Extension of human cell lifespan by nicotinamide phosphoribosyltransferase.
Extending the productive lifespan of human cells could have major implications for diseases of aging, such as atherosclerosis. We identified a relationship between aging of human vascular smooth muscle cells (SMCs) and nicotinamide phosphoribosyltransferase (Nampt/PBEF/Visfatin), the rate-limiting enzyme for NAD+ salvage from nicotinamide. Replicative senescence of SMCs was preceded by a marked decline in the expression and activity of Nampt. Furthermore, reducing Nampt activity with the antagonist FK866 induced premature senescence in SMCs, assessed by serial quantification of the proportion of cells with senescence-associated beta-galactosidase activity. In contrast, introducing the Nampt gene into aging human SMCs delayed senescence and substantially lengthened cell lifespan, together with enhanced resistance to oxidative stress. Nampt-mediated SMC lifespan extension was associated with increased activity of the NAD+-dependent longevity enzyme SIRT1 and was abrogated in Nampt-overexpressing cells transduced with a dominant-negative form of SIRT1 (H363Y). Nampt overexpression also reduced the fraction of p53 that was acetylated on lysine 382, a target of SIRT1, suppressed an age-related increase in p53 expression, and increased the rate of p53 degradation. Moreover, add-back of p53 with recombinant adenovirus blocked the anti-aging effects of Nampt. These data indicate that Nampt is a longevity protein that can add stress-resistant life to human SMCs by optimizing SIRT1-mediated p53 degradation.
van der Veer
Eric
E
Robarts Research Institute and London Health Sciences Centre, Department of Medicine (Cardiology), University of Western Ontario, London, Ontario Canada N6A 5K8.
Ho
Cynthia
C
O'Neil
Caroline
C
Barbosa
Nicole
N
Scott
Robert
R
Cregan
Sean P
SP
Pickering
J Geoffrey
JG
D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase; D018384:Oxidative Stress; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D009243:NAD; D010430:Pentosyltransferases; D054409:Nicotinamide Phosphoribosyltransferase