Journal
FASEB JOURNAL
Volume 30, Issue 4, Pages 1634-1642Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.15-282475
Keywords
aging; gene expression; glucose; insulin; transcription; food anticipation
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Funding
- U.S. National Institutes of Health/National Institute on Aging [1R01AG039547]
- Center for Gene Regulation in Health and Disease (Cleveland State University)
- Cleveland State University
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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 an ad libitum (AL) diet but failed to increase life span of Bmal1(-/-) 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 CR vs. AL by 50 to 70% in WT mice at several daily time points tested, while in Bmal1(-/-) the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, while Bmal1(-/-) induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression of Bmal1 (by 150%) and its downstream target genes Periods (by 470% for Per1 and by 130% for Per2). We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.
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