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The Claims Against Resveratrol: Debunked

Recently there has been a sea of controversy around resveratrol. Does resveratrol actually activate sirtuins? Can it actually extend lifespan in animal models? Does resveratrol have any real benefits to humans? Below we address these questions and other claims against the molecule, and what the scientific evidence shows: 

Claim 1) Resveratrol doesn’t activate SIRT1 outside of the petri dish.

A brief recap of the significance of SIRT1: SIRT1 is a longevity gene belonging to the sirtuin family. Sirtuins are proteins associated with longer healthspan and lifespan. There are 7 types of sirtuins in mammals, including SIRT1-SIRT7. They regulate metabolism transcription of genes, which include releasing insulin, increasing stress resistance as a response to hormetic effects, and modulating lifespan through processes like autophagy. The activation of SIRT1 by resveratrol has been one of the more prominent longevity  impacts of the compound, contributing to it being considered one of the more promising compounds for healthspan and lifespan. 

A common claim in the argument against resveratrol is that it only activates SIRT1 in the petri dish – to add on to that claim, opponents detail that this activation is only because of a research flaw, the addition of a fluorescent substrate into the petri dish. The most cited paper in relation to this claim, a 2009 paper, summarizes:

  1. The Fluor de Lys-SIRT1 peptide added into the petri dish with resveratrol is an artificial activator SIRT1
  2. Resveratrol does not activate SIRT1 in vitro without this added peptide, or in the presence of other natural substrates

The researchers also write that “no data have been published to date demonstrating that resveratrol directly activates SIRT1 in cells or cell-free enzyme assays(1).“ Since this 2009 paper, a variety of research has been published showing that resveratrol alone activates SIRT1 in mice and human cell assays (2-5). For instance, Ghosh et al found that resveratrol increases the binding of SIRT1 to another compound (lamin A) in mice, thereby increasing SIRT1 activation. This paper also found that rescue of adult stem cell function in prematurely aging mice is dependent on the ability of resveratrol to activate SIRT1 (2). However, in an effort to avoid cherry-picking studies, systematic reviews (comprehensive reviews of research), are critical. A comprehensive systematic review published in 2021, concluded that “resveratrol supplementation has beneficial effects on protein and gene expression of SIRT1” (6). For the sake of clarity, more systematic reviews are needed to understand if resveratrol activates SIRT1 in animal models. Additionally, research to determine the ability of resveratrol to activate SIRT1 in humans, outside of the petri dish, is also needed. 

However, research has also shown that not all of the age-related benefits of resveratrol are dependent on its ability to activate sirtuins (7). 

Claim 2) Resveratrol doesn’t extend lifespan for organism/animal models

Another common claim by those who refute resveratrol’s potential as a longevity compound is that it doesn’t actually extend the lifespan of organisms or animals. However, this claim also comes from dated research. A 2015 review which summarized the research on resveratrol detailed that supplementation with resveratrol in research has led to increased lifespan for yeast, worms, flies, fish, bees and mice (8).

Claim 3) Resveratrol causes replicative stress 

A third claim is that resveratrol is actually detrimental because it causes replicative stress, a phenomenon with negative impacts on genome stability, cell survival, and disease development. Replicative stress ensues DNA damage, stem cell attrition, cancer and aging. 

Concerns surrounding resveratrol and replicative stress are derived from an in vitro study which found that resveratrol treatment induced replicative stress in human cells (9). Similarly, another recent study found that low doses of resveratrol are protective for human cells in vitro, but high doses are detrimental (10). It has been acknowledged that depending on the dose, resveratrol can either have beneficial effects or detrimental ones (11). This dosage differs between concentrations applied directly to cells in in vitro studies, and doses taken as a supplement. In vitro research, which is necessary and contributes largely to the field, can’t always be directly translated to real-world applications.

Claim 4) Resveratrol has no real benefits in human trials, rather it harms cholesterol levels and blunts exercise benefits 

Another claim is that resveratrol has no real benefits in human trials. Instead, those who oppose its use claim that it is harmful especially for cholesterol levels and exercise benefits. To start, we know that resveratrol (150 mg/day – 2,000 mg/day) offers many benefits to humans. For instance, a consensus in research shows that for those with type 2 diabetes, resveratrol may improve insulin sensitivity, decrease fasting blood glucose and insulin levels, and ameliorate oxidative stress (12). Several other studies show that resveratrol improves heart function for those with heart failure, and motor function for those with muscular dystrophy (13,14).

To address the second part of the claim regarding exercise benefits and cholesterol, a trial found that resveratrol supplementation blunted the beneficial effects of exercise including the cholesterol-lowering effects (12). There are human trials which suggest resveratrol supports cholesterol levels, and others that find resveratrol is detrimental or negligent to cholesterol levels(15, 16). Due to the vast array of potential issues in ways that combining resveratrol and exercise could negate benefits, including combining two hormetic stressors which might result in pro-oxidant effects, and methodological issues in resveratrol trials like whether or not participants took the resveratrol on an empty stomach or with food, standardized research is needed. Research should further explore what direct impact resveratrol has on cholesterol, as well as how it impacts other benefits of exercise alone and in combination with exercise – addressing confounding factors.

