Sirtuins - Revision history

Andrea at 01:11, 16 August 2023

2023-08-16T01:11:55Z

← Older revision		Revision as of 01:11, 16 August 2023
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	David Gems and his collaborators at UCL eventually discovered that overexpression of SIR-2.1 in hands of the Guarente lab led to a lifespan extension due to an unrelated background mutation.<ref name=":1" /> This background mutation in a sensory neuron gene had already been previously linked to longevity. When this mutation was bred out, there was no evidence that SIR-2.1 significantly boosted lifespan. Eventually, Guarente together with David Sinclair, a post-doc at the time in Guarente's lab, argued that when the sensory neuron mutation was removed there was still a lifespan extension, although a more modest one. Instead of up to 50% increased lifespan reported initially, there was now a small effect of only 14%.<ref>Viswanathan, M., & Guarente, L. (2011). Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. ''Nature'', ''477''(7365), E1-E2. doi: 10.1038/nature10440</ref> Of note, lifespan effects of this mild magnitude in C. ''elegans'' are generally not considered significant, given the high inherent variability of survival curves generated from different groups.		David Gems and his collaborators at UCL eventually discovered that overexpression of SIR-2.1 in hands of the Guarente lab led to a lifespan extension due to an unrelated background mutation.<ref name=":1" /> This background mutation in a sensory neuron gene had already been previously linked to longevity. When this mutation was bred out, there was no evidence that SIR-2.1 significantly boosted lifespan. Eventually, Guarente together with David Sinclair, a post-doc at the time in Guarente's lab, argued that when the sensory neuron mutation was removed there was still a lifespan extension, although a more modest one. Instead of up to 50% increased lifespan reported initially, there was now a small effect of only 14%.<ref>Viswanathan, M., & Guarente, L. (2011). Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. ''Nature'', ''477''(7365), E1-E2. doi: 10.1038/nature10440</ref> Of note, lifespan effects of this mild magnitude in C. ''elegans'' are generally not considered significant, given the high inherent variability of survival curves generated from different groups.

	~~== Sirtuin-activating compounds (STAC) ==~~
	Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins. They are '''caloric restriction mimetic compounds''' that may be helpful in treating various aging-related diseases. It is well known that [[CD38#CD38_inhibitors\|'''CD38 inhibitors''']], by restoring [[NAD+\|NAD<sup>+</sup>]] levels, thus activate SIRT6 protecting from cell senescence and aging.<ref>Zhou, H., Liu, S., Zhang, N., Fang, K., Zong, J., An, Y., & Chang, X. (2022). Downregulation of Sirt6 by CD38 promotes cell senescence and aging. Aging (Albany NY), 14(23), 9730. PMID: 36490326 PMCID: PMC9792202 DOI: 10.18632/aging.204425</ref>
	The first synthetic direct activator of SIRT6 deacetylase activity was the pyrrolo[1,2-a]quinoxaline derivative '''UBCS039''', which showed specific binding on SIRT6, with no significant effects on basal SIRT1, 2, and 3 deacetylation activities. Although, it also stimulated SIRT5 desuccinylation activity (2-fold increase at 100 μM), the physiologically dominant activity of this enzyme.<ref>Fiorentino, F., Mai, A., & Rotili, D. (2021). Emerging therapeutic potential of SIRT6 modulators. Journal of medicinal chemistry, 64(14), 9732-9758. PMID: 34213345 PMC8389836 DOI: 10.1021/acs.jmedchem.1c00601</ref><ref>Fiorentino, F., Mautone, N., Menna, M., D'Acunzo, F., Mai, A., & Rotili, D. (2022). Sirtuin modulators: past, present, and future perspectives. Future Medicinal Chemistry, 14(12), 915-939. PMID: 35583203 PMC9185222 DOI: 10.4155/fmc-2022-0031</ref>

	Chinese researchers more recently discovered a new potent SIRT6 activator - '''21q''', which can be taken as a lead compound for later studies.<ref>Zhang, Z., Sun, W., Zhang, G., Fang, Z., Chen, X., & Li, L. (2023). Design, synthesis, and biological screening of a series of pyrazolo [1, 5-a] quina-zoline derivatives as SIRT6 activators. European Journal of Pharmaceutical Sciences, 185, 106424. PMID: 36918058 [https://doi.org/10.1016/j.ejps.2023.106424 DOI: 10.1016/j.ejps.2023.106424]</ref>

	It was also found a natural compound with the ability to activate SIRT6 such as the seaweed long chain sulfated polysaccharide fucoidan.<ref>Rahnasto-Rilla, M. K., McLoughlin, P., Kulikowicz, T., Doyle, M., Bohr, V. A., Lahtela-Kakkonen, M., ... & Moaddel, R. (2017). The identification of a SIRT6 activator from brown algae Fucus distichus. Marine drugs, 15(6), 190. PMID: 28635654 PMC5484140 DOI: 10.3390/md15060190</ref> NAD<sup>+</sup> precursor [[Nicotinamide mononucleotide (NMN)]] has been recognized as a promising bio-active compound in relieving aging-related mitochondrial dysfunction. Self-assembled nanoparticles were prepared based on interaction between ovalbumin and fucoidan to improve the stability and bio-accessibility of NMN and for its synergy with fucoidan.<ref>Sun, S., Zhang, X., Li, J., Li, Y., Zhou, C., Xiang, S., & Tan, M. (2023). Preparation and evaluation of ovalbumin-fucoidan nanoparticles for nicotinamide mononucleotide encapsulation with enhanced stability and anti-aging activity. Food Chemistry, 418, 135982. PMID: 36996645 DOI: 10.1016/j.foodchem.2023.135982</ref>

	=== Conclusions of the controversy ===		=== Conclusions of the controversy ===

Dmitry Dzhagarov: /* Sirtuin-activating compounds (STAC) */

2023-07-30T21:03:10Z

Sirtuin-activating compounds (STAC)

