View source for Sirtuin

{{Short description|Enzyme}}
{{cs1 config|name-list-style=vanc}}
{{Pfam_box
| Symbol = SIR2
| Name =  Sir2 family
| image = 1SZD.png
| width =
| caption = Crystallographic structure of yeast [[sir2]] (rainbow colored cartoon, [[N-terminus]] = blue, [[C-terminus]] = red) complexed with [[Adenosine diphosphate|ADP]] ([[space-filling model]], carbon = white, oxygen = red, nitrogen = blue, phosphorus = orange) and a [[histone H4]] peptide (magenta) containing an acylated lysine residue (displayed as spheres)<ref name="pmid15150415">{{PDB|1szd}}; {{cite journal | vauthors = Zhao K, Harshaw R, Chai X, Marmorstein R | title = Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 23 | pages = 8563–8 | date = June 2004 | pmid = 15150415 | pmc = 423234 | doi = 10.1073/pnas.0401057101 | bibcode = 2004PNAS..101.8563Z | doi-access = free }}</ref>
| Pfam = PF02146
| Pfam_clan = CL0085
| InterPro = IPR003000
| SMART =
| PROSITE = PS50305
| SCOP = 1j8f
| TCDB =
| OPM family =
| OPM protein =
| PDB= {{PDB2|1ici}}, {{PDB2|1j8f}}, {{PDB2|1m2g}}, {{PDB2|1m2h}}, {{PDB2|1m2j}}, {{PDB2|1m2k}}, {{PDB2|1m2n}}, {{PDB2|1ma3}}, {{PDB2|1q14}}, {{PDB2|1q17}}, {{PDB2|1q1a}}, {{PDB2|1s5p}}, {{PDB2|1s7g}}, {{PDB2|1szc}}, {{PDB2|1szd}}, {{PDB2|1yc2}}, {{PDB2|1yc5}}
}}

'''Sirtuins''' are a family of [[cell signaling|signaling]] [[protein]]s involved in [[metabolic regulation]].<ref name=Ye2017>{{cite journal |last1=Ye |first1=X |last2=Li |first2=M |last3=Hou |first3=T |last4=Gao |first4=T |last5=Zhu |first5=WG |last6=Yang |first6=Y |title=Sirtuins in glucose and lipid metabolism. |journal=Oncotarget |date=3 January 2017 |volume=8 |issue=1 |pages=1845–1859 |doi=10.18632/oncotarget.12157 |pmid=27659520 |pmc=5352102 |type=Review}}</ref><ref name="pmid17456799">{{cite journal | vauthors = Yamamoto H, Schoonjans K, Auwerx J | title = Sirtuin functions in health and disease | journal = Molecular Endocrinology | volume = 21 | issue = 8 | pages = 1745–55 | date = August 2007 | pmid = 17456799 | doi = 10.1210/me.2007-0079 | doi-access = free }}</ref> They are ancient in animal evolution and appear to possess a [[Conserved sequence|highly conserved]] structure throughout all kingdoms of life.<ref name=Ye2017/> Chemically, sirtuins are a class of proteins that possess either mono-[[ADP-ribosylation|ADP-ribosyltransferase]] or [[wikt:deacylase|deacylase]] activity, including deacetylase, [[wikt:desuccinylase|desuccinylase]], [[wikt:demalonylase|demalonylase]], demyristoylase and [[wikt:depalmitoylase|depalmitoylase]] activity.<ref name="pmid22076378">{{cite journal | vauthors = Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH, He B, Chen W, Zhang S, Cerione RA, Auwerx J, Hao Q, Lin H | title = Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase | journal = Science | volume = 334 | issue = 6057 | pages = 806–9 | date = November 2011 | pmid = 22076378 | pmc = 3217313 | doi = 10.1126/science.1207861 | bibcode = 2011Sci...334..806D }}</ref><ref name="pmid23552949">{{cite journal | vauthors = Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R, Hang HC, Hao Q, Lin H | title = SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine | journal = Nature | volume = 496 | issue = 7443 | pages = 110–3 | date = April 2013 | pmid = 23552949 | pmc = 3635073 | doi = 10.1038/nature12038 | bibcode = 2013Natur.496..110J }}</ref><ref name=":0">{{cite journal | vauthors = Rack JG, Morra R, Barkauskaite E, Kraehenbuehl R, Ariza A, Qu Y, Ortmayer M, Leidecker O, Cameron DR, Matic I, Peleg AY, Leys D, Traven A, Ahel I | title = Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens | journal = Molecular Cell | volume = 59 | issue = 2 | pages = 309–20 | date = July 2015 | pmid = 26166706 | pmc = 4518038 | doi = 10.1016/j.molcel.2015.06.013 }}</ref> The name Sir2 comes from the yeast gene '<u>s</u>ilent mating-type <u>i</u>nformation <u>r</u>egulation <u>2</u>',<ref>{{EntrezGene|23410}}</ref> the gene responsible for cellular regulation in [[yeast]].

