Project Summary As the world's population ages, improving the health and well being of elderly adults has become a social and economic imperative. Decreased function of the circadian clock is at the crossroad of aging, dysmetabolism and chronic diseases. Time-restricted feeding (TRF) is a new dietary intervention that recommends daily caloric intake to be limited in time independently of caloric content. TRF can preserve clock oscillations in metabolic organs and can prevent and reverse metabolic disease in young mice fed a high fat diet. This proposal combines extensive health and cognitive assessments throughout lifespan with sophisticated tissue- specific genome-wide transcriptome analysis of mice under TRF and caloric restriction (CR) to understand how dietary interventions can support circadian clock function and promote healthy aging. Aim 1 focuses on the health effects of TRF compared to ad libitum feeding (ALF) and CR. Middle-aged mice raised on a western-diet will be placed on ALF or TRF or CR. Periodic assessments of wide-ranging health parameters, behavioral and cognitive functions and maximum lifespan will test the hypothesis that TRF can delay the onset of diet- and age-related decline and increase longevity. Aim 2 focuses on the effect of the different dietary interventions on the function of the circadian clock. In the same animal cohort, periodic assessments of physiological outputs of the circadian clock coupled to tissue-specific genome-wide characterization of the diurnal transcriptome will test the hypothesis that TRF can sustain circadian clock function across lifespan. These studies will provide an in depth characterization of the effects of dietary interventions such as TRF and CR on age-related health, cognitive and circadian rhythms decline. Together, the integrative study proposed here will lead to a more fundamental understanding of how the timing of food consumption impacts circadian rhythmicity in gene transcription and function and how this affects healthspan and longevity. Such findings are important to test and develop new circadian-based therapies to extend health and lifespan.