1. PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases
- Author
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R. Wayne Alexander, Nikolay Patrushev, Farshad Forouzandeh, Lula Hilenski, and Shiqin Xiong
- Subjects
Senescence ,Telomerase ,NF-E2-Related Factor 2 ,DNA damage ,Inflammation ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Mice ,medicine ,Animals ,Telomerase reverse transcriptase ,lcsh:QH301-705.5 ,Transcription factor ,Telomere Shortening ,Thioctic Acid ,Telomere ,Atherosclerosis ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Molecular biology ,Antioxidant Response Elements ,Cell biology ,Mice, Inbred C57BL ,lcsh:Biology (General) ,Blood Vessels ,Ectopic expression ,Tumor Suppressor Protein p53 ,medicine.symptom ,DNA Damage ,Transcription Factors - Abstract
SummaryCellular 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.
- Published
- 2015
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