From ''[[in vitro]]'' studies, sirtuins were thought to be implicated in influencing cellular processes like [[aging]], [[transcription (genetics)|transcription]], [[apoptosis]], [[inflammation]]<ref name="pmid23325925">{{cite journal | vauthors = Preyat N, Leo O | title = Sirtuin deacylases: a molecular link between metabolism and immunity | journal = Journal of Leukocyte Biology | volume = 93 | issue = 5 | pages = 669–80 | date = May 2013 | pmid = 23325925 | doi = 10.1189/jlb.1112557 | s2cid = 3070941 }}</ref> and stress resistance, as well as energy efficiency and alertness during [[Calorie restriction|low-calorie situations]].<ref name="pmid20668205">{{cite journal | vauthors = Satoh A, Brace CS, Ben-Josef G, West T, Wozniak DF, Holtzman DM, Herzog ED, Imai S | title = SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus | journal = The Journal of Neuroscience | volume = 30 | issue = 30 | pages = 10220–32 | date = July 2010 | pmid = 20668205 | pmc = 2922851 | doi = 10.1523/JNEUROSCI.1385-10.2010 }}</ref> As of 2018, there was no [[evidence-based medicine|clinical evidence]] that sirtuins affect human aging,<ref name="Shetty">{{cite journal | last1=Shetty | first1=Ashok K. | last2=Kodali | first2=Maheedhar | last3=Upadhya | first3=Raghavendra | last4=Madhu | first4=Leelavathi N. | title=Emerging anti-aging strategies - scientific basis and efficacy (Review)| journal=Aging and Disease | volume=9 | issue=6 | pages=1165–1184 | year=2018 | issn=2152-5250 | doi=10.14336/ad.2018.1026 |pmid=30574426|pmc=6284760}}</ref> and a 2022 review criticized researchers who propagate this claim.<ref>{{Cite journal |last=Brenner |first=Charles |date=2022-09-22 |title=Sirtuins are not conserved longevity genes |journal=Life Metabolism |volume=1 |issue=2 |pages=122–133 |doi=10.1093/lifemeta/loac025 |issn=2755-0230 |doi-access=free|pmid=37035412 |pmc=10081735 }}</ref>

Yeast Sir2 and some, but not all, sirtuins are [[protein deacetylase]]s. Unlike other known protein deacetylases, which simply [[hydrolyzation|hydrolyze]] [[Acetylated#Lysine acetylation and deacetylation|acetyl]]-[[lysine]] residues, the sirtuin-mediated deacetylation reaction couples [[lysine]] [[deacetylation]] to [[nicotinamide adenine dinucleotide|NAD]]+ hydrolysis.<ref name="pmid32518153">{{cite journal | vauthors=Klein MA, Denu JM | title=Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators | journal=[[Journal of Biological Chemistry]] | volume=295 | issue=32 | pages=11021–11041 | year=2020 | doi = 10.1074/jbc.REV120.011438| pmc= 7415977 | pmid=32518153| doi-access=free }}</ref> This hydrolysis yields O-acetyl-ADP-[[ribose]], the deacetylated substrate and [[nicotinamide]], which is an [[Enzyme inhibitor|inhibitor]] of sirtuin activity itself. These proteins utilize NAD+ to maintain cellular health and turn NAD+ to [[Nicotinamide|nicotinamide (NAM)]].<ref>{{cite web|title=NMN vs NR: The Differences Between These 2 NAD+ Precursors|url=https://www.nmn.com/precursors/nmn-vs-nr|access-date=2021-01-04|website=www.nmn.com}}</ref> The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD+:NADH ratio, the absolute levels of NAD+, NADH or NAM or a combination of these variables.

