The Hypothalamic Basis of Aging

ABSTRACT/SUMMARY Aging is multifaceted while many hormonal and metabolic regulators are crucial, pointing to the extremely strong significance of endocrine and metabolic processes in aging physiology and intervention. The hypothalamus is the “headquarters” for regulating systemic endocrine systems and metabolic physiology as well as the autonomic nervous system for physiological homeostasis. In the past, the lab of the PI has developed a major research area of studying the significance of hypothalamus in aging, including formulation of the “hypothalamic control of aging” paradigm which subsequently led to the generation of anti-aging model by hypothalamic stem/progenitor cells. The long-term objective of this research is to study the underlying hypothalamic anti-aging basis and therefore to develop novel and effective targets for counteracting against aging-related neurodegeneration and disease. In preliminary studies of this project, it was found that hypothalamic extracellular vesicles (EVs) are strongly anti-aging and anti-neurodegenerative in multiple experimental models. Also, parathymosin in these EVs was found crucial for the anti-neurodegenerative actions in recipient neurons. Thus, this project is proposed based on the hypothesis that hypothalamic EVs are important for brain transfer and neuroprotective while restoring these EVs has a significant interventional value against aging-related neurodegeneration and disorders. Three specific aims are: (1) study hypothalamic and brain transfer of hypothalamic EVs and aging relevance; (2) study the neuroprotective and anti- neurodegenerative actions of parathymosin-containing hypothalamic EVs and the underlying basis; (3) study the significance of hypothalamic EVs for treating neurodegenerative disorders and improving aging physiology and healthspan. Experiments in these Aims will be carried out by using mouse models of hypothalamic regional and cell-specific manipulations of EVs as well as models of pharmacological intervention with hypothalamic EVs. A list of molecular, cellular and physiological methods will be used to analyze hypothalamic EVs in terms of biochemical profile of brain distribution and uptake, the cellular effects for neuroprotection in recipient neurons, and anti-aging physiological and therapeutic effects in relevant aging models. Overall, successful completion of this project will lead to new important knowledge about the hypothalamic basis of aging and novel strategy for managing healthy aging and alleviating aging-related disorders and diseases.