Cellular Senescence Impairs Circadian Expression of Clock Genes In Vitro and In Vivo

Abstract

Abstract-Circadian rhythms are regulated by a set of clock genes that form transcriptional feedback loops and generate circadian oscillation with a 24-hour cycle. Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. Although recent evidence suggests that cellular aging contributes to various age-associated diseases, its effects on the circadian rhythms have not been examined. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum-stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. Stimulation by serum activated the cAMP response element-binding protein, but the activation of this signaling pathway was significantly weaker in senescent cells. Treatment with activators of this pathway effectively restored the impaired clock gene expression of senescent cells. When young cells were implanted into young mice or old mice, the implanted cells were effectively entrained by the circadian rhythm of the recipients. In contrast, the entrainment of implanted senescent cells was markedly impaired. These results suggest that senescence decreases the ability of cells to transmit circadian signals to their clocks and that regulation of clock gene expression may be a novel strategy for the treatment of age-associated impairment of circadian rhythmicity. (Circ Res. 2006;98:532-539.)Key Words: senescence Ⅲ clock gene Ⅲ aging Ⅲ CREB Ⅲ ERK C ellular senescence is a limited ability of primary human cells to divide when cultured in vitro and is accompanied by a specific set of phenotypic changes in morphology and gene expression and function. These phenotypic changes have been suggested to play a role in human aging and age-associated diseases. 1 This hypothesis of cellular aging was established by Hayflick 2 and is supported by the evidence that the replicative potential of primary cultured human cells is dependent on donor age and that the growth potential of cultured cells is correlated well with the mean maximum lifespan of the species of origin. 2 We have previously reported that senescent vascular cells are predominately localized in the plaque of human atherosclerosis but not in normal lesions and that vascular cell senescence results in vascular dysfunction. 3 Recently, we also demonstrated that atherogenic stimulation induces vascular cell senescence and vascular inflammation, thereby contributing to the development of atheroma. 4 There is also evidence indicating that progressive telomere shortening, a biomarker of cellular aging, occurs in human blood vessels, which may be related to age-associated vascular diseases. 5-10 Thus, vascular cell senescence in vivo may contribute to the pathogenesis of vascular aging. 11Aging is associated with a variety of alterations of circadian rhythms. 12,13 These include impairment of the rhythms for blood pressure, locomoto...

Rapid forgetting of social transmission of food preferences in aged rats: Relationship to hippocampal CREB activation

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Aging in male primates: reproductive decline, effects of calorie restriction and future research potential

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