Sirtuins that deacetylate histones are structurally and mechanistically distinct from other classes of [[histone deacetylase]]s (classes I, IIA, IIB and IV), which have a different protein fold and use Zn<sup>2+</sup> as a [[Cofactor (biochemistry)|cofactor]].<ref>{{cite journal | vauthors = Bürger M, Chory J | title = Structural and chemical biology of deacetylases for carbohydrates, proteins, small molecules and histones | journal = Communications Biology | volume = 1 | pages = 217 | date = 2018 | pmid = 30534609 | pmc = 6281622 | doi = 10.1038/s42003-018-0214-4 }}</ref><ref>{{cite journal | vauthors = Marks PA, Xu WS | title = Histone deacetylase inhibitors: Potential in cancer therapy | journal = Journal of Cellular Biochemistry | volume = 107 | issue = 4 | pages = 600–8 | date = July 2009 | pmid = 19459166 | pmc = 2766855 | doi = 10.1002/jcb.22185 }}</ref>

== Actions and species distribution ==
Sirtuins are a family of signaling proteins involved in metabolic regulation.<ref name=Ye2017/><ref name=pmid17456799/> They are ancient in animal evolution and appear to possess a [[Conserved sequence|highly conserved]] structure throughout all kingdoms of life.<ref name=Ye2017/> Whereas bacteria and archaea encode either one or two sirtuins, eukaryotes encode several sirtuins in their genomes. In yeast, roundworms, and fruitflies, [[sir2]] is the name of one of the sirtuin-type proteins (see table below).<ref name="pmid15189148">{{cite journal | vauthors = Blander G, Guarente L | title = The Sir2 family of protein deacetylases | journal = Annual Review of Biochemistry | volume = 73 | issue = 1 | pages = 417–35 | year = 2004 | pmid = 15189148 | doi = 10.1146/annurev.biochem.73.011303.073651 | s2cid = 27494475 }}</ref>  Mammals possess seven sirtuins (SIRT1–7) that occupy different subcellular compartments: SIRT1, SIRT6 and SIRT7 are predominantly in the nucleus, SIRT2 in the cytoplasm, and SIRT3, SIRT4 and SIRT5 in the mitochondria.<ref name="Ye2017" />

== History ==
Research on sirtuin protein was started in 1991 by [[Leonard Guarente]] of [[Massachusetts Institute of Technology|MIT]].<ref name="url_MIT_PR">{{cite web | url = http://www.iht.com/articles/2006/11/08/healthscience/snwonder.php | title = The quest for a way around aging | author = Wade N | date = 2006-11-08  | work = Health & Science | publisher = International Herald Tribune | access-date = 2008-11-30}}</ref><ref name="urlMIT researchers uncover new information about anti-aging gene - MIT News Office">{{cite web | url = http://web.mit.edu/newsoffice/2000/guarente.html | title = MIT researchers uncover new information about anti-aging gene | date = 2000-02-16 | publisher = Massachusetts Institute of Technology, News Office | access-date = 2008-11-30}}</ref> Interest in the metabolism of NAD{{+}} heightened after the year 2000 discovery by Shin-ichiro Imai and coworkers in the Guarente laboratory that sirtuins are NAD+-dependent protein deacetylases .<ref>{{cite journal |vauthors=Imai S, Armstrong CM, Kaeberlein M, Guarente L |s2cid= 2967911 |title= Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase |journal= Nature |volume= 403 |issue= 6771 |pages= 795–800 |year= 2000 |pmid= 10693811 |doi= 10.1038/35001622 |bibcode= 2000Natur.403..795I}}</ref>

