Large genome rearrangements as a primary cause of aging
Introduction
In 1986, Bernard Strehler pointed out that classical mutations (i.e. point mutations) in structural genes were unlikely to be a cause of aging, because the rate of aging does not depend on gene copy number (i.e. ploidy level) and the dose of mutagen required to shorten life span is much greater than the dose required to produce a lifetime's worth of classical somatic mutations (Strehler, 1986). The ploidy problem became evident by experiments in which survival of haploid and diploid wasps of the genus Habrobracon were compared after normal aging and X-irradiation. Although X-irradiation reduced lifespan of the haploid variant more than that of its diploid counterpart, their normal aging rate was the same (Clark and Rubin, 1961). However, as pointed out by Morley (Morley, 1982), all that the Habrobracon experiments demonstrated was that recessive mutations appeared not to be a cause of aging (at least, in insects). Dominant and co-dominant mutations could still be important. Strehler himself presented evidence that deletions of tandemly duplicated copies of ribosomal RNA genes rather than classical mutations account for the major losses in function during aging. This specific mechanism has recently also emerged as a major cause of aging in yeast, as discussed extensively elsewhere in this special issue. The argument that the life-time dose of spontaneous mutagens would not be high enough to cause aging was also used by John Maynard Smith (Maynard Smith, 1959) in his original critique on Szilard's proposal that random hits, rendering the genes of a whole chromosome ineffective, could be a main causal factor in aging (Szilard, 1959). According to Maynard Smith, such types of mutations do not seem likely to be common enough to be the main cause of aging. However, at the time quantitative information on the possible age-related accumulation of different types of mutations in various tissues of mammals was completely lacking. The question, therefore, whether somatic mutations are a cause of aging, has not been resolved, more than four decades after the first somatic mutation theories of aging were formulated.
Section snippets
DNA repair, mutations and aging
Mutations can generally be defined as all possible changes in the base sequence of DNA. They occur in different types, varying from one-basepair substitutions or deletions (Strehler's classical mutations) to large deletions or translocations involving millions of basepairs. The latter are often referred to as chromosomal mutations, since the largest ones can be readily observed in metaphase plates of actively proliferating cells. It is generally believed that the first step in mutation
A model for measuring mutations in vivo
Due to a lack of methods to quantify and characterize mutations in vivo, i.e. in different organs and tissues, it has proved difficult to test the premise that mutations accumulate during aging of mammals in a sufficiently high number to cause some of the pathophysiological symptoms of aging (Curtis, 1963). To address this problem, transgenic mouse models have been developed harboring reporter genes, which can be recovered from their integrated state and analyzed for mutations in Escherichia
Possible role of genome rearrangements in aging
Evidence that genome rearrangements could contribute to aging-related phenotypes in humans can be obtained from studies of patients with Werner syndrome. This segmental progeroid syndrome is based on a recessive mutation in the WRN gene causing increased risk for atherosclerosis, cancer, osteoporosis and type two diabetes as well as early hair loss, graying of the hair, atrophy of the skin and cataracts. Cultured somatic cells from Werner patients display an increased rate of genome
Acknowledgments
The research described in this paper was supported by NIH grants AG 17242, AG13319 and ES11044. We are greatly indebted to the late Bernard Strehler for the inspiration provided by his early work on genome instability and aging and (the first author of this paper) for spirited discussion on the somatic mutation theory of aging.
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