In 2008, GlaxoSmithKline paid $720 million for Sirtris Pharmaceuticals, a young company built on one idea: that resveratrol, the polyphenol in red grape skins, could switch on a family of longevity-linked proteins called sirtuins. Five years later, GSK shut Sirtris down.
Yet today resveratrol is sold alongside NAD+ more than ever. That isn't just marketing inertia. The research that dismantled the original story also produced a better argument for pairing the two, one that runs straight through NAD+.
This article follows that argument from the 2003 yeast experiment to the human trials, including the ones that found nothing and one that found a downside. It ends with what the evidence supports today and who should skip the combination.
- Sirtuins run on NAD+. Every time a sirtuin enzyme does its job, it consumes a molecule of NAD+. Resveratrol was proposed as the accelerator, and NAD+ is the fuel.
- The "direct switch" story didn't hold up cleanly. A 2012 study in Cell found resveratrol's main metabolic effect works indirectly, through a chain that ends by raising NAD+ levels, which then activates SIRT1 (Park et al., 2012).
- Human results are mixed. 150 mg a day produced calorie-restriction-like changes in obese men over 30 days. 75 mg and 1,500 mg a day did nothing measurable in other groups, and a 2025 meta-analysis of 11 trials found no overall effect on SIRT1.
- There's a real trade-off for active people. In older men doing interval training, 250 mg a day of resveratrol blunted the gains in blood pressure, cholesterol and aerobic capacity.
- No trial has tested NAD+ and resveratrol together. The closest is NR combined with pterostilbene, a resveratrol relative, which raised blood NAD+ by 40%.
The One-Paragraph Version
Sirtuins are enzymes that remove acetyl tags from other proteins, changing how those proteins behave. SIRT1, the most studied, is involved in metabolism, stress responses and DNA maintenance. Each reaction a sirtuin carries out consumes a molecule of NAD+, so sirtuin activity is limited by how much NAD+ is available, and NAD+ levels tend to fall with age. Resveratrol entered the picture as a molecule that seemed to make SIRT1 work harder. Pairing the two follows simple logic: supply the fuel and press the accelerator. Twenty years of research later, the fuel half of that logic is on firmer ground than the accelerator half.
How Resveratrol Became the Sirtuin Molecule
The story starts in 2003, when researchers screening for sirtuin activators reported in Nature that resveratrol activated SIRT1 in the test tube and extended the lifespan of yeast (Howitz et al., 2003). In 2006, a second Nature paper showed that resveratrol improved health and survival in mice fed a high-calorie diet, shifting their physiology toward that of mice on a standard diet (Baur et al., 2006).
That was enough to launch an industry. Sirtris went public, developed its own resveratrol formulations and synthetic activators, and in 2008 GSK bought it for $720 million.
Then the Mechanism Came Apart, and Was Partly Rebuilt
The first crack was technical. The original SIRT1 assays used a test substrate carrying a fluorescent label. In 2010, a team at Pfizer reported that resveratrol and several Sirtris compounds didn't activate SIRT1 when that label was removed, suggesting the activation was an artifact of the assay (Pacholec et al., Journal of Biological Chemistry, 2010).
The same year, GSK halted a trial of SRT501, a high-dose resveratrol formulation, in patients with multiple myeloma. Several patients developed kidney failure. GSK said the formulation was poorly tolerated, and the nausea, vomiting and diarrhea it caused may have led to dehydration that worsened the kidney injury. The drug was also only minimally effective (Fierce Biotech). In a large lifespan program run by the U.S. National Institute on Aging, resveratrol didn't extend the lifespan of genetically diverse mice on a normal diet (Miller et al., 2011). In 2013, GSK closed Sirtris and folded its work into the parent company.
Two papers then partly rebuilt the story, in different ways:
- Direct activation is real, but conditional. In 2013, researchers showed in Science that activators like resveratrol can bind SIRT1 and speed it up, but only with substrates that have particular structural features. The fluorescent label had been mimicking those features (Hubbard et al., 2013).