== Types ==
{{more citations needed|section|date=November 2019}}

The first sirtuin was identified in yeast (a lower eukaryote) and named sir2. In more complex mammals, there are seven known enzymes that act in cellular regulation, as sir2 does in yeast. These genes are designated as belonging to different classes (I-IV), depending on their amino acid sequence structure.<ref>{{cite journal | vauthors = Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA | title = Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle | journal = Molecular and Cellular Biology | volume = 23 | issue = 9 | pages = 3173–85 | date = May 2003 | pmid = 12697818 | pmc = 153197 | doi = 10.1128/MCB.23.9.3173-3185.2003 }}</ref> Several gram-positive prokaryotes as well as the gram-negative hyperthermophilic bacterium ''[[Thermotoga maritima]]'' possess sirtuins that are intermediate in sequence between classes, and these are placed in the "undifferentiated" or "U" class. In addition, several gram-positive bacteria, including ''[[Staphylococcus aureus]]'' and ''[[Streptococcus pyogenes]]'', as well as several fungi carry [[Macro domain|macrodomain]]-linked sirtuins (termed "class M" sirtuins).<ref name=":0" />

{{hatnote|Yeast protein names may also be suffixed with "p" (e.g. Sir2p) to indicate the fact that it is a protein. This table does not use this convention to minimize cross-species confusion.}}
{| class="wikitable" style="text-align:center"
|-
! rowspan="2" | Class
! rowspan="2" | Subclass
! colspan="4" | Species
! rowspan="2" | Intracellular<br />location
! rowspan="2" width=250pt| Activity
! rowspan="2" width=150pt| Cellular Function
! rowspan="2" |'''Catalytic Domains'''<ref>{{cite journal |last1=Chang |first1=Andrew R. |last2=Ferrer |first2=Christina M. |last3=Mostoslavsky |first3=Raul |date=2020-01-01 |title=SIRT6, a Mammalian Deacylase with Multitasking Abilities |journal=Physiological Reviews |language=en |volume=100 |issue=1 |pages=145–169 |doi=10.1152/physrev.00030.2018 |pmid=31437090|pmc=7002868 |doi-access=free }}</ref>
! rowspan="2" |'''Histone Deacetylation Target'''<ref name=":1">{{cite journal |last1=Carafa |first1=Vincenzo |last2=Rotili |first2=Dante |last3=Forgione |first3=Mariantonietta |last4=Cuomo |first4=Francesca |last5=Serretiello |first5=Enrica |last6=Hailu |first6=Gebremedhin Solomon |last7=Jarho |first7=Elina |last8=Lahtela-Kakkonen |first8=Maija |last9=Mai |first9=Antonello |last10=Altucci |first10=Lucia |date=2016-05-25 |title=Sirtuin functions and modulation: from chemistry to the clinic |journal=Clinical Epigenetics |volume=8 |pages=61 |doi=10.1186/s13148-016-0224-3 |issn=1868-7075 |pmc=4879741 |pmid=27226812 |doi-access=free }}</ref>
! rowspan="2" |'''Non-Histone Deacetylation Target'''<ref name=":1" />
! rowspan="2" |'''Pathology'''<ref name=":1" />
|-
!  Bacteria || Yeast || Mouse || Human
|-
| rowspan="4" | I || a || || Sir2,<br />Hst1 || Sirt1 || [[SIRT1]] || Nucleus, cytoplasm || Deacetylase || Metabolism inflammation
|244-498 (of 766aa)
|[[H3K9ac]], H1K26ac, [[H4K16ac]]
|Hif-1α, Hif-2α, MYC, P53, BRCA1, FOXO3A, MyoD, Ku70, PPARγ, PCAF, Suv39h1, TGFB1, WRN, NBS1
|Neurodegenerative diseases, Cancer: acute myeloid leukemia, colon, prostate, ovarian, glioma, breast, melanoma, lung adenocarcinoma
|-
| rowspan="2" | b || || Hst2 || Sirt2 || [[SIRT2]] || Nucleus and cytoplasm || Deacetylase || Cell cycle, tumorigenesis
|65-340 (of 388aa)
|[[H3K56ac]], [[H4K16ac]]
|Tubulin, Foxo3a, EIF5A, P53, G6PD, MYC
|Neurodegenerative diseases, Cancer: brain tissue, glioma
|-
| || || Sirt3 || [[SIRT3]] || Mitochondria || Deacetylase || Metabolism
|126-382 (of 399aa)
|[[H3K56ac]], H4K14ac
|SOD2, PDH, IDH2, GOT2, FoxO3a
|Neurodegenerative diseases, Cancer: B cell chronic lymphocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, breast, gastric
|-
| c || || Hst3,<br />Hst4 || || || || ||
|
|
|
|
|-
| II || || || || Sirt4 || [[SIRT4]] || Mitochondria || ADP-ribosyl transferase || Insulin secretion
|45-314 (of 314aa)
|Unknown
|GDH, PDH
|Cancer: breast, colorectal
|-
|  style="height:38px" | III || || || || Sirt5 || [[SIRT5]] || Mitochondria || Demalonylase, desuccinylase and deacetylase || Ammonia detoxification
|41-309 (of 310aa)
|Unknown
|CPS1
|Cancer: pancreatic, breast, non-small cell lung carcinoma
|-
| rowspan="2" | IV || a || || || Sirt6 || [[SIRT6]] || Nucleus || Demyristoylase, depalmitoylase, ADP-ribosyl transferase and deacetylase || DNA repair, metabolism, [[TNF]] secretion
|35-274 (of 355aa)
|[[H3K9ac]], [[H3K56ac]]
|Unknown
|Cancer: breast, colon
|-
| b || || || Sirt7 || [[SIRT7]] || Nucleolus || Deacetylase || [[ribosomal RNA|rRNA]] [[Transcription (genetics)|transcription]]
|90-331 (of 400aa)
|H3K18ac
|Hif-1α, Hif-2α
|Cancer: liver, testis, spleen, thyroid, breast
|-
| U || || [[cobB]]<ref name="pmid15019790">{{cite journal | vauthors = Zhao K, Chai X, Marmorstein R | title = Structure and substrate binding properties of cobB, a Sir2 homolog protein deacetylase from Escherichia coli | journal = Journal of Molecular Biology | volume = 337 | issue = 3 | pages = 731–41 | date = March 2004 | pmid = 15019790 | doi = 10.1016/j.jmb.2004.01.060 }}</ref>

