Small-molecule targeting of kinesin-13 KIF2C enhances double-strand break DNA repair and slows down aging

DNA damage is a central driver of the aging process. We previously found that the kinesin-13 KIF2C, shown to play a role in DNA repair, is repressed in aged cells. Here, we investigate whether increased KIF2C activity can counteract DNA damage and alleviate aging-related phenotypes. We demonstrate that a small-molecule agonist of KIF2C enhances DNA repair in two distinct genetic disorders characterized by pervasive DNA damage and accelerated aging: the Hutchinson-Gilford progeria syndrome (HGPS) and the Down syndrome (DS). Mechanistically, the KIF2C agonist improves double-strand break (DSB) DNA repair in aged and patient-derived cells by restoring the assembly of nuclear envelope invaginations driven by cytoplasmic microtubules. Enhanced DSB DNA repair in HGPS and DS cells translates into amended nuclear structure and transcriptional signatures. Moreover, subcutaneous administration of the KIF2C agonist in progeria mice mitigates aging phenotypes and extends both health and lifespan. Our study discloses a geroprotective pharmacological approach that acts by hindering DSB DNA damage, and thus we demonstrate that enhanced genome stability can delay aging. DNA damage is associated with aging and premature aging disorders. Here, the authors show that small molecule activation of the kinesin-13 KIF2C improves double-strand break DNA repair in aged cells and extends lifespan in progeria mice.