- The main metabolic effect is indirect, and it runs through NAD+. A 2012 study in Cell found that resveratrol's metabolic benefits in mice came from inhibiting enzymes called phosphodiesterases. That raised a signaling molecule (cAMP), which triggered a chain ending in the energy sensor AMPK. Downstream of AMPK, "an increase in NAD+ levels" activated SIRT1 (Park et al., Cell, 2012).
What Human Trials Found
Resveratrol has been tested in people far more than oral NAD+ has. The results depend heavily on who was studied and at what dose.
| Trial | Who | Dose and length | Result |
|---|---|---|---|
| Timmers et al., 2011 | 11 obese men | 150 mg/day, 30 days | Calorie-restriction-like changes: lower resting metabolic rate, AMPK activated, SIRT1 and PGC-1α up in muscle, lower liver fat, glucose and triglycerides |
| Yoshino et al., 2012 | Non-obese postmenopausal women | 75 mg/day, 12 weeks | No improvement in insulin sensitivity in liver, muscle or fat |
| Poulsen et al., 2013 | 24 obese men | 1,500 mg/day, 4 weeks | No improvement in insulin sensitivity, metabolism or body composition |
| Gliemann et al., 2013 | 27 inactive men, about 65, doing interval training | 250 mg/day, 8 weeks | Blunted the training gains in blood pressure, cholesterol and aerobic capacity |
| JAND meta-analysis, 2025 | 11 randomized trials | Various | No significant overall effect on SIRT1 gene expression, protein or blood levels |
The Timmers study stands out, and it's worth being precise about it. It was the first published clinical trial of resveratrol. It was small, a crossover design in 11 men over 30 days, and the effects it found didn't reappear in leaner or healthier groups. When a 2025 GRADE-assessed meta-analysis pooled 11 trials measuring SIRT1 directly, the overall effect was not significant. Subgroup results hinted at an increase in SIRT1 gene expression in blood over shorter periods, which is suggestive rather than conclusive.
The Gliemann result deserves more attention than it gets. In 27 older men doing high-intensity training three times a week, exercise alone improved blood pressure, cholesterol and maximal oxygen uptake. Adding 250 mg of resveratrol a day reduced those improvements. The finding has been debated, but it's a reason to think twice before taking resveratrol specifically to boost the results of training.
Is There Any Trial of NAD+ and Resveratrol Together?
Not directly. No published trial has combined NAD+ itself with resveratrol. The closest human evidence pairs an NAD+ precursor with a close chemical relative of resveratrol.
In 2017, a randomized, placebo-controlled trial gave 120 adults aged 60 to 80 either placebo, a combination of 250 mg nicotinamide riboside (NR) plus 50 mg pterostilbene, or double that dose, every day at breakfast for eight weeks. The standard dose raised whole-blood NAD+ by about 40%, and the increase was sustained (Dellinger et al., npj Aging and Mechanisms of Disease, 2017). The double-dose group showed a rise in total and LDL cholesterol, although the authors noted that baseline differences between groups confound that finding.
Two caveats keep this from being a direct answer. Pterostilbene is a methylated cousin of resveratrol with different absorption, not resveratrol itself. And NR is a precursor, not NAD+. The trial shows that an NAD+ precursor plus a resveratrol-type polyphenol can raise NAD+ in older adults over two months, which is a narrower claim than "NAD+ and resveratrol work together."
The Absorption Problem Nobody Puts on the Label
Both halves of the pairing have trouble reaching your cells intact.
Resveratrol is well absorbed but quickly transformed. In a study using labeled resveratrol, about 75% of an oral dose was absorbed, but "extensive metabolism in the intestine and liver" left an oral bioavailability of "considerably less than 1%" as unchanged resveratrol (Walle et al., Drug Metabolism and Disposition, 2004). What circulates is mostly glucuronide and sulfate conjugates. Whether those conjugates act as a reservoir that releases active resveratrol in tissues is still an open question.
NAD+ taken by mouth is largely broken down in the small intestine into smaller molecules like NMN, NR and nicotinamide before absorption (Alegre & Pastore, 2023). Your cells then rebuild NAD+ from those pieces.
