The NIA Interventions Testing Program is a multi-site translational research program to evaluate agents hypothesized to extend mouse lifespan;this part of the program is not under review, and will be expanded 2 fold at each site, as mandated by the RFA. Each site has special skills - mouse expertise and measures of age-sensitive traits at The Jackson Laboratory (Jackson), pathology and statistical analysis at the University of Michigan (UM), and pharmacology/toxicology at the University of Texas Health Science Center at San Antonio (UT) - which will be expanded as mandated by the RFA. Jackson currently supplies diets (control and with interventions added) and performs pilot mouse studies;these jobs will expand. Also, Jackson will routinely supply old, middle-aged and young untreated controls to collaborators, and some "positive" controls treated with established, effective interventions. In mandated healthspan studies, Jackson will specialize in non- invasive assays to measure changes with age in a variety of physiological systems without harm to the mouse. Treated and control mice will be longitudinally tested at 16 and 22 months of age to follow individual changes with age before disease sets in;most interventions start by 4-10 months, so effects may be detectable by 16 months. Longitudinal testing compared to cross-sectional, permits a more powerful quantification of treatment effects during aging in the genetically heterogeneous UM-HET3 population because genetic variance can be statistically "removed." In addition, the relative influence of individual differences in response to the treatment during aging can be quantified. Current plans are to test: body weight;circulating hemoglobin;circulating white blood cell populations, including na?ve CD4 T cells;short-term memory (5-minute T maze);activity and anxiety (10-minute open field test);grip strength;kidney function (urinary albumin/creatinine ratio);cataracts;collagen aging (tail tendon collagen denaturation);and wound healing (using the incision to remove tail tendon). All tests are designed to minimize stress and optimize quantitative definition of "health." Many of these tests have already been shown to change with age in UM-HET3 mice;age-sensitivity will be confirmed for all tests in pilot studies before use with interventions. Benefits of interventions indicated by any of these tests will guide more extensive physiological and biochemical studies, both in the ITP laboratories and elsewhere. Two interventions already shown to extend lifespan in UM-HET3 mice - diet restriction and rapamycin - will be used as positive controls when appropriate.

Public Health Relevance

Identification of interventions that retard aging 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 #
2U01AG022308-11
Application #
8754073
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M2))
Program Officer
Fuldner, Rebecca A
Project Start
2003-04-15
Project End
2019-03-31
Budget Start
2014-08-15
Budget End
2015-03-31
Support Year
11
Fiscal Year
2014
Total Cost
$1,739,497
Indirect Cost
$739,499
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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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
Gong, Huan; Qian, Hong; Ertl, Robin et al. (2015) Histone modifications change with age, dietary restriction and rapamycin treatment in mouse brain. Oncotarget 6:15882-90
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Harrison, David E; Astle, Clinton M; Niazi, M Khalid Khan et al. (2014) Genetically diverse mice are novel and valuable models of age-associated susceptibility to Mycobacterium tuberculosis. Immun Ageing 11:24
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
Lamming, Dudley W; Ye, Lan; Astle, Clinton M et al. (2013) Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. Aging Cell 12:712-8
Strong, Randy; Miller, Richard A; Astle, Clinton M et al. (2013) Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 68:6-16

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