← Older revision		Revision as of 21:03, 30 July 2023
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	== Sirtuin-activating compounds (STAC) ==		== Sirtuin-activating compounds (STAC) ==
	Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins. They are '''caloric restriction mimetic compounds''' that may be helpful in treating various aging-related diseases. It is well known that [[CD38#CD38_inhibitors\|'''CD38 inhibitors''']], by restoring [[NAD+\|NAD<sup>+</sup>]] levels, thus activate SIRT6 protecting from cell senescence and aging.<ref>Zhou, H., Liu, S., Zhang, N., Fang, K., Zong, J., An, Y., & Chang, X. (2022). Downregulation of Sirt6 by CD38 promotes cell senescence and aging. Aging (Albany NY), 14(23), 9730. PMID: 36490326 PMCID: PMC9792202 DOI: 10.18632/aging.204425</ref>		Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins. They are '''caloric restriction mimetic compounds''' that may be helpful in treating various aging-related diseases. It is well known that [[CD38#CD38_inhibitors\|'''CD38 inhibitors''']], by restoring [[NAD+\|NAD<sup>+</sup>]] levels, thus activate SIRT6 protecting from cell senescence and aging.<ref>Zhou, H., Liu, S., Zhang, N., Fang, K., Zong, J., An, Y., & Chang, X. (2022). Downregulation of Sirt6 by CD38 promotes cell senescence and aging. Aging (Albany NY), 14(23), 9730. PMID: 36490326 PMCID: PMC9792202 DOI: 10.18632/aging.204425</ref>
	The first synthetic direct activator of SIRT6 deacetylase activity was the pyrrolo[1,2-a]quinoxaline derivative '''UBCS039''', which showed specific binding on SIRT6, with no significant effects on basal SIRT1, 2, and 3 deacetylation activities. Although, it also stimulated SIRT5 desuccinylation activity (2-fold increase at 100 μM), the physiologically dominant activity of this enzyme.<ref>Fiorentino, F., Mai, A., & Rotili, D. (2021). Emerging therapeutic potential of SIRT6 modulators. Journal of medicinal chemistry, 64(14), 9732-9758. PMID: 34213345 PMC8389836 DOI: 10.1021/acs.jmedchem.1c00601</ref><ref>Fiorentino, F., Mautone, N., Menna, M., D'Acunzo, F., Mai, A., & Rotili, D. (2022). Sirtuin modulators: past, present, and future perspectives. Future Medicinal Chemistry, 14(12), 915-939. PMID: 35583203 PMC9185222 DOI: 10.4155/fmc-2022-0031</ref>		The first synthetic direct activator of SIRT6 deacetylase activity was the pyrrolo[1,2-a]quinoxaline derivative '''UBCS039''', which showed specific binding on SIRT6, with no significant effects on basal SIRT1, 2, and 3 deacetylation activities. Although, it also stimulated SIRT5 desuccinylation activity (2-fold increase at 100 μM), the physiologically dominant activity of this enzyme.<ref>Fiorentino, F., Mai, A., & Rotili, D. (2021). Emerging therapeutic potential of SIRT6 modulators. Journal of medicinal chemistry, 64(14), 9732-9758. PMID: 34213345 PMC8389836 DOI: 10.1021/acs.jmedchem.1c00601</ref><ref>Fiorentino, F., Mautone, N., Menna, M., D'Acunzo, F., Mai, A., & Rotili, D. (2022). Sirtuin modulators: past, present, and future perspectives. Future Medicinal Chemistry, 14(12), 915-939. PMID: 35583203 PMC9185222 DOI: 10.4155/fmc-2022-0031</ref>
	Chinese researchers more recently discovered a new potent SIRT6 activator - '''21q''', which can be taken as a lead compound for later studies.<ref>Zhang, Z., Sun, W., Zhang, G., Fang, Z., Chen, X., & Li, L. (2023). Design, synthesis, and biological screening of a series of pyrazolo [1, 5-a] quina-zoline derivatives as SIRT6 activators. European Journal of Pharmaceutical Sciences, 185, 106424. PMID: 36918058 [https://doi.org/10.1016/j.ejps.2023.106424 DOI: 10.1016/j.ejps.2023.106424]</ref>
			Chinese researchers more recently discovered a new potent SIRT6 activator - '''21q''', which can be taken as a lead compound for later studies.<ref>Zhang, Z., Sun, W., Zhang, G., Fang, Z., Chen, X., & Li, L. (2023). Design, synthesis, and biological screening of a series of pyrazolo [1, 5-a] quina-zoline derivatives as SIRT6 activators. European Journal of Pharmaceutical Sciences, 185, 106424. PMID: 36918058 [https://doi.org/10.1016/j.ejps.2023.106424 DOI: 10.1016/j.ejps.2023.106424]</ref>

			It was also found a natural compound with the ability to activate SIRT6 such as the seaweed long chain sulfated polysaccharide fucoidan.<ref>Rahnasto-Rilla, M. K., McLoughlin, P., Kulikowicz, T., Doyle, M., Bohr, V. A., Lahtela-Kakkonen, M., ... & Moaddel, R. (2017). The identification of a SIRT6 activator from brown algae Fucus distichus. Marine drugs, 15(6), 190. PMID: 28635654 PMC5484140 DOI: 10.3390/md15060190</ref> NAD<sup>+</sup> precursor [[Nicotinamide mononucleotide (NMN)]] has been recognized as a promising bio-active compound in relieving aging-related mitochondrial dysfunction. Self-assembled nanoparticles were prepared based on interaction between ovalbumin and fucoidan to improve the stability and bio-accessibility of NMN and for its synergy with fucoidan.<ref>Sun, S., Zhang, X., Li, J., Li, Y., Zhou, C., Xiang, S., & Tan, M. (2023). Preparation and evaluation of ovalbumin-fucoidan nanoparticles for nicotinamide mononucleotide encapsulation with enhanced stability and anti-aging activity. Food Chemistry, 418, 135982. PMID: 36996645 DOI: 10.1016/j.foodchem.2023.135982</ref>

