title: PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases.
abstract: Cellular senescence and organismal aging predispose age-related chronic diseases, such as neurodegenerative, metabolic, and cardiovascular disorders. These diseases emerge coincidently from elevated oxidative/electrophilic stress, inflammation, mitochondrial dysfunction, DNA damage, and telomere dysfunction and shortening. Mechanistic linkages are incompletely understood. Here, we show that ablation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) accelerates vascular aging and atherosclerosis, coinciding with telomere dysfunction and shortening and DNA damage. PGC-1α deletion reduces expression and activity of telomerase reverse transcriptase (TERT) and increases p53 levels. Ectopic expression of PGC-1α coactivates TERT transcription and reverses telomere malfunction and DNA damage. Furthermore, alpha lipoic acid (ALA), a non-dispensable mitochondrial cofactor, upregulates PGC-1α-dependent TERT and the cytoprotective Nrf-2-mediated antioxidant/electrophile-responsive element (ARE/ERE) signaling cascades, and counteracts high-fat-diet-induced, age-dependent arteriopathy. These results illustrate the pivotal importance of PGC-1α in ameliorating senescence, aging, and associated chronic diseases, and may inform novel therapeutic approaches involving electrophilic specificity.
authors: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Shiqin
authors: S
authors: Xiong
authors: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Nikolay
authors: N
authors: Patrushev
authors: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Farshad
authors: F
authors: Forouzandeh
authors: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Lula
authors: L
authors: Hilenski
authors: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: ralexan@emory.edu.
authors: R Wayne
authors: RW
authors: Alexander
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements; D050197:Atherosclerosis / Q000235:genetics*; D001808:Blood Vessels / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics; D059506:Telomere Shortening; D008063:Thioctic Acid / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008063:Thioctic Acid; D019098:Telomerase; C509187:Tert protein, mouse