How the evolutionary theory of aging can guide us in the search for aging genes

a stroke of irony that lifespan — the principal phenotype used to search for aging genes — is a terrible phenotype for genetic analysis. Lifespan has relatively low heritability under most conditions, and it is affected by chronic, age-related diseases that confound its use as a biomarker of aging. If the majority of aging genes are pleiotropic, as proposed by the evolutionary theory of aging, an opportunity is provided to identify these genes through the " back door, " using phenotypes that are more amenable to genetic analysis. To choose the pleiotropic phenotype for our studies, we went back more than 50 years to Williams [1], who, in his seminal paper, specified four " physiological expectations that follow from the theory, " two of which we applied: " Rapid individual development should be correlated with rapid senescence, " and, to specify a particular developmental phenotype, " The time of reproductive maturation should mark the onset of senescence. " Therefore, to search for genes that regulate lifespan, we looked in the other direction — for genes that govern reproductive maturation. We started our search for pleiotropic aging genes by evaluating the age of female sexual maturity in the highly diverse, 32-inbred strain panel provided by The Jackson Laboratory Nathan Shock Center. As predicted by the evolutionary theory of aging, age of vaginal patency (VP) correlated positively with lifespan across strains. Interestingly, it also correlated negatively with circulating IGF1. And, because, in the same 32 strains of mice, 6-month IGF1 levels also correlate negatively with lifespan [2], it is likely that IGF1 mediates a significant portion of the linkage of reproductive maturation with aging and lifespan. We tested this idea in a congenic C57BL/6J (B6) mouse that carries a portion of Chr 10 from the C3H/HeJ strain. In congenic females, circulating IGF1 was elevated and as predicted, age of VP was accelerated and lifespan was shortened. (In males, IGF1 was not elevated and lifespan was not shortened.) Thus, the stage was set to begin a search for pleiotropic genes that influence both female reproductive maturation and lifespan in the strain panel. Using haplotype association mapping, we identified three loci (Vpq1 [Chr 4], Vpq2 and Vpq3 [both on Chr Editorial 16]) that accounted for 76% of the variance in age of VP across strains. Again, IGF1 may be involved. Age of VP was delayed and circulating IGF1 was diminished in the B6.PWD–Chr 16 …