The genes that control basic aging mechanisms in mammals are unknown. By using two four-way crosses, each including a strain derived from wild, undomesticated stocks, we identified two quantitative trait loci that extend murine life spans by approximately 10%. In one cross, the longest-lived 18% of carriers of the D8MH171 marker allele from the MOLD/Rk strain, Mus m. molossinus, outlived the longest lived 18% of noncarriers by 129 days (P = 5.4 × 10–5); in a second cross, carriers of the D10Mit267 allele from the CAST/El strain, Mus m. castaneus, outlived noncarriers by 125 days (P = 1.6 × 10–6). In both crosses, P < 1.0 × 10–4 is considered significant. Because these life span increases required that all essential biological systems function longer than normal, these alleles most likely retarded basic aging mechanisms in multiple biological systems simultaneously.
ComfortA. The Biology of Senescence. New York: Elsevier North Holland, 1979.
2.
HarrisonDE, RoderickTH. Selection for maximum longevity in mice. Exp Gerontol32: 65–78, 1997.
3.
KimuraKD, TissenbaumHA, LiuY, RuvkunG. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.Science277: 942–946, 1997.
4.
LakowskiB, HekimiS. Determination of life-span in Caenorhabditis elegans by four clock genes. Science272: 1010–1013, 1996.
5.
LinYJ, SeroudeL, BenzerS. Extended life-span and stress resistance in the Drosophila mutant mrthuselah.Science282: 943–946, 1998.
6.
YunisEJ, WatsonALM, GelmanRS, SylviaSJ, BronsonRT. Traits that influence longevity in mice. Genetics108: 999–1011, 1984.
7.
GelmanR, WatsonA, BronsonR, YunisE. Murine chromosomal regions correlated with longevity. Genetics118: 693–704, 1988.
8.
GelmanR, WatsonA, YunisE, WilliamsRM. Genetics of survival in mice: Subregions of the major histocompatibility complex. Genetics125: 167–174, 1990.
9.
MillerRA, ChrispC, JacksonAU, BurkeD. Marker loci associated with lifespan in genetically heterogeneous mice. J Gerontol Med Sci53A: M257–M263, 1998.
10.
BonhommeF, GuenetJL. The laboratory mouse and its wild relatives. In: LyonMF, RastanS, BrownSDM, Eds. Genetic Variants and Strains of the Laboratory Mouse. Oxford: Oxford University Press, pp 1577–1596, 1996.
11.
WilliamsGC. Pleiotropy, natural selection and the evolution of senescence. Evolution11: 398–411, 1957.
12.
HarrisonDE. Potential misinterpretations using models of accelerated aging (Guest Editorial and Response). J Gerontol49: B245–B246, 1994.
13.
KirkwoodTBL, RoseMR. Evolution of senescence: Late survival sacrificed for reproduction. Phil Trans R Soc Lond B332: 15–24, 1991.
14.
McCayCM, CrowellMF, MaynardLA. The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr10: 63–79, 1935.
15.
YuBP, MasoroEJ, MurataI, BertrandHA, LyndFT. Life span study of SPF Fischer 344 male rats fed ad libitum or restricted diets: Longevity, growth, lean body mass and disease. J Gerontol37: 130–141, 1982.
16.
RoderickTH. Selection for radiation resistance in mice. Genetics48: 205–216, 1963.
CoschiganoKT, ClemmonsD, BellushLL, KopchickJJ. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology141: 2608–2613, 2000.
31.
FlurkeyK, PapaconstantinouJ, MillerRA, HarrisonDE. Life span extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A98: 6736–6741, 2001.
32.
MigliaccioE, GiorgioM, MeleS, PelicciG, ReboldiP, PandolfiPP, LanfranconeL, PelicciPG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature402: 309–313, 1999.
33.
KlebanovS, FlurkeyF, RoderickTH, ArcherJR, AstleMC, ChenJ, HarrisonDE. Heritability of life span in mice and its implication for direct and indirect selection for longevity. Genetica BG69: 1–10, 2001.
