Is resveratrol a true anti-aging compound?

Richard A. Baxter, MD, FACS

Abstract

As anti-aging science has progressed on both a molecular and clinical basis, resveratrol, a

naturally occurring polyphenol antioxidant, has emerged as a candidate for comprehensive

therapy. Laboratory evidence indicates that resveratrol protects skin against the effects of

photoaging, and counters age-related diseases via protection against ischemia-reperfusion

injury, Alzheimer’s disease, cancer, and diabetes. Resveratrol is a potent phytoestrogen and has

potential related benefits and risks. Resveratrol has become a popular supplement in large part

due to reports that it is a sirtuin activator, thereby acting as a caloric restriction mimetic and

prolonging lifespan. However, questions about the bioavailability of resveratrol remain, clinical

evidence is scant, and recent research indicates that resveratrol is not a direct sirtuin activator

and does not extend lifespan in mammals. These controversies and the potential clinical role

for resveratrol are reviewed.

Introduction

Resveratrol, a phytoalexin from red wine, has become a popular anti-aging supplement and

the focus of escalating research efforts in recent years. Phytoalexins are naturally occurring

compounds synthesized by plants as part of their defense against environmental challenges

such as microbial. Because of this, they possess antibiotic and antioxidant properties, and in the

case of resveratrol a long list of other potentially useful capabilities. These have been reported

to include activation of sirtuins, the enzymes that mediate the metabolic shift that produces the

increase in lifespan from caloric restriction. Resveratrol’s pleiotropic properties place it as a

contender for a comprehensive anti-aging compound.

In order to consider the possibility of a “true” anti-aging intervention, a definition is need.

Though there are various ways to define anti-aging, for purposes of discussion here a

comprehensive approach is taken, to include the following:

Maintenance and restoration of youthful appearance

Slowing of age-related cellular processes leading to reduced rates of degenerative

diseases

Lifespan extension

Bioavailability

A Medline database search returns more than 3 500 citations for resveratrol, with annual

listings increasing exponentially. In 1991 there were only two articles in the biomedical

literature on resveratrol, whereas there were approximately two each day in 2010, reflecting

increasing interest on several fronts. However, only a few articles are based on clinical trials in

human subjects, so if resveratrol is to be clinically useful a systematic approach is required.

Given that red wine is the primary source or resveratrol in the diet, the theory has been

advanced that resveratrol provides the benefit attributed to regular wine consumption, a

phenomenon characterized by a “J-shaped curve” of relative risk vs. disease incidence

(moderate consumption has a lower relative risk than nondrinkers, high consumption has a

steeply rising risk.) The numerous other anti-aging benefits of red wine consumption also hold a

potential relationship to resveratrol, so epidemiologic studies on red wine and health may serve

as a useful starting point.

Once a clear relationship between wine consumption and a specific anti-aging benefit

emerges, the next step is to formulate a plausible cause-effect explanation. Several lines of

research support the role of resveratrol in specific mechanisms believed to be involved in

wine’s healthful benefits, so experimental evidence for the proposed cause-effect relationship

is also necessary. Ideally, this would culminate in clinical trial data leading to level I evidence as

required for evidence-based practice. Recent publications have cast doubt on whether

resveratrol functions at a biochemical level as previously reported, so clinical trial data is

especially important.

Figure 1. Typical J-shaped curve

Resveratrol chemistry

Resveratrol was first described in 19781 as an isolate from rhizomes of Rheum rhaponicum,

a type of rhubarb. The best known source is red wine, which derives it from the skins of the

grapes, where it serves to protect the fruit as it ripens from environmental pathogens and

oxidative damage from ultraviolet light. Compounds present in the skin of wine grapes give

what oenophiles call “structure” so vineyard management employs various techniques to

encourage formation of these compounds by intentionally stressing the vines. Cultivars of wine

grapes have been selected over the centuries to predispose to formation of these compounds,

unlike table or juice grapes where they impart an undesirable astringent or bitter flavor.

Further, because red wine is made by fermenting the whole crushed grape (called maceration),

the compounds are extracted more thoroughly than in white wine or pressed juice. As the

alcohol develops it serves as a solvent for further extraction. Aging in oak may add additional

phenolic compounds. For all of these reasons wine is a much more concentrated source of

resveratrol as compared to table grapes or grape juice. Resveratrol is also made by other plants

including the non-edible parts of the peanut plant and the Japanese giant knotweed, this latter

serving as a commercial source but also inedible.

Resveratrol (trihydroxystilbene) is a polyphenol, as are many other compounds in grape

skins. Broadly, these are categorized into flavonoids including anthocyanins which give the wine

its color, tannins (many similar to those found in tea), other flavonoids such as quercetin, and

non-flavonoids. This latter class includes stilbenes such as resveratrol and benzoic, caffeic, and

cinnamic acids. Some compounds derive from the seeds of the grape, including oligomeric

proanthocyanidins, the tetramers and pentamers believed to be most important. Although

resveratrol may be the most thoroughly investigated molecule, others have revealed significant

properties and some lines of evidence point to a synergistic relationship between wine

compounds.

Resveratrol exists in two isomers, trans-resveratrol being the biologically active form.

Exposure to light may cause the trans form to convert to the cis form, so storage conditions are

important. Several related molecules in the stilbene family have been identified, many of which

have biologic activity, especially tetrameric oligomers which have been reported to be matrix

metalloproteinase inhibitors.2 As MMP’s activity contributes to collagen breakdown, this points

to potential applications in anti-aging skin treatments and cancer therapy, though this remains

to be explored further. In addition to the naturally occurring stilbenes, numerous synthetic

derivatives have been developed, many of which have greatly increased potency for specific

applications.

Figure 2. Isoforms of resveratrol.