Are you wondering about GlaxoSmithKline’s failed resveratrol trial?

In 2010, GSK halted a trial of a highly concentrated form of resveratrol. The trial’s purpose was to assess the safety profile and effectiveness of this form of resveratrol (SRT501) either by itself, or in combination with bortezomib (anti-cancer medication) in those with multiple myeloma. The trial was stopped because participants developed “myeloma kidney” or kidney failure, exclusively in the group taking SRT501 alone and five participants died. There is much that is unknown about this trial. Based on what is known, there are a couple of important points regarding this trial, including dosage of this form of resveratrol (SRT501), and resveratrol’s inconclusive impacts on cancer.

The exact formula of SRT501 is unknown, but it is known that it was highly concentrated which might have led to negative impacts considering that each participant took five grams of the drug daily – which you will not find in supplements or much research. Due to their disease state, these participants were also already at risk of kidney impairment. This dosage could have influenced taxing effects on the kidney, and the experienced side effects of nausea, vomiting and consequent loss of fluid which may have exacerbated the issue. Additionally, reviews of clinical trials suggest that resveratrol is beneficial for heart disease, as well as metabolic and neurological conditions, but the evidence regarding resveratrol and cancer is less clear (17). It is important to understand that SRT501 was not a conventional formulation of resveratrol. 

What about other conflicting trials? 

Inconsistencies between trials could be due to several methodological issues and confounding variables. One of the most clear issues is whether or not resveratrol is taken with or without food. It has been shown that resveratrol is most effective when it is eaten with food because it is otherwise highly insoluble (18). When research doesn’t include supplementation with food, this can drastically change study outcomes. 

The bottom line on resveratrol

To take the most evidence-based approach, it is important to acknowledge that more research is needed to determine how or when resveratrol activates sirtuins, whether or not this activation occurs in humans and the exact impact of this to human health. It is also important to acknowledge that research takes years. More research is needed. We know that resveratrol has been shown to extend lifespan among an array of organism and animal models and also shown to provide benefits to humans through numerous human RCT’s, especially with normal and safe dosages. Activation of SIRT1 is still a potential mechanism for resveratrol’s health benefits. However, it is not the only one. 

Much of the controversy has resulted from individuals cherry-picking studies which have not had favorable results, although credible science requires a more holistic overview of the research to reach a conclusion: looking into systematic reviews and meta-analysis regarding the compound is important to the story. With that in mind, results from systematic reviews and meta-analysis’, such as the one mentioned above, have a much less controversial take on resveratrol. As with most supplements, research is limited. When making a decision to take a supplement, always reach out to your doctor, read through research and weigh in the pros and cons.

Click here to read all about resveratrol

Click here to read all about sirtuins

Click here to read all about dosage

Click here to read about sirtuins and centenarians

Author: Jacqueline Seymour
Jacki is a Master’s student at USC, home of Dr. Valter Longo’s Longevity Institute, where she’s studying her passion for life: Gerontology(the science of aging) and Nutrition. 


References 

1. 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. doi: 10.1111/j.1747-0285.2009.00901.x. Epub 2009 Oct 20. PMID: 19843076.

2. Ghosh S, Liu B, Zhou Z. Resveratrol activates SIRT1 in a Lamin A-dependent manner. Cell Cycle. 2013 Mar 15;12(6):872-6. doi: 10.4161/cc.24061. Epub 2013 Feb 25. PMID: 23439428; PMCID: PMC3637344.

3. Ma S, Feng J, Zhang R, Chen J, Han D, Li X, Yang B, Li X, Fan M, Li C, Tian Z, Wang Y, Cao F. SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice. Oxid Med Cell Longev. 2017;2017:4602715. doi: 10.1155/2017/4602715. Epub 2017 Aug 13. PMID: 28883902; PMCID: PMC5572590.

4. Shi Y, Li Y, Huang C, Ying L, Xue J, Wu H, Chen Z, Yang Z. Resveratrol enhances HBV replication through activating Sirt1-PGC-1α-PPARα pathway. Sci Rep. 2016 Apr 21;6:24744. doi: 10.1038/srep24744. PMID: 27098390; PMCID: PMC4838842.

5. Côté CD, Rasmussen BA, Duca FA, Zadeh-Tahmasebi M, Baur JA, Daljeet M, Breen DM, Filippi BM, Lam TK. Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network. Nat Med. 2015 May;21(5):498-505. doi: 10.1038/nm.3821. Epub 2015 Apr 6. PMID: 25849131.

