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

Research output: Contribution to journalArticle

809 Citations (Scopus)

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

Fingerprint

Phosphoric Diester Hydrolases
Aging of materials
Phenotype
Phosphodiesterase 4 Inhibitors
Rolipram
Ryanodine Receptor Calcium Release Channel
AMP-Activated Protein Kinases
Wine
Metabolic Diseases
Polyphenols
Type C Phospholipases
Nutrition
NAD
Obesity
Chemical activation
Diet
Glucose
resveratrol
Proteins

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., ... 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

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. / Park, Sung Jun; Ahmad, Faiyaz; Philp, Andrew; Baar, Keith; Williams, Tishan; Luo, Haibin; Ke, Hengming; Rehmann, Holger; Taussig, Ronald; Brown, Alexandra L.; Kim, Myung K.; Beaven, Michael A.; Burgin, Alex B.; Manganiello, Vincent; Chung, Jay H.

In: Cell, Vol. 148, No. 3, 03.02.2012, p. 421-433.

Research output: Contribution to journalArticle

Park, SJ, Ahmad, F, Philp, A, Baar, K, Williams, T, Luo, H, Ke, H, Rehmann, H, Taussig, R, Brown, AL, Kim, MK, Beaven, MA, Burgin, AB, Manganiello, V & Chung, JH 2012, 'Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases', Cell, vol. 148, no. 3, pp. 421-433. https://doi.org/10.1016/j.cell.2012.01.017
Park, Sung Jun ; Ahmad, Faiyaz ; Philp, Andrew ; Baar, Keith ; Williams, Tishan ; Luo, Haibin ; Ke, Hengming ; Rehmann, Holger ; Taussig, Ronald ; Brown, Alexandra L. ; Kim, Myung K. ; Beaven, Michael A. ; Burgin, Alex B. ; Manganiello, Vincent ; Chung, Jay H. / Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. In: Cell. 2012 ; Vol. 148, No. 3. pp. 421-433.
@article{7be52feddd73426d84eef07c6064e030,
title = "Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases",
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.",
author = "Park, {Sung Jun} and Faiyaz Ahmad and Andrew Philp and Keith Baar and Tishan Williams and Haibin Luo and Hengming Ke and Holger Rehmann and Ronald Taussig and Brown, {Alexandra L.} and Kim, {Myung K.} and Beaven, {Michael A.} and Burgin, {Alex B.} and Vincent Manganiello and Chung, {Jay H.}",
year = "2012",
month = "2",
day = "3",
doi = "10.1016/j.cell.2012.01.017",
language = "English (US)",
volume = "148",
pages = "421--433",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases

AU - Park, Sung Jun

AU - Ahmad, Faiyaz

AU - Philp, Andrew

AU - Baar, Keith

AU - Williams, Tishan

AU - Luo, Haibin

AU - Ke, Hengming

AU - Rehmann, Holger

AU - Taussig, Ronald

AU - Brown, Alexandra L.

AU - Kim, Myung K.

AU - Beaven, Michael A.

AU - Burgin, Alex B.

AU - Manganiello, Vincent

AU - Chung, Jay H.

PY - 2012/2/3

Y1 - 2012/2/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863011114&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863011114&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2012.01.017

DO - 10.1016/j.cell.2012.01.017

M3 - Article

C2 - 22304913

AN - SCOPUS:84863011114

VL - 148

SP - 421

EP - 433

JO - Cell

JF - Cell

SN - 0092-8674

IS - 3

ER -