The role of sirtuins in cellular senescence and the development of age-associated diseases

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

The increasing proportion of the older age group population is an Irreversible global trend. There is an increasing number of studies that support the hypotheses that age-associated diseases and geriatric conditions share a common set of basic biological mechanisms. Numerous endogenous molecules counteract cellular senescence mechanisms. Several anti-aging molecules have been identified to date and their role has been evaluated in the pathophysiology of various diseases. NAD-dependent protein deacetylases and ADP-ribosyl transferases from the sirtuin family are considered as potential factors affecting cellular senescence processes. Sirtuins are involved in antioxidant and oxidative stress responses, regulation of mitochondrial function, DNA damage repair, and metabolism. Sirtuins and associated signaling pathways of the cellular senescence regulatory network have a significant impact on the development of age-associated diseases. Review presents the results of a comprehensive analysis of the results of fundamental and clinical studies in order to actualize the role of sirtuins in cellular senescence and the development of age-associated diseases. Data on the mechanisms of cellular senescence, the function of sirtuins (SIRT1-7), their interaction with key regulators of cellular senescence signaling pathways, and the association of polymorphic variants of sirtuin genes with multifactorial diseases and longevity are presented.

Full Text

Restricted Access

About the authors

V. A. Markelov

Ufa Federal Research Center, Russian Academy of Sciences; Bashkir State Medical University

Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

Russian Federation, Ufa, 450054; Ufa, 450008

L. Z. Akhmadishina

Ufa Federal Research Center, Russian Academy of Sciences; Ufa State Petroleum Technological University

Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

Russian Federation, Ufa, 450054; Ufa, 450064

O. V. Kochetova

Ufa Federal Research Center, Russian Academy of Sciences; Bashkir State Medical University

Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

Russian Federation, Ufa, 450054; Ufa, 450008

V. V. Erdman

Ufa Federal Research Center, Russian Academy of Sciences; Bashkir State Medical University

Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

Russian Federation, Ufa, 450054; Ufa, 450008

G. F. Korytina

Ufa Federal Research Center, Russian Academy of Sciences; Bashkir State Medical University

