Identification of small molecules that extend mouse lifespan provides new insights into mechanisms of longevity determination in mammals, and may lay the groundwork for eventual anti-aging therapies in humans. The NIA Interventions Testing Program (ITP) evaluates agents proposed to extend mouse lifespan by retardation of aging or postponement of late life diseases. Interventions proposed by multiple collaborating scientists from the research community are tested, in parallel, at three sites (Jackson Laboratories, University of Michigan and University of Texas), using identical, standardized protocols, and using sufficient numbers of genetically heterogeneous mice to provide 80% power for detecting changes in lifespan of 10%, for either sex, after pooling data from any two of the test sites. Seventy-two such lifespan experiments, involving various doses of 44 distinct agents, have been initiated in the first fifteen years of the ITP. Thirty-seven experiments have involved comparative tests of multiple doses of effective agents, variable starting ages, or alternative dosing schedules. Significant effects on longevity, 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 trials are now underway for 18 new agents. ITP survival results have also documented longevity benefits from three agents started in middle-age: rapamycin, acarbose, and 17aE2. The previous five year period has introduced three new features to the ITP: increased emphasis on health outcomes (functional tests relevant to human health not necessarily linked to lifespan), a Collaborative Interactions Program to provide tissues from ITP drug-treated mice to an open, growing, international network of scientific collaborators, and a publicly accessible data repository and display engine hosted by the Mouse Phenome Database at the Jackson Laboratory. 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 on health outcomes, and collaborative work with scientists to study drug effects on postulated aging mechanisms and links to disease. Studies at Michigan will follow up our analyses of cellular pathways relevant to stress resistance and inflammation, by continuing ongoing studies of cap-independent protein translation, chaperone mediated autophagy, and browning of white adipose cells. The work proposed should allow the ITP to continue to make major contributions to mammalian aging biology.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project--Cooperative Agreements (U01)
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Study Section
Special Emphasis Panel (ZAG1)
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Fuldner, Rebecca A
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Garratt, Michael; Lagerborg, Kim A; Tsai, Yi-Miau et al. (2018) Male lifespan extension with 17-? estradiol is linked to a sex-specific metabolomic response modulated by gonadal hormones in mice. Aging Cell :e12786
Bielas, Jason; Herbst, Allen; Widjaja, Kevin et al. (2018) Long term rapamycin treatment improves mitochondrial DNA quality in aging mice. Exp Gerontol 106:125-131
Altschuler, R A; Kanicki, A; Martin, C et al. (2018) Rapamycin but not acarbose decreases age-related loss of outer hair cells in the mouse Cochlea. Hear Res 370:11-15
An, Jonathan Y; Quarles, Ellen K; Mekvanich, Surapat et al. (2017) Rapamycin treatment attenuates age-associated periodontitis in mice. Geroscience 39:457-463
Berkowitz, Bruce A; Miller, Richard A; Roberts, Robin (2017) Genetically heterogeneous mice show age-related vision deficits not related to increased rod cell L-type calcium channel function in vivo. Neurobiol Aging 49:198-203
Garratt, Michael; Bower, Brian; Garcia, Gonzalo G et al. (2017) Sex differences in lifespan extension with acarbose and 17-? estradiol: gonadal hormones underlie male-specific improvements in glucose tolerance and mTORC2 signaling. Aging Cell 16:1256-1266
Cady, Gillian; Landeryou, Taylor; Garratt, Michael et al. (2017) Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons. Mol Metab 6:393-405
Nadon, Nancy L; Strong, Randy; Miller, Richard A et al. (2017) NIA Interventions Testing Program: Investigating Putative Aging Intervention Agents in a Genetically Heterogeneous Mouse Model. EBioMedicine 21:3-4
Dominick, Graham; Bowman, Jacqueline; Li, Xinna et al. (2017) mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging Cell 16:52-60
Cole, John J; Robertson, Neil A; Rather, Mohammed Iqbal et al. (2017) Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Genome Biol 18:58

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