The aging clock and circadian control of metabolism and genome stability

Abstract

It is widely accepted that aging is characterized by a gradual decline in the efficiency and accuracy of biological processes, leading to deterioration of physiological functions and development of age-associated diseases. Age-dependent accumulation of genomic instability and development of metabolic syndrome are well-recognized components of the aging phenotype, both of which have been extensively studied. Existing findings strongly support the view that the integrity of the cellular genome and metabolic function can be influenced by light at night (LAN) and associated suppression of circadian melatonin production. While LAN is reported to accelerate aging by promoting age-associated carcinogenesis in several animal models, the specific molecular mechanism(s) of its action are not fully understood. Here, we review literature supporting a connection between LAN-induced central circadian disruption of peripheral circadian rhythms and clock function, LINE-1 retrotransposon-associated genomic instability, metabolic deregulation, and aging. We propose that aging is a progressive decline in the stability, continuity, and synchronization of multi-frequency oscillations in biological processes to a temporally disorganized state. By extension, healthy aging is the ability to maintain the most consistent, stable, and entrainable rhythmicity and coordination of these oscillations, at the molecular, cellular, and systemic levels.

Keywords: LINE-1; aging; light exposure at night; metabolism; retroelements.

FIGURE 1

Light exposure at night accelerates aging by impeding or enhancing processes associated with aging. (A) Usually aging involves normal light exposure that is characterized by alternating intervals of light and dark over a 24-h period, which result in circadian production of nocturnal melatonin. This leads to the synchronization of peripheral clock (PC) function controlling many biochemical processes in cells including L1 expression and activity (Deharo et al., 2014) and the DNA damage response (DDR). (B) Exposure to light at night (LAN) is reported to accelerate aging. LAN blocks nocturnal melatonin production which prevents synchronization of PCs, leading to the disruption of timely function of many biochemical processes in cells including L1 expression and activity, DDR, and metabolism.

FIGURE 2

Longitudinal effect of LAN on PC function, DDR, and metabolism. Schematic representation of the effect of normal light exposure versus LAN on the age-associated deterioration of PCs. The maintenance of the normal light/dark cycle promotes circadian melatonin output and synchronization of the PC (black line) with DDR and metabolic function (red line). An age-associated decline in melatonin production and melatonin receptor expression (Hill et al., 2010) leads to the gradual decline in the amplitude of the peripheral rhythms and potentially their synchronization with DDR and metabolic function. We hypothesize that LAN accelerates aging by promoting age-associated decline in the amplitude of the peripheral rhythms and their synchronization with DDR and metabolic function at early age. Individual genomes may provide molecular machinery to resist adverse effects of LAN, explaining the variation in lifespan observed in the human population.