SUMMARY The functionality of stem cells declines during aging thereby contributing to aging-associated impairments in tissue regeneration and function1. Alterations in developmental pathways have been associated with declines in stem cell function during aging2–6 but the nature of this process remains poorly defined. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in aging7,8. This study identifies an altered epigenetic stress response in muscle stem cells (also known as satellite cells = SCs) of aged compared to young mice. This includes aberrant global and site-specific induction of active chromatin marks in activated SCs from aged mice resulting in the specific induction of Hoxa9 among all Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor separating gene expression of SCs from aged compared to young mice. This includes most of the currently known inhibitors of SC function in aging muscle such as Wnt-, TGFß-, JAK/STAT- and senescence signaling2–4,6. Inhibition of aberrant chromatin activation or deletion of Hoxa9 suffices to improve SC function and muscle regeneration in aged mice, while overexpression of Hoxa9 mimics aging-associated defects in SCs from young mice, which can be rescued by inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated SCs from aged mice, which limits SC function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.

Accumulation of DNA damage and myeloid-skewed differentiation characterize aging of the hematopoietic system, yet underlying mechanisms remain incompletely understood. Here, we show that aging hematopoietic progenitor cells particularly of the myeloid branch exhibit enhanced resistance to bulky DNA lesions-a relevant type of DNA damage induced by toxins such as cancer drugs or endogenous aldehydes. We identified aging-associated activation of the Hedgehog (Hh) pathway to be connected to this phenotype. Inhibition of Hh signaling reverts DNA damage tolerance and DNA damage-resistant proliferation in aged hematopoietic progenitors. Vice versa, elevating Hh activity in young hematopoietic progenitors is sufficient to impair DNA damage responses. Altogether, these findings provide experimental evidence for aging-associated increases in Hh activity driving DNA damage tolerance in myeloid progenitors and myeloid-skewed differentiation. Modulation of Hh activity could thus be explored as a therapeutic strategy to prevent DNA damage tolerance, myeloid skewing, and disease development in the aging hematopoietic system.

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