Laboratory for Anti-Geric Testing, Evaluation and Research Funding is sought for a series of investigations of interventions thought likely to extend life span in a population of genetically heterogeneous mice. The protocol will test five new interventions each year in Phase I screening studies, as well as conducting more comprehensive Phase II studies for selected interventions in Years 3, 4, and 5. Key features of the Phase I protocol include: (a) use of asymmetric group assignment to maximize statistical power by over sampling control animals; (b) use of separate monitor mice to document drug distribution and effectiveness; and (c) complete assessment of life table for all Phase I interventions. Phase I studies will include assessments of several age-sensitive traits as indirect indices of biological age, including (a) spontaneous activity; (b) IGF-I, glucocorticoid, and glycated hemoglobin levels, (c) five T cell subsets; (d) cataract severity; and (e) tests of learning and memory. Limited necropsy analyses will be done on all Phase I mice, and comprehensive necropsy analysis will be available for all Phase II mice and for those Phase I mice exposed to interventions found either to increase or to decrease longevity to a significant extent. Phase II studies will, in addition to replication of tests used in Phase I, add more comprehensive examinations of immune function, liver enzyme heat stability, eye lens protein extraction rates, tail tendon break time, and array-based analysis of age-sensitive liver and muscle mRNAs. Four interventions are suggested for initial exploration: (a) piaglitazone, an enhancer of insulin sensitivity, (b) pyridoxamine, which inhibits glycation-based cross links, (c) a-phenyl-N-tert-butyl nitrone (PBN), a scavenger of free radicals, and (d) pegvisomant, an inhibitor of GH action. The project as a whole should serve two important functions: providing critical tests of hypotheses that specific varieties of intervention will delay aging or late life illnesses in mammals; and, perhaps more importantly, provide important new leads to biochemical or hormonal pathways that can indeed modulate aging and delay late life illnesses and disabilities.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG022303-05
Application #
7244326
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (J2))
Program Officer
Sierra, Felipe
Project Start
2003-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$703,168
Indirect Cost
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
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
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
Bajwa, Preety; Nielsen, Sarah; Lombard, Janine M et al. (2017) Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice. Oncotarget 8:7265-7275
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

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