Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
Universitat Pompeu Fabra (UPF), Department of Experimental and Health Sciences (DCEXS) and CIBER on Neurodegenerative Diseases (CIBERNED), 08003 Barcelona, Spain.
Cell. 2017 Aug 10;170(4):678-692.e20. doi: 10.1016/j.cell.2017.07.035.
Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during aging. Unexpectedly, we find that aged mice remain behaviorally circadian and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging. While age-associated rewiring of the oscillatory diurnal transcriptome is not recapitulated by a high-fat diet in young adult mice, it is significantly prevented by long-term caloric restriction in aged mice. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age-related traits.
成人干细胞的正常动态平衡功能具有节律性的日常波动，这种波动据信在衰老过程中会变得无节律。出乎意料的是，我们发现老年小鼠仍然具有行为性昼夜节律，并且它们的表皮和肌肉干细胞保留了强大的节律核心生物钟机制。然而，衰老干细胞中转录组的振荡被广泛重新编程，从参与动态平衡的基因切换到参与组织特异性应激的基因，如 DNA 损伤或自噬效率低下。重要的是，敲除生物钟成分并没有复制这种重新编程的特征，这强调了与生理衰老相关的是重布线，而不是无节律性。虽然高脂肪饮食在年轻成年小鼠中不能重现与年龄相关的振荡昼夜转录组的重布线，但长期热量限制可显著预防老年小鼠中这种重布线的发生。因此，干细胞重新布线其昼夜定时功能以适应代谢线索和组织特异性与年龄相关的特征。
