In vivo and in vitro systems to validate geronic proteins and their mechanisms of action

Yale University, New Haven CT

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Late onset chronic diseases associated with aging, including cardiovascular disorders, dementias, Alzheimer's and Parkinson's disease, diabetes and tissue malignancies, are the leading causes of morbidity and mortality creating the greatest emotional and financial burden on the individual and society. As the aging population continues to expand, late onset chronic diseases will further dominate the attention of biomedicine and society at large. We have been pursuing the role of the brain circuits and humoral factors in health and aging. We have identified the hypothalamus as an intersection point between CNS and peripheral tissue communications, defined serum proteins differentially expressed in young and old animals, and recognized cardiovascular health as a principal determinant of lifespan. We and others have established that hypothalamic neurons sense the changing peripheral milieu and also send out signals to control complex behaviors and organ system and peripheral tissue functions to appropriately adapt to changes in the environment. Our own preliminary data and the work of others have identified these same hypothalamic circuits to control the aging process. For example, we found that neurons of the hypothalamus that control hunger as well as other complex behaviors and peripheral tissue functions have significant impact on survival and lifespan. We also identified that these neurons mediate the action of peripheral hormones implicated in the lifespan extending impact of calorie restriction. We hypothesize that action of circulating geronic substances on age-related central and peripheral processes are mediated, at least in part, by the hypothalamus, and that they manifest critically in functional capacity of the cardiovascular, central nervous system and other critical organ systems. Our preliminary data revealed distinct differences (and some similarities) between circulating putative anti- and pro-geronic peptides and proteins between mice and nonhuman primates. We propose to establish a high throughput in vitro system to assess the cellular effects of putative geronic targets identified in our screen using nonhuman primate fibroblasts and cells derived from nonhuman primate iPS cells. We will validate in vivo test systems in primates to evaluate anti- and pro-geronic interventions on CNS and cardiovascular systems. We will analyze the effects of known anti- and pro-geronic peptides and those newly defined by in vitro analyses on cognitive brain functions of extensively behavioral characterized young (~4 years), middle aged (~14 years) and old (~30 years) nonhuman primates, and the modulation of cardiovascular age in old and young primates by similar putative geronic interventions. Overall, our aims will deliver new insights regarding the mechanisms of action of geronic substances, new circulating geronic molecules and establish and validate robust test systems that will lend themselves to collaborative work with other projects and investigators and the advance of defined biology to clinically relevant application. Thus, we believe that our application is fully responsive to the letter and spirit of this RFA.