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.
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.
|Reifsnyder, Peter C; Ryzhov, Sergey; Flurkey, Kevin et al. (2018) Cardioprotective effects of dietary rapamycin on adult female C57BLKS/J-Leprdb mice. Ann N Y Acad Sci 1418:106-117|
|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|
|Lee, Benjamin P; Buri?, Ivana; George-Pandeth, Anupriya et al. (2017) MicroRNAs miR-203-3p, miR-664-3p and miR-708-5p are associated with median strain lifespan in mice. Sci Rep 7:44620|
|Reifsnyder, Peter C; Flurkey, Kevin; Te, Austen et al. (2016) Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes. Aging (Albany NY) 8:3120-3130|
|Thompson, Airlia C S; Bruss, Matthew D; Price, John C et al. (2016) Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice. Aging Cell 15:118-27|
|Lee, Benjamin P; Pilling, Luke C; Emond, Florence et al. (2016) Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans. Aging Cell 15:903-13|
|Strong, Randy; Miller, Richard A; Antebi, Adam et al. (2016) Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an ?-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15:872-84|
|Yuan, Rong; Gatti, Daniel M; Krier, Rebecca et al. (2015) Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1. J Gerontol A Biol Sci Med Sci 70:817-26|
|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|
|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|
Showing the most recent 10 out of 22 publications