Research Paper Volume 16, Issue 13 pp 10670—10693

Roles of pigment epithelium-derived factor in exercise-induced suppression of senescence and its impact on lung pathology in mice

Hiromichi Tsushima1, , Hirobumi Tada2,3, , Azusa Asai3, , Mikako Hirose1, , Tohru Hosoyama3, , Atsushi Watanabe3, , Taro Murakami2, , Masataka Sugimoto1,3, ,

  • 1 Laboratory of Molecular and Cellular Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo 173-0015, Japan
  • 2 Department of Nutrition, Shigakkan University, Aichi 474-8651, Japan
  • 3 Research Institute, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan

Received: March 6, 2024       Accepted: June 3, 2024       Published: June 26, 2024
How to Cite

Copyright: © 2024 Tsushima et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Senescent cells contribute to tissue aging and underlie the pathology of chronic diseases. The benefits of eliminating senescent cells have been demonstrated in several disease models, and the efficacy of senolytic drugs is currently being tested in humans. Exercise training has been shown to reduce cellular senescence in several tissues; however, the mechanisms responsible remain unclear. We found that myocyte-derived factors significantly extended the replicative lifespan of fibroblasts, suggesting that myokines mediate the anti-senescence effects of exercise. A number of proteins within myocyte-derived factors were identified by mass spectrometry. Among these, pigment epithelium-derived factor (PEDF) exerted inhibitory effects on cellular senescence. Eight weeks of voluntary running increased Pedf levels in skeletal muscles and suppressed senescence markers in the lungs. The administration of PEDF reduced senescence markers in multiple tissues and attenuated the decline in respiratory function in the pulmonary emphysema mouse model. We also showed that blood levels of PEDF inversely correlated with the severity of COPD in patients. Collectively, these results strongly suggest that PEDF contributes to the beneficial effects of exercise, potentially suppressing cellular senescence and its associated pathologies.


BALF: bronchoalveolar lavage fluid; BCL: B-cell lymphoma; COPD: chronic obstructive pulmonary disease; CM: conditioned medium; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; Il-1b and Il-6: interleukin-1beta and interleukin-6; MEF: mouse embryonic fibroblast; Mmp-12: matrix metalloproteinase-12; PEDF: pigment epithelium-derived factor; PPE: porcine pancreatic elastase; ROS: reactive oxygen species; SA-β-Gal: senescence-associated β-galactosidase; SASP: senescence-associated secretory phenotype; SD: standard deviation; SEM: standard error of the mean; SOL: soleus muscle; TA: tibialis anterior muscle.