Resveratrol

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The chemical structure of trans-resveratrol.

Resveratrol (trans‐3,5,4′‐trihydroxystilbene) is a compound produced naturally by various plants in response to injury or microbial infection. Its main dietary sources include grapes, blueberry, cranberry, peanuts, and legumes.[1] Resveratrol has gained widespread attention, in part due to reports of its lifespan extension properties in a range of model organisms.[2] However, there has also been significant controversy and criticism.[3] Resveratrol is currently considered a dietary supplement and is not an approved medicine.

As of today, resveratrol is known to have widespread effects in physiology but is not considered to be a lifespan extending agent.[4] Additionally, despite years of widespread misinformation resveratrol has been debunked as a specific in vivo activator of the sirtuin protein SIR2.[5][6]

Evidence of lifespan extension

Resveratrol has been shown to extend healthy lifespan in yeast, worms, fruit flies, bees, and fish by 10-70% [7][8][9][10][11] In mice on a high-calorie diet, resveratrol reduced the risk of death from the diet by 31%.[12] However, many of these studies come from Sinclair's lab, which in the past had conflicting monetary interests given he was the founder of the company Sirtris Pharmaceuticals, a biotechnology company focused on using resveratrol and other potential sirtuin activators to extend human lifespan.[13]

Independent laboratories demonstrated there is no lifespan extension in healthy mice and rats.[14][15][16][17] Resveratrol has been shown to delay aspects of vascular aging in rodents, improving aging-impaired cognitive function.[17][18] However given the lack of evidence of resveratrol to extend lifespan in rodent models, it does not appear likely to produce meaningful benefit for human aging.

Currently, it is unclear whether resveratrol will exert meaningful biological effects in humans.[3] This is an ongoing area of research, but evidence for human lifespan extension will need to be shown in large, randomized controlled trials.

Human clinical trials

A range of clinical trials investigating the health benefits of resveratrol supplementation has been performed, some carrying conflicting results.[19][20] Resveratrol has been shown to improve glucose control and insulin sensitivity in persons with type 2 diabetes, and modulate some cancer-related genes.[21][22][23] Resveratrol supplementation in postmenopausal women (150 mg per day for 12 months) resulted in improvement of overall cognitive performance.[24] The study suggested that resveratrol supplementation could potentially reverse cognitive ageing by up to 10 years.

The ¨Invecchiare in Chianti (InCHIANTI) Study¨ (literally meaning “Aging in the Chianti Region”), conducted a prospective cohort study of 783 people over the age of 65 in the Chianti region of Italy, and demonstrated that urinary concentration of resveratrol metabolite was not associated to age-related diseases nor was predictive of all-cause mortality.[25] Therefore, they concluded that resveratrol had no significant influence on healthspan nor lifespan of the individuals in the study.

Safety and bioavailability

It has been shown that resveratrol is generally safe in humans.[19][20] Mild adverse effects such as nausea, diarrhea, and abdominal pain have been reported with doses of 1 g per day and higher.[26][27]

Resveratrol is quickly metabolized and is poorly absorbed in the human body, which limits its potential for clinical use in humans.[19]

Mechanism

SIRT1 is proposed to be the main molecular target through which resveratrol delivers its health benefits. AMPK, 5′‐AMP‐activated protein kinase; SIRT1, sirtuin type 1; PGC‐1α, peroxisome proliferator‐activated receptor‐γ coactivator 1α; eNOS, endothelial nitric oxide synthase 3; NF‐κb, nuclear factor‐κB; FOXO, forkhead box O; Nrf2, nuclear factor erythroid 2 like 2. Scheme adapted from [28][29]

Resveratrol had been proposed to act via sirtuins to multiple downstream cellular targets involved in regulating aging. Silent Information Regulator 1 (SIRT1) protein was initially suggested as its main target in mammals,[19] whilst SIR2 was proposed to be the main resveratrol target in yeast.[30]

Resveratrol was hypothesised to induce SIRT1 either directly or through phosphorylation of AMP-activated protein kinase (AMPK). Upon induction, SIRT1 has been shown to modulate activity of molecules taking part in stimulating mitochondrial biogenesis, vasodilation, antioxidant defence, glucose and lipid homeostasis, as well as those inhibiting inflammation.[28][29] Alternative modes of action for resveratrol have been suggested, such as introduction of replicative stress in the cell.[31]

Whether resveratrol directly activates SIRT1 is controversial, with a number of studies failing to observe activation or interaction between the two molecules. [5][6] It is now generally considered that resveratrol does not activate sirtuins in vivo. Studies in vitro had apparently used a modified peptide on resveratrol which changed its conformation and allowed it to bind SIR2 and SIRT1.[5]

This story is somewhat reminiscent of experiments in which sirtuins had been reported to extend lifespan in C. elegans by 50%.[32] When independent scientists failed to recapitulate such findings, it came to light that the original experiments had been performed in an animal with a sensory neuronal background mutation previously linked to longevity, whilst it had no sifnificant effect in wild-type strains.[33] Therefore sirtuins have similarly been debunked as longevity genes.