Author for correspondence.
Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

Russian Federation, Ufa, 450054; Ufa, 450008

References

  1. Department of economic and social affairs, Wilmoth J.R., United nations department of economic and social affairs et al. World social report 2023: leaving no one behind in an ageing world. UN, 2023. 149 p.
  2. Franceschi C., Garagnani P., Morsiani C. et al. The continuum of aging and age-related diseases: Сommon mechanisms but different rates // Front. in Medicine. 2018. V. 5. https://doi.org/10.3389/fmed.2018.00061
  3. Li Y., Tian X., Luo J. et al. Molecular mechanisms of aging and anti-aging strategies // Cell Communication аnd Signaling. 2024. V. 22. № 1. P. 285. https://doi.org/10.1186/s12964-024-01663-1
  4. Evangelou K., Vasileiou P.V.S., Papaspyropoulos A. et al. Cellular senescence and cardiovascular diseases: moving to the “heart” of the problem // Physiol. Rev. 2023. V. 103. № 1. P. 609–647. https://doi.org/10.1152/physrev.00007.2022
  5. Klapp V., Álvarez-Abril B., Leuzzi G. et al. The DNA damage response and inflammation in cancer // Cancer Discovery. 2023. V. 13. № 7. P. 1521–1545. https://doi.org/10.1158/2159-8290.CD-22-1220
  6. Wu X., Zhou X., Wang S. et al. DNA damage response (DDR): A link between cellular senescence and human cytomegalovirus // Virology J. 2023. V. 20. № 1. P. 250. https://doi.org/10.1186/s12985-023-02203-y
  7. Xu D., Liu L., Zhao Y. et al. Melatonin protects mouse testes from palmitic acid – induced lipotoxicity by attenuating oxidative stress and DNA damage in a SIRT1‐dependent manner // J. Pineal Res. 2020. V. 69. № 4. https://doi.org/10.1111/jpi.12690
  8. Imai S., Guarente L. NAD+ and sirtuins in aging and disease // Trends in Cell Biology. 2014. V. 24. № 8. P. 464–471. https://doi.org/10.1016/j.tcb.2014.04.002
  9. Covarrubias A.J., Perrone R., Grozio A., Verdin E. NAD+ metabolism and its roles in cellular processes during ageing // Nat. Rev. Mol. Cell Biol. 2021. V. 22. № 2. P. 119–141. https://doi.org/10.1038/s41580-020-00313-x
  10. Carrico C., Meyer J.G., He W. et al. The mitochondrial acylome emerges: Рroteomics, regulation by sirtuins, and metabolic and disease implications // Cell Metabolism. 2018. V. 27. № 3. P. 497–512. https://doi.org/10.1016/j.cmet.2018.01.016
  11. Wang J., Song X., Tan G. et al. NAD+ improved experimental autoimmune encephalomyelitis by regulating SIRT1 to inhibit PI3K/Akt/mTOR signaling pathway // Aging (Albany NY). 2021. V. 13. № 24. P. 25931. https://doi.org/10.18632/aging.203781
  12. Kida Y., Goligorsky M.S. Sirtuins, cell senescence, and vascular aging // Canadian J. Cardiol. 2016. V. 32. № 5. P. 634–641. https://doi.org/10.1016/j.cjca.2015.11.022
  13. Gámez-García A., Vazquez B.N. Nuclear sirtuins and the aging of the immune system // Genes. 2021. V. 12. № 12. https://doi.org/10.3390/genes12121856
  14. Roger L., Tomas F., Gire V. Mechanisms and regulation of cellular senescence // Int. J. Mol. Sci. 2021. V. 22. № 23. https://doi.org/10.3390/ijms222313173
  15. Krizhanovsky V., Yon M., Dickins R.A. et al. Senescence of activated stellate cells limits liver fibrosis // Cell. 2008. V. 134. № 4. P. 657–667. https://doi.org/10.1016/j.cell.2008.06.049
  16. Zhang L., Pitcher L.E., Yousefzadeh M.J. et al. Cellular senescence: А key therapeutic target in aging and diseases // J. Clin. Invest. 2022. V. 132. № 15. https://doi.org/10.1172/JCI158450
  17. Pizzul P., Rinaldi C., Bonetti D. The multistep path to replicative senescence onset: zooming on triggering and inhibitory events at telomeric DNA // Front. in Cell аnd Development. Biol. 2023. V. 11. https://doi.org/10.3389/fcell.2023.1250264
