Cellular senescence impairs circadian expression of clock genes in vitro and in vivo.
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.
Kunieda
Takeshige
T
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Japan.
Minamino
Tohru
T
Katsuno
Taro
T
Tateno
Kaoru
K
Nishi
Jun-ichiro
J
Miyauchi
Hideyuki
H
Orimo
Masayuki
M
Okada
Sho
S
Komuro
Issei
I
D000818:Animals; D056926:CLOCK Proteins; D002478:Cells, Cultured; D016922:Cellular Senescence; D002940:Circadian Rhythm; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D016615:Telomere; D015534:Trans-Activators / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D015534:Trans-Activators; D056926:CLOCK Proteins; C538943:CLOCK protein, human; C538944:Clock protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases