Caloric restriction (CR) is one of the few regimens that enhances longevity in mammals, yet the mechanisms underlying this beneficial effect have been elusive. A confound in the majority of CR studies is that temporal restriction of food intake almost always accompanies caloric restriction. Temporal restriction or restricted feeding (RF) is known to be a potent entraining stimulus for circadian rhythms in mammals and can shift the entire circadian metabolic profile of peripheral organ systems such as the liver. Interestingly, CR combined with RF has been shown to be an even more potent entraining signal and can reset both the central pacemaker in the suprachiasmatic nucleus (SCN) as well as circadian oscillators in peripheral tissues. Given that deterioration of circadian rhythms is one of the hallmarks of aging and given that circadian disruptions in both human and animal models lead to cardiovascular and metabolic disorders, such temporal disruptions of "circadian order" (coherence and synchrony of internal rhythms) could contribute significantly to aging and longevity. In preliminary data we have found that RF has wide-ranging and complex effects on genome-wide circadian transcriptional architecture, gene expression and RNA polymerase II recruitment and initiation as well as chromatin modifications involving histone methylation and acetylation. These changes result in large shifts in the phases of rhythmic gene expression patterns and impact pathways that are central to the aging process including energy utilization and metabolic pathways, insulin signaling, mTOR signaling, xenobiotic detoxification, and ubiquitin mediated proteolysis. Lowered circadian amplitude and inappropriately phased rhythms are hallmarks of aging, and treatments that improve circadian function have been linked to well-being and longer lifespan. Therefore, it is possible that the beneficial effects of caloric restriction paradigms originates partially or fully from the temporal restriction of food intake, rather than the reduction in calories. Thus, we hypothesize that synchronization of central and peripheral oscillators during caloric restriction improves hormonal, biochemical and physiological functions, which can then lead to attenuation of aging and increased life span. In these experiments we will generate comprehensive circadian profiles of circadian clock transcription factor binding, gene expression and chromatin modifications to assess genome-wide changes that occur during the aging process. We will use an experimental design that distinguishes the contributions of caloric restriction from those of temporal restrictions. Analyse of the circadian transcriptional landscape as a function of aging using Hidden Markov Models and correlation matrices will provide a foundation for discovery of genomic and epigenomic signatures and mechanisms critical to circadian rhythms, aging and longevity.
Caloric restriction is the most powerful treatment for the extension of lifespan but the mechanism behind its anti-aging effect is not known. Recent evidence has emerged that suggests that a strong effect of caloric restriction is to synchronize the internal daily timing mechanisms called circadian clocks in tissues such as liver. This proposal will explore how resetting the clocks in the liver with various feeding paradigms such as caloric restriction can lead to extensive and complex changes in rhythmic gene expression patterns that ultimately impact how the organism ages.
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