 || || || || || Regulation of [[acetyl-CoA]] synthetase<ref name="pmid18249170">{{cite journal | vauthors = Schwer B, Verdin E | title = Conserved metabolic regulatory functions of sirtuins | journal = Cell Metabolism | volume = 7 | issue = 2 | pages = 104–12 | date = February 2008 | pmid = 18249170 | doi = 10.1016/j.cmet.2007.11.006 | doi-access = free }}</ref> || metabolism
|
|
|
|
|-
|M
|
|SirTM<ref name=":0" />
|
|
|
|
|ADP-ribosyl transferase
|ROS detoxification
|
|
|
|
|}

SIRT3, a mitochondrial protein deacetylase, plays a role in the regulation of multiple metabolic proteins like isocitrate dehydrogenase of the TCA cycle. It also plays a role in skeletal muscle as a metabolic adaptive response. Since glutamine is a source of α-ketoglutarate used to replenish the TCA cycle, SIRT4 is involved in glutamine metabolism.<ref name = "Choi_2014">{{cite journal | vauthors = Choi JE, Mostoslavsky R | title = Sirtuins, metabolism, and DNA repair | journal = Current Opinion in Genetics & Development | volume = 26 | pages = 24–32 | date = June 2014 | pmid = 25005742 | doi = 10.1016/j.gde.2014.05.005 | pmc = 4254145 }}</ref>

