Report
PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases
Publication stage: In Press Corrected Proof
Open Access
Open access funded by the Author(s)
Highlights
- •PGC-1α disruption promotes vascular aging and atherosclerosis
- •PGC-1α modulates telomere function and length as well as DNA damage
- •High-fat diet reduces PGC-1α-TERT signaling to drive vascular aging and arteriopathy
- •Enabling PGC-1α-modulated TERT and ARE/ERE signaling obviates age-related pathology
Summary
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.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Received: March 6, 2015; Received in revised form: June 18, 2015; Accepted: July 23, 2015; Published Online: August 20, 2015
© 2015 The Authors. Published by Elsevier Inc.
ALPHA - LIPOIC ACID
Other Names:
Acetate Replacing Factor, A-Lipoic Acid, Acide Alpha-Lipoïque, Acide Alpha-Lipoïque R, Acide DL-Alpha-Lipoïque, Acide Lipoïque, Acide Thioctique, Acide 1,2-dithiolane-3-pentanoïque, Acide 1,2-dithiolane-3-valérique, Acide 5 Valérique (1,2-dithio...
See All Names
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ALPHA LIPOIC ACID (ALPHA-LIPOIC ACID) OVERVIEW INFORMATION
Alpha-lipoic acid is a vitamin-like chemical called an antioxidant. Yeast, liver, kidney, spinach, broccoli, and potatoes are good sources of alpha-lipoic acid. It is also made in the laboratory for use as medicine.
Alpha-lipoic acid is used for diabetes and nerve-related symptoms of diabetesincluding burning, pain, and numbness in the legs and arms. High doses of alpha-lipoic acid are approved in Germany for the treatment of these symptoms.
Some people use alpha-lipoic acid for memory loss, chronic fatigue syndrome (CFS),HIV/AIDS, cancer, liver disease, diseases of the heart and blood vessels (including a disorder called cardiac autonomic neuropathy) and Lyme disease.
Alpha-lipoic acid is also used to treat eye-related disorders, such as damage to the retina, cataracts, glaucoma, and an eye disease called Wilson’s disease.
Alpha-lipoic acid is used for diabetes and nerve-related symptoms of diabetesincluding burning, pain, and numbness in the legs and arms. High doses of alpha-lipoic acid are approved in Germany for the treatment of these symptoms.
Some people use alpha-lipoic acid for memory loss, chronic fatigue syndrome (CFS),HIV/AIDS, cancer, liver disease, diseases of the heart and blood vessels (including a disorder called cardiac autonomic neuropathy) and Lyme disease.
Alpha-lipoic acid is also used to treat eye-related disorders, such as damage to the retina, cataracts, glaucoma, and an eye disease called Wilson’s disease.
How does it work?
Alpha-lipoic acid seems to help prevent certain kinds of cell damage in the body, and also restores vitamin levels such as vitamin E and vitamin C. There is also evidence that alpha-lipoic acid can improve the function and conduction of neurons in diabetes.
Alpha-lipoic acid is used in the body to break down carbohydrates and to make energy for the other organs in the body.
Alpha-lipoic acid seems to work as an antioxidant, which means that it might provide protection to the brain under conditions of damage or injury. The antioxidant effects might also be helpful in certain liver diseases.
Alpha-lipoic acid is used in the body to break down carbohydrates and to make energy for the other organs in the body.
Alpha-lipoic acid seems to work as an antioxidant, which means that it might provide protection to the brain under conditions of damage or injury. The antioxidant effects might also be helpful in certain liver diseases.
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