Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases

被引:1164
作者
Park, Sung-Jun [1 ]
Ahmad, Faiyaz [2 ]
Philp, Andrew [4 ]
Baar, Keith [4 ]
Williams, Tishan [5 ]
Luo, Haibin [6 ]
Ke, Hengming [5 ]
Rehmann, Holger [7 ,8 ]
Taussig, Ronald [9 ]
Brown, Alexandra L. [1 ]
Kim, Myung K. [1 ]
Beaven, Michael A. [3 ]
Burgin, Alex B. [10 ]
Manganiello, Vincent [2 ]
Chung, Jay H. [1 ]
机构
[1] NHLBI, Lab Obes & Aging Res, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA
[2] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA
[3] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA
[4] Univ Calif Davis, Funct Mol Biol Lab, Davis, CA 95616 USA
[5] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA
[6] Sun Yat Sen Univ, Sch Pharmaceut Sci, Struct Biol Lab, Guangzhou 510006, Guangdong, Peoples R China
[7] Univ Med Ctr, Dept Mol Canc Res, Ctr Biomed Genet, NL-3584 CG Utrecht, Netherlands
[8] Univ Med Ctr, Canc Genom Ctr, NL-3584 CG Utrecht, Netherlands
[9] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA
[10] Emerald BioStruct, Bainbridge Isl, WA 98110 USA
基金
美国国家卫生研究院;
关键词
ACTIVATED PROTEIN-KINASE; SMALL-MOLECULE ACTIVATORS; LIFE-SPAN; PHOSPHOLIPASE-C; CYCLIC-AMP; SACCHAROMYCES-CEREVISIAE; MITOCHONDRIAL-FUNCTION; CALORIE RESTRICTION; SIGNALING PATHWAY; CARDIAC MYOCYTES;
D O I
10.1016/j.cell.2012.01.017
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
Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca2+ levels and activates the CamKK beta-AMPK pathway via phospholipase C and the ryanodine receptor Ca2+-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.
引用
收藏
页码:421 / 433
页数:13
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