Resveratrol Made Mice on a Junk Diet Live Longer. Mice Eating Normally Lived No Longer, and in Older Men It Blunted the Benefits of Exercise.
Resveratrol is the polyphenol in grape skins and red wine that turned longevity into a business. In 2003 a Harvard team reported in Nature that it activated sirtuin enzymes and stretched yeast lifespan by 70%. Three years later the same group showed that resveratrol kept middle-aged mice on a high-calorie diet alive longer. In 2008 GlaxoSmithKline agreed to buy Sirtris, the company built to turn the idea into drugs, for approximately $720 million. Resveratrol capsules are still sold as an anti-aging supplement. This article walks through what came after those headlines: the lab papers that questioned how resveratrol touches sirtuins at all, the mouse studies on normal diets, the bioavailability problem, the small human trials in men, and a 9-year cohort in Italy that measured resveratrol in urine and compared it with death rates. The short version is that resveratrol does several things in a test tube and in overfed mice, and very little of it has been shown to carry over to people.
Key Takeaways: What the Research Shows About Resveratrol and Aging
Resveratrol extended survival in mice fed a high-calorie diet (Baur and colleagues, Nature, 2006), but mice on a standard diet given resveratrol from 12 months of age did not live longer (Pearson and colleagues, Cell Metabolism, 2008). The National Institute on Aging Interventions Testing Program found no significant lifespan effect of resveratrol in male or female mice when treatment started at 4 months of age (Strong and colleagues, 2013). In 6 volunteers, at least 70% of a 25 mg oral dose of resveratrol was absorbed, yet unchanged resveratrol in the blood stayed below 5 ng/ml because the liver and gut converted it almost immediately (Walle and colleagues, 2004). In 24 obese men, 4 weeks of high-dose resveratrol did not improve insulin sensitivity, blood pressure, visceral fat or inflammatory markers (Poulsen and colleagues, Diabetes, 2013). In 27 inactive men around 65 years old, 250 mg of resveratrol a day during 8 weeks of training cut the gain in maximal oxygen uptake, which rose 45% more on placebo (Gliemann and colleagues, Journal of Physiology, 2013). In 783 older Italians followed for 9 years, dietary resveratrol levels did not predict death, inflammation, heart disease or cancer (Semba and colleagues, JAMA Internal Medicine, 2014).
How Many People the Key Human Resveratrol Studies Enrolled
Participants in five of the most cited human resveratrol studies: a 6-person absorption study (Drug Metabolism and Disposition, 2004), an 11-man crossover trial (Cell Metabolism, 2011), a 24-man placebo-controlled trial (Diabetes, 2013), a 27-man exercise trial (Journal of Physiology, 2013) and a 40-person dosing study (Cancer Research, 2010). None ran longer than 8 weeks.
Why did resveratrol become the original anti-aging molecule?
Resveratrol became the original anti-aging molecule because it was the first small compound reported to activate sirtuins, the enzyme family that was then thought to carry the lifespan benefit of calorie restriction. Howitz, Sinclair and colleagues reported in Nature in 2003 that resveratrol lowered the Michaelis constant of human SIRT1 for its substrates, stimulated the yeast sirtuin Sir2, and extended yeast lifespan by 70%. The paper framed resveratrol as a calorie restriction mimic: a pill that might deliver some of the effects of eating less without the hunger. That framing drew enormous commercial interest. In 2008 GlaxoSmithKline agreed to acquire Sirtris Pharmaceuticals, the company developing sirtuin activators, through a cash tender offer of $22.50 per share, or approximately $720 million, according to Drug Discovery News. Resveratrol supplements rode the same wave, and the red wine connection made the story easy to sell.
Does resveratrol actually activate sirtuins?
Whether resveratrol activates sirtuins directly is still argued, and the early evidence turned out to depend on an artifact in the test. In 2005 Kaeberlein, Kennedy and colleagues reported in the Journal of Biological Chemistry that resveratrol boosted SIRT1 only when the peptide substrate carried Fluor de Lys, a fluorescent tag used in the commercial assay. Without the tag, resveratrol had no effect, and in 3 different yeast strain backgrounds it did not change Sir2 activity or lifespan. In 2010 a team led by Pacholec reached the same conclusion in the same journal for resveratrol and for Sirtris compounds including SRT1720, and reported that these molecules hit multiple off-target receptors, enzymes, transporters and ion channels. Sinclair's group answered in Science in 2013 with evidence that SIRT1 can be activated allosterically, through a single amino acid, Glu230, when the natural substrate has the right hydrophobic shape. So the mechanism is not dead. But the original lifespan story was built on an assay that overstated the effect.
Did resveratrol extend lifespan in worms and flies?