6. Najafi M, Nikpayam O, Tavakoli-Rouzbehani OM, Papi S, Amrollahi Bioky A, Ahmadiani ES, Sohrab G. A comprehensive insight into the potential effects of resveratrol supplementation on SIRT-1: A systematic review. Diabetes Metab Syndr. 2021 Sep-Oct;15(5):102224. doi: 10.1016/j.dsx.2021.102224. Epub 2021 Jul 18. PMID: 34403949.

7. González-Rodríguez Á, Santamaría B, Mas-Gutierrez JA, Rada P, Fernández-Millán E, Pardo V, Álvarez C, Cuadrado A, Ros M, Serrano M, Valverde ÁM. Resveratrol treatment restores peripheral insulin sensitivity in diabetic mice in a sirt1-independent manner. Mol Nutr Food Res. 2015 Aug;59(8):1431-42. doi: 10.1002/mnfr.201400933. Epub 2015 Apr 28. PMID: 25808216.

8. Khushwant S. Bhullar, Basil P. Hubbard, Lifespan and healthspan extension by resveratrol,Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, Volume 1852, Issue 6, 2015, Pages 1209-1218, ISSN 0925-4439, https://doi.org/10.1016/j.bbadis.2015.01.012.

9. Benslimane Y, Bertomeu T, Coulombe-Huntington J, McQuaid M, Sánchez-Osuna M, Papadopoli D, Avizonis D, Russo MST, Huard C, Topisirovic I, Wurtele H, Tyers M, Harrington L. Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells. Mol Cell. 2020 Sep 3;79(5):846-856.e8. doi: 10.1016/j.molcel.2020.07.010. Epub 2020 Aug 4. PMID: 32755594.

10. Moreira-Pinto, Beatriz et al. “Low Doses of Resveratrol Protect Human Granulosa Cells from Induced-Oxidative Stress.” Antioxidants (Basel, Switzerland) vol. 10,4 561. 4 Apr. 2021, doi:10.3390/antiox10040561.

11. Martins LA, Coelho BP, Behr G, Pettenuzzo LF, Souza IC, Moreira JC, Borojevic R, Gottfried C, Guma FC. Resveratrol induces pro-oxidant effects and time-dependent resistance to cytotoxicity in activated hepatic stellate cells. Cell Biochem Biophys. 2014 Mar;68(2):247-57. doi: 10.1007/s12013-013-9703-8. PMID: 23793960.

12. Gliemann L, Schmidt JF, Olesen J, Biensø RS, Peronard SL, Grandjean SU, Mortensen SP, Nyberg M, Bangsbo J, Pilegaard H, Hellsten Y. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol. 2013 Oct 15;591(20):5047-59. doi: 10.1113/jphysiol.2013.258061. Epub 2013 Jul 22. PMID: 23878368; PMCID: PMC3810808.

13. Gal R, Deres L, Horvath O, Eros K, Sandor B, Urban P, Soos S, Marton Z, Sumegi B, Toth K, Habon T, Halmosi R. Resveratrol Improves Heart Function by Moderating Inflammatory Processes in Patients with Systolic Heart Failure. Antioxidants. 2020; 9(11):1108. https://doi.org/10.3390/antiox9111108.

14. Kawamura, K., Fukumura, S., Nikaido, K. et al. Resveratrol improves motor function in patients with muscular dystrophies: an open-label, single-arm, phase IIa study. Sci Rep 10, 20585 (2020). https://doi.org/10.1038/s41598-020-77197-6.

15. Zhu, X., Wu, C., Qiu, S., Yuan, X., & Li, L. (2017). Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: systematic review and meta-analysis. Nutrition & metabolism, 14, 60. https://doi.org/10.1186/s12986-017-0217-z

16. Jill P. Crandall, Valerie Oram, Georgeta Trandafirescu, Migdalia Reid, Preeti Kishore, Meredith Hawkins, Hillel W. Cohen, Nir Barzilai, Pilot Study of Resveratrol in Older Adults With Impaired Glucose Tolerance, The Journals of Gerontology: Series A, Volume 67, Issue 12, December 2012, Pages 1307–1312, https://doi.org/10.1093/gerona/glr235.

17. Berman, A. Y., Motechin, R. A., Wiesenfeld, M. Y., & Holz, M. K. (2017). The therapeutic potential of resveratrol: a review of clinical trials. NPJ precision oncology, 1, 35. https://doi.org/10.1038/s41698-017-0038-6.

18. La Porte, C., Voduc, N., Zhang, G. et al. Steady-State Pharmacokinetics and Tolerability of Trans-Resveratrol 2000mg Twice Daily with Food, Quercetin and Alcohol (Ethanol) in Healthy Human Subjects. Clin Pharmacokinet 49, 449–454 (2010). https://doi.org/10.2165/11531820-000000000-00000.

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