Biologic activity of resveratrol

Resveratrol has a unique range of documented biologic properties. It is a potent antioxidant,

as are many polyphenols, though this is better documented in vitro than in human trials. The

addition of whole red wine to the diet improves plasma antioxidant status.3 One randomized

study compared a 40 mg daily dose of resveratrol for 6 weeks vs placebo, with 10 subjects in

each group.4 Fasting blood draws were done at intervals for isolation of mononuclear cells

which were tested for indices of oxidative and inflammatory stress, with significant reduction in

generation of reactive oxygen species observed. Additionally, production of pro-inflammatory

cytokines and C-reactive protein, another marker of inflammation, were suppressed in the

resveratrol group.

A partial list of additional properties of resveratrol is itemized below.

Antibiotic

Multiple enzyme inhibition including cyclo-oxygenase (COX-1 and COX-2)

Multiple enzyme activation including Mitogen-Activated Protein kinase

Phyto-hormonal

Protection against ultraviolet radiation

Anti-cancer: multiple pathways

Ischemia-reperfusion

Radiation fibrosis

Youthful beauty: resveratrol and healthy skin

Much of the clinical practice of anti-aging medicine is directed at appearance, and means of

countering the visible manifestations of age. The cumulative effects of photodamage in

addition to intrinsic aging contribute to an aged appearance, and botanical antioxidants are

finding utility in reversing and preventing some of this damage. There is evidence that wine

drinkers have fewer signs of photoaging such as actinic keratoses, and consumption of red wine

high in polyphenols confers protection against UV damage as measured by minimal erythema

dose.5 A topical preparation of 1% resveratrol was tested against 1% idebenone, previously

advertized as the most potent antioxidant in a skin care product, with the resveratrol formula

found to be 17 times more potent as measured by the Oxygen Radical Absorption Capacity

(ORAC) test, an industry standard.6 Resveratrol appears to provide significant photoprotection

though it may work best in combination with other wine polyphenols, as the oral dose from

wine consumption would be inadequate to produce effective tissue levels in skin unless it is

selectively taken up. Resveratrol appears to hold potential as a cosmeceutical skin care product.

Resveratrol and cardiovascular health

The original “French paradox,” a term from the ABC television show 60 Minutes in 1991, was

based on the epidemiologic observation that citizens of southern France enjoyed low rates of

cardiovascular disease despite a lifestyle renowned for flaunting the known risk factors such as

smoking and high fat intake. The proposed explanation was their high level of wine

consumption, a hypothesis initially met with much skepticism but now well-accepted. In fact,

the idea was not new, having been documented as early as 19797 and wine consumption would

later be recognized as a previously overlooked but central component of the Mediterranean

diet. As a result of this new focus on the potential healthful properties of wine as a food,

attention turned to the question of what chemical constituents of wine were responsible.

Resveratrol, in addition to other wine phenolics, has been found to be involved in a number of

specific processes that counter atherosclerotic disease.8

A primary action of resveratrol is up-regulation of nitric oxide (NO), a vasodilator. There is

some clinical evidence that resveratrol produces a short-term relaxation of the arterial wall and

lowers blood pressure after oral administration. Additionally, production of the pro-

inflammatory cytokine endothelin-1 is suppressed, which helps retard plaque formation in the

vessel wall. COX inhibition similarly slows plaque progression due to suppression of eicosanoid

synthesis. Impairment of platelet aggregation via COX inhibition also provides an explanation

for the clinical finding that myocardial infarction and stroke are less likely to occur if wine has

been consumed within the previous 24 hours. Further, resveratrol’s antioxidant capacity serves

to lower levels of oxidized low-density lipoprotein . (It should be pointed out however that

alcohol independently improves the HDL/LDL ratio so the beneficial effects of wine cannot be

attributed solely to its polyphenol components.)

Resveratrol and ischemia-reperfusion injury

Once an arterial clot is lysed and blood flow restored, a cascade of events ensues which may

paradoxically hasten tissue damage. Much of this is mediated by oxidative mechanisms, and a

growing body of experimental evidence indicates that there may be significant improvement in

tissue survival with administration of resveratrol. (Clinically, this correlates to better outcomes

after cardiac events among wine drinkers.) This effect has been reported in experimental

models for intestine, brain, spinal cord, skeletal muscle, and heart muscle.9 A stroke model in

gerbils demonstrated significant improvement in brain tissue with resveratrol following global

ischemia induced by carotid clamping.10 Of particular significance to this study is that it also

demonstrated that resveratrol could traverse the blood-brain barrier, with implications for its

role in degenerative neurological diseases presuming that adequate blood levels could be

achieved. However, the potential role of resveratrol for clinical use in treating ischemia-

reperfusion remains to be studied.

Alzheimer’s disease and senile dementia

It is difficult to overestimate the impact of Alzheimer’s disease (AD), with some 5 million

cases in the U.S. and the “baby boom” demographic curve entering old age. The financial and

social costs are incalculable, but certainly count in the billions of dollars. According to a recent

consensus panel report from the U.S National Institutes of Health, “firm conclusions cannot be

drawn about the association of any modifiable risk factor with cognitive decline or Alzheimer’s

disease” and “evidence is insufficient to support the use of pharmaceutical agents or dietary

supplements to prevent cognitive decline or Alzheimer’s disease.”

Progress has been made however in understanding the etiology of AD, notably the association

of the apolipoprotein E (ApoE) gene variation, and misfolded beta amyloid plaques that

characterize the neuropathology of the disease. Certain lifestyle factors have an association

with lowered incidence of AD, including physical activity, higher educational attainment,

cognitive engagement behaviors, adequate folic acid intake, low dietary saturated fat, and high

fruit and vegetable consumption. The NIH panel report does include a mention of low-to-

moderate alcohol consumption as having a favorable impact on risk, but with a focus on wine

specifically a clearer picture emerges. In fact, every large-scale epidemiologic survey that

included a question on wine consumption has found a clear reduction in incidence among wine

drinkers, up to 80% lower. A representative study is the Gruppo Italiano multicenter survey of

more than 15 000 subjects who underwent cognitive testing, with the highest scores in men

drinking up to a liter of red wine per day and women consuming half that amount.11 The

resulting J-shaped curve did not show an increase in cognitive decline until more than 2 liters

daily consumption (for men) was reached. This dramatic relationship not only confirms the

consistent relationship of wine consumption to lower incidence of AD, but suggests a powerful

protective constituent to counter the adverse neural effects of high levels of alcohol

consumption.