Resveratrol's lifespan effect in worms and flies has not replicated reliably. In 2007 Bass and colleagues at University College London, a team that included Partridge and Gems, re-tested resveratrol in fruit flies and saw no significant effect on lifespan in 7 independent trials, after confirming their resveratrol was chemically intact. In C. elegans worms the results were variable, with slight increases in some trials and none in others, and the small gains appeared even in worms lacking the sirtuin gene sir-2.1, which argues against the sirtuin explanation. A 2012 meta-analysis by Hector and colleagues in Biology Letters pooled data from 19 papers across 6 species. It found the life-extending effect was most consistent in yeast and nematodes and became less reliable in more complex animals. The authors wrote that few species conclusively show life extension and questioned marketing resveratrol as a life-extending supplement for humans.
Does resveratrol make mice live longer?
Resveratrol made mice live longer only when they were eating a high-calorie diet. Baur, Sinclair and colleagues reported in Nature in 2006 that resveratrol significantly increased survival of middle-aged mice on a high-calorie diet, improved insulin sensitivity and motor function, and reversed the effect of the diet in 144 of 153 altered gene pathways. The follow-up, by Pearson and the same groups in Cell Metabolism in 2008, tested mice on a standard diet starting at 12 months of age. Those mice showed fewer signs of aging, including better aortic elasticity, better motor coordination, fewer cataracts and preserved bone density, but they did not live longer. The strictest test came from the National Institute on Aging Interventions Testing Program, which runs each compound at 3 sites in genetically mixed mice and commits to publishing every result. Starting at 4 months of age, resveratrol had no statistically significant effect on lifespan in males or females (Strong and colleagues, Journals of Gerontology, 2013). In mammals, resveratrol looks more like protection against an unhealthy diet than a brake on aging itself.
How much resveratrol actually reaches the blood?
Very little resveratrol reaches the blood unchanged, even though most of a dose is absorbed. Walle and colleagues at the Medical University of South Carolina gave radiolabelled resveratrol to 6 volunteers and reported in Drug Metabolism and Disposition in 2004 that at least 70% of a 25 mg oral dose was absorbed. Total resveratrol plus its metabolites peaked at 491 ng/ml, but unchanged resveratrol was below 5 ng/ml. The bottleneck is extremely fast sulfate and glucuronide conjugation in the gut wall and liver. A 2010 study in Cancer Research by Brown and colleagues pushed the dose much higher, giving 40 healthy volunteers 0.5, 1.0, 2.5 or 5.0 g a day for 29 days. Exposure to the conjugated metabolites exceeded that of parent resveratrol by up to 20.3-fold, and the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Whether those metabolites are active in human tissue is an open question, which is one reason lab results at micromolar concentrations are hard to translate to a capsule.
What Actually Reaches the Blood After a 25 mg Dose
Peak plasma levels (ng/ml) in 6 volunteers after a 25 mg oral dose. At least 70% was absorbed, but almost all of it circulated as sulfate and glucuronide conjugates; unchanged resveratrol stayed below 5 ng/ml (Walle and colleagues, Drug Metabolism and Disposition, 2004).
Does resveratrol improve metabolism in men?
Resveratrol's metabolic effects in men are inconsistent: one small industry-linked trial found calorie restriction-like changes and a larger independent trial found none. Timmers, Schrauwen and colleagues gave 11 healthy obese men 150 mg a day of resveratrol (resVida) or placebo for 30 days each in a crossover trial, published in Cell Metabolism in 2011. Sleeping and resting metabolic rate fell, liver fat, blood glucose and triglycerides decreased, and systolic blood pressure dropped. DSM Nutritional Products, the maker of resVida, is listed among the author affiliations. A year later, Poulsen and colleagues at Aarhus University ran an investigator-initiated, double-blind trial in 24 obese but otherwise healthy men given high-dose resveratrol or placebo for 4 weeks, published in Diabetes in 2013. Insulin sensitivity, measured with the gold-standard clamp, did not improve. Resveratrol also had no effect on blood pressure, energy expenditure, visceral or liver fat, or inflammatory markers. The Aarhus authors wrote that the lack of effect raises doubt about resveratrol as a supplement for metabolic disorders.
Does resveratrol interfere with the benefits of exercise?
