Telomeres

2022-07-11T12:17:40Z

ElaR: /* References */

Telomeres

2022-07-11T12:11:56Z

ElaR: Basic information about telomeres and telomerase - functiona and structure. Reorganisation of the existing draft, addition of citations

Resveratrol

2021-07-13T09:01:14Z

ElaR: /* Evidence of lifespan extension */

[[File:Resveratrol.png|thumb|200x200px|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.<ref>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</ref> Resveratrol has gained widespread scientific attention after reports of its lifespan extension properties in a range of model organisms.<ref>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</ref> 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%. <ref>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</ref><ref>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</ref><ref>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</ref><ref>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</ref><ref>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</ref> In mice on a high-calorie diet, resveratrol reduced the risk of death from the diet by 31%.<ref>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</ref> No lifespan extension has been observed in healthy mice and rats.<ref>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</ref><ref>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</ref><ref>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</ref><ref name=":4">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</ref> Resveratrol has been shown to delay senescence at the cellular level in rodents, by increasings telomerase activity and reversing aging impaired cognitive functions.<ref name=":4" /><ref>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</ref>

== Human clinical trials ==
A range of clinical trials investigating the health benefits of resveratrol supplementation has been performed, some carrying conflicting results.<ref name=":0" /><ref name=":1" /> Resveratrol has been shown to improve glucose control and insulin sensitivity in persons with type 2 diabetes, and modulate some cancer-related genes.<ref>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</ref><ref>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</ref><ref>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</ref> Resveratrol supplementation in postmenopausal women (150 mg per day for 12 months) resulted in improvement of overall cognitive performance.<ref>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</ref> The study concluded that resveratrol supplementation could potentially reverse cognitive ageing by up to 10 years.

== Safety and bioavailability ==
[[File:SIRT1.png|alt=|thumb|400x400px|'''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 <ref name=":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</ref><ref name=":3">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</ref>]]
It has been shown that resveratrol is generally safe in humans.<ref name=":0">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</ref><ref name=":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</ref> Mild adverse effects such as nausea, diarrhea, and abdominal pain have been reported with doses of 1 g per day and higher.<ref>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</ref><ref>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</ref>

Resveratrol is quickly metabolized and is poorly absorbed in the human body, which limits its potential for clinical use.<ref name=":0" />

== Mechanism ==
Resveratrol most likely acts through multiple mechanisms in the cell. Silent Information Regulator 1 (SIRT1) protein was initially suggested as one of its crucial targets.<ref name=":0" /> 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.<ref name=":2" /><ref name=":3" />

Direct activation of SIRT1 by resveratrol is being debated, with a number of studies failing to observe the activation or interaction between the two molecules. <ref>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</ref><ref name=":5">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</ref> Alternative modes of action for resveratrol have been suggested, such as introduction of replication stress in a cell.<ref name=":5" />

== 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 GlaxoSmithKline. Works on SRT501 were terminated in 2010, due to its side effects and lack of specificity to SIRT1, followed by shut down of Sirtis in 2013. <ref>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 </ref>

== References ==
<references />
[[Category:Longevity]]
[[Category:Supplement]]

File:Trans-resveratrol.png

2021-06-13T10:48:37Z

ElaR:

The chemical structure of trans-resveratrol.

Resveratrol

2021-06-13T10:06:39Z

ElaR: creating the page

== Evidence of lifespan extension ==

== Safety ==

== Mechanism ==