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Cell Rep. 2015 Sep 1;12(9):1391-9. doi: 10.1016/j.celrep.2015.07.047. Epub 2015 Aug 20.

PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases.

Author information

1
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
2
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: ralexan@emory.edu.

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.

PMID:
26299964
PMCID:
PMC4549794
DOI:
10.1016/j.celrep.2015.07.047
[Indexed for MEDLINE]
Free PMC Article

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