Dietary restriction (DR) is a powerful intervention, which slows the aging process and increases the lifespan of organisms, from yeast to mammals. The TOR signaling pathway is an evolutionarily conserved pathway implicated in the control of aging, and TOR is necessary for the full effect of DR. Hi95 /sestrin2 is a negative regulator of TOR pathways in mammals and invertebrates. We have found that Hi95/sestrin2 expression is significantly reduced in the brain, muscles and liver of BMAL1-deficient mice, and is increased in the same tissues of CRY-deficient mice;furthermore, BMAL1 deficiency results in up regulation of TOR signaling, suggesting that BMAL1 is a negative regulator of the TOR pathway. BMAL1 and CRYs are components of the circadian clock system. Thus, our preliminary data suggest a previously unknown interaction between the TOR signaling pathway and the circadian clock which may explain the role of the circadian clock in aging. We hypothesize that DR regulates the activity of the circadian clock proteins BMAL1 and CRYs, and these proteins mediate the effect of DR on longevity through the regulation of TOR pathways. We will address this hypothesis through the following Specific Aims:
Aim 1. To study the molecular mechanisms of regulation of BMAL1 transcriptional activity by glucose.
Aim 2. To investigate the role of the circadian clock proteins in the regulation of the Hi95-mTOR pathway.
Aim 3. To study the role of the circadian clock and circadian clock proteins BMAL1 and CRYs in dietary restriction.

Public Health Relevance

This project addresses the role of the circadian clock in dietary restriction. Dietary restriction is a powerful intervention demonstrated to increase longevity in a variety of organisms, including humans. Data obtained as a result of this study will help to understand the molecular basis of aging and age-associated diseases, and to develop physiological and pharmacological strategies for the treatment and prevention of such age-associated pathologies as heart diseases, cancer, diabetes and osteoporosis.

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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Finkelstein, David B
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Cleveland State University
Schools of Arts and Sciences
United States
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Patel, Sonal A; Chaudhari, Amol; Gupta, Richa et al. (2016) Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms. FASEB J 30:1634-42
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
Samsa, William E; Vasanji, Amit; Midura, Ronald J et al. (2016) Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype. Bone 84:194-203
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
Khapre, Rohini V; Patel, Sonal A; Kondratova, Anna A et al. (2014) Metabolic clock generates nutrient anticipation rhythms in mTOR signaling. Aging (Albany NY) 6:675-89
Patel, Sonal A; Velingkaar, Nikkhil S; Kondratov, Roman V (2014) Transcriptional control of antioxidant defense by the circadian clock. Antioxid Redox Signal 20:2997-3006
Khapre, Rohini V; Kondratova, Anna A; Patel, Sonal et al. (2014) BMAL1-dependent regulation of the mTOR signaling pathway delays aging. Aging (Albany NY) 6:48-57
Antoch, Marina P; Kondratov, Roman V (2013) Pharmacological modulators of the circadian clock as potential therapeutic drugs: focus on genotoxic/anticancer therapy. Handb Exp Pharmacol :289-309
Kondratova, Anna A; Kondratov, Roman V (2012) The circadian clock and pathology of the ageing brain. Nat Rev Neurosci 13:325-35