Understanding the roles of prolonged fasting, calorie intake, and mTORC1 in the response to calorie restriction

Project Summary Age-related diseases are the major causes of morbidity and mortality in the US. Many elderly people suffer from multiple age-related diseases simultaneously; while the risk of almost every individual disease rises with age, they also interact, with age-related disease such as diabetes and obesity serving as additional risk factors for neurodegenerative diseases including AD. Targeting the aging process through interventions like calorie restriction (CR), which extends lifespan while delaying or preventing multiple age-related diseases simultaneously, is one plausible approach to lessen the burden of these diseases. However, reduced-calorie diets are notoriously difficult to sustain. Understanding identifying the physiological and molecular mechanisms by which CR influences metabolism, healthspan, and longevity will provide mechanistic insight into the regulation of healthy aging as well as potential therapies for AD. As typically implemented in the laboratory, CR-fed animals are subject to a period of prolonged daily fasting. We and others have found that fasting itself has beneficial effects on metabolic health and longevity, mimicking the effects of a CR diet at both the physiological and molecular levels. Here, we will use a series of distinct feeding regimens to rigorously identify the unique contributions of caloric intake and fasting to the effects of a CR diet on the lifespan, metabolic health, frailty and healthspan of wild-type mice. CR slows or prevents the development and progression of AD in mouse models, and our preliminary data suggests that fasting plays a key role in the beneficial effects of CR on cognition and AD pathology. Here, we will interrogate the ability of fasting to preserve cognition in mouse Aβ and Tau models of AD. Finally, we will use genetic mouse models with altered function of the mTORC1 protein kinase to gain insight into the role of this kinase in the metabolic response to CR. The proposed work will address long-standing questions regarding the physiological, metabolic, and molecular mechanisms by which a CR diet promotes healthy aging and slows or prevents age-related diseases, with a particular emphasis on understanding the potentially therapeutic role of fasting in AD. In the long term, this work will enable our laboratory and others to develop a mechanistic understanding of how when, how much, and what we eat regulates health and disease vulnerability, and to identify new targets for the pharmacological treatment of age-related diseases including AD, and to promote healthy aging.