Research Article: Replicative senescent human cells possess altered circadian clocks with a prolonged period and delayed peak-time

Date Published: February 15, 2019

Publisher: Impact Journals

Author(s): Rezwana Ahmed, Atsushige Ashimori, Satoshi Iwamoto, Takaaki Matsui, Yasukazu Nakahata, Yasumasa Bessho.

http://doi.org/10.18632/aging.101794

Abstract

Over the last decade, a wide array of evidence has been accumulated that disruption of circadian clock is prone to cause age-related diseases and premature aging. On the other hand, aging has been identified as one of the risk factors linked to the alteration of circadian clock. These evidences suggest that the processes of aging and circadian clock feedback on each other at the animal level. However, at the cellular level, we recently revealed that the primary fibroblast cells derived from Bmal1-/- mouse embryo, in which circadian clock is completely disrupted, do not demonstrate the acceleration of cellular aging, i.e., cellular senescence. In addition, little is known about the impact of cellular senescence on circadian clock. In this study, we show for the first time that senescent cells possess a longer circadian period with delayed peak-time and that the variability in peak-time is wider in the senescent cells compared to their proliferative counterparts, indicating that senescent cells show alterations of circadian clock. We, furthermore, propose that investigation at cellular level is a powerful and useful approach to dissect molecular mechanisms of aging in the circadian clock.

Partial Text

Cellular senescence is a process that imposes permanent proliferative arrest in response to various stresses [1,2]. A wide array of evidence suggests that in vivo cellular senescence causes a loss of tissue stem/progenitor cells, and extracellular environment and cells surrounding senescent cells could be functionally disrupted by inflammatory cytokines, growth factors and proteases, which are secreted by senescent cells. In addition, senescent cells have been found at sites of age-related pathologies e.g. atherosclerosis and osteoarthritis [3]. Recent studies demonstrated that pharmacological or genetic eliminations of senescent cells from aging mice extend median lifespan, delayed tumorigenesis and attenuated progression of already established age-related disorders [4–10]. These findings strongly suggest that senescent cells play a key role in these pathological conditions and hence cellular senescence has been termed as the basic driver of the aging phenotype [1]. Despite these clear negative implications, one system on which the impacts of cellular senescence still remain unexplored is the circadian clock.

Aging has been identified as one of the risk factors linked to the alteration of circadian physiology and behavior [24–28]. On the other hand, disruption of circadian clock has been recognized to bring about many physiological abnormalities, leading to a wide variety of age-related diseases and premature aging [16,17]. These pieces of information demonstrate that the mechanisms of aging and circadian clock are intimately regulated by each other at the animal level. However, little is known about their mutual regulations at the cellular level. Intriguingly, we have recently reported that the primary fibroblast cells derived from Bmal1-/- mouse embryo, in which circadian clock is completely disrupted, do not demonstrate the acceleration of replicative and stress-induced senescence [29], suggesting that circadian clock does not control cell-autonomous cellular senescence. Therefore, the current study addressed the reverse question, i.e. whether cellular senescence could affect the circadian clock, and provided evidence for the first time that senescent cells demonstrate a prolonged period and delayed peak-time (Figs. 2 and 6), which was successfully achieved due to the performance of high time-resolution (10 min) real-time luciferase monitoring system. Importantly, these findings were observed by two different entrainment factors, Dex and Fsk, and senescence had no effect on input pathways to the oscillator (Fig.3). Our current study, therefore, indicate that the altered circadian clock with a prolonged period and delayed peak-time is the general hallmark of senescence of the “oscillator” of circadian clock. Furthermore, we uncovered at the cellular level that aging could affect the circadian clock, but not vice versa.

 

Source:

http://doi.org/10.18632/aging.101794

 

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