The NIA Interventions Testing Program represents a multi-site translational research program to evaluate agents hypothesized 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 initially tested, in parallel, at three sites (Jackson Laboratories, Michigan and 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. Eighteen such 'Phase I'trials have been started in the first four years of the ITP, with 4-5 new agents tested in each annual cycle. Two agents tested in the first annual mouse cohort, aspirin and NDGA, produced significant increases in survival of male mice. Rapamycin, given to mice at 20 months of age and then evaluated at a point (Dec 1, 2008) where 92% of 867 female mice, and 96% of 1098 male mice from Cohort 2 had died, produced robust lifespan increases with p <0.0001 for males and p <0.0001 for females, with significant parallel results at all three sites. Rapamycin treatment also led to a significant increase in maximum lifespan both in males and in females (p <0.001 in each sex). Rapamycin also shows a beneficial effect when initiated at 9 months of age, in a Cohort 3 study now reaching the median survival age, significant in both male (p = 0.008) and female (p = 0.0001) mice. Plans for the next five years include completion of all ongoing Phase I trials and initiation of three or more new Phase I trials each year. In addition, a more elaborate Phase II study of Rapamycin will evaluate the effects of varying doses of this agent on survival, test a range of age-sensitive traits and proposed mechanistic pathways, document cross-sectional pathology, and provide mice and tissues for analyses by others. Each of the three laboratories has experience in lifespan and biomarker analysis in mice, and in addition will bring special expertise to the collaboration: measures of age-sensitive traits at the Jackson Laboratory, pathology and statistical analysis at Michigan, and pharmacology/toxicology at Texas.

Public Health Relevance

Identification of agents that can extend mean and/or maximum longevity in genetically heterogeneous mice in multiple laboratories will suggest research directions leading to clinical treatments designed to prevent or retard deleterious changes with age. In addition, identifying health dangers of unproven treatments that are purported to have anti-aging actions will also have public health benefits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG022303-09
Application #
8305571
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M2))
Program Officer
Sierra, Felipe
Project Start
2003-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$621,726
Indirect Cost
$170,756
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Strong, Randy; Miller, Richard A; Antebi, Adam et al. (2016) Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15:872-84
Bajwa, Preety; Nagendra, Prathima B; Nielsen, Sarah et al. (2016) Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium. Oncotarget 7:19214-27
Richardson, Arlan; Fischer, Kathleen E; Speakman, John R et al. (2016) Measures of Healthspan as Indices of Aging in Mice-A Recommendation. J Gerontol A Biol Sci Med Sci 71:427-30
Li, Weiquan; Miller, Richard A (2015) Elevated ATF4 function in fibroblasts and liver of slow-aging mutant mice. J Gerontol A Biol Sci Med Sci 70:263-72
Hofmann, Jeffrey W; Zhao, Xiaoai; De Cecco, Marco et al. (2015) Reduced expression of MYC increases longevity and enhances healthspan. Cell 160:477-88
Pickering, Andrew M; Lehr, Marcus; Miller, Richard A (2015) Lifespan of mice and primates correlates with immunoproteasome expression. J Clin Invest 125:2059-68
Herranz, Nicolás; Gallage, Suchira; Mellone, Massimiliano et al. (2015) mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol 17:1205-17
Miller, Richard A; Harrison, David E; Astle, Clinton M et al. (2014) Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13:468-77
Harrison, David E; Strong, Randy; Allison, David B et al. (2014) Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 13:273-82
Li, Weiquan; Li, Xinna; Miller, Richard A (2014) ATF4 activity: a common feature shared by many kinds of slow-aging mice. Aging Cell 13:1012-8

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