Accumulating evidence indicates an association between the circadian clock and the aging process. However, it remains elusive whether the deregulation of circadian clock proteins underlies stem cell aging and whether they are targetable for the alleviation of aging-associated syndromes. Here, we identified a transcription factor-independent role of CLOCK, a core component of the molecular circadian clock machinery, in counteracting human mesenchymal stem cell (hMSC) decay. CLOCK expression was decreased during hMSC aging. In addition, CLOCK deficiency accelerated hMSC senescence, whereas the overexpression of CLOCK, even as a transcriptionally inactive form, rejuvenated physiologically and pathologically aged hMSCs. Mechanistic studies revealed that CLOCK formed complexes with nuclear lamina proteins and KAP1, thus maintaining heterochromatin architecture and stabilizing repetitive genomic sequences. Finally, gene therapy with lentiviral vectors encoding CLOCK promoted cartilage regeneration and attenuated age-related articular degeneration in mice. These findings demonstrate a noncanonical role of CLOCK in stabilizing heterochromatin, promoting tissue regeneration, and mitigating aging-associated chronic diseases.

越来越多的证据表明生物钟与衰老过程之间存在关联。然而，生物钟蛋白的失调是否是干细胞衰老的基础，以及它们是否可作为缓解衰老相关综合征的目标，仍然难以捉摸。在这里，我们确定了 CLOCK（分子生物钟机制的核心组成部分）在抵消人间充质干细胞 (hMSC) 衰变方面的独立于转录因子的作用。在 hMSC 老化过程中，CLOCK 表达降低。此外，CLOCK 缺陷加速了 hMSC 的衰老，而 CLOCK 的过度表达，即使是转录失活形式，也能使生理和病理老化的 hMSC 恢复活力。机理研究表明 CLOCK 与核层蛋白和 KAP1 形成复合物，从而维持异染色质结构并稳定重复的基因组序列。最后，使用编码 CLOCK 的慢病毒载体进行基因治疗可促进软骨再生并减轻小鼠与年龄相关的关节退化。这些发现证明了 CLOCK 在稳定异染色质、促进组织再生和减轻与衰老相关的慢性疾病方面的非典型作用。