Circadian clocks govern calorie restriction—mediated life span extension through BMAL1‐ and IGF‐1‐dependent mechanisms

Dec 25, 2015FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Body clocks may help calorie restriction extend life through BMAL1 and IGF-1 pathways

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

A 30% calorie restriction diet increased the lifespan of wild-type mice by 20% compared to those on a normal diet.

BMAL1 deficiency in mice did not allow for lifespan extension from calorie restriction.
Calorie restriction significantly reduced plasma IGF-1 levels by 50 to 70% in wild-type mice, while the reduction was not significant in BMAL1-deficient mice.
Insulin levels decreased by 5 to 9% in wild-type mice due to calorie restriction, whereas BMAL1-deficient mice showed an increase of 10 to 35%.
Calorie restriction increased the daily average expression of BMAL1 by 150% and its target genes Period1 and Period2 by 470% and 130%, respectively.
These findings suggest that BMAL1 may play a key role in mediating the effects of calorie restriction on lifespan.

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Calorie restriction (CR) increases longevity in many species by unknown mechanisms. The circadian clock was proposed as a potential mediator of CR. Deficiency of the core component of the circadian clock-transcriptional factor BMAL1 (brain and muscle ARNT [aryl hydrocarbon receptor nuclear translocator]-like protein 1)-results in accelerated aging. Here we investigated the role of BMAL1 in mechanisms of CR. The 30% CR diet increased the life span of wild-type (WT) mice by 20% compared to mice on anad libitum(AL) diet but failed to increase life span ofBmal1(-/-)mice. BMAL1 deficiency impaired CR-mediated changes in the plasma levels of IGF-1 and insulin. We detected a statistically significantly reduction of IGF-1 in CRvs.AL by 50 to 70% in WT mice at several daily time points tested, while inBmal1(-/-)the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, whileBmal1(-/-)induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression ofBmal1(by 150%) and its downstream target genesPeriods(by 470% forPer1and by 130% forPer2). We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.-Patel, S. A., Chaudhari, A., Gupta, R., Velingkaar, N., Kondratov, R. V. Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms.

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Circadian clocks govern calorie restriction—mediated life span extension through BMAL1‐ and IGF‐1‐dependent mechanisms

Abstract

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