== Ageing ==
Although preliminary studies with [[resveratrol]], an activator of deacetylases such as [[SIRT1]],<ref name="Aunan2016">{{cite journal |last1=Aunan |first1=JR |last2=Watson |first2=MM |last3=Hagland |first3=HR |last4=Søreide |first4=K |title=Molecular and biological hallmarks of ageing. |journal=The British Journal of Surgery |date=January 2016 |volume=103 |issue=2 |pages=e29-46 |doi=10.1002/bjs.10053 |pmid=26771470 |s2cid=12847291 |type=Review (in vitro)|doi-access=free }}</ref> led some scientists to speculate that resveratrol may extend lifespan, no [[evidence-based medicine|clinical evidence]] for such an effect has been discovered, as of 2018.<ref name=Shetty/>

==Tissue fibrosis==
{{more medical citations needed|section|date=November 2019}}
A 2018 review indicated that SIRT levels are lower in tissues from people with [[scleroderma]], and such reduced SIRT levels may increase risk of [[fibrosis]] through modulation of the [[TGF-β]] [[signaling pathway]].<ref>{{cite journal | vauthors = Wyman AE, Atamas SP | title = Sirtuins and accelerated aging in scleroderma | journal = Current Rheumatology Reports | volume = 20 | issue = 4 | pages = 16 | date = March 2018 | pmid = 29550994 | pmc = 5942182 | doi = 10.1007/s11926-018-0724-6 }}</ref>

==DNA repair in laboratory studies==
[[Sirtuin 1|SIRT1]], [[SIRT6]] and [[SIRT7]] proteins are employed in [[DNA repair]].<ref name="pmid28406750">{{cite journal | vauthors = Vazquez BN, Thackray JK, Serrano L | title = Sirtuins and DNA damage repair: SIRT7 comes to play | journal = Nucleus | volume = 8 | issue = 2 | pages = 107–115 | date = March 2017 | pmid = 28406750 | pmc = 5403131 | doi = 10.1080/19491034.2016.1264552 }}</ref>  SIRT1 protein promotes [[homologous recombination]] in human cells and is involved in recombinational repair of [[DNA]] breaks.<ref name="pmid20097625">{{cite journal | vauthors = Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmüller L, Gatz SA | title = Role of SIRT1 in homologous recombination | journal = DNA Repair | volume = 9 | issue = 4 | pages = 383–93 | date = April 2010 | pmid = 20097625 | doi = 10.1016/j.dnarep.2009.12.020 }}</ref>

SIRT6 is a [[chromatin]]-associated protein and in mammalian cells is required for [[base excision repair]] of [[DNA damage (naturally occurring)|DNA damage]].<ref name="pmid16439206">{{cite journal |display-authors=3| vauthors = Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, Hong AL, Ford E, Cheng HL, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger MO, Hursting S, Barrett JC, Guarente L, Mulligan R, Demple B, Yancopoulos GD, Alt FW | title = Genomic instability and aging-like phenotype in the absence of mammalian SIRT6 | journal = Cell | volume = 124 | issue = 2 | pages = 315–29 | date = January 2006 | pmid = 16439206 | doi = 10.1016/j.cell.2005.11.044 | s2cid = 18517518 | doi-access = free }}</ref>  SIRT6 deficiency in mice leads to a degenerative aging-like phenotype.<ref name="pmid16439206" />   In addition, SIRT6 promotes the repair of DNA double-strand breaks.<ref name="pmid20157594">{{cite journal|display-authors=3| vauthors = McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R, Guan S, Shi X, Gozani O, Burlingame AL, Bohr VA, Chua KF | title = SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair | journal = Aging | volume = 1 | issue = 1 | pages = 109–21 | date = January 2009 | pmid = 20157594 | pmc = 2815768 | doi = 10.18632/aging.100011 }}</ref>  Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair.<ref name="pmid22753495">{{cite journal | vauthors = Mao Z, Tian X, Van Meter M, Ke Z, Gorbunova V, Seluanov A | title = Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 29 | pages = 11800–5 | date = July 2012 | pmid = 22753495 | pmc = 3406824 | doi = 10.1073/pnas.1200583109 | bibcode = 2012PNAS..10911800M | doi-access = free }}</ref>

