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Potentially important new mechanisms found for the anti-aging effects of resveratrol, a phenolic compound found in red wine 

Park S-J, 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.  Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.  Cell 2012;148:421-433.  DOI 10.1016/j.cell.2012.01.017.
Authors’ 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 Ca2+ levels and activates the CamKKb-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.

Forum Comments
Background:  More than two decades ago, particularly through publicity related to the so-called ‘French Paradox’, the public became aware of the potential reduction in the risk of coronary heart disease from the moderate consumption of red wine.  Initially, the media focused on a single constituent in red wine, resveratrol, as being the “key” factor.  Very extensive research since then has shown that (1) resveratrol is only one of hundreds of phenolic compounds in wine, many of which have been shown to have beneficial effects on vascular function; (2) alcohol itself (present in wine, beer or spirits) provides considerable protection against heart disease; and (3) in many experimental settings, resveratrol and like compounds improve the longevity of life. 
Extensive scientific research on resveratrol and other substances that stimulate sirtuins has shown in many laboratory models to increase longevity of life and reduce metabolic diseases of aging.  These have led to human trials of high concentrations of resveratrol or other sirtuin-stimulating chemicals, the final results of which are not yet known.  Further, the particular biologic pathways by which resveratrol and similar substances could improve health outcomes remain unclear.
The present paper by Park et al,1 and an accompanying comment by Tennen et al,2 provide potentially important new insights into the association of the intake of resveratrol and like compounds with health benefits.  Tennen et al2 conclude that the paper shows that “resveratrol directly inhibits cAMP-dependent phosphodiesterases, triggering a cascade of events that converge on the important energy-sensing metabolic regulators AMPK, SIRT1, and PGC-1a.”  Such mechanisms could provide key new approaches for the prevention or treatment of a number of chronic diseases in humans.
Comments on specific aspects of the study:  Forum reviewers had very favorable comments on this experimental study in mice, thinking that the design, implementation, and analysis were well done.  As one reviewer commented: “In this paper, the signaling pathway, alleged to produce the beneficial effects of resveratrol on major metabolic phenotypes previously described, has been dissected in detail. Apparently, the increase of cAMP, due to the inhibition of cAMP phosphodiesterase, primes the series of events leading to (welcome) activation of Sirt1 and AMPkinase.
“Moreover, this study further supports the concept that resveratrol, apparently protecting plants by mimicking (or signaling) a stress condition and thus activating the response, also protects animals by the same or similar mechanism.  In fact, the notion that cAMP signaling is involved in response to stress is corroborated by this study, and expands the significance of xeno-hormesis.”  Said another reviewer: “This paper provides cell signaling measurements for a previously described pathway.  Hypothetically, ‘better aging’ would be a necessary consequence.  Indeed, a number of studies have shown that such a pathway may relate to better physiological states.”3-5
Concerns about the paper:  On the other hand, other reviewers had some problems with the paper.  Stated one reviewer: “It doesn’t seem credible that resveratrol could act as a PDE inhibitor in vivo after oral consumption.  Where is the in vivo data to support this mechanism of action?  The only data seem to be an increase in mitochondrial DNA after 14 weeks treatment with resveratrol at 400 mg/kg/day and an increase in fasting core temperature and GLP-1.  It appears that groups of mice were treated in parallel with resveratrol or rolipram, but while the rolipram data are shown in full there is only selective inclusion of resveratrol data when it supports the alleged mechanism of action.  The question we should be asking is: where are the missing resveratrol data from these in vivo studies?”
Another reviewer states: “From a biochemical point of view, I feel the absence of a stronger evidence of specificity.  The competitive inhibition of the esterase indicates a similarity between resveratrol and cAMP and docking calculations support the interaction between resveratrol and the enzyme.  However, there are not controls ruling out the option that other phenolic compounds can do the same.  This could be of some relevance since different polyphenols have been shown inhibiting several protein kinases by competing with ATP (similar H bonding network in polyphenols and adenine), and this minimises, instead of demonstrating, their actual relevance as pharmacologically (or nutritionally) relevant kinase inhibitors.”
