at least beyond middle age (Finch and Goodman, 1997; Evans et al., 1995). The molecular analysis so far shows that the reversions result from clustered replacements of amino acids. Moreover, if the mutant rats are given vasopressin hormone replacements, then the rate of reversion is slowed. Ongoing studies are evaluating whether other genes show these processes. The present findings point to an utterly different form of plasticity in molecular aging processes, which suggest that physiological manipulations could be used to intervene and reduce mutational changes in DNA.
Many laboratories are actively pursuing genes that influence life spans in short-lived animal models of aging, particularly nematodes (Johnson and Shook, in this volume), fruit lies (Rose, in this volume) (reviewed in Finch and Tanzi, 1997). Efforts to breed long-lived mice by selecting for reproduction at later ages are showing some success (Ngai et al, 1995) in parallel with similar studies on fruit flies (Rose, in this volume). In humans, genes that cause specific age-related diseases that shorten the life span are continuing to be identified, as in familial breast cancer, vascular disease, and Alzheimer disease. One of the progerias, Werner syndrome, which is characterized by intensified atherosclerosis and malignancy (both proliferative disorders), has been mapped to a gene predicted to encode a helicase, an enzyme that, by modifying DNA structure, may alter telomere replication (Yu et al., 1996).
The genetics of centenarians promises to reveal alleles that may favor extreme longevity, including the apoE2 allele (Schächter et al., 1994) and certain HLA haplotypes (Schächter, in press). There may be other general classes of genes that promote longevity through similar physiological mechanisms in widely different organisms, so-called "longevity assurance genes" or "gerogenes" (Jazwinski, 1996; Johnson and Shook, in this volume). One class of such genes may prove to reduce the effects of oxidative damage, a challenge to all organisms that exist in an oxidizing atmosphere and must cope with the myriad by-products of oxidative metabolism, including the continuing production of free radicals through oxidative phosphorylation. Atmospheric oxygen concentration increased steadily, if not monotonically, during the great radiations of the extant animal phyla more than 550 million years ago (Figure 13-2) and progressed to a maximum of 35 percent during the late Paleozoic Era (Graham et al., 1995). The machinery for combating oxidative stress was presumably subject to strong evolutionary pressures long before ancestors of the present long-lived birds and mammals had evolved in the Mesozoic Era. There is every reason to expect a continuing parade of genes controlling such protective mechanisms from diverse organisms that can shorten or lengthen life span.
At present, we do not understand the basis for the striking recent historical trends in increased life expectancy at the oldest ages in humans. It is unlikely that