SIRT7 knockout mice display features of [[Progeroid syndromes|premature aging]].<ref name="pmid27225932">{{cite journal |display-authors=3|vauthors = Vazquez BN, Thackray JK, Simonet NG, Kane-Goldsmith N, Martinez-Redondo P, Nguyen T, Bunting S, Vaquero A, Tischfield JA, Serrano L | title = SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair | journal = The EMBO Journal | volume = 35 | issue = 14 | pages = 1488–503 | date = July 2016 | pmid = 27225932 | pmc = 4884211 | doi = 10.15252/embj.201593499 }}</ref>  SIRT7 protein is required for repair of double-strand breaks by [[non-homologous end joining]].<ref name="pmid27225932" />

== Inhibitors ==

Certain sirtuin activity is inhibited by [[nicotinamide]], which binds to a specific receptor site.<ref name="pmid15780941">{{cite journal | vauthors = Avalos JL, Bever KM, Wolberger C | title = Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme | journal = Molecular Cell | volume = 17 | issue = 6 | pages = 855–68 | date = March 2005 | pmid = 15780941 | doi = 10.1016/j.molcel.2005.02.022 | doi-access = free }}</ref> It is an inhibitor in vitro of SIRT1, but can be a stimulator in cells.<ref name=“pmid28417163”>{{cite journal | vauthors = Hwang ES, Song SB | title = Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells | journal = Cell Mol Life Sci | volume = 74 | issue = 18 | pages = 3347–3362 | date = September 2017 | pmid = 28417163 | doi = 10.1007/s00018-017-2527-8 | doi-access = free | pmc = 11107671 }}</ref>