Implications of the results:  The media, in particular, have suggested that this study relates to the effects on health of red wine consumption.  Forum reviewers were worried that the dosages used in the experiment were not in the physiological range, and thus implications for human effects are limited.  “In relation to nutritional (or pharmacological) importance of resveratrol, in this study the usual conundrum emerges: the concentration used in vitro would correspond to an intake of several liters of wine per day.  About this, we must recall that the effects are produced by interactions among macromolecules and ligands, and thus on the rate of this interaction.  Lower concentration produces a slower rate of interaction and thus more time to get the effect.  Provided a continuous supply of the ligand, we could expect effects in vivo at a concentration much lower than suggested by in vitro studies.
“Finally, on the basis of the described molecular mechanism (inhibition of PDE), we would expect a similar protective mechanism for coffee or tea, containing methylxanthines that also inhibit PDE.  Incidentally, the structure of the reference PDE inhibiting compound used in the study (rolipram) is much closer to methylxanthine that to resveratrol.”  The results of this study relate primarily to the use of resveratrol as a pharmaceutical, not as a nutraceutical from wine or other components of the diet.
Another reviewer added: “I would like to emphasise that the dose used in these experiments is far beyond the physiological concentration from the consumption of wine or other nutrients.  Is this concentration not being an activator of salvage pathways that wouldn’t be recruited in any other conditions?  It seems that concentrations of 0.1 and 1 µM (more likely to be physiological) have very low activity on PDE (although a statistically non-significant trend in the displacement of 8-azido-[DY-547]-cAMP bound to PDE3 is observed is observed in this study).  Furthermore, a number of studies have demonstrated that resveratrol has very low bioavailability, leading to concern that many of the beneficial effects observed in either cells or biochemical assays may not be achievable in humans due to rapid metabolism.  Indeed, following consumption resveratrol is mainly metabolised into glucuronide and sulphate derivatives.  The question about the bio-activity of such metabolites remains unanswered and future work is needed to fully understand the role of such derivatives in vivo.”
Do the results relate the consumption of red wine or other constituents in the diet?:  “With regard to wine and health, any link to resveratrol seems exceedingly unlikely if 30 g mice have to consume the equivalent of several liters of resveratrol-rich wine (typically 2 – 5 mg/L) per day for these effects.”  Another reviewer stated: “I agree with the other comments regarding the paucity of resveratrol available to tissues.  These amounts may be accessible with pharmaceutical doses, but not with wine consumption: the connection with red wine is misleading.”
Another reviewer: “Functional foods work synergistically with other micronutrients, and it is not possible to isolate one specific compound responsible for a specific metabolic effect.  The in vivo effect may be the response to a metabolite of resveratrol interacting with other chemicals to achieve an effect.  Whole plant extracts consists of many active and inactive micronutrients that may play a role in health and disease.  To ascribe a specific effect to one chemical found in wine could be misleading.  In the post-modern approach, we must take the whole picture into consideration; there are just too many confounding variables in in vivo studies complicating matters”  Another adds: “I have always supported the view that we should analyze food patterns and relate them to health.  As soon as we go into much detail of individual constituents of the diet we lose the thread because the thousands of nutrients confuse us and we get lost.”
As a reviewer summarised: “There is, indeed, a major gap between concentration of resveratrol active in in vitro tests and concentration measurable in plasma.  However, is this enough to rule out any ‘nutraceutical’ relevance of resveratrol?  If so, also a vast majority of ‘health protecting’ compounds in fruit and vegetables identified by epidemiology and studied in vitro would be rated as inefficient.  It is very common, indeed, observing such a gap.”
Said another reviewer: “Dietary resveratrol, nutritionally supplemented resveratrol, and therapeutic levels of resveratrol are three completely distinct molecules in medicine.”  Said another, “The point is that the experimental condition in vitro and in vivo are extremely different.  The time scale, the effect of accumulation, the synergy with other compounds, and the concentration in specific microenvironments are extremely different.  While considering all this, a different effective concentration by one order of magnitude is not so dramatic.  My message is that what has been reported in the current paper ‘could be’ relevant, although it cannot be the final word on the topic.”  A Forum biochemist concludes: “Even though not all the biochemical evidence conclusively fits epidemiologic findings (for example, of protection against cardiovascular disease and the risk of mortality by wine and other beverages containing alcohol), we must remember what F.G. Hopkins said: ‘The biochemist may not be the last word in the description of life, but without his help the last word will never be said.’”
References from Forum review:


