John E. Wilkinson

A GENTSthatcanextendthe lifespanofmiceareof interestfortworeasons:theycanprovidenewmodels of delayed aging to teach us more about what controls agingrateandhowagingleadstodisease;andinaddition, they serve as a first step toward eventual development of pharmaceuticals to slow aging and retard diseases in humans. The National Institute on Aging Intervention Testingprogram(ITP)haspreviouslyreportedsignificant increases in life span caused by aspirin and nordihydroguaiareticacid inmalemice(1)andbyrapamycinin bothmaleandfemalemice(2).ThedesignoftheITP(3) emphasizestheuseofgeneticallyheterogeneousmiceto mitigate against idiosyncrasies that can complicate inter-pretationofdatafromasingleinbredorF1hybridstock andincludesparallelreplicationofprotocolsatthreesites, the University of Texas (UT), University of Michigan (UM), and The Jackson Laboratory (TJL), with standard operatingprotocolsthatattempttoreproducekeyelements of the environmental conditions at each site. Sufficient numbers of mice are used in each yearly cohort to give morethan80%powertodetectanincreaseordecreaseof 10%inmeanlifespan,withrespecttocontrolsofthesame sex,evenifonlytwoofthethreesitescancontributedata tothepooledanalysis.

Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action.