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.

Public Health Relevance

. Thisprojectinvestigatesmolecularmechanismsofcircadianclocksincalorierestriction. Boththeclocksandcalorierestrictionaremajorregulatorsofmetabolismandimplicated intheregulationofagingandageassociateddiseases,therefore,theobtaineddatawill helptodeveloparationalstrategyforthediseasetreatmentandprevention.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Aging Systems and Geriatrics Study Section (ASG)
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Fridell, Yih-Woei
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Cleveland State University
Schools of Arts and Sciences
United States
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Tulsian, Richa; Velingkaar, Nikkhil; Kondratov, Roman (2018) Caloric restriction effects on liver mTOR signaling are time-of-day dependent. Aging (Albany NY) 10:1640-1648
Makwana, Kuldeep; Patel, Sonal Arvind; Velingkaar, Nikkhil et al. (2017) Aging and calorie restriction regulate the expression of miR-125a-5p and its target genes Stat3, Casp2 and Stard13. Aging (Albany NY) 9:1825-1843
Chaudhari, Amol; Gupta, Richa; Patel, Sonal et al. (2017) Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation. Mol Biol Cell 28:834-842
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Patel, Sonal A; Velingkaar, Nikkhil; Makwana, Kuldeep et al. (2016) Calorie restriction regulates circadian clock gene expression through BMAL1 dependent and independent mechanisms. Sci Rep 6:25970
Malik, Astha; Kondratov, Roman V; Jamasbi, Roudabeh J et al. (2015) Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination. PLoS One 10:e0139655
Malik, Astha; Jamasbi, Roudabeh J; Kondratov, Roman V et al. (2015) Development of circadian oscillators in neurosphere cultures during adult neurogenesis. PLoS One 10:e0122937

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