	=== Conclusions of the controversy ===		=== Conclusions of the controversy ===
	Whilst the important role of sirtuin genes in maintaining metabolic homeostasis and several aspects of health is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes.<ref>Charles Brenner. (2022). Sirtuins are not conserved longevity genes, ''Life Metabolism'', loac025, <nowiki>https://doi.org/10.1093/lifemeta/loac025</nowiki> </ref> The exception might be SIRT6, which has more recently shown able to extend lifespan in a variety of organisms.<ref name=":5" /><ref name=":6" /><ref name=":7" />		Whilst the important role of sirtuin genes in maintaining metabolic homeostasis and several aspects of health is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes.<ref>Charles Brenner. (2022). Sirtuins are not conserved longevity genes, ''Life Metabolism'', loac025, <nowiki>https://doi.org/10.1093/lifemeta/loac025</nowiki> </ref> The exception might be SIRT6, which has more recently shown able to extend lifespan in a variety of organisms.<ref name=":5" /><ref name=":6" /><ref name=":7" />

	However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>		However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>

	== References ==		== References ==

Dmitry Dzhagarov: /* Sirtuins in lifespan */

2023-07-30T20:32:57Z

Sirtuins in lifespan

← Older revision		Revision as of 20:32, 30 July 2023
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	Specific SIRT genes like SIRT6 have been shown to extend healthy lifespan in one study in mice (increased median lifespan in males and females by 27% and 15%; maximum lifespan by 11% and 15%), as well as in fruit flies.<ref name=":5">Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., ... & Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. ''Nature communications'', ''12''(1), 1-18.</ref><ref name=":6">Taylor, J. R., Wood, J. G., Mizerak, E., Hinthorn, S., Liu, J., Finn, M., ... & Helfand, S. L. (2022). Sirt6 regulates lifespan in Drosophila melanogaster. ''Proceedings of the National Academy of Sciences'', ''119''(5), e2111176119.</ref>		Specific SIRT genes like SIRT6 have been shown to extend healthy lifespan in one study in mice (increased median lifespan in males and females by 27% and 15%; maximum lifespan by 11% and 15%), as well as in fruit flies.<ref name=":5">Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., ... & Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. ''Nature communications'', ''12''(1), 1-18.</ref><ref name=":6">Taylor, J. R., Wood, J. G., Mizerak, E., Hinthorn, S., Liu, J., Finn, M., ... & Helfand, S. L. (2022). Sirt6 regulates lifespan in Drosophila melanogaster. ''Proceedings of the National Academy of Sciences'', ''119''(5), e2111176119.</ref>

	SIRT6 activity has also been linked to more efficient double-strand break (DSB) repair mechanisms in long-lived rodent species and showed a positive correlation to maximum lifespan.<ref name=":7">Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., ... & Gorbunova, V. (2019). SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. ''Cell'', ''177''(3), 622-638.</ref> It has also been shown to act as a co-repressor of hypoxia-inducible factor 1-alpha (HIF1α), a transcription factor that responds to oxidative stress and oxygen consumption and which might be a regulator of aging.<ref>Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R., & Vadysirisack, D. et al. (2010). The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. ''Cell'', ''140''(2), 280-293. doi: 10.1016/j.cell.2009.12.041</ref><ref>Alique, M., Sánchez-López, E., Bodega, G., Giannarelli, C., Carracedo, J., & Ramírez, R. (2020). Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging. ''Cells'', ''9''(1), 195. doi: 10.3390/cells9010195</ref> Additionally, removal of SIRT6 has been linked to a >5-year decrease in lifespan in mice according to several health biomarkers.<ref>TenNapel, M., Lynch, C., Burns, T., Wallace, R., Smith, B., Button, A., & Domann, F. (2014). SIRT6 Minor Allele Genotype Is Associated with &gt;5-Year Decrease in Lifespan in an Aged Cohort. ''Plos ONE'', ''9''(12), e115616. doi: 10.1371/journal.pone.0115616</ref>		SIRT6 activity has also been linked to more efficient [[DNA damage and repair\|double-strand break (DSB) repair mechanisms]] in long-lived rodent species and showed a positive correlation to maximum lifespan.<ref name=":7">Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., ... & Gorbunova, V. (2019). SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. ''Cell'', ''177''(3), 622-638.</ref> It has also been shown to act as a co-repressor of hypoxia-inducible factor 1-alpha (HIF1α), a transcription factor that responds to oxidative stress and oxygen consumption and which might be a regulator of aging.<ref>Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R., & Vadysirisack, D. et al. (2010). The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. ''Cell'', ''140''(2), 280-293. doi: 10.1016/j.cell.2009.12.041</ref><ref>Alique, M., Sánchez-López, E., Bodega, G., Giannarelli, C., Carracedo, J., & Ramírez, R. (2020). Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging. ''Cells'', ''9''(1), 195. doi: 10.3390/cells9010195</ref> Additionally, removal of SIRT6 has been linked to a >5-year decrease in lifespan in mice according to several health biomarkers.<ref>TenNapel, M., Lynch, C., Burns, T., Wallace, R., Smith, B., Button, A., & Domann, F. (2014). SIRT6 Minor Allele Genotype Is Associated with &gt;5-Year Decrease in Lifespan in an Aged Cohort. ''Plos ONE'', ''9''(12), e115616. doi: 10.1371/journal.pone.0115616</ref>

	=== Sirtuins in health ===		=== Sirtuins in health ===
	Several members of the sirtuin family have demonstrated beneficial effects in maintaining metabolic homeostasis and health.<ref name=":3">Houtkooper, R., Pirinen, E., & Auwerx, J. (2012). Sirtuins as regulators of metabolism and healthspan. ''Nature Reviews Molecular Cell Biology'', ''13''(4), 225-238. doi: 10.1038/nrm3293</ref>		Several members of the sirtuin family have demonstrated beneficial effects in maintaining metabolic homeostasis and health.<ref name=":3">Houtkooper, R., Pirinen, E., & Auwerx, J. (2012). Sirtuins as regulators of metabolism and healthspan. ''Nature Reviews Molecular Cell Biology'', ''13''(4), 225-238. doi: 10.1038/nrm3293</ref>