  18. Савицкий Д.В., Линькова Н.С., Кожевникова Е.О. и др. Сиртуины и хемокины – маркеры репликативного и индуцированного старения эндотелиоцитов человека // Acta Biomedica Scientifica. 2022. Т. 7. № 5–2. С. 12–20. https://doi.org/10.29413/ABS.2022-7.5-2.2
  19. Galli M., Frigerio C., Longhese M.P. et al. The regulation of the DNA damage response at telomeres: Focus on kinases // Biochem. Soc. Transactions. 2021. V. 49. № 2. P. 933–943. https://doi.org/10.1042/BST20200856
  20. Yamashita S., Ogawa K., Ikei T. et al. SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene // Bioch. Biophys. Res. Communications. 2012. V. 417. № 1. P. 630–634. https://doi.org/10.1016/j.bbrc.2011.12.021
  21. Gorgoulis V., Adams P.D., Alimonti A. et al. Cellular senescence: defining a path forward // Cell. 2019. V. 179. № 4. P. 813–827. https://doi.org/10.1016/j.cell.2019.10.005
  22. Mao Z., Ke Z., Gorbunova V. et al. Replicatively senescent cells are arrested in G1 and G2 phases // Aging (Albany NY). 2012. V. 4. № 6. P. 431. https://doi.org/10.18632/aging.100467
  23. Morisaki H., Ando A., Nagata Y. et al. Complex mechanisms underlying impaired activation of Cdk4 and Cdk2 in replicative senescence: Roles of p16, p21, and cyclin D1 // Experim. Сell Res. 1999. V. 253. № 2. P. 503–510. https://doi.org/10.1006/excr.1999.4698
  24. Berthet C., Klarmann K.D., Hilton M.B. et al. Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation // Developmental Сell. 2006. V. 10. № 5. P. 563–573. https://doi.org/10.1016/j.devcel.2006.03.004
  25. Wang F., Li Z., Zhou J. et al. SIRT1 regulates the phosphorylation and degradation of P27 by deacetylating CDK2 to promote T-cell acute lymphoblastic leukemia progression // J. Experim. & Clin. Cancer Res. 2021. V. 40. P. 1–16. https://doi.org/10.1186/s13046-021-02071-w
  26. Krenning L., Feringa F.M., Shaltiel I.A. et al. Transient activation of p53 in G2 phase is sufficient to induce senescence // Mol. Cell. 2014. V. 55. № 1. P. 59–72. https://doi.org/10.1016/j.molcel.2014.05.007
  27. Baker D.J., Childs B.G., Durik M. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan // Nature. 2016. V. 530. № 7589. P. 184–189. https://doi.org/10.1038/nature16932
  28. Chua K.F., Mostoslavsky R., Lombard D.B. et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress // Cell Metabolism. 2005. V. 2. № 1. P. 67–76. https://doi.org/10.1016/j.cmet.2005.06.007
  29. Yin J., Lu X.T., Hou M.L. et al. Sirtuin1-p53: А potential axis for cancer therapy // Biochem. Pharmacology. 2023. V. 212. https://doi.org/10.1016/j.bcp.2023.115543
  30. Bloom S.I., Tucker J.R., Lim J. et al. Aging results in DNA damage and telomere dysfunction that is greater in endothelial versus vascular smooth muscle cells and is exacerbated in atheroprone regions // Geroscience. 2022. V. 44. № 6. P. 2741–2755. https://doi.org/10.1007/s11357-022-00681-6
  31. Sanokawa-Akakura R., Akakura S., Ostrakhovitch E.A. et al. Replicative senescence is distinguishable from DNA damage-induced senescence by increased methylation of promoter of rDNA and reduced expression of rRNA // Mechanisms Ageing аnd Development. 2019. V. 183. https://doi.org/10.1016/j.mad.2019.111149
  32. Swift M.L., Sell C., Azizkhan-Clifford J. DNA damage-induced degradation of Sp1 promotes cellular senescence // Geroscience. 2022. V. 44. № 2. P. 683–698. https://doi.org/10.1007/s11357-021-00456-5
  33. Menolfi D., Zha S. ATM, DNA-PKcs and ATR: Shaping development through the regulation of the DNA damage responses // Genome Instability & Disease. 2021. V. 1. P. 47–68. https://doi.org/10.1007/s42764-019-00003-9
  34. Sharma A., Almasan A. Autophagy and PTEN in DNA damage-induced senescence // Adv. in Cancer Res. 2021. V. 150. P. 249–284. https://doi.org/10.1016/bs.acr.2021.01.006
  35. Mao Z., Tian X., Van Meter M. et al. Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence // Proc. Natl Acad. Sci. USA. 2012. V. 109. № 29. P. 11800–11805. https://doi.org/10.1073/pnas.1200583109
