Calorie restriction (CR) was shown to extend longevity in many organisms; however, the mechanisms of CR are still mostly unknown. In our previous study we found that the circadian clock is an important component of CR mechanisms in mammals. We established that CR regulates expression of the circadian clock genes by controlling activity of circadian transcriptional regulators BMAL1 and CRY1. In agreement with that, BMAL1 is necessary for the full metabolic benefits of CR including lifespan extension. Indeed, we found that BMAL1 negatively regulates activity of mTORC1, which is implicated in the regulation of aging and CR-mediated increase in longevity. We will continue the study by exploring our hypothesis that circadian clock recruitment is essential for resource allocation and the full beneficial effects of CR on physiology; in particular, CR recruits the circadian clocks by regulating the level and activity of CRY1 and BMAL1 proteins, which in turn contributes to differential regulation of mTORC1 and mTORC2. We will explore the hypothesis through three specific aims.
Aim 1. To decipher the mechanisms of regulation of the circadian clock gene expression by CR.
Aim 2. To investigate circadian clock-mediated mechanisms of CR-imposed effects on mTORC1 and mTORC2 activity and signaling.
Aim 3. To dissect the effects of periodic feeding with or without reduced calorie intake on CR- induced metabolic changes and longevity.
. Thisprojectinvestigatesmolecularmechanismsofcircadianclocksincalorierestriction. Boththeclocksandcalorierestrictionaremajorregulatorsofmetabolismandimplicated intheregulationofagingandageassociateddiseases,therefore,theobtaineddatawill helptodeveloparationalstrategyforthediseasetreatmentandprevention.
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