SIRT1 promotes endothelial activity and osteogenesis in vitro and ameliorates age-related skeletal regeneration defects in vivo.

Understanding age-driven bone weakening mechanisms is essential for developing precision therapeutic strategies. This study systematically investigated skeletal aging, focusing on the critical decline of SIRT1 and its impact on type H vessels and osteogenic cells. We found that SIRT1 markedly enhanced both endothelial tube formation and osteogenic differentiation in senescent bone marrow-derived mesenchymal stem cell (BMSC)/human umbilical vein endothelial cell (HUVEC) co-cultures. In vivo validation studies revealed that pharmacological activation of SIRT1 significantly improved bone regeneration in age-related osteoporotic defects in both femoral and mandibular sites. Mechanistically, β-catenin served as a downstream mediator of these effects in our experimental systems, with SIRT1 promoting β-catenin deacetylation and nuclear translocation to activate Wnt signaling. By demonstrating that SIRT1 enhances both endothelial and osteogenic functions in the aged bone microenvironment, this work provides a rationale for targeted bone rejuvenation strategies and mechanistically informed therapeutic innovation against geriatric osteoporosis.