Dmitry Dzhagarov: /* References */

2023-07-30T20:08:59Z

References

← Older revision		Revision as of 20:08, 30 July 2023
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	Chinese researchers more recently discovered a new potent SIRT6 activator - '''21q''', which can be taken as a lead compound for later studies.<ref>Zhang, Z., Sun, W., Zhang, G., Fang, Z., Chen, X., & Li, L. (2023). Design, synthesis, and biological screening of a series of pyrazolo [1, 5-a] quina-zoline derivatives as SIRT6 activators. European Journal of Pharmaceutical Sciences, 185, 106424. PMID: 36918058 [https://doi.org/10.1016/j.ejps.2023.106424 DOI: 10.1016/j.ejps.2023.106424]</ref>		Chinese researchers more recently discovered a new potent SIRT6 activator - '''21q''', which can be taken as a lead compound for later studies.<ref>Zhang, Z., Sun, W., Zhang, G., Fang, Z., Chen, X., & Li, L. (2023). Design, synthesis, and biological screening of a series of pyrazolo [1, 5-a] quina-zoline derivatives as SIRT6 activators. European Journal of Pharmaceutical Sciences, 185, 106424. PMID: 36918058 [https://doi.org/10.1016/j.ejps.2023.106424 DOI: 10.1016/j.ejps.2023.106424]</ref>

	~~== References ==~~
	~~<references />~~

	=== Conclusions of the controversy ===		=== Conclusions of the controversy ===
Line 48:		Line 46:

	However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>		However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>

			== References ==
	<references />		<references />
	[[Category:Main list]]		[[Category:Main list]]
	[[Category:Longevity genes]]		[[Category:Longevity genes]]
	[[Category:Aging pathways and hallmarks]]		[[Category:Aging pathways and hallmarks]]

Dmitry Dzhagarov: /* Members of the sirtuins family */

2023-07-30T20:07:30Z

Members of the sirtuins family

← Older revision		Revision as of 20:07, 30 July 2023
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	* '''SIRT1''' is found both in the nucleus and the cytosol. It is largely involved in metabolic regulation and has been associated with insulin resistance, obesity and oocyte maturation.<ref>Nevoral, J., Landsmann, L., Stiavnicka, M., Hosek, P., Moravec, J., & Prokesova, S. et al. (2019). Epigenetic and non-epigenetic mode of SIRT1 action during oocyte meiosis progression. ''Journal Of Animal Science And Biotechnology'', ''10''(1). doi: 10.1186/s40104-019-0372-3</ref><ref>Sun, C., Zhang, F., Ge, X., Yan, T., Chen, X., Shi, X., & Zhai, Q. (2007). SIRT1 Improves Insulin Sensitivity under Insulin-Resistant Conditions by Repressing PTP1B. ''Cell Metabolism'', ''6''(4), 307-319. doi: 10.1016/j.cmet.2007.08.014</ref> It also modulates the activity of certain transcription factors such as p53 and [[FOXO longevity genes\|FOXO]]<nowiki/>.<ref>Mouchiroud, L., Houtkooper, R., Moullan, N., Katsyuba, E., Ryu, D., & Cantó, C. et al. (2013). The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. ''Cell'', ''154''(2), 430-441. doi: 10.1016/j.cell.2013.06.016</ref><ref>Vaziri, H., Dessain, S., Eaton, E., Imai, S., Frye, R., & Pandita, T. et al. (2001). hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase. ''Cell'', ''107''(2), 149-159. doi: 10.1016/s0092-8674(01)00527-x</ref>		* '''SIRT1''' is found both in the nucleus and the cytosol. It is largely involved in metabolic regulation and has been associated with insulin resistance, obesity and oocyte maturation.<ref>Nevoral, J., Landsmann, L., Stiavnicka, M., Hosek, P., Moravec, J., & Prokesova, S. et al. (2019). Epigenetic and non-epigenetic mode of SIRT1 action during oocyte meiosis progression. ''Journal Of Animal Science And Biotechnology'', ''10''(1). doi: 10.1186/s40104-019-0372-3</ref><ref>Sun, C., Zhang, F., Ge, X., Yan, T., Chen, X., Shi, X., & Zhai, Q. (2007). SIRT1 Improves Insulin Sensitivity under Insulin-Resistant Conditions by Repressing PTP1B. ''Cell Metabolism'', ''6''(4), 307-319. doi: 10.1016/j.cmet.2007.08.014</ref> It also modulates the activity of certain transcription factors such as p53 and [[FOXO longevity genes\|FOXO]]<nowiki/>.<ref>Mouchiroud, L., Houtkooper, R., Moullan, N., Katsyuba, E., Ryu, D., & Cantó, C. et al. (2013). The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. ''Cell'', ''154''(2), 430-441. doi: 10.1016/j.cell.2013.06.016</ref><ref>Vaziri, H., Dessain, S., Eaton, E., Imai, S., Frye, R., & Pandita, T. et al. (2001). hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase. ''Cell'', ''107''(2), 149-159. doi: 10.1016/s0092-8674(01)00527-x</ref>
	* '''SIRT2''' is considered to be the founding member of the sirtuin family. It is found in the cytosol and has key roles in regulation of the cell cycle during mitosis and in regulating cell proliferation, motility and apoptosis.<ref>Pandithage, R., Lilischkis, R., Harting, K., Wolf, A., Jedamzik, B., & Lüscher-Firzlaff, J. et al. (2008). The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility. ''Journal Of Cell Biology'', ''180''(5), 915-929. doi: 10.1083/jcb.200707126</ref> It has also been associated with tumour growth in certain cancers.<ref>Zhang, L., Kim, S., & Ren, X. (2020). The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene?. ''Frontiers In Oncology'', ''10''. doi: 10.3389/fonc.2020.01721</ref>		* '''SIRT2''' is considered to be the founding member of the sirtuin family. It is found in the cytosol and has key roles in regulation of the cell cycle during mitosis and in regulating cell proliferation, motility and apoptosis.<ref>Pandithage, R., Lilischkis, R., Harting, K., Wolf, A., Jedamzik, B., & Lüscher-Firzlaff, J. et al. (2008). The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility. ''Journal Of Cell Biology'', ''180''(5), 915-929. doi: 10.1083/jcb.200707126</ref> It has also been associated with tumour growth in certain cancers.<ref>Zhang, L., Kim, S., & Ren, X. (2020). The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene?. ''Frontiers In Oncology'', ''10''. doi: 10.3389/fonc.2020.01721</ref>
			* '''SIRT4''' has been studied less among the sirtuin family. Some studies have demonstrated the involvement of SIRT4 in age-related processes.<ref>He, L., Liu, Q., Cheng, J., Cao, M., Zhang, S., Wan, X., ... & Tu, H. (2023). SIRT4 in ageing. Biogerontology, 1-16. PMID: 37067687 DOI: 10.1007/s10522-023-10022-5</ref>
	* '''SIRT3-5''' are located in the mitochondria and have roles in oxidative stress and lipid metabolism.<ref>Hirschey, M., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., & Lombard, D. et al. (2010). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. ''Nature'', ''464''(7285), 121-125. doi: 10.1038/nature08778</ref>		* '''SIRT3-5''' are located in the mitochondria and have roles in oxidative stress and lipid metabolism.<ref>Hirschey, M., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., & Lombard, D. et al. (2010). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. ''Nature'', ''464''(7285), 121-125. doi: 10.1038/nature08778</ref>
	* '''SIRT6-7''' are nuclear sirtuins involved in regulating gene expression and DNA repair mechanisms.<ref>Li, L., Shi, L., Yang, S., Yan, R., Zhang, D., & Yang, J. et al. (2016). SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. ''Nature Communications'', ''7''(1). doi: 10.1038/ncomms12235</ref><ref>McCord, R., Michishita, E., Hong, T., Berber, E., Boxer, L., & Kusumoto, R. et al. (2009). SIRT6 stabilizes DNA-dependent Protein Kinase at chromatin for DNA double-strand break repair. ''Aging'', ''1''(1), 109-121. doi: 10.18632/aging.100011</ref>		* '''SIRT6-7''' are nuclear sirtuins involved in regulating gene expression and DNA repair mechanisms.<ref>Li, L., Shi, L., Yang, S., Yan, R., Zhang, D., & Yang, J. et al. (2016). SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. ''Nature Communications'', ''7''(1). doi: 10.1038/ncomms12235</ref><ref>McCord, R., Michishita, E., Hong, T., Berber, E., Boxer, L., & Kusumoto, R. et al. (2009). SIRT6 stabilizes DNA-dependent Protein Kinase at chromatin for DNA double-strand break repair. ''Aging'', ''1''(1), 109-121. doi: 10.18632/aging.100011</ref>

