CENTER FOR TESTING POTENTIAL ANTI-AGING INTERVENTIONS

Identification of small molecules that extend mouse lifespan provides new insights intomechanisms of longevity determination in mammals, and may lay the groundwork for eventualanti-aging therapies in humans. The NIA Interventions Testing Program (ITP) evaluates agentsproposed to extend mouse lifespan by retardation of aging or postponement of late lifediseases. Interventions proposed by multiple collaborating scientists from the researchcommunity are tested, in parallel, at three sites (Jackson Laboratories, University of Michiganand University of Texas), using identical, standardized protocols, and using sufficient numbersof genetically heterogeneous mice to provide 80% power for detecting changes in lifespan of10%, for either sex, after pooling data from any two of the test sites. Seventy-two such lifespanexperiments, involving various doses of 44 distinct agents, have been initiated in the first fifteenyears of the ITP. Thirty-seven experiments have involved comparative tests of multiple doses ofeffective agents, variable starting ages, or alternative dosing schedules. Significant effects onlongevity, in one or both sexes, have been documented and then confirmed for NDGA,rapamycin, acarbose, and 17-?-estradiol (17aE2), with significant (but currently unconfirmed)effects also noted for Protandim, glycine and, in an interim analysis, canagliflozin. Lifespan trialsare now underway for 18 new agents. ITP survival results have also documented longevitybenefits from three agents started in middle-age: rapamycin, acarbose, and 17aE2. Theprevious five year period has introduced three new features to the ITP: increased emphasis onhealth outcomes (functional tests relevant to human health not necessarily linked to lifespan), aCollaborative Interactions Program to provide tissues from ITP drug-treated mice to an open,growing, international network of scientific collaborators, and a publicly accessible datarepository and display engine hosted by the Mouse Phenome Database at the JacksonLaboratory. Plans for the next five-year period include additional lifespan ('Stage I') trials,detailed analyses ('Stage II') of agents found to increase lifespan, continued growth in data onhealth outcomes, and collaborative work with scientists to study drug effects on postulatedaging mechanisms and links to disease. Studies at Texas, aimed to complement and extendjoint ITP discoveries, will continue our research on the age specificity of and basis for the sexualdimorphism of life-extending drugs. We will continue pre-clinical work on the effects of theseagents on healthspan and functional deficits in aging mice. The work proposed should allow theITP to continue making major contributions to mammalian aging biology.