Resveratrol has emerged as a potential explanation for wine’s protective effects against AD,

though other wine phenolics have been reported to have significant roles as well. In animal

models, resveratrol has been shown to promote clearance of beta amyloid from neural tissues,

and to be a potent inhibitor of beta amyloid deposition. 12 Resveratrol is also a

neuroprotectant, countering the toxic effects of beta amyloid in experimental models. This

effect appears to be specific and unrelated to its antioxidant capacity. Whether or not

therapeutic levels of resveratrol within the central nervous system can be achieved remains a

matter of speculation however.

Via separate pathways, resveratrol may enhance neural function by up-regulation of

mitogen-activated protein kinases active in the learning and memory centers of the brain. One

small clinical study showed a dose-dependent increase in cerebral blood flow and increase in

oxygen extraction by the brain with cognitive testing after taking resveratrol as compared to

placebo, though no improvement in test scores was achieved.13 This, along with the findings in

the gerbil global cerebral ischemia study, suggest that some degree of activity with central

nervous system tissue can be achieved with resveratrol, though the cognitive testing results

may be related to vasodilation rather than a neural effect. Long-term clinical trials will be

required in order to obtain high-level evidence for a role of resveratrol in reducing age-related

cognitive decline. A handful of these are underway, though results will likely be years off.

Resveratrol as an antimicrobial

A primary function of phytoalexins is protection against environmental pathogens. For this

reason, they may possess broad-spectrum antibacterial, antiviral, and antifungal properties, as

is the case with resveratrol. In particular, resveratrol has been shown to inhibit proliferation of

common bacteria and fungi on the skin, similar to the putative role it plays in grape skins.

Additional targets are Streptomyces mutans, which contributes to dental disease, and

Helicobacter pylori, which is associated with peptic ulcer disease. Isolated resveratrol is less

effective than whole wine against Salmonella species and Escherichia coli, though it does

possess a degree of activity independent of alcohol and other wine constituents.

For millennia, wine served as an important antibacterial, most especially on sea voyages and

military campaigns, but its antiviral properties have not been studied until recently. An

important clue comes from epidemiologic evidence that red wine drinkers have fewer and less

severe colds, as compared to nondrinkers, and the benefit is greater with red than with white

wine. Resveratrol has been demonstrated to have anti-rhinoviral activity in vitro, providing a

plausible cause-effect explanation for the effect. A more dramatic finding comes from a mouse

model of influenza type A, in which an LD50 dose (average inoculum required to produce 50%

mortality in the test population) could be improved to 100% survival with the concurrent

administration of resveratrol.14 It should be noted that quercetin also has a significant

inhibitory effect on viral replication, so there may be synergies between the various wine

phenolics in terms of antiviral activity.

Resveratrol and cancer

Unlike beer or spirits, wine consumption follows a J-shaped curve for overall cancer

mortality. Though this may be explained in part as a statistical marker for a healthier lifestyle, it

has opened the door to a broad field of research into the role of wine phenolics as anti-cancer

agents. The topic has been well-reviewed in recent years15 and clinical trials are in progress.

Resveratrol has been proposed to function at several stages including reduced risk of cancer

(chemoprevention), anti-cancer therapy via several pathways, and in ameliorating some of the

adverse effects of cancer treatments.

Early evidence for this came from studies of resveratrol on cancer cell progression in tissue

culture. With several cell types, resveratrol was reported to exert a dose-dependent inhibitory

effect, though in specific circumstances the effect is reversed and resveratrol promotes cell

proliferation. Nevertheless, the variety of cancer types that are inhibited suggest that

resveratrol acts at a fundamental level.

These pathways can be understood by dividing cancer therapeutics into three categories

according to the stage at which they exert their activity. At the first stage, anti-initiation,

resveratrol functions as an anti-oxidant, suppresses mutations by supporting DNA stability, and

inhibits activation of pro-carcinogens. Resveratrol has at least four distinct influences in the

second stage of cancer, known as promotion. These are inhibition of cyclo-oxygenase-2, which

is expressed in many if not all types of carcinoma; induction of apoptosis, which is suppressed

in cancer cells; decrease in anti-apoptotic proteins, another mechanism by which cancer cells

bypass regulatory processes; and down-regulation of cancer activation cellular pathways. The

third stage, progression, is where the tumor becomes invasive and spreads. This requires

activation of growth factor signaling pathways, on which resveratrol has a specific inhibitory

effect. There are also specific effects via other mechanisms on cancer cell invasiveness and

growth. A final requirement for tumor proliferation is angiogenesis, which has also been shown

to be suppressed by resveratrol. (This latter property suggests other applications for

resveratrol in wound healing and conditions such as rosacea.)

The nuclear signaling pathways by which resveratrol is involved have been mapped in

considerable detail. Interestingly, many of the points of influence are also targets for curcumin

(the spice turmeric), and epigallocatechin gallate (EGCG), a constituent of green tea. This would

explain the similar epidemiologic patterns of tea and wine consumption as they relate to

cancer.

Wine consumption has also been reported to be associated with less severe fibrosis from

radiation treatment in women with breast cancer. As an added benefit, evidence indicates that

resveratrol and other wine components help to sensitize tumor cells to radiation while

protecting normal cells. A similar paradox applies to chemotherapy, at least in tissue culture

and animal studies. This was dramatically demonstrated with doxorubicin and cisplatin in

human gynecologic cancer cell lines and in isolated rat hearts.16 If confirmed in clinical trials,

these would be very exciting findings but level 1 evidence has not been published so caution is

in order.

