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      Effect of feeding regimens on circadian rhythms: Implications for aging and longevity

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          Abstract

          Increased longevity and improved health can be achieved in mammals by two feeding regimens, caloric restriction (CR), which limits the amount of daily calorie intake, and intermittent fasting (IF), which allows the food to be availablead libitum every other day. The precise mechanisms mediating these beneficial effects are still unresolved. Resetting the circadian clock is another intervention that can lead to increased life span and well being, while clock disruption is associated with aging and morbidity. Currently, a large body of evidence links circadian rhythms with metabolism and feeding regimens. In particular, CR, and possibly also IF, can entrain the master clock located in the suprachiasmatic nuclei (SCN) of the brain hypothalamus. These findings raise the hypothesis that the beneficial effects exerted by these feeding regimens could be mediated, at least in part, through resetting of the circadian clock, thus leading to synchrony in metabolism and physiology. This hypothesis is reinforced by a transgenic mouse model showing spontaneously reduced eating alongside robust circadian rhythms and increased life span. This review will summarize recent findings concerning the relationships between feeding regimens, circadian rhythms, and metabolism with implications for ageing attenuation and life span extension.

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          Most cited references213

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          Coordinated transcription of key pathways in the mouse by the circadian clock.

          In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed approximately 650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver. Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components. Major processes regulated by the SCN and liver were found to be under circadian regulation. Importantly, rate-limiting steps in these various pathways were key sites of circadian control, highlighting the fundamental role that circadian clocks play in cellular and organismal physiology.
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            The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.

            Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb. Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms. Here, we identify the orphan nuclear receptor REV-ERBalpha as the major regulator of cyclic Bmal1 transcription. Circadian Rev-erbalpha expression is controlled by components of the general feedback loop. Thus, REV-ERBalpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERBalpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation.
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              Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock.

              Mice deficient in the circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Here we report that Bmal1(-/-) mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early aging phenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1(-/- )animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses, may provide a mechanistic explanation for the early onset of age-related pathologies in the absence of BMAL1.
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                Author and article information

                Journal
                Aging (Albany NY)
                ImpactJ
                Aging (Albany NY)
                Impact Journals LLC
                1945-4589
                January 2010
                11 January 2010
                : 2
                : 1
                : 7-27
                Affiliations
                1 Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel
                2 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
                Author notes
                Correspondence: Oren Froy, PhD, Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, POB 12, Rehovot 76100, Israel ; Ruth Miskin, PhD, Department of Biological Chemistry, Weizmann Institute of Science, PO Box 26, Rehovot 76100, Israel froy@ 123456agri.huji.ac.il ruth.miskin@ 123456weizmann.ac.il
                Article
                10.18632/aging.100116
                2837202
                20228939
                3bccd467-13ec-4f02-ae64-861d674b9658
                Copyright: ©2010 Froy et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 December 2009
                : 9 January 2010
                Categories
                Review

                Cell biology
                clock; circadian rhythms; caloric restriction; intermittent fasting; metabolism; αmupa; life span; aging

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