Environmentally driven metabolic dysregulation as a model of accelerated aging

Washington State University, Pullman WA

Investigators

Linked publications & trials

Abstract

? 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.