	=== Sirtuins in lifespan ===		=== Sirtuins in lifespan ===

Dmitry Dzhagarov: /* Controversies on sirtuins as longevity genes */

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Controversies on sirtuins as longevity genes

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	David Gems and his collaborators at UCL eventually discovered that overexpression of SIR-2.1 in hands of the Guarente lab led to a lifespan extension due to an unrelated background mutation.<ref name=":1" /> This background mutation in a sensory neuron gene had already been previously linked to longevity. When this mutation was bred out, there was no evidence that SIR-2.1 significantly boosted lifespan. Eventually, Guarente together with David Sinclair, a post-doc at the time in Guarente's lab, argued that when the sensory neuron mutation was removed there was still a lifespan extension, although a more modest one. Instead of up to 50% increased lifespan reported initially, there was now a small effect of only 14%.<ref>Viswanathan, M., & Guarente, L. (2011). Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. ''Nature'', ''477''(7365), E1-E2. doi: 10.1038/nature10440</ref> Of note, lifespan effects of this mild magnitude in C. ''elegans'' are generally not considered significant, given the high inherent variability of survival curves generated from different groups.		David Gems and his collaborators at UCL eventually discovered that overexpression of SIR-2.1 in hands of the Guarente lab led to a lifespan extension due to an unrelated background mutation.<ref name=":1" /> This background mutation in a sensory neuron gene had already been previously linked to longevity. When this mutation was bred out, there was no evidence that SIR-2.1 significantly boosted lifespan. Eventually, Guarente together with David Sinclair, a post-doc at the time in Guarente's lab, argued that when the sensory neuron mutation was removed there was still a lifespan extension, although a more modest one. Instead of up to 50% increased lifespan reported initially, there was now a small effect of only 14%.<ref>Viswanathan, M., & Guarente, L. (2011). Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. ''Nature'', ''477''(7365), E1-E2. doi: 10.1038/nature10440</ref> Of note, lifespan effects of this mild magnitude in C. ''elegans'' are generally not considered significant, given the high inherent variability of survival curves generated from different groups.

			== Sirtuin-activating compounds (STAC) ==
			Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins. They are '''caloric restriction mimetic compounds''' that may be helpful in treating various aging-related diseases. It is well known that [[CD38#CD38_inhibitors\|'''CD38 inhibitors''']], by restoring [[NAD+\|NAD<sup>+</sup>]] levels, thus activate SIRT6 protecting from cell senescence and aging.<ref>Zhou, H., Liu, S., Zhang, N., Fang, K., Zong, J., An, Y., & Chang, X. (2022). Downregulation of Sirt6 by CD38 promotes cell senescence and aging. Aging (Albany NY), 14(23), 9730. PMID: 36490326 PMCID: PMC9792202 DOI: 10.18632/aging.204425</ref>
			The first synthetic direct activator of SIRT6 deacetylase activity was the pyrrolo[1,2-a]quinoxaline derivative '''UBCS039''', which showed specific binding on SIRT6, with no significant effects on basal SIRT1, 2, and 3 deacetylation activities. Although, it also stimulated SIRT5 desuccinylation activity (2-fold increase at 100 μM), the physiologically dominant activity of this enzyme.<ref>Fiorentino, F., Mai, A., & Rotili, D. (2021). Emerging therapeutic potential of SIRT6 modulators. Journal of medicinal chemistry, 64(14), 9732-9758. PMID: 34213345 PMC8389836 DOI: 10.1021/acs.jmedchem.1c00601</ref><ref>Fiorentino, F., Mautone, N., Menna, M., D'Acunzo, F., Mai, A., & Rotili, D. (2022). Sirtuin modulators: past, present, and future perspectives. Future Medicinal Chemistry, 14(12), 915-939. PMID: 35583203 PMC9185222 DOI: 10.4155/fmc-2022-0031</ref>
			Chinese researchers more recently discovered a new potent SIRT6 activator - '''21q''', which can be taken as a lead compound for later studies.<ref>Zhang, Z., Sun, W., Zhang, G., Fang, Z., Chen, X., & Li, L. (2023). Design, synthesis, and biological screening of a series of pyrazolo [1, 5-a] quina-zoline derivatives as SIRT6 activators. European Journal of Pharmaceutical Sciences, 185, 106424. PMID: 36918058 [https://doi.org/10.1016/j.ejps.2023.106424 DOI: 10.1016/j.ejps.2023.106424]</ref>