Wine, resveratrol, and breast cancer: special considerations

One of the first cell lines to be proven sensitive to resveratrol is breast cancer, and the effect

applies regardless of estrogen receptor status. However, the relationship of wine consumption

and breast cancer has been problematically reported, causing confusion as to whether

resveratrol is useful or even safe for breast cancer patients, and whether wine consumption has

the same risk as alcohol. Several meta-analyses have been done on the subject of alcohol and

breast cancer, with a linear dose-response correlation generally observed. More recent studies

employ mathematical modeling to account for the well-known self-reporting bias on drinking

levels, but the effect of moderate consumption remains at least in part a matter of

extrapolation. Given the anti-cancer activity of resveratrol and other wine phenolics in vitro,

the question of whether wine drinkers obtain any benefit in terms of relative cancer risk has

been of intense interest.

Conflicting results from the various studies that have attempted to stratify results for

different types of alcohol consumed has led to even greater confusion however. A 2010 study

from the Fred Hutchinson Cancer Research Center in Seattle concluded that there was “no

difference between red wine or white wine consumption and breast cancer risk” while a 2009

report from Kaiser-Permanente found “red wine carries the same risk of breast cancer as white

wine.” These authors went on to state that “women who consume any type of alcohol are at

greater risk for breast cancer” and there is “no difference between types of drinks.” Earlier

studies suggested that as little as 1.5 glasses of wine a day was enough to double lifetime risk of

breast cancer.

Yet closer reading of the Fred Hutchinson Center study reveals that “Wine consumption was

not associated with risk of breast cancer and no differential was observed between red and

white wine.” The reason for the lack of difference in risk was that there was no increased risk in

the wine drinking cohort for either type. About the same time as the Kaiser-Permanente results

were being presented, a new meta-analysis from Japan was published that concluded that

“epidemiologic evidence on the association between alcohol drinking and breast cancer risk

remains insufficient” despite the dozens of studies available for review.

Studies from European populations, meanwhile, give a different picture. A 2008 report from

the University of Montpelier in France found that “women who consumed at least a glass of

wine a day had about 50% less breast cancer than nondrinkers.”17 Contradictory results such as

these can best be explained by differences in the study populations rather than as statistical

outliers. In order to know the true effect of wine consumption, and by inference wine’s

constituent polyphenols, a study population must have a consistent drinking pattern; for

example one glass of red wine daily, with dinner, rarely in excess, and generally not overlapping

with other types of alcoholic beverages. Traditional lifestyles in southern France fit this

description, while American and other populations have a more mixed drinking pattern. In

contrast to the Mediterranean lifestyle, the woman who consumes a glass or two of red wine

on a daily basis and nothing else is uncommon, despite indicating a preference for wine in

survey responses. On balance then, consideration should be given to giving greater weight to

the European data.

What does this mean to the woman concerned about alcohol and breast cancer risk? A case

could certainly be made for allowing a glass or two of red wine without concern about added

risk, and perhaps even some benefit in terms of reduced risk applies. Resveratrol is however an

estrogen receptor agonist, so supplementing resveratrol in place of a healthy drinking habit

may have greater risks for certain types of breast cancer. This remains to be clarified.

Resveratrol as a phytoestrogen

A dose-dependent relationship exists between wine consumption and bone density. Given

the significant morbidity from osteoporosis with age, this translates to a benefit in terms of

both quality of life and mortality. Here again resveratrol provides a plausible cause-effect

relationship, as an estrogen receptor (ER) agonist with high degree of affinity.18 Hormone

replacement therapy for post-menopausal women remains highly controversial, so

phytoestrogens may provide an alternative if they can be proven selective and effective.

Estrogen receptors exist in many tissues throughout the body, including brain, kidney, heart,

vascular endothelium, prostate, and bone, in addition to breast, ovary, and endometrium. They

are broadly divided into 2 types, though many isoforms exist within each category, and

receptor binding produces different effects from different agonists. For example, tamoxifen is

an ER antagonist in breast tissue but an agonist in bone and endometrium. Furthermore, any

given molecule may act as both a transcriptional co-activator and co-repressor within the same

tissue, depending on dose and homeostatic compensation. This results in a considerable

challenge in identifying all of the actions of a given ER modulator, and the various effects of

phytoestrogens are incompletely known.

Resveratrol has been shown to be an ER agonist in vascular endothelium, and release of the

vasodilator NO may be driven by this interaction. This may mimic the role of endogenous

estrogen in protecting against atherosclerosis. Resveratrol also stimulates ER’s in bone,

resulting in up-regulation of bone morphogenic proteins. A more complex picture characterizes

the interactions of resveratrol and ER’s in breast tissue. Though it has a strong binding affinity,

there is evidence that resveratrol may block the formation of estrogen-DNA adducts and

estrogen-induced cell transformation at multiple sites, independent of its other anti-tumor

actions. Additionally, resveratrol appears to reverse the epigenetic silencing of BRCA-1, a tumor

suppressor involved in DNA repair, which is down-regulated in some types of breast cancer.

This effect is mediated via the aromatic hydrocarbon receptor (AhR), in parallel with reduced

occupancy of the alpha type ER. On balance then, the role of resveratrol appears protective but

not thoroughly understood.

Figure 3. Diethylstilbestrol

A cursory look at ER agonists reveals a common ligand, shared by resveratrol and other

phytoestrogens. Among the most similar to resveratrol is the synthetic estrogen

diethylstilbestrol, or DES. This was widely prescribed for estrogen replacement in the mid-

twentieth century, and eventually withdrawn from the market when it was found to be

associated with clear cell vaginal and cervical adenocarcinoma in adult offspring of women who

were took it during pregnancy. Additionally, the mothers were found to be at increased risk for

breast cancer. Given the several decades that it took to discover these problems, caution must

be observed with the use of similar compounds especially for pregnant women. The use of

phytoestrogens in men has not been well studied and should also be viewed with prudence.

