Alpha-lipoic acid stimulates telomerase in vascular smooth muscle. Telomerase is the enzyme that lengthens chromosomes’ protective caps, with positive effects in a mouse model of atherosclerosis. The discovery highlights a potential avenue for the treatment for chronic diseases.
“Alpha-lipoic acid has an essential role in mitochondria, the energy-generating elements of the cell,” says Wayne Alexander, MD, PhD, professor of medicine at Emory University School of Medicine. “It is widely available and has been called a ‘natural antioxidant’. Yet ALA’s effects in human clinical studies have been a mixed bag.”
ALA appears to exert its effects against atherosclerosis by spurring the smooth muscle cells that surround blood vessels to make PGC1 (peroxisome proliferator-activated receptor gamma co-activator 1)-alpha. PGC1-alpha was already well known to scientists as controlling several aspects of how skeletal muscles respond to exercise. “The effects of chronic diseases such as atherosclerosis and diabetes on blood vessels can be traced back to telomere shortening,” Alexander says.
METHOD: Xiong and Alexander used a model of atherosclerosis where mice lacked ApoE cholesterol processing gene and were fed a high-fat diet. In this model, mice also lacking PGC1-alpha have more advanced plaques in their blood vessels, but only in older animals.
RESULTS: Aortic cells from PGC1-alpha-disrupted mice had shorter telomeres and reduced telomerase activity. Having shortened telomeres led the smooth muscle cells to display more oxidative stress and damage to the rest of their DNA. Introducing PGC1-alpha back into vascular smooth muscle cells lacking that gene with a gene-therapy adenovirus could restore telomerase activity and lengthen the cells’ telomeres.
MOA: Telomerase is off in most healthy cell types and only becomes turned on when cells proliferate. Because telomerase is active in cancer cells and enables their continued growth, researchers have been concerned that stimulating telomerase in all cells might encourage cancer growth or have other adverse effects. As a way to boost PGC1-alpha in cells more conveniently, Xiong and Alexander turned to alpha lipoic acid or ALA. ALA is a sulfur-containing fatty acid used to treat diabetic neuropathy in Germany, and has previously been shown to combat atherosclerosis in animal models.
Treating isolated smooth muscle cells with ALA for one day could both stimulate PGC1-alpha and telomerase, the authors found. ALA’s effects on vascular smooth muscle cells could also be seen when it was injected into mice. Xiong and Alexander say they are now investigating the effects of ALA on other tissues in mice. They have not observed increased cancers in ALA-treated mice, but say more thorough investigation is needed to fully assess cancer risk.
They are designing ways to formulate/deliver ALA-related compounds to resolve poor solubility, stability and bioavailability. http://news.emory.edu/stories/2015/08/pgc_telomeres_alexander/
•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
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