			== References ==
			<references />

	=== Conclusions of the controversy ===		=== Conclusions of the controversy ===

Andrea: category change

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category change

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	However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>		However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>
	<references />		<references />
	[[Category:Longevity]]		[[Category:Main list]]
	[[Category:~~Drafts~~]]		[[Category:Longevity genes]]
			[[Category:Aging pathways and hallmarks]]

Andrea: /* reference edit */

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reference edit

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	=== Conclusions of the controversy ===		=== Conclusions of the controversy ===
	Whilst the important role of sirtuin genes in maintaining metabolic homeostasis and several aspects of health is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes.<ref>https://~~www~~.~~researchgate~~.~~net~~/~~publication~~/~~361471876_Sirtuins_are_Not_Conserved_Longevity_Genes~~</ref> The exception might be SIRT6, which has more recently shown able to extend lifespan in a variety of organisms.<ref name=":5" /><ref name=":6" /><ref name=":7" />		Whilst the important role of sirtuin genes in maintaining metabolic homeostasis and several aspects of health is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes.<ref>Charles Brenner. (2022). Sirtuins are not conserved longevity genes, ''Life Metabolism'', loac025, <nowiki>https://doi.org/10.1093/lifemeta/loac025</nowiki> </ref> The exception might be SIRT6, which has more recently shown able to extend lifespan in a variety of organisms.<ref name=":5" /><ref name=":6" /><ref name=":7" />

	However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>		However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>

Andrea: /* Conclusions of the controversy */

2022-09-13T09:31:52Z

Conclusions of the controversy

← Older revision		Revision as of 09:31, 13 September 2022
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	Whilst the important role of sirtuin genes in maintaining metabolic homeostasis and several aspects of health is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes.<ref>https://www.researchgate.net/publication/361471876_Sirtuins_are_Not_Conserved_Longevity_Genes</ref> The exception might be SIRT6, which has more recently shown able to extend lifespan in a variety of organisms.<ref name=":5" /><ref name=":6" /><ref name=":7" />		Whilst the important role of sirtuin genes in maintaining metabolic homeostasis and several aspects of health is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes.<ref>https://www.researchgate.net/publication/361471876_Sirtuins_are_Not_Conserved_Longevity_Genes</ref> The exception might be SIRT6, which has more recently shown able to extend lifespan in a variety of organisms.<ref name=":5" /><ref name=":6" /><ref name=":7" />

	~~Despite this~~, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, despite lack of robust evidence, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>		However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>
	<references />		<references />
	[[Category:Longevity]]		[[Category:Longevity]]
	[[Category:Drafts]]		[[Category:Drafts]]

Andrea: /* */

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	=== Sirtuins in lifespan ===		=== Sirtuins in lifespan ===
	There is generally a lack of direct evidence for all sirtuin genes playing a role ~~in extending~~ lifespan in animals.		There is generally a lack of direct evidence for all sirtuin genes, except for potentially SIRT6, in playing a role to extend lifespan in animals.

	Specific SIRT genes like SIRT6 have been shown to extend healthy lifespan in one study in mice (increased median lifespan in males and females by 27% and 15%; maximum lifespan by 11% and 15%), as well as in fruit flies.<ref>Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., ... & Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. ''Nature communications'', ''12''(1), 1-18.</ref><ref>Taylor, J. R., Wood, J. G., Mizerak, E., Hinthorn, S., Liu, J., Finn, M., ... & Helfand, S. L. (2022). Sirt6 regulates lifespan in Drosophila melanogaster. ''Proceedings of the National Academy of Sciences'', ''119''(5), e2111176119.</ref>		Specific SIRT genes like SIRT6 have been shown to extend healthy lifespan in one study in mice (increased median lifespan in males and females by 27% and 15%; maximum lifespan by 11% and 15%), as well as in fruit flies.<ref name=":5">Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., ... & Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. ''Nature communications'', ''12''(1), 1-18.</ref><ref name=":6">Taylor, J. R., Wood, J. G., Mizerak, E., Hinthorn, S., Liu, J., Finn, M., ... & Helfand, S. L. (2022). Sirt6 regulates lifespan in Drosophila melanogaster. ''Proceedings of the National Academy of Sciences'', ''119''(5), e2111176119.</ref>

			SIRT6 activity has also been linked to more efficient double-strand break (DSB) repair mechanisms in long-lived rodent species and showed a positive correlation to maximum lifespan.<ref name=":7">Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., ... & Gorbunova, V. (2019). SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. ''Cell'', ''177''(3), 622-638.</ref> It has also been shown to act as a co-repressor of hypoxia-inducible factor 1-alpha (HIF1α), a transcription factor that responds to oxidative stress and oxygen consumption and which might be a regulator of aging.<ref>Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R., & Vadysirisack, D. et al. (2010). The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. ''Cell'', ''140''(2), 280-293. doi: 10.1016/j.cell.2009.12.041</ref><ref>Alique, M., Sánchez-López, E., Bodega, G., Giannarelli, C., Carracedo, J., & Ramírez, R. (2020). Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging. ''Cells'', ''9''(1), 195. doi: 10.3390/cells9010195</ref> Additionally, removal of SIRT6 has been linked to a >5-year decrease in lifespan in mice according to several health biomarkers.<ref>TenNapel, M., Lynch, C., Burns, T., Wallace, R., Smith, B., Button, A., & Domann, F. (2014). SIRT6 Minor Allele Genotype Is Associated with &gt;5-Year Decrease in Lifespan in an Aged Cohort. ''Plos ONE'', ''9''(12), e115616. doi: 10.1371/journal.pone.0115616</ref>
	=== Sirtuins in health ===		=== Sirtuins in health ===
	~~Whilst sirtuins are not able to significantly extend lifespan in mammals, several~~ members of the sirtuin family have demonstrated beneficial effects in health ~~span~~.<ref name=":3">Houtkooper, R., Pirinen, E., & Auwerx, J. (2012). Sirtuins as regulators of metabolism and healthspan. ''Nature Reviews Molecular Cell Biology'', ''13''(4), 225-238. doi: 10.1038/nrm3293</ref> ~~Of note, the effect of sirtuins in longevity is still controversial to this day.~~		Several members of the sirtuin family have demonstrated beneficial effects in maintaining metabolic homeostasis and health.<ref name=":3">Houtkooper, R., Pirinen, E., & Auwerx, J. (2012). Sirtuins as regulators of metabolism and healthspan. ''Nature Reviews Molecular Cell Biology'', ''13''(4), 225-238. doi: 10.1038/nrm3293</ref>