  36. Criscione S.W., Teo Y.V., Neretti N. The chromatin landscape of cellular senescence // Trends in Genet. 2016. V. 32. № 11. P. 751–761. https://doi.org/10.1016/j.tig.2016.09.005
  37. Chansard A., Pobega E., Caron P. et al. Imaging the response to DNA damage in heterochromatin domains // Front. in Cell аnd Development. Biol. 2022. V. 10. https://doi.org/10.3389/fcell.2022.920267
  38. Samoilova E.M., Romanov S.E., Chudakova D.A. et al. Role of sirtuins in epigenetic regulation and aging control // Vavilov J. Genet. аnd Breeding. 2024. V. 28. № 2. P. 215. https://doi.org/10.18699/vjgb-24-26
  39. Vaquero A., Scher M., Lee D. et al. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin // Mol. Cell. 2004. V. 16. № 1. P. 93–105. https://doi.org/10.1016/j.molcel.2004.08.031
  40. Tu Z., Zhuang X., Yao Y.G. et al. BRG1 is required for formation of senescence-associated heterochromatin foci induced by oncogenic RAS or BRCA1 loss // Mol. аnd Cell. Biol. 2013. V. 33. № 9. P. 1819–1829. https://doi.org/10.1128/MCB.01744-12
  41. Narita M., Nūnez S., Heard E. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence // Cell. 2003. V. 113. № 6. P. 703–716. https://doi.org/10.1016/s0092-8674(03)00401-x
  42. Sulli G., Di Micco R., di Fagagna F.A. Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer // Nat. Rev. Cancer. 2012. V. 12. № 10. P. 709–720. https://doi.org/10.1038/nrc3344
  43. Kosar M., Bartkova J., Hubackova S. et al. Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type-and insult-dependent manner and follow expression of p16ink4a // Cell Cycle. 2011. V. 10. № 3. P. 457–468. https://doi.org/10.4161/cc.10.3.14707
  44. Di Micco R., Sulli G., Dobreva M. et al. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer // Nat. Cell Biol. 2011. V. 13. № 3. P. 292–302. https://doi.org/10.1038/ncb2170
  45. Olan I., Handa T., Narita M. Beyond SAHF: An integrative view of chromatin compartmentalization during senescence // Current Opinion In Cell Biology. 2023. V. 83. https://doi.org/10.1016/j.ceb.2023.102206
  46. Sadaie M., Salama R., Carroll T. et al. Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence // Genes & Development. 2013. V. 27. № 16. P. 1800–1808. https://doi.org/10.1101/gad.217281.113
  47. Lv T., Wang C., Zhou J. et al. Mechanism and role of nuclear laminin B1 in cell senescence and malignant tumors // Cell Death Discovery. 2024. V. 10. № 1. P. 269. https://doi.org/10.1038/s41420-024-02045-9
  48. Swanson E.C., Manning B., Zhang H., Lawrence J.B. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence // J. Cell Biol. 2013. V. 203. № 6. P. 929–942. https://doi.org/10.1083/jcb.201306073
  49. De Cecco M., Criscione S.W., Peterson A.L. et al. Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues // Aging (Albany NY). 2013. V. 5. № 12. P. 867. https://doi.org/10.18632/aging.100621
  50. Tasselli L., Xi Y., Zheng W. et al. SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence // Nat. Structural & Mol. Biol. 2016. V. 23. № 5. P. 434–440. https://doi.org/10.1038/nsmb.3202
  51. De Cecco M., Ito T., Petrashen A.P. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation // Nature. 2019. V. 566. № 7742. P. 73–78. https://doi.org/10.1038/s41586-018-0784-9
  52. Пухальская А.Э., Кветной И.М., Инькова Н.С. и др. Сиртуины и старение // Успехи физиол. наук. 2022. Т. 53. № 1. С. 16–27. https://doi.org/10.31857/S0301179821040056
  53. Diao Z., Ji Q., Wu Z. et al. SIRT3 consolidates heterochromatin and counteracts senescence // Nucl. Acids. Res. 2021. V. 49. № 8. P. 4203–4219. https://doi.org/10.1093/nar/gkab161
