Integrated Healthspan Phenotyping

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CORE C: SUMMARY Pignolo The overall objective of Core C: Integrated Healthspan Phenotyping Core (IHPC) is to characterize novel animal models of senescent cell clearance by a variety of functional assessments across multiple domains. The IHPC will characterize two common models of senescent cell clearance in vivo, and integrate the use of these models across all four projects. One model will use the ATTAC cassette, which is a caspase-8/Fkbp fusion protein that causes cell death in the presence of the drug AP20187. In this model, a p16-INK-ATTAC transgenic rat model, the ATTAC cassette is driven by the p16 promoter. The second model is a physiological aging model treated with senotherapeutic drugs identified by Core B: Drug Discovery & Development. We anticipate that three or more potential senolytic (i.e., compounds that kill senescent cells)/senomorphic (i.e., compounds that inhibit the senescence-associated secretory phenotype [SASP]) drugs will be evaluated for effects on normal (physiologic) aging in mice. The lead senotherapeutic agent identified in mice will also be evaluated for healthspan benefits in the p16-INK-ATTAC transgenic rat model. These common animal models will be bred, maintained, and characterized for health span measures by the IHPC. By identifying animal models with extended health (e.g., models that reduce senescent cell burden) we will determine strategies capable of compressing morbidity as well as enhancing and extending health span in humans. The following functional domains related to Projects 1-4 will be assessed to characterize the healthspan across animal models: (i) metabolic homeostasis, body composition and energetics, (ii) skeletal integrity, (iii) cardiovascular function, (iv) muscle performance, and (v) immunologic/inflammatory status. A health index checklist will be utilized as a global assessment of functional status. These outcomes of healthspan have been selected for their stand-alone importance, clinical relevance, and established relationships with frailty, disability, institutionalization, and longevity in older persons. The ability to determine these outcomes in rodents will greatly enhance our ability to translate the basic biology of aging into clinical application-- the overarching goal of the Program Project. The IHPC will interact closely with Core D: Geroscience Pathology & Cellular Histology to facilitate examination of tissue samples from these models for a wide range of standard and innovative histological and pathophysiological analyses. The IHPC will also interact closely with Core A: Administrative and Biostatistics Core, to collect, curate, and manage data related to tissue sample collection, functional parameters, and histopathological findings as well as to oversee the distribution of animal models to Project Leads and other, non-PPG investigators, upon request.