Restoration of CPEB4 prevents muscle stem cell senescence during aging

Age-associated impairments in adult stem cell functions correlate with a decline in somatic tissue regeneration capacity. However, the mechanisms underlying the molecular regulation of adult stem cell aging remain elusive. Here, we provide a proteomic analysis of physiologically aged murine muscle stem cells (MuSCs), illustrating a pre-senescent proteomic signature. During aging, the mitochondrial proteome and activity are impaired in MuSCs. In addition, the inhibition of mitochondrial function results in cellular senescence. We identified an RNA-binding protein, CPEB4, downregulated in various aged tissues, which is required for MuSC functions. CPEB4 regulates the mitochondrial proteome and activity through mitochondrial translational control. MuSCs devoid of CPEB4 induced cellular senescence. Importantly, restoring CPEB4 expression rescued impaired mitochondrial metabolism, improved geriatric MuSC functions, and prevented cellular senescence in various human cell lines. Our findings provide the basis for the possibility that CPEB4 regulates mitochondrial metabolism to govern cellular senescence, with an implication of therapeutic intervention for age-related senescence.

Automated summary

Age-associated impairments in adult stem cell functions and tissue regeneration are linked to mitochondrial dysfunction and cellular senescence. The RNA-binding protein CPEB4 is downregulated in aged tissues and plays a critical role in regulating mitochondrial proteome and activity. Restoration of CPEB4 expression improves mitochondrial metabolism, enhances stem cell functions, and prevents cellular senescence, suggesting therapeutic potential for age-related senescence.