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

与衰老相关的晚发性慢性疾病，包括心血管疾病、阿尔茨海默病和

Late onset chronic diseases associated with aging, including cardiovascular disorders, 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. 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. Our preliminary data and the work of others identified the same hypothalamic circuits to control the aging process. For example, we found that neurons of the hypothalamus that control hunger 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. We will interrogate this question using mouse models in Specific Aim 1. We will analyze complex behaviors, cardiac, muscle, bone and immune functions in control and experimental animals, including animals with different age and genotype in a state of parabiosis. From a translational perspective, it is crucial that the presence and relevance of geronic peptides are confirmed in higher species such as primates, including humans. In an effort to address this issue, we have analyzed plasma from young and aged nonhuman primates. Proteomics analysis identified candidate molecules in primates that have not been identified in mice. In Specific Aim 2, we propose to utilize our newly established, high throughput in vitro system to assess the cellular effects of putative geronic targets identified in our screen using nonhuman primate fibroblasts. We will focus on intracellular events that are associated with aging cells. In Specific Aim 3, we will test primates to evaluate anti- and pro-geronic interventions on CNS and cardiovascular systems. We will analyze the effects of young and aged plasma treatment of animals, known anti- and pro-geronic peptides and those newly defined by in vivo analyses on cognitive brain functions of young, middle aged and old nonhuman primates. Overall, execution of our aims will deliver new insights regarding the mechanisms of action of geronic substances, new circulating geronic molecules and exploit robust test systems that will lend themselves for collaborative work with other projects and investigators and the advance of defined biology to clinically relevant application.