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

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 available ad 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.

Keywords: aging; caloric restriction; circadian rhythms; clock; intermittent fasting; life span; metabolism; αMUPA.

Figure 1.. Resetting signals of the central and peripheral clocks.

The SCN resets peripheral oscillators via humoral factors or autonomic innervation leading to circadian hormone expression and secretion and rhythmic activity of metabolic pathways. In addition, the SCN dictates rhythms of locomotor activity, sleep-wake cycle, blood pressure, and body temperature. Light, food, and feeding regimens affect either the central clock in the SCN or peripheral clocks. Input to central or peripheral clocks are in blue. Outputs from the central clock to the periphery are in green.

Figure 2.. The core mechanism of the mammalian circadian clock and its link to energy metabolism.

(A) High NAD(P)H levels promote CLOCK:BMAL1 binding to E-box sequences leading to the acetylation of BMAL1 and expression of Pers, Crys, and other clock-controlled genes. The negative feedback loop, PERs:CRYs, binds to CLOCK:BMAL1 and consequently PERs are acetylated. Activated AMPK leads to a rise in NAD+ levels, phosphorylation of CRYs, and phosphorylation of CKI?, which then phosphorylates the PERs. As a result of increased NAD+ levels, SIRT1 deacetylates PERs and BMAL1. This and the destabilization of phosphorylated PERs and CRYs relieves PERs:CRYs repression and another cycle starts. (B) Expression of Bmal1 and Rev-erbα genes are controlled by PPARα and binding of RORs to RORE sequences. RORs need a co-activator, PGC-1α, which is phosphorylated by activated AMPK. In parallel, AMPK activation leads to an increase in NAD+ levels, which, in turn activate SIRT1. SIRT1 activation leads to PGC-1α deacetylation and activation. Acetyl adenosine diphosphate ribose (Ac-ADP-r) and nicotinamide (NAM) are released after deacetylation by SIRT1.

Figure 3.. Effect of night vs. day RF and night vs. day IF on clock gene expression.

Expression of a representative clock gene mCry1 was measured in the liver of C57BL mice during ad libitum (AL), day and night RF, and day and night IF.Total RNA extracted from liver tissue collected every 3 h around the circadian cycle (mean ± SEM; n=3 for each time-point and each mouse group) was reverse transcribed and analyzed by quantitative real time PCR. Clock gene levels were normalized using Gapdh as the reference gene. The grey and black bars designate the subjective light and dark cycles, respectively.

Figure 4.. 18-month-old αMUPA and FVB/N WT mice.

αMUPA mice maintain a youthful and healthy appearance, whereas WT mice look old.

Figure 5.. Clock gene expression in the liver under various feeding and lighting conditions in αMUPA (M) and WT mice.

Expression levels of the following clock genes are presented under light-dark or disruptive light conditions:mPer2during ad libitum (AL) feeding, mCry1 under RF, and Bmal1 under IF.Total RNA extracted from liver tissue collected every 3 h around the circadian cycle (mean ± SEM; n=3 for each time-point and each mouse group) was reverse transcribed and analyzed by quantitative real time PCR. Clock gene levels were normalized using Gapdh as the reference gene.

Figure 6.. A schematic model describing the effect of feeding regimens on longevity through peripheral and SCN clock resetting.

CR and IF reset circadian rhythms in the periphery and the SCN. The synchronized, robust circadian rhythms could be the mediator though which these feeding regimens lead to aging attenuation and life span extension. RF resets circadian rhythms only in the periphery, but its effect on life span is not known.