	Sirtuins have a broad range of effects and affect health in a pleiotropic manner by potentially up-regulating cytoprotective pathways.<ref name=":3" /> It has been hypothesised that their activity heightens under conditions of stress, such as in a high-fat diet or during ageing, and might protect against obesity.<ref>Lee, J., Padhye, A., Sharma, A., Song, G., Miao, J., & Mo, Y. et al. (2010). A Pathway Involving Farnesoid X Receptor and Small Heterodimer Partner Positively Regulates Hepatic Sirtuin 1 Levels via MicroRNA-34a Inhibition. ''Journal Of Biological Chemistry'', ''285''(17), 12604-12611. doi: 10.1074/jbc.m109.094524</ref><ref>Bai, P., Canto, C., Brunyánszki, A., Huber, A., Szántó, M., & Cen, Y. et al. (2011). PARP-2 Regulates SIRT1 Expression and Whole-Body Energy Expenditure. ''Cell Metabolism'', ''13''(4), 450-460. doi: 10.1016/j.cmet.2011.03.013</ref><ref>Bai, P., Cantó, C., Oudart, H., Brunyánszki, A., Cen, Y., & Thomas, C. et al. (2011). PARP-1 Inhibition Increases Mitochondrial Metabolism through SIRT1 Activation. ''Cell Metabolism'', ''13''(4), 461-468. doi: 10.1016/j.cmet.2011.03.004</ref> Sirtuins also appear to both act in response to inflammation and mediate its effects by activating tumour necrosis factor NF''κ''B in conditions of extreme infection such as sepsis.<ref>Vachharajani, V., Liu, T., Wang, X., Hoth, J., Yoza, B., & McCall, C. (2016). Sirtuins Link Inflammation and Metabolism. ''Journal Of Immunology Research'', ''2016'', 1-10. doi: 10.1155/2016/8167273</ref> This highlights the importance of sirtuins in restoring homeostasis during states of cellular stress.		Sirtuins have a broad range of effects and can affect health in a pleiotropic manner by potentially up-regulating cytoprotective pathways.<ref name=":3" /> It has been hypothesised that their activity heightens under conditions of stress, such as in a high-fat diet or during ageing, and might protect against obesity.<ref>Lee, J., Padhye, A., Sharma, A., Song, G., Miao, J., & Mo, Y. et al. (2010). A Pathway Involving Farnesoid X Receptor and Small Heterodimer Partner Positively Regulates Hepatic Sirtuin 1 Levels via MicroRNA-34a Inhibition. ''Journal Of Biological Chemistry'', ''285''(17), 12604-12611. doi: 10.1074/jbc.m109.094524</ref><ref>Bai, P., Canto, C., Brunyánszki, A., Huber, A., Szántó, M., & Cen, Y. et al. (2011). PARP-2 Regulates SIRT1 Expression and Whole-Body Energy Expenditure. ''Cell Metabolism'', ''13''(4), 450-460. doi: 10.1016/j.cmet.2011.03.013</ref><ref>Bai, P., Cantó, C., Oudart, H., Brunyánszki, A., Cen, Y., & Thomas, C. et al. (2011). PARP-1 Inhibition Increases Mitochondrial Metabolism through SIRT1 Activation. ''Cell Metabolism'', ''13''(4), 461-468. doi: 10.1016/j.cmet.2011.03.004</ref> Sirtuins also appear to both act in response to inflammation and mediate its effects by activating tumour necrosis factor NF''κ''B in conditions of extreme infection such as sepsis.<ref>Vachharajani, V., Liu, T., Wang, X., Hoth, J., Yoza, B., & McCall, C. (2016). Sirtuins Link Inflammation and Metabolism. ''Journal Of Immunology Research'', ''2016'', 1-10. doi: 10.1155/2016/8167273</ref> This highlights the importance of sirtuins in restoring homeostasis during states of cellular stress.

	Other studies have shown that increasing the activity of sirtuins stabilises telomeres and improves telomere-dependent disease.<ref name=":4">Amano, H., & Sahin, E. (2019). Telomeres and sirtuins: at the end we meet again. ''Molecular &Amp; Cellular Oncology'', ''6''(5), e1632613. doi: 10.1080/23723556.2019.1632613</ref> In wild-type conditions, SIRT1 and SIRT6 might regulate telomere length in a time- and context-specific manner.<ref>Palacios, J., Herranz, D., De Bonis, M., Velasco, S., Serrano, M., & Blasco, M. (2010). SIRT1 contributes to telomere maintenance and augments global homologous recombination. ''Journal Of Cell Biology'', ''191''(7), 1299-1313. doi: 10.1083/jcb.201005160</ref><ref>Tennen, R., & Chua, K. (2011). Chromatin regulation and genome maintenance by mammalian SIRT6. ''Trends In Biochemical Sciences'', ''36''(1), 39-46. doi: 10.1016/j.tibs.2010.07.009</ref> However, it remains unclear what is the relevance of sirtuins during telomere dysfunction and, viceversa, how telomere shortening impacts the activity of sirtuins.<ref name=":4" />		Other studies have shown that increasing the activity of sirtuins stabilises telomeres and improves telomere-dependent disease.<ref name=":4">Amano, H., & Sahin, E. (2019). Telomeres and sirtuins: at the end we meet again. ''Molecular &Amp; Cellular Oncology'', ''6''(5), e1632613. doi: 10.1080/23723556.2019.1632613</ref> In wild-type conditions, SIRT1 and SIRT6 might regulate telomere length in a time- and context-specific manner.<ref>Palacios, J., Herranz, D., De Bonis, M., Velasco, S., Serrano, M., & Blasco, M. (2010). SIRT1 contributes to telomere maintenance and augments global homologous recombination. ''Journal Of Cell Biology'', ''191''(7), 1299-1313. doi: 10.1083/jcb.201005160</ref><ref>Tennen, R., & Chua, K. (2011). Chromatin regulation and genome maintenance by mammalian SIRT6. ''Trends In Biochemical Sciences'', ''36''(1), 39-46. doi: 10.1016/j.tibs.2010.07.009</ref> However, it remains unclear what is the relevance of sirtuins during telomere dysfunction and, viceversa, how telomere shortening impacts the activity of sirtuins.<ref name=":4" />

