Caloric restriction effects on liver mTOR signaling are time-of-day dependent.

Richa Tulsian,Roman Kondratov,Nikkhil Velingkaar

doi:10.18632/aging.101498

Abstract

The regulation of mechanistic target of rapamycin (mTOR) signaling contributes to the metabolic effects of a calorie restriction (CR) diet. We assayed the effect of CR on the activity of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) in the liver of mice at six different times across the day. CR effects on mTORC1 and mTORC2 activities were time-of-day dependent. CR induced mTORC1 activity at one time, reduced at two times and has no effect during other times. CR induced mTORC2 activity at one time of the day and has no effects at other times. Circadian clocks are implemented in the regulation of mTOR signaling in mammals and mechanisms of CR. We assayed the effect of CR on mTOR signaling in the liver of mice deficient for circadian transcriptional regulators BMAL1 and CRYs. The CR induced suppression of mTORC1 activity was observed in both clock mutants, while up regulation of mTORC2 was observed in the liver of CRY deficient but not in the liver of BMAL1 deficient mice. Our finding revealed that CR has different time dependent effect on the activity of mTOR complexes 1 and 2 and suggest that circadian clock protein BMAL1 is involved in the up regulation of mTORC2 upon CR in mammals.

Highlights

Calorie restriction (CR) is a feeding regimen that increases longevity in organisms from yeast to primates [1]
MTORC1 activity was assayed based on the phosphorylation of ribosomal protein S6 on S235/236 sites (S6 is not a direct target but it is often used as a surrogate marker of mTOR complex 1 (mTORC1) activity) [4,5] in the liver of wild type mice
We found that the effect of caloric restriction (CR) on mTORC1 activity depends on the time of the day

Summary

Introduction

Calorie restriction (CR) is a feeding regimen that increases longevity in organisms from yeast to primates [1]. The mechanisms of CR are not well known: multiple physiological and metabolic changes induced by CR have been reported and several signaling pathways are proposed mediators of CR effects. CR inhibits the activity of the mechanistic target of rapamycin (mTOR) [2,3]. Genetic or pharmacological inhibition of mTORC1 signaling leads to increased lifespan. It was proposed that high activity of mTORC1 is a major driving force of aging, while the suppression of mTORC1contributes to many benefits of CR, including lifespan extension [6]. The suppression of mTORC1 activity by CR was demonstrated in several model organisms such as yeast, nematodes and flies, at the same time, studies conducted in mammals have not yet arrived at a consensus. Some observed suppression of mTORC1 signaling upon CR [7], while others detected no suppression and even induction in mTORC1 activity [8]. mTORC2 is implicated in the control of aging, much less is known about its exact role in aging and the effect of CR on mTORC2 activity

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