Derivatives of resveratrol and drug development attempts

In 2004 a company called Sirtris Pharmaceuticals, Inc. was conceived to study potential of resveratrol as a drug for type 2 diabetes, cancer, and other diseases. The company's initial product was called SRT501, and was a formulation of reservatrol. In 2008 Sirtris was purchased by the pharma giant GlaxoSmithKline (GSK).[34] Further development of SRT501 were terminated in 2010, in part due to its side effects and lack of specificity to SIRT1, followed by shutdown of Sirtis in 2013. [35]

References

  1. ↑ Tian, B., & Liu, J. (2020). Resveratrol: A review of plant sources, synthesis, stability, modification and food application. Journal of the Science of Food and Agriculture, 100(4), 1392-1404. https://doi.org/10.1002/jsfa.10152
  2. ↑ Bhullar, K. S., & Hubbard, B. P. (2015). Lifespan and healthspan extension by resveratrol. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1852(6), 1209-1218. https://doi.org/10.1016/j.bbadis.2015.01.012
  3. ↑ 3.0 3.1 Kaeberlein, M. (2010). Resveratrol and rapamycin: are they anti‐aging drugs?. Bioessays, 32(2), 96-99.
  4. ↑ Pearson, K., Baur, J., Lewis, K., Peshkin, L., Price, N., & Labinskyy, N. et al. (2008). Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metabolism, 8(2), 157-168. doi: 10.1016/j.cmet.2008.06.011
  5. ↑ 5.0 5.1 5.2 Beher, D., Wu, J., Cumine, S., Kim, K., Lu, S., Atangan, L., & Wang, M. (2009). Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity. Chemical Biology &Amp; Drug Design, 74(6), 619-624. doi: 10.1111/j.1747-0285.2009.00901.x
  6. ↑ 6.0 6.1 Pacholec, M., Bleasdale, J., Chrunyk, B., Cunningham, D., Flynn, D., & Garofalo, R. et al. (2010). SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1. Journal Of Biological Chemistry, 285(11), 8340-8351. doi: 10.1074/jbc.m109.088682
  7. ↑ Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425(6954), 191-196. https://doi.org/10.1038/nature01960
  8. ↑ Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature, 430(7000), 686-689. https://doi.org/10.1038/nature02789
  9. ↑ Rascón, B., Hubbard, B. P., Sinclair, D. A., & Amdam, G. V. (2012). The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. Aging (Albany NY), 4(7), 499. https://doi.org/10.18632/aging.100474
  10. ↑ Valenzano, D. R., Terzibasi, E., Genade, T., Cattaneo, A., Domenici, L., & Cellerino, A. (2006). Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Current biology, 16(3), 296-300. https://doi.org/10.1016/j.cub.2005.12.038
  11. ↑ Yu, X., & Li, G. (2012). Effects of resveratrol on longevity, cognitive ability and aging-related histological markers in the annual fish Nothobranchius guentheri. Experimental gerontology, 47(12), 940-949. https://doi.org/10.1016/j.exger.2012.08.009
  12. ↑ Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., ... & Sinclair, D. A. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 444(7117), 337-342. https://dx.doi.org/10.1038/nature05354
  13. ↑ https://www.sec.gov/Archives/edgar/data/1388775/000104746907001505/a2176355zs-1.htm
  14. ↑ Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., ... & de Cabo, R. (2008). Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell metabolism, 8(2), 157-168. https://doi.org/10.1016/j.cmet.2008.06.011
  15. ↑ Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., De Cabo, R., ... & Strong, R. (2011). Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. The Journals of Gerontology: Series A, 66(2), 191-201. https://doi.org/10.1093/gerona/glq178
  16. ↑ Strong, R., Miller, R. A., Astle, C. M., Baur, J. A., De Cabo, R., Fernandez, E., ... & Harrison, D. E. (2013). Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 68(1), 6-16. https://dx.doi.org/10.1093/gerona/gls070
  17. ↑ 17.0 17.1 da Luz, P. L., Tanaka, L., Brum, P. C., Dourado, P. M. M., Favarato, D., Krieger, J. E., & Laurindo, F. R. M. (2012). Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. Atherosclerosis, 224(1), 136-142. https://doi.org/10.1016/j.atherosclerosis.2012.06.007