== Activators ==

{| class="wikitable sortable"
|+ List of known sirtuin activator ''in vitro''
|-
! Compound !! Target/Specificity !! References
|-
| [[Piceatannol]]|| SIRT1 || <ref name="ManjulaEtal">{{cite journal |last1=Manjula |first1=Ramu |last2=Anuja |first2=Kumari |last3=Alcain |first3=Francisco J. |title=SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases |journal=Frontiers in Pharmacology |date=12 January 2021 |volume=11 |page=585821 |doi=10.3389/fphar.2020.585821 |pmid=33597872 |pmc=7883599 |doi-access=free}}</ref>
|-
| [[SRT-1720]]|| SIRT1 || <ref name="ManjulaEtal" />
|-
| [[SRT-2104]]|| SIRT1 || <ref name="ManjulaEtal" />
|-
| [[Beta-Lapachone]]|| SIRT1 || <ref name="ManjulaEtal" />
|-
| [[Cilostazol]]|| SIRT1|| <ref name="ManjulaEtal" />
|-
| [[Quercetin]] and rutin derivatives || SIRT6 || <ref name="RahnastoRillaPolyphenols">{{cite journal |last1=Rahnasto-Rilla |first1=Minna |last2=Tyni |first2=Jonna |last3=Huovinen |first3=Marjo |last4=Jarho |first4=Elina |last5=Kulikowicz |first5=Tomasz |last6=Ravichandran |first6=Sarangan |last7=A. Bohr |first7=Vilhelm |last8=Ferrucci |first8=Luigi |last9=Lahtela-Kakkonen |first9=Maija |last10=Moaddel |first10=Ruin |display-authors=3 |date=7 March 2018 |title=Natural polyphenols as sirtuin 6 modulators |journal=Scientific Reports |language=en |volume=8 |issue=1 |pages=4163 |bibcode=2018NatSR...8.4163R |doi=10.1038/s41598-018-22388-5 |pmc=5841289 |pmid=29515203}}</ref>
|-
| [[Luteolin]]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" />
|-
| [[Fisetin]]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" />
|-
| [[Phenolic acid]]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" />
|-
| [[Fucoidan]]|| SIRT6 || <ref>{{cite journal|display-authors=3|last1=Rahnasto-Rilla |first1=Minna K. |last2=McLoughlin |first2=Padraig |last3=Kulikowicz |first3=Tomasz |last4=Doyle |first4=Maire |last5=Bohr |first5=Vilhelm A. |last6=Lahtela-Kakkonen |first6=Maija |last7=Ferrucci |first7=Luigi |last8=Hayes |first8=Maria |last9=Moaddel |first9=Ruin |title=The Identification of a SIRT6 Activator from Brown Algae Fucus distichus |journal=Marine Drugs |date=21 June 2017 |volume=15 |issue=6 |page=190 |doi=10.3390/md15060190 |pmid=28635654 |pmc=5484140 |doi-access=free }}</ref>
|-
| [[Curcumin]]|| SIRT1, SIRT6 || <ref>{{cite journal|display-authors=3|last1=Grabowska |first1=Wioleta |last2=Suszek |first2=Małgorzata |last3=Wnuk |first3=Maciej |last4=Lewinska |first4=Anna |last5=Wasiak |first5=Emilia |last6=Sikora |first6=Ewa |last7=Bielak-Zmijewska |first7=Anna |title=Curcumin elevates sirtuin level but does not postpone in vitro senescence of human cells building the vasculature |journal=Oncotarget |date=28 March 2016 |volume=7 |issue=15 |pages=19201–19213 |doi=10.18632/oncotarget.8450 |pmid=27034011 |pmc=4991376 }}</ref>
|-
| [[Pirfenidone]]|| SIRT1 || <ref>{{cite journal |last1=Sandoval-Rodriguez |first1=Ana |last2=Monroy-Ramirez |first2=Hugo Christian |last3=Meza-Rios |first3=Alejandra |last4=Garcia-Bañuelos |first4=Jesus |last5=Vera-Cruz |first5=Jose |last6=Gutiérrez-Cuevas |first6=Jorge |last7=Silva-Gomez |first7=Jorge |last8=Staels |first8=Bart |last9=Dominguez-Rosales |first9=Jose |last10=Galicia-Moreno |first10=Marina |last11=Vazquez-Del Mercado |first11=Monica |last12=Navarro-Partida |first12=Jose |last13=Santos-Garcia |first13=Arturo |last14=Armendariz-Borunda |first14=Juan| display-authors=3|title=Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK |journal=Hepatology Communications |date=March 2020 |volume=4 |issue=3 |pages=434–449 |doi=10.1002/hep4.1474 |pmid=32140659 |pmc=7049672 }}</ref>
|-
| [[Myricetin]]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" />
|-
| [[Cyanidin]]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" />
|-
| [[Delphinidin]]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" />
|-
| [[Apigenin]]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" />
|-
| [[Butein]]|| SIRT6 || <ref name="DaSilva">{{cite thesis |last1=da Silva |first1=Julie Pires |title=Rôle de la sirtuine 1 dans la modulation des réponses apoptotique et autophagique du coeur au stress du réticulum endoplasmique |date=31 May 2018 |publisher=Université Paris Saclay (COmUE) |url=https://tel.archives-ouvertes.fr/tel-01894468 |type=phdthesis |language=fr}}</ref>
|-
| [[Isoliquiritigenin]]|| SIRT6 || <ref name="DaSilva" />
|-
| [[Ferulic acid]]|| SIRT1 || <ref name="DaSilva" />
|-
| [[Berberine]]|| SIRT1 || <ref name="DaSilva" />
|-
| [[Catechin]]|| SIRT1 || <ref name="DaSilva" />
|-
| [[Malvidin]]|| SIRT1 || <ref name="DaSilva" />
|-
| [[Pterostilbene]]|| SIRT1 || <ref name="DaSilva" />
|-
| [[Tyrosol]]|| SIRT1 || <ref name="DaSilva" />
|}


== See also ==
* [[Biological immortality]]
* [[Histone deacetylase|Histone deacetylases or HDACs]]
* [[Trichostatin A]]

== References ==
{{Reflist}}

== External links ==
* {{MeshName|Sirtuins}}

{{Carbon-nitrogen non-peptide hydrolases}}
{{Glycosyltransferases}}
{{Intracellular signaling peptides and proteins}}
{{Authority control}}

[[Category:Enzymes]]
[[Category:Aging-related enzymes]]
[[Category:Aging-related proteins]]