  54. Zhou Z., Zhang X., Lei X. et al. Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection // Signal Transduction аnd Targeted Therapy. 2021. V. 6. № 1. P. 382. https://doi.org/10.1038/s41392-021-00800-3
  55. Wang T., Liu W., Shen Q. et al. Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING-dependent therapy‐induced senescence and provides “one–two punch” opportunity with anti‐PD‐L1 therapy in colorectal cancer // Cancer Sci. 2023. V. 114. № 11. P. 4184–4201. https://doi.org/10.1111/cas.15961
  56. Li Y., Cui J., Liu L. et al. mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells // Cell Death & Disease. 2024. V. 15. № 7. P. 523. https://doi.org/10.1038/s41419-024-06863-8
  57. Sun Y., Xu L., Li Y. et al. Mitophagy defect mediates the aging‐associated hallmarks in Hutchinson–Gilford progeria syndrome // Aging Cell. 2024. V. 23. № 6. https://doi.org/10.1111/acel.14143
  58. Wiley C.D., Campisi J. The metabolic roots of senescence: mechanisms and opportunities for intervention // Nat. Metabolism. 2021. V. 3. № 10. P. 1290–1301. https://doi.org/10.1038/s42255-021-00483-8
  59. Sturm Á., Sharma H., Bodnár F. et al. N6-methyladenine progressively accumulates in mitochondrial DNA during aging // Int. J. Mol. Sci. 2023. V. 24. № 19. https://doi.org/10.3390/ijms241914858
  60. Vizioli M.G., Liu T., Miller K.N. et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence // Genes & Development. 2020. V. 34. № 5–6. P. 428–445. https://doi.org/10.1101/gad.331272.119
  61. Wenz T. Mitochondria and PGC-1α in aging and age-associated diseases // J. Aging Res. 2011. V. 2011. https://doi.org/10.4061/2011/810619
  62. Jin Q., Zhang Y., Cui Y. et al. PGC 1α-mediates mitochondrial damage in the liver by Inhibiting the mitochondrial respiratory chain as a non-cholinergic mechanism of repeated low-level soman exposure // Biol. аnd Pharmaceutical Bulletin. 2023. V. 46. № 4. P. 563–573. https://doi.org/10.1248/bpb.b22-00633
  63. Ye B., Pei Y., Wang L. et al. NAD+ supplementation prevents STING – induced senescence in CD8+ T cells by improving mitochondrial homeostasis // J. Cell. Biochemistry. 2024. V. 125. № 3. https://doi.org/10.1002/jcb.30522
  64. Drake J.C., Wilson R.J., Laker R.C. et al. Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy // Proc. Natl Acad. Sci. USA. 2021. V. 118. № 37. https://doi.org/10.1073/pnas.2025932118
  65. Morsczeck C., Reck A., Reichert T.E. Changes in AMPK activity induces cellular senescence in human dental follicle cells // Experim. Gerontology. 2023. V. 172. https://doi.org/10.1016/j.exger.2022.112071
  66. Pei S., Minhajuddin M., Adane B. et al. AMPK/FIS1-mediated mitophagy is required for self-renewal of human AML stem cells // Cell Stem Cell. 2018. V. 23. № 1. P. 86–100. https://doi.org/10.1016/j.stem.2018.05.021
  67. Zeng K., Yu X., Mahaman Y.A.R. et al. Defective mitophagy and the etiopathogenesis of Alzheimer’s disease // Translational Neurodegeneration. 2022. V. 11. № 1. P. 32. https://doi.org/10.1186/s40035-022-00305-1
  68. Mai S., Klinkenberg M., Auburger G. et al. Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1 // J. Cell Sci. 2010. V. 123. № 6. P. 917–926. https://doi.org/10.1242/jcs.059246
  69. Tong M., Mukai R., Mareedu S. et al. Distinct roles of DRP1 in conventional and alternative mitophagy in obesity cardiomyopathy // Circulation Res. 2023. V. 133. № 1. P. 6–21. https://doi.org/10.1161/CIRCRESAHA.123.322512
  70. Huang W., Xie W., Zhong H. et al. Cytosolic p53 inhibits parkin-mediated mitophagy and promotes acute liver injury induced by heat stroke // Front. in Immunology. 2022. V. 13. https://doi.org/10.3389/fimmu.2022.859231
  71. Zhang F., Peng W., Zhang J. et al. P53 and parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head // Cell Death & Disease. 2020. V. 11. № 1. P. 42. https://doi.org/10.1038/s41419-020-2238-1
