Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases

Sung Jun Park, Faiyaz Ahmad, Andrew Philp, Keith Baar, Tishan Williams, Haibin Luo, Hengming Ke, Holger Rehmann, Ronald Taussig, Alexandra L. Brown, Myung K. Kim, Michael A. Beaven, Alex B. Burgin, Vincent Manganiello, Jay H. Chung

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Abstract

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 Ca 2+ levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca 2+-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.

Original languageEnglish (US)
Pages (from-to)421-433
Number of pages13
JournalCell
Volume148
Issue number3
DOIs
StatePublished - Feb 3 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Park, S. J., Ahmad, F., Philp, A., Baar, K., Williams, T., Luo, H., Ke, H., Rehmann, H., Taussig, R., Brown, A. L., Kim, M. K., Beaven, M. A., Burgin, A. B., Manganiello, V., & Chung, J. H. (2012). Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell, 148(3), 421-433. https://doi.org/10.1016/j.cell.2012.01.017