I. Natural genetic variation and senescence
I.A. QTL analysis of maximum life span in wild-derived inbred lines of mice
In our search to discover genes that regulate maximum life spans, we studied two 4-way cross populations derived from a total of 8 mouse strains. Each 4-way cross included 1 wild-derived strain and 3 diverse inbred strains. We recently found alleles at 2 loci (5–10 cM chromosome regions identified by genetic markers) that extend maximum life spans (the longest lived 16–40%, giving maximum power [Klebonov & Harrison, 2002]) by at least 10–15% (Klebanov et al., 2001).
In the first cross, the longest-lived carriers of the D8Mit171 marker allele from the MOLD/Rk strain, Mus musculus molossinus, outlived the longest-lived noncarriers by more than 4 months. We identified this gene as Leg1 (longevity extending gene 1). In the second cross, the longest-lived carriers of the D10Mit267 allele from the CAST/Ei strain, Mus musculus castaneus, also outlived the longest-lived noncarriers by more than 4 months. We identified this gene as Leg2 (longevity extending gene 2). In both crosses, the effects were significant, and each effect required only 1 copy of the allele (dominant or additive). Importantly, the effects occurred in both wild-derived strains and none of the conventional strains.
Because these life span increases require a delay in the aging of all essential biological systems, it is likely that these "longevity" alleles retard basic aging mechanisms in multiple biological systems simultaneously. These results have led us in 2 directions: 1) We are conducting fine mapping and candidate gene analysis of Leg1 (Leg1a) and Leg2 (Leg2a). This process includes construction of congenics and studies on the effects of the genes in the context of various F1 hybrids. 2) Because the alleles that affected the increased life span came from the 2 wild-derived strains, we are conducting an extensive search for additional alleles using 4, new, wild-derived strains.
I.B. Biomarker analysis of aging in a wild-derived stock (Pohnpei mice)
One of our most exciting programs involves Pohnpei (Pohn) mice, a stock of mice (Mus musculus) that was trapped on the Pacific island of Pohnpei. Pohnpei has few murine predators, and evolutionary theory predicts that the expected reduction in ecological mortality will promote the evolution of retarded aging. We imported 1 female and 3 male Pohn mice into The Jackson Lab and bred 5 "families." Although 1 family showed increased life span, in general, total life span is comparable to long-lived inbred strains. However, in all 5 families, female reproductive life span is greatly increased in comparison to laboratory (C57BL/6J [B6]) and 4-way cross mice. This phenotype is associated with increased ovarian follicle numbers (Flurkey et al. 2007).
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Figure I.B. This graphic shows mean litter size per mother. When young, Pohn mice produce smaller litters than 4-way cross mice; when old, Pohn mice produce larger litters. Pohn mice also continue producing litters at an older age than 4-way cross mice. The long-lived, inbred laboratory strain, B6, is included without statistical comparison. |
Pohn mice also show characteristics of delayed senescence in other biomarkers. When tail skin fibroblasts are cultured in vitro, they produce a low proportion of small clones, a marker of cellular senescence. Tail skin fibroblasts also resist oxidative damage more effectively than fibroblasts from B6 mice, suggesting that oxidative protection might mediate the difference in expression of fibroblast senescence markers between Pohn and B6 mice. We currently are using QTL analysis to map loci that regulate tail skin fibroblast clone size. We also are measuring immunologic and metabolic markers of aging (Yuan et al., 2006).
