Aging is the predominant risk factor for cardiovascular diseases (1) and contributes to a significantly more severe outcome in patients with acute myocardial infarction (2). This risk is partly attributable to an age-related decline in the ability of vascular cells to resist stress and effectively remodel the arterial wall. Vascular smooth muscle cells are especially important in this regard. Strategies to prevent the premature senescence of vascular smooth muscle cells could be an effective approach for reducing vascular disease. During the past decade dietary supplementation with the plant-derived polyphenol resveratrol (3,5,4´-trihydroxystilbene) has emerged as a promising approach to counteract age-induced pro-atherogenic phenotypic changes in the vasculature. Resveratrol has been shown to exert significant anti-aging action in vertebrates (3). Resveratrol induced gene expression patterns resembled those induced by caloric restriction (CR) and delayed ...view middle of the document...
The telomerase enzyme is responsible for the maintenance of telomeres through the addition of nucleotides. Tchirkov and Lansdorp proposed the importance of both sufficient telomerase activity and maintenance of telomere length for aging in primary human fibroblast (6). Stimulation of the catalytic subunit of telomerase, the telomerase reverse transcriptase (TERT), stabilized telomere length and provided the cells with unlimited replicative potential without generating malignant properties (7). Thus, telomerase reactivation can prevent or delay the cellular aging process triggered by significant telomere shortening.
Nicotinamide phosphoribosyltransferase (NAMPT), also known as Pre-B-cell colony-enhancing factor and Visfatin, is the rate-limiting enzyme for NAD+ biosynthesis of a mammalian salvage pathway from nicotinamide (8). The intracellular levels of NAD+ and nicotinamide have recently been identified as important for certain cell survival reactions, including those linked to the sirtuin family of protein deacetylases (9) . Overexpression of NAMPT has been shown to increase SIRT1 activity (8), and protect cells from apoptosis through activation of SIRT3 and SIRT4 (10). NAMPT has also been suggested to extend the lifespan of human vascular smooth muscle cells by activating SIRT1 and preventing the accumulation of p53 (11). Therefore, because both resveratrol and NAMPT have been shown to be effective protective agents in the vasculature, we sought to identify a potential mechanistic link between the two agents in their anti-aging effect.
In this study, we tested the hypothesis that resveratrol may trigger hTERT, which stabilizes telomere length, in human aortic smooth muscle cells as a potential mechanism for its role in the prevention and treatment of vascular diseases. Our results indicate that resveratrol treatment indeed leads to activation of hTERT. Further investigation identified that hTERT activation is dependent upon resveratrol first inducting the expression of NAMPT followed by SIRT4. We present here evidence of a NAMPT-SIRT4-hTERT axis as the novel mechanism of anti-aging effects of resveratrol in human aortic smooth muscle cells, and propose that this pathway contributes to the positive outcomes observed in the vasculature that coincide with increased exposure to resveratrol.