	SIRT6 in particular has been shown to improve DNA repair, and its activity is associated with longevity in longer-lived rodents.<ref>Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., ... & Gorbunova, V. (2019). SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. ''Cell'', ''177''(3), 622-638.</ref> It has also been shown to act as a co-repressor of hypoxia-inducible factor 1-alpha (HIF1α), a transcription factor that responds to oxidative stress and oxygen consumption and which might be a regulator of aging.<ref>Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R., & Vadysirisack, D. et al. (2010). The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. ''Cell'', ''140''(2), 280-293. doi: 10.1016/j.cell.2009.12.041</ref><ref>Alique, M., Sánchez-López, E., Bodega, G., Giannarelli, C., Carracedo, J., & Ramírez, R. (2020). Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging. ''Cells'', ''9''(1), 195. doi: 10.3390/cells9010195</ref> Additionally, removal of SIRT6 has been linked to a >5-year decrease in lifespan in mice according to several health biomarkers.<ref>TenNapel, M., Lynch, C., Burns, T., Wallace, R., Smith, B., Button, A., & Domann, F. (2014). SIRT6 Minor Allele Genotype Is Associated with &gt;5-Year Decrease in Lifespan in an Aged Cohort. ''Plos ONE'', ''9''(12), e115616. doi: 10.1371/journal.pone.0115616</ref>

	=== Controversies on sirtuins as longevity genes ===		=== Controversies on sirtuins as longevity genes ===
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	The controversy sparked when a number of independent groups (including scientists such as Linda Partridge, David Gems and Matt Kaeberlein, who was no longer at Guarente's lab) announced that such findings were not reproducible in C. ''elegans'' or ''Drosophila''.<ref name=":1">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</ref> Despite the non-reproducibility of their findings, the Guarente lab continues defending their results.		The controversy sparked when a number of independent groups (including scientists such as Linda Partridge, David Gems and Matt Kaeberlein, who was no longer at Guarente's lab) announced that such findings were not reproducible in C. ''elegans'' or ''Drosophila''.<ref name=":1">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</ref> Despite the non-reproducibility of their findings, the Guarente lab continues defending their results.

	David Gems and his collaborators at UCL eventually discovered that overexpression of SIR-2.1 in hands of the Guarente lab led to a lifespan extension due to an unrelated background mutation.<ref name=":1" /> This background mutation in a sensory neuron gene had already been previously linked to longevity. When this mutation was bred out, there was no evidence that SIR-2.1 significantly boosted lifespan. Eventually, Guarente together with David Sinclair, a post-doc at the time in Guarente's lab, argued that when the sensory neuron mutation was removed there was still a lifespan extension, although a more modest one. Instead of up to 50% increased lifespan reported initially, there was now a small effect of only 14%.<ref>Viswanathan, M., & Guarente, L. (2011). Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. ''Nature'', ''477''(7365), E1-E2. doi: 10.1038/nature10440</ref> Of note, lifespan effects ~~below 20%~~ in C. ''elegans'' are generally not considered significant, given the high inherent variability of survival curves generated from different groups.		David Gems and his collaborators at UCL eventually discovered that overexpression of SIR-2.1 in hands of the Guarente lab led to a lifespan extension due to an unrelated background mutation.<ref name=":1" /> This background mutation in a sensory neuron gene had already been previously linked to longevity. When this mutation was bred out, there was no evidence that SIR-2.1 significantly boosted lifespan. Eventually, Guarente together with David Sinclair, a post-doc at the time in Guarente's lab, argued that when the sensory neuron mutation was removed there was still a lifespan extension, although a more modest one. Instead of up to 50% increased lifespan reported initially, there was now a small effect of only 14%.<ref>Viswanathan, M., & Guarente, L. (2011). Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. ''Nature'', ''477''(7365), E1-E2. doi: 10.1038/nature10440</ref> Of note, lifespan effects of this mild magnitude in C. ''elegans'' are generally not considered significant, given the high inherent variability of survival curves generated from different groups.

	=== Conclusions of the controversy ===		=== Conclusions of the controversy ===
	Whilst the important role of sirtuin genes maintaining metabolic homeostasis and health ~~span~~ is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes.<ref>https://www.researchgate.net/publication/361471876_Sirtuins_are_Not_Conserved_Longevity_Genes</ref>		Whilst the important role of sirtuin genes in maintaining metabolic homeostasis and several aspects of health is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes.<ref>https://www.researchgate.net/publication/361471876_Sirtuins_are_Not_Conserved_Longevity_Genes</ref> The exception might be SIRT6, which has more recently shown able to extend lifespan in a variety of organisms.<ref name=":5" /><ref name=":6" /><ref name=":7" />

	Despite this, high-profile longevity researchers ~~such as David Sinclair~~ continue to ~~advance sirtuin genes~~ as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> ~~In fact~~, despite lack of robust evidence, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] ~~would~~ be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>		Despite this, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, despite lack of robust evidence, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<ref>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</ref>
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	[[Category:Longevity]]		[[Category:Longevity]]
	[[Category:Drafts]]		[[Category:Drafts]]