Environmentally driven metabolic dysregulation as a model of accelerated aging

 描述（由申请人提供）：衰老是一个自然过程，发生在所有生物体中。虽然这一过程可能是正常的，但与年龄有关的病理学的代价是巨大的。NIH估计，治疗与年龄相关的痴呆症的费用超过6000亿美元。代谢功能紊乱是衰老的标志。代谢紊乱，包括II型糖尿病，在老年人群中的患病率增加，超过25%的65岁以上的美国人口患有II型糖尿病，达到超过1000亿美元的成本。糖尿病相关的代谢失调包括肥胖增加、血脂异常、胰岛素抵抗和葡萄糖耐量降低。众所周知，代谢干预，包括热量限制和运动，对寿命和健康寿命都有积极影响。鉴于衰老与代谢之间的关系，可以利用导致代谢功能改变的动物模型为衰老研究提供新的模型。为此，我们建议使用一个在我们实验室中表征的模型，该模型导致环境驱动的代谢失调，这似乎模拟了衰老中观察到的代谢变化。我们的模型在其简单性方面是优雅的，因为我们通过将小鼠置于10小时光照和10小时黑暗的缩短的一天中来引起代谢失调，而正常的一天为12小时光照和12小时黑暗。我们已经证明，这会导致激素和行为节律的慢性失调、代谢失调（包括体重增加和高胰岛素血症）、前额叶皮层神经结构的变化以及认知异常。此外，这发生在仅4- 6周的短时间范围内。这个模型的另一个好处是，内部生物节律与外部环境的失调也是衰老的标志。目前的建议的目的是确定使用环境昼夜节律破坏产生“加速老化”表型的可行性，特别是在外周和大脑代谢的背景下。我们提出了一系列的综合实验，以测试的假设，环境代谢失调，扰乱时钟导致加速老化。我们将比较我们的模型与正常衰老的外周代谢，脑功能和局部代谢，并确定我们的模型是否缩短寿命。鉴于在衰老和我们的模型中观察到皮质酮激素节律的破坏，我们将探索在老年小鼠中恢复皮质酮的“年轻样”节律是否可以改善代谢功能并延长寿命。未来使用该模型的实验将为正常衰老的分子，细胞和生理过程提供新的见解。

 DESCRIPTION (provided by applicant): Aging is a natural process, occurring in all organisms. While this process may be normal, the costs of age- related pathologies are enormous. The NIH estimates the cost of treating people with age-related dementia of being in excess of US$600 Billion. Disrupted metabolic function is a hallmark of aging. Metabolic disorders, including Type II Diabetes, have increased prevalence in aged populations, with over 25% of the US population over 65 having Type II Diabetes, reaching a cost of over US$100 Billion. Age-related dysregulation of metabolism includes increased adiposity, dyslipidemia, insulin resistance, and reduced glucose tolerance. It is known that metabolic interventions, including caloric restriction and exercise, positively impact both lifespan and healthspan. Given the relationship between aging and metabolism, animal models that result in altered metabolic function may be leveraged to provide new models for aging research. To this end, we propose to use a model characterized in our lab that results in environmentally driven metabolic dysregulation that seems to mimic metabolic changes observed in aging. Our model is elegant in its simplicity, in that we cause metabolic dysregulation by housing mice in a shortened day of 10h light and 10h darkness as compared to the normal day of 12h light and 12h darkness. We have shown this results in chronic misalignment of hormone and behavioral rhythms, metabolic dysregulation (including weight gain and hyperinsulinemia), changes in neural structure in the prefrontal cortex, and cognitive abnormalities. Further, this occurs in a short time frame of only 4-6wks. An additional benefit of this model is that misalignment of internal biological rhythms to the externa environment is also a hallmark of aging. The objective of the current proposal is to determine the feasibility of using environmental circadian disruption to produce an "accelerated aging" phenotype, particularly in the context of peripheral and brain metabolism. We propose a series of integrative experiments to test the hypothesis that environmental metabolic dysregulation by disrupting clocks leads to accelerated aging. We will compare our model to normal aging with respect to peripheral metabolism, brain function and local metabolism, and determine if our model shortens lifespan. Given that disruption of corticosterone hormone rhythms is observed in aging and our model, we will explore if restoring "young like" rhythms of corticosterone in aged mice can improve metabolic function, and increase lifespan. Future experiments using this model will provide new insights into molecular, cellular, and physiological processes underlying normal aging.