Resveratrol and telomerase

The question of extending replicative cellular lifespan applies to both disease risk reduction

and to the broader issue of overall lifespan extension. A highlight of recent research is the

recognition that enhanced expression of telomerase, extends replicative lifespan in several

models. Telomeres, repetitive DNA sequences at the ends of chromosomes, function to provide

genetic stability by shortening with each replication cycle and thereby prevent loss of integrity

to genes within the chromosome. The number of replication cycles is therefore predetermined

in somatic cells, known as the Hayflick limit, at which point the cells enter senescence. A major

emphasis of anti-aging research has therefore been directed at unearthing methods of

activating telomerase and rebuilding telomeres.

Key to understanding and manipulating telomerase is determining its function in immortal

cancer cells versus normal cells. In tissue culture of metastatic breast cancer, resveratrol has

been shown to down-regulate telomerase expression, resulting in enhanced anti-tumor activity

beyond its pro-apoptotic and other inhibitory effects. Similar effects have been documented

with colon cancer cells in vitro, in a dose-dependent manner, though suppression of telomerase

expression requires relatively high concentrations of resveratrol. On the other hand, resveratrol

delays the onset of senescence in endothelial progenitor cells by significantly up-regulating

telomerase activity.19 Immortalization of normal cells has been accomplished with resveratrol

under certain conditions in epithelial progenitor cells. This involves converting telomerase from

discontinuous to continuous expression, but only in the presence of a mutation in the p53

tumor suppressor protein, which is involved in cell replication. The effect is prevented in the

presence of progesterone.

These findings, while they provide important clues to controlling telomerase activity, are

somewhat contradictory and these systems are highly complex. Resveratrol may prove to be

useful as a telomerase regulator but its use remains highly speculative and adverse effects are

possible. Further research is required and it may be many years before the answers are in.

Resveratrol and diabetes

A pandemic of type 2 diabetes is emerging in developed countries, and if trends continue it

will overwhelm health care systems. While diet and obesity are certainly the primary

contributors to this problem, the relationship of wine consumption and type 2 diabetes follows

the now-familiar J-shaped curve. To some extent this is likely a statistical marker for other

healthy behaviors, in that wine drinkers tend to be better educated, exercise more, and eat

healthier diets, but recently there has been a convergence of diabetes research and anti-aging.

Resveratrol and its derivatives are central to understanding the biochemistry of diabetes on a

molecular level.

Type 2 diabetes is characterized by reduced insulin sensitivity and relative insulin deficiency,

marked by inflammation in islet cells with deposition of amyloid oligopolymers. Therapies may

be based on either enhancing insulin production by targeted reduction of islet cell inflammation

or improving insulin sensitivity and glucose metabolism. As with amyloid in neural tissues,

resveratrol has an inhibitory effect in islet cells.

An experimental model for diabetes can be produced by administration of streptozotocin,

which has specific toxicity for mammalian pancreatic islet cells. Oral administration of

resveratrol to streptozotocin-induced diabetic rats for 30 days reduces blood glucose,

glycosylated hemoglobin, and downstream markers of diabetes to a degree comparable to

standard diabetes medications. Additionally, insulin levels are increased and key enzymes of

carbohydrate metabolism are returned to near-normal levels, along with improved hepatic

glycogen levels.20 In an obese rat model of metabolic syndrome, long-term administration of

resveratrol near-normalizes serum lipids, reverses hypertension, reduces hepatic lipid content,

and reduces inflammatory status as measured by increased adiponectin and decreased tumor

necrosis factor-alpha. Resveratrol has been shown to improve insulin sensitivity and up-

regulate adipokine expression in adipose tissue, which plays an important role in metabolic

homeostasis.

Glucose metabolism is mediated by adenosine monophosphate protein (AMP) kinase, an

evolutionarily conserved enzyme which regulates cellular glucose uptake. AMP kinase also

inhibits cholesterol and triglyceride synthesis and adipocytes lipolysis, and modulates insulin

secretion. Mice on a high-fat diet but deficient in AMP kinase do not respond to resveratrol as

do wild-type mice, who experience an increase in metabolic rate, insulin sensitivity, and

physical endurance along with decreased fat accumulation. This indicates that resveratrol

functions as an AMP kinase activator. The adipose-derived cytokine adiponectin, also an AMP

kinase activator, is independently up-regulated by resveratrol. Leptin, which regulates appetite

and energy expenditure, is elevated in obesity and down-regulated by resveratrol in a dose-

dependent manner in isolated adipocytes.

The role of resveratrol in modulating the complex endocrine functions of adipose tissue are

still being deciphered, but on balance appear to be beneficial based mostly on in vitro studies. It

should be noted that another wine phenolic, quercetin, has also been reported to have anti-

diabetic activity via many of the same pathways as resveratrol.

Sirtuins and lifespan extension: is resveratrol a sirtuin activator?

Beyond reduction in the incidence of degenerative and life-threatening diseases, the best-

known means of extending lifespan is caloric restriction. This phenomenon has been known for

many years, at least on an experimental basis. In order to achieve the effect, a reduction in

caloric intake of at least 30-40% from ad libitum consumption is required to produce the

change in metabolism that characterizes the effect. Prolongation of natural lifespan in the

range of 30% or more, along with reduced incidence of diseases and markers of aging can be

achieved in rhesus monkeys. It is believed to be an evolutionary adaptation to periods of

famine or environmental stress, and is conserved from primitive organisms to mammals.

However, dietary restriction of this magnitude is severe and impractical, so deciphering the

underlying mechanisms and means of harnessing these processes has been one of the primary

goals of anti-aging research.

