Sirtuin-activating compound

Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are caloric restriction mimetic candidates, molecules able to prevent aging-related diseases like Alzheimer's,[1] diabetes, and obesity.

Context

Leonard P. Guarente is recognized as the leading proponent of the hypothesis that caloric restriction slows aging by activation of Sirtuins.

STACs have been discovered by Konrad Howitz of Biomol Inc and biologist David Sinclair. In September 2003, Howitz and Sinclair et al. published a highly cited paper reporting that polyphenols such as resveratrol[2] activate human SIRT1 and extend the lifespan of budding yeast (Howitz et al., Nature, 2003). Other examples of such products are butein, piceatannol, isoliquiritigenin, fisetin, and quercetin.

Some STACs can cause artificial effects in the assay initially used for their identification, but it has been shown that STACs also activate SIRT1 against regular polypeptide substrates, with an influence of the substrate sequence. [3][4]

Sirtris Pharmaceuticals, Sinclair's company, is currently developing drugs of this class like SRT1720.

References

  1. ↑ Gan, L. (2007). "Therapeutic potential of sirtuin-activating compounds in Alzheimer's disease". Drug News & Perspectives 20 (4): 233–239. doi:10.1358/dnp.2007.20.4.1101162. PMID 17637936.
  2. ↑ Kaeberlein, M.; McDonagh, T.; Heltweg, B.; Hixon, J.; Westman, E. A.; Caldwell, S. D.; Napper, A.; Curtis, R.; Distefano, P. S.; Fields, S.; Bedalov, A.; Kennedy, B. K. (2005). "Substrate-specific Activation of Sirtuins by Resveratrol". Journal of Biological Chemistry 280 (17): 17038–17045. doi:10.1074/jbc.M500655200. PMID 15684413.
  3. ↑ Lakshminarasimhan, M; Rauh, D; Schutkowski, M; Steegborn, C (Mar 2013). "Sirt1 activation by resveratrol is substrate sequence-selective". Aging 5 (3): 151–4. PMID 23524286.
  4. ↑ Hubbard, BP; et al. (Mar 2013). "Evidence for a common mechanism of SIRT1 regulation by allosteric activators". Science 339 (6124): 1216–9. doi:10.1126/science.1231097. PMID 23471411.

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See also


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