Circadian Clock Mechanisms are Required for Longevity via Calorie Restriction?

Researchers have recently suggested that the practice of calorie restriction requires elements of the circadian clock to be present and functional in order to extend life, implying that adjustment of these mechanisms is a part of the way in which calorie restriction works to slow aging. There has been an increased interest in the circadian clock in aging research of late, a system of regulation that governs changes in cellular metabolism and tissue function over the course of a day. Elements of the clock become dysregulated with advancing age, though as for most of the catalog of known age-related changes in cellular behavior it is unclear as to where this failure sits in the grand chain of cause and consequence in aging. This chain spans the processes that lead from fundamental molecular damage through complex and poorly understood interactions all the way to the end stage of age-related disease and death. Is disarray of the circadian clock closer to the damage end, and thus produces many detrimental consequences in and of itself, or is it closer to being a final consequence, with little further damage done as a result? In this context research of the sort linked here is interesting:

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 - 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 50-70% 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.

Link: http://dx.doi.org/10.1096/fj.15-282475

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