Extension of human cell lifespan by nicotinamide phosphoribosyltransferase

被引:259
作者
van der Veer, Eric
Ho, Cynthia
O'Neil, Caroline
Barbosa, Nicole
Scott, Robert
Cregan, Sean P.
Pickering, J. Geoffrey
机构
[1] Univ Western Ontario, London Hlth Sci Ctr, Dept Med Cardiol, London, ON N6A 5K8, Canada
[2] Univ Western Ontario, London Hlth Sci Ctr, Dept Biochem, London, ON N6A 5K8, Canada
[3] Univ Western Ontario, London Hlth Sci Ctr, Dept Med Biophys, London, ON N6A 5K8, Canada
[4] Univ Western Ontario, London Hlth Sci Ctr, Dept Biol, London, ON N6A 5K8, Canada
[5] Univ Western Ontario, Robarts Res Inst, London, ON N6A 5K8, Canada
关键词
D O I
10.1074/jbc.C700018200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 SMClifespan 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.
引用
收藏
页码:10841 / 10845
页数:5
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