Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Is a Central Negative Regulator of Vascular Senescence

Objective-Cellular senescence influences organismal aging and increases predisposition to age-related diseases, in particular cardiovascular disease, a leading cause of death and disability worldwide. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a master regulator of mitochondrial biogenesis and function, oxidative stress, and insulin resistance. Senescence is associated with telomere and mitochondrial dysfunction and oxidative stress, implying a potential causal role of PGC-1 alpha in senescence pathogenesis. Approach and Results-We generated a PGC-1 alpha(+/-)/apolipoprotein E-/- mouse model and showed that PGC-1 alpha deficiency promotes a vascular senescence phenotype that is associated with increased oxidative stress, mitochondrial abnormalities, and reduced telomerase activity. PGC-1 alpha disruption results in reduced expression of the longevity-related deacetylase sirtuin 1 (SIRT1) and the antioxidant catalase, and increased expression of the senescence marker p53 in aortas. Further, angiotensin II, a major hormonal inducer of vascular senescence, induces prolonged lysine acetylation of PGC-1 alpha and releases the PGC-1 alpha-FoxO1 complex from the SIRT1 promoter, thus reducing SIRT1 expression. The phosphorylation-defective mutant PGC-1 alpha S570A is not acetylated, is constitutively active for forkhead box O1-dependent SIRT1 transcription, and prevents angiotensin II-induced senescence. Acetylation of PGC-1 alpha by angiotensin II interrupts the PGC-1 alpha-forkhead box O1-SIRT1 feed-forward signaling circuit leading to SIRT1 and catalase downregulation and vascular senescence. Conclusions-PGC-1 alpha is a primary negative regulator of vascular senescence. Moreover, the central role of posttranslational modification of PGC-1 alpha in regulating angiotensin II-induced vascular senescence may inform development of novel therapeutic strategies for mitigating age-associated diseases, such as atherosclerosis. (Arterioscler Thromb Vasc Biol. 2013; 33: 988-998.)