1.  Park S-J, 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.  Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.  Cell 2012;148:421-433.  DOI 10.1016/j.cell.2012.01.017.
2.  Tennen RI, Michishita-Kioi E. Chua KF.  Previews: Finding a target for resveratrol.  Cell 2012;148:357-359.  DOI 10.1016/j.cell.2012.01.032
3.  Lau L-C, Adaikan PG.  Effect of sildenafil and rolipram on adrenergic responses in isolated human and monkey corpus cavernosum.  European Urology 2007;52:253–260.
4.  Dallas C, Gerbi A, Tenca G, Juchaux F, Bernard FX.  Lipolytic effect of a polyphenolic citrus dry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes.Mechanism of action of inhibition of cAMP phosphodiesterase (PDE).  Phytomedicine 2008;15:783-792.
5.  Dell’Agli M, Galli GV, Vrhovsek U, Mattivi F, Bosisio E.  In vitro inhibition of human cGMP-specific phosphodiesterase-5 by polyphenols from red grapes.  J Agric Food Chem 2005;53:1960-1965.

Forum Summary
A well-conducted experimental study in mice has provided potentially important new insights into the association of the intake of resveratrol and like compounds with health benefits.  Resveratrol is a constituent of red wine and other vegetable products, and is being evaluated in high-doses as a pharmaceutical.  The biologic mechanisms demonstrated in this study could provide key new approaches for the prevention or treatment of a number of chronic diseases in humans, especially those related to vascular and metabolic diseases and to the risk of mortality.
More than two decades ago, particularly through publicity related to the so-called ‘French Paradox’, the public became aware of the potential reduction in the risk of coronary heart disease from the moderate consumption of red wine, and the media focused on a single constituent in red wine, resveratrol, as being the ‘key’ factor.  We now know that resveratrol is only one of hundreds of phenolic compounds in wine, many of which have been shown to have beneficial effects on vascular function, and that alcohol itself (present in wine, beer or spirits) also provides considerable protection against heart disease.  Still, there has remained considerable attention paid to resveratrol, and extensive scientific research on resveratrol and related  substances have shown that, in high doses, they may increase longevity of life and reduce metabolic diseases of aging.
In general, Forum reviewers thought that this was a very well-done study.  Their concerns related to the dose used in these experiments; while the levels of resveratrol and like compounds might be accessible with pharmaceutical doses, the suggestion that similar levels could be connected with wine consumption is misleading.  Further, in humans, resveratrol in the diet will interact with many other chemicals to achieve an effect, as whole plant extracts consist of many active and inactive micronutrients that may play a role in health and disease.  To ascribe a specific effect on health from one chemical found in wine or other plant products could be misleading.”
Still, the reviewers believed that this paper was an important contribution to our knowledge about the mechanisms by which resveratrol and other chemicals may play a role in cardiovascular and other diseases.  Such knowledge could help develop approaches for the prevention and treatment of human disease and for increasing the longevity of a healthy life.
Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
 Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA
Federico Leighton, MD, Laboratorio de Nutricion Molecular, Facultad de Ciencias Biologicas, Universidad Catolica de Chile, Santiago, Chile
Francesco Orlandi, MD, Dept. of Gastroenterology, Università degli Studi di Ancona, Italy
David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Creina Stockley, clinical pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia


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