The Hypothalamic Basis of Aging

摘要/总结 衰老是多方面的，而许多激素和代谢调节剂是至关重要的， 内分泌和代谢过程在衰老生理学和干预中的重要性。的 下丘脑是调节全身内分泌系统和代谢生理的“总部”， 以及自主神经系统的生理稳态。在过去，私家侦探的实验室 发展了一个主要的研究领域，研究下丘脑在衰老中的意义，包括制定 “下丘脑控制衰老”的范例，随后导致抗衰老模型的产生， 下丘脑干/祖细胞这项研究的长期目标是研究潜在的 下丘脑抗衰老的基础，因此开发新的和有效的目标， 衰老相关的神经变性和疾病。在该项目的初步研究中，发现， 下丘脑细胞外囊泡（EV）在多种神经系统疾病中具有强烈的抗衰老和抗神经变性作用， 实验模型此外，发现这些EV中的甲状旁腺素对于抗神经退行性变至关重要。 受体神经元的活动。因此，该项目是基于下丘脑EV是 重要的是脑转移和神经保护，同时恢复这些EV具有显著的介入价值 对抗衰老相关的神经变性和紊乱。三个具体目标是：（1）研究下丘脑和 下丘脑EV脑转移与增龄的相关性;（2）研究神经保护和抗 含甲状旁腺素的下丘脑EV的神经变性作用及其基础;（3）研究 下丘脑EV对治疗神经退行性疾病和改善衰老生理的意义 和健康。这些目的的实验将通过使用小鼠下丘脑模型进行。 EV的区域和细胞特异性操作以及药物干预模型， 下丘脑EV。分子、细胞和生理学方法将用于分析下丘脑 EV在脑分布和摄取的生化特征方面， 受体神经元，以及在相关衰老模型中的抗衰老生理和治疗作用。总的来说， 该项目的成功完成将导致下丘脑基础的新的重要知识， 以及用于管理健康老龄化和减轻与老龄化相关的障碍和疾病的新策略。

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.