A popular piece of advice says to take resveratrol with fat, often yogurt or olive oil, to improve absorption. The evidence doesn't back it: the Linus Pauling Institute notes that in one study, resveratrol bioavailability "was reduced by the amount of fat in the diet, but not by the co-administration of quercetin or alcohol" (Linus Pauling Institute). Taking it with an ordinary breakfast is reasonable. Adding extra fat specifically to boost it isn't supported.
This is also why many formulas add a third ingredient. Quercetin inhibits CD38, the main enzyme that degrades NAD+ inside the body. We cover that mechanism in detail in our article on quercetin and NAD+.
Can You Take NAD+ and Resveratrol Together? Safety and Interactions
For most healthy adults, the doses used in human trials were well tolerated. The cautions come mainly from resveratrol:
- Digestive upset at high doses. Nausea, abdominal pain, gas and diarrhea have been reported above 1,000 mg a day (Linus Pauling Institute), and more often at 2.5 to 5 grams a day (MSKCC).
- Blood thinners and antiplatelet drugs. Resveratrol inhibits platelet aggregation and "may increase your risk of bleeding" with drugs like warfarin (MSKCC). Talk to your doctor first, and stop before surgery.
- Drugs processed by liver enzymes. At 1 gram a day for four weeks, resveratrol inhibited CYP3A4, CYP2D6 and CYP2C9 in healthy volunteers (Chow et al., 2010). Statins and calcium channel blockers are among the medications that could be affected. Ask your pharmacist.
- Hormone-sensitive cancers. MSKCC advises caution because resveratrol has estrogen-like properties.
- Active cancer treatment. NAD+ precursors helped pancreatic cancer cells resist chemotherapy in 2026 lab and mouse research. See our full guide to NAD+ side effects.
- Pregnancy and breastfeeding. There's no safety data for either ingredient at supplement doses.
Doses Used in Research, and How to Take Them
Human resveratrol trials have used anywhere from 75 mg to 1,500 mg a day, and higher in cancer research. 150 mg is the dose from the Timmers trial, the one that produced measurable metabolic changes. NAD+ precursor trials have typically used 250 to 1,000 mg a day. For comparison, the average red wine contains about 1.9 mg of resveratrol per liter, roughly 0.3 mg in a five-ounce glass (Linus Pauling Institute). Getting 150 mg from wine would take about 500 glasses.
Practical points that follow from the evidence:
- Take it with breakfast. That's how the NR and pterostilbene trial was dosed, and food eases the stomach.
- Don't stack resveratrol products. A combination formula plus a separate resveratrol capsule can quietly push you toward the doses where digestive side effects and enzyme interactions start.
- Give it two to three months before judging, and judge it on something you can measure with your doctor, not on how you feel on day three.
- If training is central to your routine, weigh the Gliemann finding before adding resveratrol.
Where Soleu's NAD+ Formula Fits
Soleu's formula combines the three ingredients discussed across these articles, at doses printed on the label.
NAD+ Supplement with Resveratrol & Quercetin
Per two-capsule serving: 500 mg NAD+, 150 mg resveratrol (98%, from Japanese knotweed root; the same daily amount used in the Timmers trial), and 250 mg quercetin dihydrate. 60 vegetable capsules, 30 servings, no proprietary blend.
See the full ingredient panelTo be clear about what that means: the formula hasn't been tested in its own clinical trial, and matching a trial's resveratrol dose doesn't mean matching its results. What a disclosed formula gives you is the ability to compare your actual intake against the studies above. And if you take a blood thinner, have a hormone-sensitive condition, or are in cancer treatment, talk to your doctor before you start.
Frequently Asked Questions
Can you take NAD+ and resveratrol together?
For most healthy adults, yes. Both have been well tolerated at typical supplement doses in human studies, and they're commonly combined. Check with your doctor first if you take blood thinners, antiplatelet drugs, or medications processed by the liver's CYP enzymes, or if you're pregnant, breastfeeding, or in cancer treatment.
What are the benefits of NAD+ and resveratrol together?
