Panorama Research Institute, Sunnyvale, California, USA.
Regenerative Sciences Institute, Sunnyvale, California, USA.
Rejuvenation Res. 2020 Jun;23(3):262-265. doi: 10.1089/rej.2020.2359.
Exercise has long been known to extend health and lifespan in humans and other mammals. However, typically exercise is thought to slow the loss of function that accompanies aging. Brett et al. have now shown that exercise restores functional competency to regenerate muscle stem cells (MuSCs) in mice as well as restore a significant portion of the transcriptional signature associated with young MuSCs. The mechanism involves the likely induction of plasma-borne factors that upregulate cell cycle regulator cyclin D1, which otherwise decreases with increasing age. Cyclin D1, in turn, through its noncanonical attenuation of TGF-beta/Smad3 signaling, helps maintain the regenerative capacity of MuSCs, which is lost as TGF-beta signaling increases with age. Interestingly, elevated levels of some proinflammatory regulators including NF-κB, TNF-alpha, and interleukin 6 (IL-6) are also reduced by exercise or ectopic expression of cyclin D1. Importantly, the rejuvenation is not complete, as Notch signaling, which also decreases with age, remains at old levels and the rejuvenative effect is not permanent: wearing off in ∼2 weeks after cessation of exercise. Understanding the limitations of the rejuvenative effect of exercise on MuSCs at the molecular level, including changes in the epigenome such as altered DNA methylation age, will be critical in developing more significant rejuvenative therapies including some for aged people wherein morbidities limit exercise.
运动早已被证实可以延长人类和其他哺乳动物的健康寿命。然而，通常情况下，运动被认为可以减缓衰老带来的功能丧失。Brett 等人现在表明，运动可以恢复小鼠肌肉干细胞（MuSCs）的功能，恢复与年轻 MuSCs 相关的大部分转录特征。该机制涉及到可能诱导血浆来源的因子，这些因子上调细胞周期调节剂细胞周期蛋白 D1，否则细胞周期蛋白 D1 会随着年龄的增长而减少。反过来，细胞周期蛋白 D1 通过其非经典的 TGF-β/Smad3 信号转导的衰减，有助于维持 MuSCs 的再生能力，而随着年龄的增长，TGF-β 信号转导的增加会导致 MuSCs 的再生能力丧失。有趣的是，一些促炎调节剂的水平升高，包括 NF-κB、TNF-α 和白细胞介素 6（IL-6），也可以通过运动或细胞周期蛋白 D1 的异位表达来降低。重要的是，这种年轻化并不完全，因为 Notch 信号也会随着年龄的增长而下降，仍然保持在老年水平，而且这种年轻化效果不是永久性的：在停止运动约 2 周后就会消失。在分子水平上理解运动对 MuSCs 的年轻化效果的局限性，包括表观基因组的变化，如改变 DNA 甲基化年龄，对于开发更显著的年轻化疗法至关重要，包括一些针对年龄较大的人群的疗法，因为这些人群的病态限制了运动。
