Epigenetic Clock and Circadian Rhythms in Stem Cell Aging and Rejuvenation.

Ekaterina M Samoilova,Alexander V Troitskiy,Chao Zhang,Vladimir V Belopasov,Evgenia V Ekusheva,Vladimir P Baklaushev

doi:10.3390/jpm11111050

Abstract

This review summarizes the current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the senescence of all somatic cells and stem cells in particular. Basic mechanisms of regulation for circadian genes CLOCK-BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by the finely tuned regulation of transcription and rely on various epigenetic mechanisms including the activation of enhancers/suppressors, acetylation/deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Additionally included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for cell aging, and oncogenesis. Eliminating some of them (for example, Sirt1) accelerates the aging process, while the overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, the main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock and stem cells rejuvenation as part of antiaging therapy are discussed.

Highlights

The aging process is characterized by a progressive decline in multiple physiological functions
Endogenous as well as external aging factors operate through such mechanisms as circadian rhythms and epigenetic clocks
Methyltransferases have been observed to change in the aging stem cells [105,188]. These results indicate that changes in the epigenetic clocks are an integral universal feature of aging in stem cells, which determines their decline in function

Summary

Introduction

The aging process is characterized by a progressive decline in multiple physiological functions. It is accompanied with reduced metabolic activity, increase in adipose tissue, loss of muscle mass and function [1,2], de-regulation of circadian rhythms controlling sleep/wake cycles, weaker immunity [3,4], impaired cognitive functions, retinal dysfunction, etc. Circadian rhythms, which are diurnal fluctuations in genetic expression, have been known about for a long time, and their physiological influence can hardly be overestimated. The circadian clock, synchronizing with external signals, sets the rhythm for almost all physiological parameters from cognitive functions, caused by the level of activity of neurotransmitter systems, to fluctuations of metabolic parameters in each individual cell. In our opinion, the role of circadian clocks in aging and cell senescence remains underappreciated

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