Hypoxia-induced autophagic degradation of HIF-1α attenuates cellular aging and extends mammalian lifespan.

Organs age at different rates, yet the protective mechanisms contributing to decelerated aging in certain tissues remain unclear. Applying cross-tissue comparisons to molecular readouts of aging, here we report that the intervertebral disc (IVD) ages slowly. We link the rate of aging to the persistently hypoxic environment of the IVD, and its unique ability to degrade hypoxia-inducible factor-1α (HIF-1α) in nucleus pulposus cells through optineurin-mediated selective autophagy, thereby uncoupling hypoxia from HIF-1α accumulation and limiting cellular stress. Further, we developed a small-molecule HIF-1α-targeting autophagy-tethering compound (HATC) to pharmacologically export the protective mechanism to other tissues. In aged mice, systemic weekly administration of HATC reduced HIF-1α levels across multiple organs, ameliorated a range of age-related pathologies and significantly extended both median (~14%) and maximum lifespan (~12%). These findings define a regulatory axis in which HIF-1α degradation under hypoxia contributes to longevity, and support HATC as a geroprotective strategy to improve healthspan.