Novel SIRT1 Up-regulator F1462 Attenuates Endothelial Cell Senescence and Vascular Aging by Promoting Mitochondrial Biogenesis via Activating the SIRT1/PGC-1α/TFAM Pathway.

Abstract

Vascular aging constitutes a critical driver of age-related cardiovascular diseases (CVDs). Sirtuin 1 (SIRT1) is well established to confer protection against aging and aging-associated pathologies. In the present study, we identified and elucidated the protective effects and mechanisms of F1462, a novel SIRT1 up-regulator, against vascular endothelial cell (EC) senescence and vascular aging. Using a doxorubicin (DOX)-induced EC senescence model, we demonstrated that F1462 dose-dependently suppressed the senescence markers p53 and p21 and lowered senescence-associated secretory phenotype (SASP)-related inflammatory factors. F1462 improved mitochondrial function by restoring mitochondrial membrane potential (MMP), diminishing the generation of total reactive oxygen species (ROS) and mitochondrial reactive oxygen species (mtROS) production, and evaluating ATP production. The beneficial effects of F1462 were further validated in an H2O2-induced EC senescence model. Mechanistically, F1462 facilitated mitochondrial biogenesis by activating the SIRT1/PGC-1α/TFAM signaling pathway. SIRT1 knockdown abrogated these protective effects against cellular senescence and mitochondrial dysfunction in the DOX-induced EC senescence model. Notably, in naturally aged mice, F1462 reduced plasma SASP inflammatory factors and vascular senescence-associated β-galactosidase (SA-β-Gal) activity, and mitigated aging-triggered vascular wall thickening. In conclusion, F1462 alleviates vascular EC senescence and vascular aging by boosting mitochondrial biogenesis through activation of the SIRT1/PGC-1α/TFAM axis, therefore representing a promosing candidate for the treatment of vascular aging and associated CVDs.