  18. ↑ Gocmez, S. S., Gacar, N., Utkan, T., Gacar, G., Scarpace, P. J., & Tumer, N. (2016). Protective effects of resveratrol on aging-induced cognitive impairment in rats. Neurobiology of learning and memory, 131, 131-136. https://doi.org/10.1016/j.nlm.2016.03.022
  19. ↑ 19.0 19.1 19.2 19.3 Singh, A. P., Singh, R., Verma, S. S., Rai, V., Kaschula, C. H., Maiti, P., & Gupta, S. C. (2019). Health benefits of resveratrol: Evidence from clinical studies. Medicinal research reviews, 39(5), 1851-1891. https://doi.org/10.1002/med.21565
  20. ↑ 20.0 20.1 Bitterman, J. L., & Chung, J. H. (2015). Metabolic effects of resveratrol: addressing the controversies. Cellular and Molecular Life Sciences, 72(8), 1473-1488. https://doi.org/10.1007/s00018-014-1808-8
  21. ↑ Liu, K., Zhou, R., Wang, B., & Mi, M. T. (2014). Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. The American journal of clinical nutrition, 99(6), 1510-1519. https://doi.org/10.3945/ajcn.113.082024
  22. ↑ 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(1), 1-10. https://doi.org/10.1186/s12986-017-0217-z
  23. ↑ Ko, J. H., Sethi, G., Um, J. Y., Shanmugam, M. K., Arfuso, F., Kumar, A. P., ... & Ahn, K. S. (2017). The role of resveratrol in cancer therapy. International journal of molecular sciences, 18(12), 2589. https://dx.doi.org/10.3390/ijms18122589
  24. ↑ Zaw, J. J. T., Howe, P. R., & Wong, R. H. (2020). Sustained cerebrovascular and cognitive benefits of resveratrol in postmenopausal women. Nutrients, 12(3), 828. https://doi.org/10.3390/nu12030828
  25. ↑ Semba, R., Ferrucci, L., Bartali, B., Urpí-Sarda, M., Zamora-Ros, R., & Sun, K. et al. (2014). Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling Adults. JAMA Internal Medicine, 174(7), 1077. doi: 10.1001/jamainternmed.2014.1582
  26. ↑ Brown, V. A., Patel, K. R., Viskaduraki, M., Crowell, J. A., Perloff, M., Booth, T. D., ... & Brenner, D. E. (2010). Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer research, 70(22), 9003-9011. https://doi.org/10.1158/0008-5472.can-10-2364
  27. ↑ Patel, K. R., Scott, E., Brown, V. A., Gescher, A. J., Steward, W. P., & Brown, K. (2011). Clinical trials of resveratrol. Annals of the New York Academy of Sciences, 1215(1), 161-169. https://doi.org/10.1111/j.1749-6632.2010.05853.x
  28. ↑ 28.0 28.1 Bhullar, K. S., & Hubbard, B. P. (2015). Lifespan and healthspan extension by resveratrol. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1852(6), 1209-1218. https://doi.org/10.1016/j.bbadis.2015.01.012
  29. ↑ 29.0 29.1 Kulkarni, S. S., & Cantó, C. (2015). The molecular targets of resveratrol. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1852(6), 1114-1123. https://doi.org/10.1016/j.bbadis.2014.10.005
  30. ↑ Howitz, K., Bitterman, K., Cohen, H., Lamming, D., Lavu, S., & Wood, J. et al. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425(6954), 191-196. doi: 10.1038/nature01960
  31. ↑ Benslimane, Y., Bertomeu, T., Coulombe-Huntington, J., McQuaid, M., Sánchez-Osuna, M., Papadopoli, D., ... & Harrington, L. (2020). Genome-wide screens reveal that resveratrol induces replicative stress in human cells. Molecular Cell, 79(5), 846-856. https://doi.org/10.1016/j.molcel.2020.07.010
  32. ↑ Tissenbaum, H., & Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410(6825), 227-230. doi: 10.1038/35065638
  33. ↑ Burnett, C., Valentini, S., Cabreiro, F., Goss, M., Somogyvári, M., & Piper, M. et al. (2011). Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature, 477(7365), 482-485. doi: 10.1038/nature10296
  34. ↑ http://blogs.nature.com/news/2013/03/gsk-absorbs-controversial-longevity-company.html
  35. ↑ Popat, R., Plesner, T., Davies, F., Cook, G., Cook, M., Elliott, P., ... & Cavenagh, J. (2012). A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. British journal of haematology, 160(5), 714-717. https://doi.org/10.1111/bjh.12154
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