Leonard Guarente is credited with the discovery of the epigenetic functions of sirtuins, now

known to be the mediators of the caloric restriction phenomenon.21 Sirtuin enzymes are highly

conserved evolutionarily, with homologs in all eukaryotic organisms. Sirtuins are histone

deacetylases (HDAC’s), whose function is gene activation or silencing, the term deriving from

genes known as “Silent Information Regualtors.” The sirtuins involved in the caloric restriction

effect, known as type III HDAC’s, are Nicotinamide Adenine Dinucleotide (NAD)-dependent,

which is how the nutritional environment is sensed. This results in fundamental alterations in

mitochondrial biogenesis, primarily in adipose tissue. (“Sirtuin” refers to the enzyme, the

abbreviation “Sir” or Sirt” refers to the corresponding gene.)

Figure 4. Sirtuin “family tree.”

In addition to promoting longevity, sirtuins mediate a range of healthspan-related effects

through actions as diverse as improving insulin sensitivity, neuroendocrine modulation,

reducing inflammation, and up-regulation of favorable adipokynes. Sirtuins are involved in

Alzheimer’s disease, telomere function, and expression of genes related to aging. Targeted

activation of sirtuins has become an active frontier of biomedical research.

The tantalizing prospect of sirtuin activation for lifespan extension without caloric restriction

appeared in 2003 with a publication claiming an increase in replicative lifespan in

Saccharomyces cerevisiae (brewer’s yeast) via activation of sirtuins by resveratrol.22 Using

chemical libraries to search for a sirtuin activator, the research group hit upon wine phenolics

HDAC’s

I = Rpd3 II = HDA1 III = Sir2

Mammals

Group I

Nucleus

Group II

mitochondria

Group III

cytoplasm

S. Cervesiae

Sir2

Hst1

Hst2

Hst3

Hst4

C. elegans

Sir1

Sir2

Sir3

Sir4

Drosophila

dSir2

dSirt2

dSirt4

dSirt6

dSirt7

IV = human

HDAC II

as a class and resveratrol in particular as the only category with significant activity. A

fluorescence assay was used to link sirtuin activation to the resveratrol trigger. Given that

sirtuins are evolutionarily conserved and the effect appeared specific, the same process should

be repeatable in more complex organisms, and considerable media attention was devoted to

the story.

The original findings were quickly followed up with reports of resveratrol activating sirtuins

and extending lifespan up the phylogenetic ladder. The effect was seen in the roundworm C.

elegans and the fruitfly Drosophila, and the homologous SIR genes identified (Sir1 and dSir2,

respectively.) An important next step up the ladder is vertebrates, with a convenient model

being a short-lived type of fish called Nothobranchius, with a similar response.

In mice however the lifespan extension phenomenon could not be duplicated, though

several other favorable results were observed. Specifically, resveratrol countered the effect of a

toxic high fat diet, leading to normalization of liver function and metabolic parameters, and

prevented the premature death normally associated with murine obesity. Exercise tolerance

was increased with a resveratrol-enhanced diet, and in primates early signs are that

degenerative diseases are lessened. However, the hope for lifespan extension with resveratrol

supplementation began to be questioned.

An early challenge came from failure to replicate the original results from yeast cells in other

labs. The effect was noted to be substrate-specific and culture strain-specific. The fluorescence

assay was questioned as producing possibly artifactual results, in that sirtuins could be made to

fluoresce by resveratrol without being active. The improvements in the mice on the high fat

diet were explained as a simple, if potent antioxidant effect to counter the hepatotoxicity of the

specific fatty diet. And roundworms live longer in a bath of the antioxidant enzyme superoxide

dismutase, indicating that for some primitive organisms life can be extended without sirtuin

activation. Despite these contradictory findings, research labs around the world began to work

on resveratrol and resveratrol derivatives, with the hope of finding variants with greater

efficacy and specific clinical applications.

Additionally, clinical trials were instituted on several fronts, including Alzheimer’s

(NCT00678431, recruiting as of January 2010, and NCT00743743, not yet recruiting); diabetes

(NCT01158417, recruiting); melanoma (NCT00721877, closed); colon cancer (NCT00920803,

closed, and NCT00256334, recruiting) and others. In November 2010, however,

GlaxoSmithKline announced the abrupt suspension of a clinical trial with the promising

resveratrol derivative SRT501, for adjunctive therapy in multiple myeloma, due to an

unexpected high incidence of renal failure. Though this may have been a statistical aberration

and related to the underlying disease or primary therapy rather than SRT501, Glaxo elected to

discontinue all development of the drug.

As the study of sirtuin physiology has advanced, it has become clear that resveratrol is not a

direct activator. Amgen and Pfizer were independently evaluating resveratrol-based sirtuin

activators, and both published peer-reviewed papers announcing that resveratrol and

derivatives were inactive.23 This confirmed earlier questions about the assay and variability of

results, but left open the question of how the lifespan increase was produced.

An answer comes from the fact that resveratrol is an activator or inhibitor of at least 15

different enzymes. Another clue is that lifespan extension has been achieved in mice with the

diabetes drug metformin and the immune suppressant rapamycin. Metformin, like resveratrol

is a potentiator of AMP kinase, which is in turn a sirtuin activator.24 It is therefore possible that

this indirect effect is responsible but that metformin is more active or less subject to variations

of substrate medium. There is also evidence that metformin has similar degenerative disease-

fighting capacity as resveratrol appears to, but may have better bioavailability. Clinical use of

metformin remains restricted to treatment of type 2 diabetes, however, with off-label use for

health maintenance unproven.

A more direct caloric restriction mimetic may be via mammalian target of rapamycin (mTOR),

a protein kinase involved in cell growth regulation, proliferation, and survival. Upstream signals

including nutrient status, oxidative stress, redox status, insulin, AMP kinase, and growth factors

all influence mTOR activity, which functions at an epigenetic level. Rapamycin is a bacterial

protein with immune suppressant and antiproliferative properties, clinically used in organ

transplantation. Rapamycin has been shown to extend lifespan in mice by up to 38%, and anti-

cancer and anti-Alzheimer’s properties are being explored. (Both rapamycin and AMP kinase

are mTOR inhibitors.)

