Resveratrol

From Longevity Wiki
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.

Evidence of lifespan extension

Resveratrol has been shown to extend healthy lifespan in yeast, worms, fruit flies, bees, and fish by 10-70%. [4][5][6][7][8] In mice on a high-calorie diet, resveratrol reduced the risk of death from the diet by 31%.[9]

No lifespan extension has been observed in healthy mice and rats.[10][11][12][13] Resveratrol has been shown to delay aspects of vascular aging in rodents, improving aging-impaired cognitive function.[13][14] 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.[15][16] Resveratrol has been shown to improve glucose control and insulin sensitivity in persons with type 2 diabetes, and modulate some cancer-related genes.[17][18][19] Resveratrol supplementation in postmenopausal women (150 mg per day for 12 months) resulted in improvement of overall cognitive performance.[20] The study suggested that resveratrol supplementation could potentially reverse cognitive ageing by up to 10 years.

Safety and bioavailability

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 [21][22]

It has been shown that resveratrol is generally safe in humans.[15][16] Mild adverse effects such as nausea, diarrhea, and abdominal pain have been reported with doses of 1 g per day and higher.[23][24]

Resveratrol is quickly metabolized and is poorly absorbed in the human body, which limits its potential for clinical use in humans.[15]

Mechanism

Resveratrol most likely acts through multiple mechanisms in the cell. Silent Information Regulator 1 (SIRT1) protein was initially suggested as one of its targets.[15] Resveratrol was proposed 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.[21][22]

Whether resveratrol directly activates SIRT1 is controversial, with a number of studies failing to observe activation or interaction between the two molecules. [25][26] Alternative modes of action for resveratrol have been suggested, such as introduction of replication stress in a cell.[26]

Derivatives of resveratrol and drug development attempts

In 2004 a company 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 pharmaceutical company GlaxoSmithKline. 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. [27]

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. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 13.0 13.1 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
  14. 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
  15. 15.0 15.1 15.2 15.3 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
  16. 16.0 16.1 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 21.0 21.1 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
  22. 22.0 22.1 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
  23. 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
  24. 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
  25. Beher, D., Wu, J., Cumine, S., Kim, K. W., Lu, S. C., Atangan, L., & Wang, M. (2009). Resveratrol is not a direct activator of SIRT1 enzyme activity. Chemical biology & drug design, 74(6), 619-624. https://doi.org/10.1111/j.1747-0285.2009.00901.x
  26. 26.0 26.1 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
  27. 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