Chemical enhancement of DNA repair in aging

DNA damage is a central driver of the aging process. We previously found that KIF2C, known to play a role in DNA repair, is repressed in aged cells. Here, we investigated if increased KIF2C activity counteracts DNA damage and its effects on aging phenotypes. We show that a small-molecule agonist of KIF2C enhances DNA repair in two distinct genetic disorders exhibiting DNA damage and accelerated aging, the Hutchinson-Gilford progeria (HGPS) and Down (DS) syndromes. Mechanistically, the KIF2C agonist improves the repair of DNA double-strand breaks by inducing nuclear envelope invaginations poked by cytoplasmic microtubules, which translated into amended epigenetic and transcriptional signatures of HGPS and DS. Moreover, subcutaneous administration of the KIF2C agonist in progeria mice mitigated aging phenotypes, extending their healthspan. Our study discloses a unique geroprotective pharmacological approach targeting DNA damage.