Figure 5. Lifespan extension pathways

The use of rapamycin as a caloric restriction mimetic is highly impractical, given its immune

suppressive properties, but does pave a more direct path. Interestingly, resveratrol, by

activating AMP kinase which then competitively binds mTOR, functions at an even further

AMP kinase

lifespan extension

(mouse)

mTOR kinase

siruin activation

resveratrol metformin rapamycin

upstream level through the same channels. Analogs of rapamycin (called rapalogs) are being

developed with targeted specificity for mTOR binding, though none appear to be at the clinical

testing stage.25 Epigallocatechin gallate (EGCG), from green tea, as well as caffeine and

curcumin are also mTOR inhibitors. These common properties may explain the similar

anticancer effects, as mTOR function may be dysregulated in cancer.

Bioavailability and metabolism of resveratrol

A primary reason for clinical failure of compounds with promising in vitro activities is limited

bioavailability. Resveratrol appears to be well-absorbed from oral mucosa, but undergoes

significant first-pass hepatic metabolism after absorption from the gastrointestinal tract. In

human subjects, blood levels indicate no more than 20% overall bioavailability. A randomized

crossover study demonstrated that when taken with food, peak levels are delayed to 1.5 hours

as compared to 30 minutes when taken during fasting after a 400 milligram oral dose, though

total absorption is unchanged.26 Other studies indicate a half-life of 1-3 hours, with high

interindividual variability. Adverse effects appear to be mild, and there is a suggestion that

bioavailability is greater when taken in the morning. Some supplement manufacturers are

developing micronized formulations to enhance bioavailability but little has been published.

Most of the research on clinical bioavailability of oral resveratrol comes from the cancer

literature, where resveratrol is being explored as adjunctive therapy because of indications of

its effectiveness in both enhancing the anticancer effects of chemotherapeutic agents while

simultaneously ameliorating side-effects. However, one of the constraints on chemotherapeutic

effectiveness is the emergence of what are known as multi-drug resistance proteins (e.g.,

MRP2, ABCC2) and breast cancer resistance protein (BCRP, ABCG2). These proteins appear to

significantly impair the absorption of resveratrol from intestinal mucosa, placing further limits

on its potential effectiveness in cancer therapy.

Resveratrol is metabolized within the intestinal lining to 3 dominant forms, resveratrol-4'-O-

glucuronide (M1), resveratrol 3-O-gucuronide (M2), and resveratrol-3-O-sulfate. These may be

preferentially absorbed and then reconverted to free resveratrol with the cell, and so serum

levels may not accurately reflect intracellular levels. Accumulation of resveratrol in epithelial

cells of the aerodigestive tract has been demonstrated despite nearly undetectable serum

levels. Analogs of resveratrol may have greater bioavailability, though the therapeutic effects

are less well-characterized. For example, the dimethylether analog pterostilbene has a 4-fold

greater bioavailability after oral administration.

Cellular uptake is necessary for many of the actions of resveratrol, as they are involved in

signal transduction. Lipid nanoparticles may facilitate the uptake of resveratrol in keratinocytes

and improve bioavailability of topical preparations. Liposome-mediated transport has been

reported to produce improved cell stress response from UV radiation. In a mouse model of

prostate cancer, liposomal encapsulation of resveratrol plus curcumin significantly reduced the

incidence of tumors and levels of cancer markers. Even without facilitated trans-membrane

transport, resveratrol appears to have good skin penetration, possibly related to its small

molecular weight. This may explain the range of benefits to in skin health observed with

resveratrol in experimental models.

Biphasic actions of resveratrol

Further complicating the picture is the recent finding that resveratrol has a biphasic effect in

several biological models, a phenomenon known as “hormesis.” In angiogenesis, for example,

resveratrol exerts anti-tumor effects through down-regulation of the expression of Vascular

Endothelial Growth Factor (VEGF) at high concentrations (>20 μM), but promotes it at low

concentrations (1-10 μM).27 In a mouse model of indomethacin-induced gastric ulcers,

resveratrol exerted a biphasic effect on COX-1 and eNOS (endothelial nitric oxide synthase)

balance.28 Low-dose resveratrol augmented eNOS expression and had minimal effect on COX-1

while higher doses suppressed COX-1. The net effect at high doses was a slower healing due to

reduced prostaglandin synthesis and angiogenesis. Additionally, resveratrol displays hormesis

with several tumor cell lines including breast, prostate, lung, uterine, and leukemia. Dosing

therefore becomes problematic in that effects at low levels oppose those at high levels and

maintenance of high tissue levels does not appear achievable due to variable bioavailability.

Conclusions

Despite the multitude of reported studies on resveratrol, the number of clinical trials

completed and reported numbers in the single digits, and its potential as an anti-aging

compound remains to be fully determined. Level 1 evidence is lacking, and so clinical use of

resveratrol is somewhat speculative at this time. In terms of the criteria established for a “true”

anti-aging compound, the first – support of youthful appearance – appears to be the closest to

fulfillment.

The second criterion, slowing of age-related cellular processes leading to delayed onset and

prevention of degenerative diseases, is well supported by in vitro and animal studies but clinical

evidence is lacking. Given the long time frame involved in conducting prospective trials for

diseases in this category, it could be many years before answers are in. Funding such studies is

an ongoing challenge, so the private sector is focusing on proprietary derivatives, which may

have more targeted and potent actions.

Resveratrol is not a direct sirtuin activator and appears unlikely to produce lifespan

extension as a caloric restriction mimetic. On an experimental basis resveratrol has been useful

in developing sirtuin science, and uncovering metabolic pathways that could possibly be

exploited to achieve that goal. It is possible and even likely that resveratrol could produce a

secondary effect of lifespan extension via reduction in the incidence of diseases of aging, but

again that remains to be proven. The marketing of resveratrol supplements based on lifespan

extension documented only in sub-mammalian organisms is therefore a questionable practice.

