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

  • Nat Aging. 2026 May;6(5):1021-1041. doi: 10.1038/s43587-026-01124-z.
Chen Yang  #  1 ,  Zeng Xu  #  1 ,  Sha-Tong He  #  1 ,  Gen-Jiang Zheng  #  1 ,  Jian-Xi Wang  1 ,  Fa-Zhi Zang  1 ,  Jin-Quan Hu  1 ,  Yun-Hao Wang  1 ,  Wen-Yu Zhang  1 ,  Chen-Fei Gao  1 ,  Teng-Hui Zhang  1 ,  Yang Ye  1 ,  Hao Chen  2 ,  Fan-Qi Kong  3 ,  Xiao Lv  4 ,  Lei Liang  1 ,  Yue-Li Sun  5 ,  Zhen-Wei Wang  6 ,  Zi-Xi Wang  1 ,  Peng Cao  1 ,  Xiao-Dong Wu  7 ,  Bo Gao  8 ,  Ye Tian  9 ,  Bo Hu  10 ,  Hua-Jiang Chen  11
Affiliations
  • 1. Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China.
  • 2. Medical College, Yangzhou University, Yangzhou, China.
  • 3. Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 4. Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5. Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 6. Department of Orthopedics, No. 905 Hospital, Naval Medical University, Shanghai, China.
  • 7. Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China. [email protected].
  • 8. Department of Orthopedics, Xijing Hospital, Air Force Medical University, Xi'an, China. [email protected].
  • 9. Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China. [email protected].
  • 10. Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China. [email protected].
  • 11. Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42120734 DOI: 10.1038/s43587-026-01124-z
Abstract

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.

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