Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases

Abstract

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.

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…Our hypothesis is that resveratrol may promote a switch of mitochondrial response to cellular stress from the overexpression of respiratory chain complexes and the consequent increased production of harmful oxidative mediators, to a more adaptive response by increasing mitochondrial biogenesis. It has also been reported that resveratrol administration promotes mitochondrial biogenesis in skeletal muscles [12,16] through AMPK activation. Further studies are needed to assess whether resveratrol benefits in SOD1 G93A mice could be partially explained by its effect on skeletal muscles.…”

“…It is known that resveratrol acts through some specific effector molecules, such as Sirt1 or AMPK [11,12]. Sirt1 is a NAD + -dependent deacetylase that plays an important role regulating cell metabolism and has recently been postulated as a neuroprotective element in several neurodegenerative disorders [13].…”

“…According to this view, Park et al [12] recently described that resveratrol promotes AMPK phosphorilation through the inhibition of cAMP phosphodiesterase, thus increasing the amount of cAMP. AMPK then activates Sirt1 indirectly by elevating intracellular levels of its cosubstrate, Fig.…”

“…Despite these well-documented beneficial effects, the mechanisms of action of resveratrol remain controversial. However, it has been recently described that resveratrol can trigger a cascade of intracellular events that converge on Sirtuin 1 (Sirt1), AMPactivated protein kinase (AMPK) and PGC-1α, as important energy-sensing regulators [11,12]. Sirt1 is a NAD + -dependent deacetylase that has emerged as an important element of the cellular metabolic network.…”

Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK‐648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction

“…However, recent evidence suggests that PDE4 plays an essential role in glucose and fat metabolism 2, 3, 4, 5. Moreover, in a diabetic mouse model, the PDE4 inhibitor roflumilast, which is approved for chronic obstructive pulmonary disease treatment, has demonstrated significant antidiabetic efficacy 6.…”