The role of hypothalamic-sympathoneural-adipocyte axis in healthy aging

描述（由申请人提供）：美国老龄化的面貌正在发生巨大变化，预计未来25年65岁或以上的美国人将达到7000万。随着预期寿命的增加，癌症、心血管疾病和神经退化等疾病的发病率也在上升。因此，我们必须更多地了解衰老的动态，它们如何与各种环境和生活方式因素相互作用，以及疾病过程与衰老之间的联系，以便开发更有效的方法来预防、诊断和治疗与年龄有关的疾病。我们最近在环境富集（一种促进心理健康的居住环境）方面的工作揭示了一种新的表型，其特征是肥胖的显著减少，对饮食引起的肥胖的抵抗，胰岛素敏感性的增强，免疫功能的增强，以及癌症生长的抑制。此外，抗癌和抗肥胖表型是由脑脂肪轴，下丘脑-交感神经-脂肪细胞（HSA）轴的激活介导的。在这个调节网络中，大脑中的关键成分是BDNF，它对活动和环境有高度反应，它控制HSA的活动，从而调节脂肪。脂肪作为外周的主要反应器官，随后影响多个器官系统。激活HSA轴的关键特征与那些已知的延长寿命的环境和遗传因素（如卡路里限制和脂肪特异性胰岛素受体敲除小鼠）相同。然而，HSA轴在老化过程中的作用尚未被研究。本研究的长期目标是了解身体、心理和社会活动环境如何影响健康寿命和寿命，并确定其潜在机制。具体来说，我们建议利用多学科方法来表征HSA轴在健康衰老中的作用。我们计划研究通过环境干预或BDNF基因转移短期激活HSA轴对衰老标志物（肥胖、代谢、激素和生长因子改变、胰岛素敏感性和免疫功能）的影响，以及长期激活HSA轴的影响

DESCRIPTION (provided by applicant): The face of aging in the United States is changing dramatically with the projection of 70 million Americans age 65 or older in the next 25 years. As life expectancy increases, the incidence of diseases such as cancer, cardiovascular disorders and neurodegeneration rises. It is vital, therefore, that we understand more about the dynamics of aging, how they interact with various environmental and lifestyle factors, and the connections between disease processes and aging in order to develop more effective ways to prevent, diagnose and treat age-related diseases. Our recent work on environmental enrichment, a housing environment boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, resistance to diet-induced obesity, enhanced insulin sensitivity, enhanced immune function, and inhibition in cancer growth. Moreover the anti-cancer and anti-obesity phenotypes are mediated by the activation of a brain-fat axis, the hypothalamic-sympathoneural-adipocyte (HSA) axis. In this regulatory network, the key component in the brain is BDNF, which is highly responsive to activity and the environment, and it controls the HSA activity and thereby regulates fat. Fat, as the principal responsive organ in the periphery, subsequently influences multiple organ systems. The key features of activation of the HSA axis are shared by those environmental and genetic factors known to increase lifespan such as calorie restriction and fat-specific insulin receptor knockout mice. However the role of the HSA axis in the aging process has not been investigated. The long-term goal of this study is to understand how a physically, mentally, and socially active environment may influence healthspan and lifespan and to define the underlying mechanisms. Specifically, we propose to utilize a multidisciplinary approach to characterize the role of HSA axis in healthy aging. We plan to investigate the effects of short-term activation of the HSA axis via environmental intervention or gene transfer of BDNF on aging markers (adiposity, metabolism, hormonal and growth factor alteration, insulin sensitivity, and immune function), as well as the effects of long term HSA axis activation on healthspan and lifespan in both normal animals and obesity and diabetes models. Accomplishing the proposed experiments will assess the role of this newly characterized brain-fat axis in healthy aging and the effects of manipulating a single gene in the brain to regulate healthspan, and furthermore may reveal potential targets for the prevention and treatment of age-related diseases.