The rationale is that sirtuins need NAD+ to function and resveratrol may increase their activity, partly by raising NAD+ itself. In people, the evidence is limited: a precursor plus a resveratrol relative raised blood NAD+ by about 40% in older adults, but no trial has shown health outcomes from combining NAD+ with resveratrol.
Is resveratrol from Japanese knotweed the same as resveratrol from grapes?
The active compound, trans-resveratrol, is the same molecule. Japanese knotweed root is used because it's a far richer source than grapes. Most resveratrol supplements sold in the U.S. use it.
Should you take resveratrol with fat to absorb it better?
The evidence doesn't support it. In one study, a higher-fat diet reduced resveratrol's bioavailability. Taking it with a normal breakfast is sensible for stomach comfort, but extra fat isn't needed.
Can red wine give you the same amount?
No. An average five-ounce glass of red wine has about 0.3 mg of resveratrol. Matching the 150 mg used in the first human trial would take around 500 glasses.
Does resveratrol interfere with exercise?
In one trial of 27 older men doing interval training, 250 mg a day blunted the improvements in blood pressure, cholesterol and aerobic capacity that exercise produced on its own. The result has been debated and not replicated at scale, but it's a reasonable caution if training is your main goal.
Is pterostilbene better than resveratrol?
Pterostilbene is a methylated relative of resveratrol that's absorbed differently and is the form used in the NR combination trial. There isn't head-to-head human evidence showing one produces better health outcomes than the other.
The Bottom Line
Resveratrol's original promise, a direct switch for longevity proteins, didn't survive intact. GSK spent $720 million on it and walked away. But the research that complicated the story also showed that resveratrol's route to SIRT1 largely runs through a rise in NAD+, and that's the real case for pairing the two.
In people, the evidence is modest and mixed: a promising 30-day result at 150 mg, null results at other doses, a meta-analysis showing no overall effect on SIRT1, and one trial suggesting resveratrol can blunt the benefits of exercise. No study has tested NAD+ and resveratrol together. If you take the combination, take it with breakfast, don't stack products, and check with your doctor if you're on blood thinners or other interacting medications.
Related Reading
- Can You Take Quercetin With NAD+? The Science of Synergy Explained: CD38 and the third ingredient in the stack.
- NAD+ Side Effects: Why a Capsule and an IV Drip Aren't the Same Risk: what the trials recorded, and who should skip NAD+.
- NMN Benefits: What Does the Science Actually Say in 2026?: the most-studied NAD+ precursor.
Sources
- Howitz KT, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 2003. PMID 12939617
- Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 2006. PMID 17086191
- Pacholec M, et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem, 2010. PMID 20061378
- Miller RA, et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A, 2011. PMID 20974732
- Park SJ, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell, 2012. PMC3393874
- Hubbard BP, et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science, 2013. PMID 23471411
- Timmers S, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab, 2011. PMID 22055504
- Yoshino J, et al. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab, 2012. PMC3496026
- Poulsen MM, et al. High-dose resveratrol supplementation in obese men. Diabetes, 2013. PMID 23193181
- Gliemann L, et al. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol, 2013. doi:10.1113/jphysiol.2013.258061
- Impact of resveratrol supplementation on human sirtuin 1: a GRADE-assessed systematic review and dose-response meta-analysis of randomized controlled trials. J Acad Nutr Diet, 2025. jandonline.org
- Dellinger RW, et al. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably. npj Aging Mech Dis, 2017. PMC5701244
- Walle T, et al. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos, 2004. PMID 15333514
- Alegre GFS, Pastore GM. NAD+ precursors NMN and NR: potential dietary contribution to health. Curr Nutr Rep, 2023. PMC10240123
- Chow HH, et al. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev Res, 2010. PMC2933312
- Linus Pauling Institute, Oregon State University. Resveratrol. lpi.oregonstate.edu
- Memorial Sloan Kettering Cancer Center. Resveratrol (About Herbs). mskcc.org
- Elbediwy A, Wehida N. Can supplements containing NMN, NAD+ and resveratrol really slow ageing? The Conversation, May 2026. theconversation.com
- Fierce Biotech. Weak efficacy, renal risks force GSK to dump a resveratrol program. fiercebiotech.com