In one controlled trial in older men, resveratrol blunted several benefits of exercise training. Gliemann, Hellsten and colleagues at the University of Copenhagen randomized 27 healthy, physically inactive men aged about 65 to 8 weeks of high-intensity training plus either 250 mg of trans-resveratrol a day (n = 14) or placebo (n = 13), and published the results in the Journal of Physiology in 2013. Maximal oxygen uptake rose 45% more in the placebo group than in the resveratrol group. Mean arterial pressure fell by 4.8 mmHg in the placebo group only. Resveratrol also abolished the training-related improvements in LDL cholesterol, the total cholesterol to HDL ratio and triglycerides. After training, the vasodilator prostacyclin measured in muscle tissue fluid was 980 pg/ml in the resveratrol group against 1174 pg/ml on placebo. SIRT1 protein in muscle did not change with resveratrol. The likely explanation is that some exercise adaptations depend on the oxidative signals that antioxidants damp down, though this trial was not designed to prove the mechanism. For men who train, this is the most practically relevant resveratrol result: taking it alongside a training program may cost part of the payoff.
A Blood Vessel Signal After 8 Weeks of Training
Interstitial prostacyclin, a vasodilator, after 8 weeks of high-intensity training in 27 inactive men around 65 years old taking 250 mg trans-resveratrol (n = 14) or placebo (n = 13). The placebo group also gained 45% more in maximal oxygen uptake (Gliemann and colleagues, Journal of Physiology, 2013).
Does resveratrol lower blood pressure?
Across randomized trials, resveratrol did not significantly lower blood pressure overall. Fogacci, Cicero and colleagues pooled 17 trials in a 2019 meta-analysis in Critical Reviews in Food Science and Nutrition. The pooled change in systolic pressure was -2.5 mmHg, with a 95% confidence interval of -5.5 to 0.6, so the result could plausibly be zero. Diastolic pressure changed by -0.5 mmHg (-2.2 to 1.3), mean arterial pressure by -1.3 mmHg (-2.8 to 0.1) and pulse pressure by -0.9 mmHg (-3.1 to 1.4). Heterogeneity was substantial, with an I2 of 62.1% for systolic pressure. Significant effects appeared only in subgroups: trials using 300 mg a day or more, and trials in people with diabetes. Subgroup findings like these are hypotheses, not proof, and the overall answer for most people is no clear effect.
Resveratrol and Blood Pressure Across 17 Trials
Pooled weighted mean difference versus control (mmHg) with the lower and upper 95% confidence limits. Every interval crosses zero, so none of the four overall effects was significant (Fogacci and colleagues, Critical Reviews in Food Science and Nutrition, 2019).
- Lower 95% limit
- Pooled estimate
- Upper 95% limit
Do people who get more resveratrol from food live longer?
People who got more resveratrol from their diet did not live longer in the one cohort that measured it directly. Semba, Ferrucci and colleagues used the InCHIANTI study, which followed 783 men and women aged 65 or older in two villages in the Chianti region of Tuscany from 1998 to 2009. Instead of relying on food questionnaires, they measured resveratrol metabolites in 24-hour urine. Over 9 years, 268 participants (34.3%) died. From the lowest to the highest quartile of urinary resveratrol, the share who died was 34.4%, 31.6%, 33.5% and 37.4%, with no significant trend. Compared with the highest quartile, the lowest had a hazard ratio for death of 0.80 (95% CI 0.54 to 1.17). Resveratrol levels were also unrelated to C-reactive protein, IL-6, cardiovascular disease and cancer. The study, published in JAMA Internal Medicine in 2014, concluded that resveratrol at the levels a Western diet provides did not meaningfully affect health or mortality. It says nothing about supplement doses, which are far higher than wine or grapes deliver.
Dietary Resveratrol and Death Over 9 Years in Chianti
Percentage of 783 adults aged 65 or older who died over 9 years, by quartile of urinary resveratrol metabolites at baseline. The trend was not significant, and the highest quartile had the most deaths (Semba and colleagues, JAMA Internal Medicine, 2014).
What should men take away from the resveratrol research?
The resveratrol research supports a narrow conclusion: resveratrol has real biological activity in cells and in overfed mice, but no controlled human trial has shown that it slows aging, and one trial in older men suggests it can blunt exercise adaptations. The sirtuin mechanism that made it famous was partly an assay artifact, and is now argued over in more specific terms. Mice on normal diets did not live longer, and the National Institute on Aging program found nothing. The human trials covered here are small, short and split, with 11 to 40 participants and durations of 8 weeks or less, plus a 6-person absorption study that measured blood levels rather than benefits. Longer resveratrol trials exist, but none has measured aging or lifespan outcomes. Bioavailability is poor, so the concentrations that work in a dish are not what a capsule delivers. Anyone already taking resveratrol, particularly at gram doses, should know that higher doses caused gastrointestinal symptoms in the Leicester study and that the long-term safety of high-dose supplementation has not been established in trials. A man weighing it against exercise, sleep and diet, all of which have stronger evidence, is choosing a weak candidate, and one that may get in the way of training. This article is educational and is not medical advice; talk with a clinician before starting any supplement.
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