress resistance is correlated with maximum life span across species. Based on the evolutionary theory of aging, Thomas Kirkwood and Steven Austad predict that key enzymes that regulate the rate of aging are those involved in maintenance and repair. A gene involved in maintenance and repair that can regulate the rate of aging is exemplified by stress-induced p53. Free radicals, oxidative stress, DNA-damaging agents, and environmental stresses (including heat) result in increased activation of p53. The activation of p53 can lead to DNA repair, to cell cycle arrest in order to limit DNA replication (cellular replicative senescence), or to cell death, which is how it acts as a tumor suppressor to prevent cancer. In a study published in Nature in January 2002, transgenic mice that express mutant-activated p53, which augments wild-type p53 activity, show a resistance to tumors and early signs of some aging phenotypes, including reduced life span, osteoporosis, and multiple organ atrophy. Importantly, these mice also display a reduced ability to tolerate stress, as shown by delayed wound healing and reduced recovery from stress in old mice. These data suggest a role for the stress-induced cellular p53 response in organismal as well as cellular aging and in acceleration of some aging changes.
Caloric restriction not only retards aging but also reverses the effects of stress during aging by putting cells in a survival mode. It decreases free radical production and oxidative stress, reduces the load of damaged molecules, decreases sensitivity to genotoxic stress, and postpones declines in DNA repair. Caloric restriction also alters the expression of genes that regulate damage and stress-response pathways. Both heat shock stress and exposure to mild oxidative stress can result in hormesis, a beneficial effect that occurs in response to very low doses of agents that are toxic at higher doses. Minimal stress not only increases survival in fruit flies and nematodes but also increases life span. Caloric restriction also results in hormesis and may slow the aging process by inducing a mild stress response, including increases in heat shock protein 70 and glucocorticoids that afford protection against stress. In contrast, premature aging syndromes with shortened life spans result from single gene mutations that result in genomic instability, inability to repair DNA, and some of the phenotypes of aging.
The psychosocial environment determines how an individual perceives stress, and coping ability plays a role in age-associated functional decline. Few studies of stress focus on the oldest old (greater than eighty-five years), although they have frequent physical, emotional, and social changes that decrease their sense of control and require adaptation to stress. It is interesting that within this group are centenarians who have greater functional reserve and adaptive capacity, enabling them to overcome a disease or injury or to cope with stresses more effectively.
NANCY R. NICHOLS
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