Resveratrol as a calorie restriction mimetic: therapeutic implications

Abstract

It is widely believed that calorie restriction (CR) can extend the lifespan of model organisms and protect against aging-related diseases. A potential CR mimetic is resveratrol, which may have beneficial effects against numerous diseases such as type 2 diabetes, cardiovascular diseases, and cancer in tissue culture and animal models. However, resveratrol in its current form is not ideal as therapy, because even at very high doses it has modest efficacy and many downstream effects. Identifying the cellular targets responsible for the effects of resveratrol and developing target-specific therapies will be helpful in increasing the efficacy of this drug without increasing its potential adverse effects. A recent discovery suggests that the metabolic effects of resveratrol may be mediated by inhibiting cAMP phosphodiesterases (PDEs), particularly PDE4. Here, we review the current literature on the metabolic and cardiovascular effects of resveratrol and attempt to shed light on the controversies surrounding its action.

Figure 1

Resveratrol protects against a wide range of aging-related diseases. Resveratrol blocks pathological processes that contribute to aging-related diseases such as type 2 diabetes, cardiovascular diseases, and neurodegenerative diseases including Alzheimer’s diseases.

Figure 2

Resveratrol mimics calorie restriction by inhibiting cAMP phosphodiesterases (PDEs). Food deprivation and exercise increase the levels of glucagon and catecholamines, which bind to their receptors and increase cAMP production by activating adenylate cyclase. Resveratrol increases cAMP levels, not by increasing cAMP production, but by inhibiting cAMP PDEs, which hydrolyze cAMP to AMP. Protein kinase A (PKA) and Epac, two effectors of cAMP signaling, activate parallel pathways that lead to AMP-activated kinase (AMPK) activation. In addition, exercise can increase AMPK activity in skeletal muscle via a decrease in ATP and also via contraction-associated Ca²⁺ release (not shown). Transcription factor CREB (cAMP response element binding protein), which is activated by PKA phosphorylation, induces transcription of PGC-1α [98] and Sirt1 [99], which are two important mediators of the beneficial effects of resveratrol on mitochondrial function. In addition to improving mitochondrial function, activation of AMPK decreases glucose production in the liver and increases glucose uptake in peripheral tissues such as skeletal muscle. Although PKA signaling increases hepatic glucose production, it also inhibits SREBP-1c and, as a result, inhibits synthesis of triglyceride and development of hepatic steatosis, which may have a dominant effect on insulin sensitivity in the obese state. This may explain why the metabolic benefits of resveratrol are largely limited to animals fed a high-fat diet.

Figure 3

Cardiovascular effects of resveratrol. Resveratrol and/or Sirt1/AMP-activated kinase (AMPK) activation and/or phosphodiesterase (PDE) inhibition have been shown to improve vascular function and reduce hypertension via increased nitric oxide (NO) production, reduced atherosclerosis, decreased oxidative stress, and reduced apoptosis. Decreased oxidative stress and reduced apoptosis also play a role in blunting cardiac hypertrophy and preventing heart failure. Resveratrol also lessens the severity of these cardiac syndromes by reducing activation of nuclear factor of activated T cells (NFAT)-mediated and increasing oxidative metabolism. Resveratrol and/or Sirt1 activation has also been shown to reduce ischemia/reperfusion injury by inducing angiogenesis, increasing NO production, and decreasing oxidative stress.

Figure 4

Understanding how resveratrol regulates AMP-activated kinase (AMPK) and Sirt1. The acetylation state of a Sirt1 substrate is determined not only by Sirt1 but also by acetyl transferases such as p300. Sirt1, p300, and AMPK regulate each other, making knock-down or knockout approaches difficult to interpret. (a) A model in which resveratrol activates Sirt1 before AMPK. (b) A model in which resveratrol activates Sirt1 via AMPK. (c) A model in which resveratrol activates AMPK but does not activate Sirt1. In this model, basal Sirt1 activity is still required for resveratrol to have an effect.

Figure 5

Proposed model of AMP-activated kinase (AMPK) dependence and Sirt1 independence of the antidiabetic effects of resveratrol. Resveratrol increases adiponectin [100], cAMP signaling [21], and AMPK activity [21], which contribute to the inhibition of SREBP-1 [101], the transcription factor [102] that promotes hepatic triglyceride synthesis and development of hepatic steatosis, a known instigator of insulin resistance [103]. AMPK also suppresses hepatic glucose production and stimulates glucose uptake in skeletal muscle [33]. It should be noted that protein kinase A (PKA) also increases hepatic glucose production (dotted line). In a parallel manner, Sirt1 also inhibits SREBP-1 [104] and stimulates AMPK activity and adiponectin production [84].