Resveratrol alone does not provide an explanation for the known health benefits of moderate

regular wine consumption, in that resveratrol content in wine is too low to produce the in vitro

effects that correspond to epidemiologic patterns.

Bioavailability and biphasic behavior in different biological pathways remain problematic as

well. Newer formulations may help to overcome current limitations on the uptake and

metabolism of resveratrol, along with better understanding of membrane transport,

intracellular/extracellular partitioning, and the actions of resveratrol metabolites. But given the

many open questions that remain, and potential risks (particularly related to its phytoestrogens

activity), a cautionary approach is prudent and the widespread use of resveratrol supplements

is not justified at the present time.

1Rupprich N, Kindl H. Stilbene synthases and stilbenecarboxylate synthases, I Enzymatic synthesis of 3,5,4-trihydroxystilbene from p-coumaroyl coenzyme A and malonyl coenzyme A. Hoppe Zeylers Z Physiol Chem 1978 Feb;359(2):165-72.

2 Abe N, Ito T, Ohguchi K, Nasu M et al. Resveratrol oligomers from Vatica albiramis. J Nat Prod 2010 Sep

24;73(9):1499-506. 3 Micallef M, Lexis L, Lewandowski P. Red wine consumption increases antioxidant status and decreases oxidative

stress in the circulation of both young and old humans. Nutr J 2007 Sep;6:27. 4 Ghanim H, Sia CL, Abuatsheh S, Korzeniewsli K et al. An anti-inflammatory and reactive oxygen species

suppressive effects of an extract of Polygonum cupsidatum containing resveratrol. J Clin Endocrinol Metab 2010 Sep;95(9):E1-8. 5 Moehrle M, Dietrich H, Patz CD, Häfner HM. Sun protection by red wine? J Dtsch Dermatol Ges 2009 Jan;7(1):29-

32. 6 Baxter R. Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care

formulation. J Cosmetic Dermatol 2008;7:2-7. 7 St Leger AS, Cochrane AL, Moore F. Factors associated with cardiac mortality in developed countries with

particular reference to the consumption of wine. Lancet 1979 May 12;1017-20. 8 Ramprasath VR, Jones PJ. Anti-atherogenic effects of resveratrol. Eur J Clin Nutr 2010 Jul;64(7):660-8.

9 Mokni M, Limam F, Elkahaoui S, Amri M, Aouani E. Strong cardioprotective effect of resveratrol, a red wine

polyphenol, on isolated rat hearts after ischemia-reperfusion injury. Arch Biochem Biophys 2007 Jan 1;457(1):1-6. 10

Wang Q, Xu J et al. Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res 2002 Dec 27;958(2):439.

11

Zuccala G, Onder G, Pedone C, Cesari M et al. Intake of flavonoids and risk of dementia. Alcohol Clin Exp Res 2001 Dec;25(12):1743-8. 12

Maramboud P, Zhao H, Davies P. Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer’s disease amyloid beta-peptides. J Biol Chem 2005; 280: 37377–82. 13

Kennedy DO, Wightman EL, Reay JL, Lietz G et al. Effect of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo controlled, crossover investigation. Am J Clin Nutr 2010 Jun;91(6):1590-7. 14

Palamara AT, Nencioni L, Aquilano K De Chiara G et al. Inhibition of influenza A virus replication by resveratrol. J Infect Dis 2005; 191: 1719–29. 15

Kraft TE, Parisotto D, Schempp C, Efferth T. Fighting cancer with red wine? Molecular mechanisms of resveratrol. Crit Rev Food Sci Nutr 2009 Oct;49(9):782-99. 16

Rezk YA, Balulad SS et al. Use of resveratrol to improve the effectiveness of cisplatin and doxorubicin: study in human gynecologic cancer cell lines and rodent heart. Am J Obstet Gynecol 2006May;194(5):e23-6. 17

Bessaoud F, Daurés JP. Patterns of alcohol (especially wine) consumption and breast cancer risk: a case-control study among a population in southern France. Ann Epidemiol 2008 Jun;18(6):467-75. 18

Gehm BD, McAndrews JM, Chien PY, Jameson JL. Resveratrol, a polyphenolic compound found in grapes and red wine, is an agonist for the estrogen receptor. Proc Nat Acad Sci USA 1997; 94: 14138–43. 19

Xia L, Wang XX, Hu XS, Guo XG et al. Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms. Br J Pharmacol 2008 Oct;155(3):387-94. 20

Palsamy P, Subramanian S. Modulatory effects of resveratrol on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats. Chem Biol Interact 2009 May 15;179(2-3):356-62. 21

Guarente L, Picard F. Calorie restriction—the Sir2 connection. Cell 2005 Feb25;120(4):473-82. 22

Howitz KT, Bitterman KJ, Cohen HY, Lamming DW et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003 Sept 11;425(6924):191-6. 23

Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des. 2009 Dec;74(6):619-24. 24

Onken B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PloS One 2010 Jan 18;5(1):e8758. 25

Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Disssecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 2010 Mar;1804(3):433-9. 26

Vaz da Silva M, Loureiro AI, Falcao A, Nunes T et al. Effect of food on the pharmacokinetic profile of trans-resveratrol. Int J Clin Pharmacol Ther 2008 Nov;46(11):564-70. 27

Wang H, Zhou H, Zou Y, Liu Q, et al. Resveratrol modulates angiogenesis through the GSK3β/β-catenin/TCF-dependent pathway in human endothelial cells. Biochem Pharmacol 2010 Nov 1;80(9):1386-95.

28

Dey A, Guha P, Chattopadhyay S, Bandyopadhyay SK. Biphasic activity of resveratrol on indomethacin-induced gastric ulcers. Biochem Biophys Res Commun 2009 Mar 27;381(1):90-5.