Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases

By Sung-Jun Park, F. Ahmad, A. Philp, K. Baar, T. Williams, Haibin Luo, H. Ke, H. Rehmann, R. Taussig, Alexandra L. Brown and 5 more. BMC Proceedings, 2012

1,330 citations recorded by the source corpus.

SUMMARY 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 CamKKβ-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.

Subfields: Geriatrics and Gerontology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/4e5a36f4ab85a37b0d98df1c8a1201c8525a956c

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In Geriatrics and Gerontology

1. Bor Luen Tang
2. Joseph A. Baur
3. D. Sinclair
4. Brian J. North
5. L. Guarente

In Molecular Biology

1. A. Johri
2. D. Sinclair
3. M. Beal
4. C. Palmeira
5. Brian J. North
6. Bo Zhang
7. Shao Li
8. A. Rolo

In Physiology

1. Bor Luen Tang
2. Joseph A. Baur
3. D. Sinclair
4. M. Beal
5. C. Palmeira
6. Brian J. North
7. A. Johri
8. A. Rolo

Citations in the corpus

• Mitochondrial Dysfunction in Neurodegenerative Diseases (2012, background): “Studies by Park et al. (2012) suggested that resveratrol does not target SIRT1 directly but instead stimulates the AMPK pathway by inhibiting cAMP-degrading phosphodiesterases (mainly phosphodiesterase 4), resulting in increased cAMP levels, which in turn increases cellular calcium levels, thereby…”
• The Immunomodulatory and Anti-Inflammatory Role of Polyphenols (2018, background): “They promote glycolysis by activation of AMPK (AMPactivated protein kinase) or inhibition of mTORC1 and PI3K/AkT in vivo (in rats), ex vivo (in rats’ muscles strips) and in vitro (in C2C12 myoblasts and HELA cells) [148,149,155,156].”
• Novel insights of dietary polyphenols and obesity. (2014, background): “Resveratrol increases the intracellular cyclic adenosine monophosphate (cAMP) concentration by inhibiting cAMP phosphodiesterases (PDEs), which degrade cAMP [101, 102].”
• Traditional Chinese medicine network pharmacology: theory, methodology and application. (2013, background): “to identify the active ingredients in TCMs and their biological targets ([5-11]).”
• SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function (2012, background): “If resveratrol induces AMPK by acting as an ATPase or Complex III inhibitor (Gledhill et al., 2007; Hawley et al., 2010; Zini et al., 1999), then ATP levels should be lower in the resveratrol-treated mice, and AMPK activation should occur independently of SIRT1.”
• Sirt1 and the Mitochondria (2016, methodology): “The work of Park et al. (2012) indicated that resveratrol inhibits cAMP phosphodiesterases, thus leading to elevated cAMP levels and the activation of AMPK and cAMP-inducible factors such as the Rap Exchange factor directly activated by cAMP 1 (Epac1).”