Physical activity promotes health primarily by decelerating the aging process. Bone is one of the tissues capable of sensing mechanical force and can adapt to different physical demands. However, its role in whole-body aging is unknown. We found that reduced mechano-sensing in osteocytes, caused by deletion of the mechanosensory channel, Piezo1, accelerated whole-body aging in mice. Dynamic tibial axial loading (DTAL) in mice at 20-24 months of age extended both healthspan and lifespan (9.4%/79.5 days). Furthermore, DTAL reversed bone marrow immunosenescence and induced anti-aging and protective factors while downregulating pro-aging and pro-inflammatory factors. We also identified pigment epithelium-derived factor (PEDF) as a novel mechano-responsive anti-aging factor that is highly associated with healthy aging in humans. Thus, our findings highlighted an essential role for bone mechano-sensing in whole-body aging. This could potentially be manipulated to prevent aging, extend health, and aid those unable to exercise or with decreased mobility.