  72. Wiley C.D., Velarde M.C., Lecot P. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype // Cell Metabolism. 2016. V. 23. № 2. P. 303–314. https://doi.org/10.1016/j.cmet.2015.11.011
  73. García-Macia M., Santos-Ledo A., Caballero B. et al. Selective autophagy, lipophagy and mitophagy, in the harderian gland along the oestrous cycle: А potential retrieval effect of melatonin // Sci. Rep. 2019. V. 9. № 1. P. 18597. https://doi.org/10.1038/s41598-019-54743-5
  74. Amin S., Liu B., Gan L. Autophagy prevents microglial senescence // Nat. Cell Biol. 2023. V. 25. № 7. P. 923–925. https://doi.org/10.1038/s41556-023-01168-y
  75. Young A.R.J., Narita M., Narita M. Spatio-temporal association between mTOR and autophagy during cellular senescence // Autophagy. 2011. V. 7. № 11. P. 1387–1388. https://doi.org/10.4161/auto.7.11.17348
  76. Kang C., Elledge S.J. How autophagy both activates and inhibits cellular senescence // Autophagy. 2016. V. 12. № 5. P. 898–899. https://doi.org/10.1080/15548627.2015.1121361
  77. Zhou J., Chen H., Du J. et al. Glutamine availability regulates the development of aging mediated by mTOR signaling and autophagy // Front. in Pharmacology. 2022. V. 13. https://doi.org/10.3389/fphar.2022.924081
  78. Gao J.W., Shi H., Gao F.P. et al. Inhibition of OLR1 reduces SASP of nucleus pulposus cells by targeting autophagy-GATA4 axis // J. Gerontology. Series A: Biol. Sci. аnd Med. Sci. 2024. https://doi.org/10.1093/gerona/glae204
  79. Ellison-Hughes G.M. Senescent cells: Targeting and therapeutic potential of senolytics in age-related diseases with a particular focus on the heart // Expert Opinion on Therapeutic Targets. 2020. V. 24. № 9. P. 819–823. https://doi.org/10.1080/14728222.2020.1798403
  80. Cuollo L., Antonangeli F., Santoni A., Soriani A. The senescence-associated secretory phenotype (SASP) in the challenging future of cancer therapy and age-related diseases // Biology. 2020. V. 9. № 12. https://doi.org/10.3390/biology9120485
  81. Zhao X., Lu J., Zhang C. et al. Methamphetamine induces cardiomyopathy through GATA4/NF-κB/SASP axis-mediated cellular senescence // Toxicol. аnd Applied Pharmacology. 2023. V. 466. https://doi.org/10.1016/j.taap.2023.116457
  82. Acosta J.C., O'Loghlen A., Banito A. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence // Cell. 2008. V. 133. № 6. P. 1006–1018. https://doi.org/10.1016/j.cell.2008.03.038
  83. Ortiz-Montero P., Londoño-Vallejo A., Vernot J.P. Senescence-associated IL-6 and IL-8 cytokines induce a self-and cross-reinforced senescence/inflammatory milieu strengthening tumorigenic capabilities in the MCF-7 breast cancer cell line // Cell Communication аnd Signaling. 2017. V. 15. № 1. P. 1–18. https://doi.org/10.1186/s12964-017-0172-3
  84. Xu M., Tchkonia T., Ding H. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age // Proc. Natl Acad. Sci. USA. 2015. V. 112. № 46. P. E6301–E6310. https://doi.org/10.1073/pnas.1515386112
  85. Chou L.Y., Ho C.T., Hung S.C. Paracrine senescence of mesenchymal stromal cells involves inflammatory cytokines and the NF-κB pathway // Cells. 2022. V. 11. № 20. https://doi.org/10.3390/cells11203324
  86. Molofsky A.V., Slutsky S.G., Joseph N.M. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing // Nature. 2006. V. 443. № 7110. P. 448–452. https://doi.org/10.1038/nature05091
  87. Kaeberlein M., McVey M., Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms // Genes & Development. 1999. V. 13. № 19. P. 2570–2580. https://doi.org/10.1101/gad.13.19.2570
  88. Ziętara P., Dziewięcka M., Augustyniak M. Why is longevity still a scientific mystery? Sirtuins – past, present and future // Int. J. Mol. Sci. 2022. V. 24. № 1. https://doi.org/10.3390/ijms24010728
  89. Chen H., Liu X., Zhu W. et al. SIRT1 ameliorates age-related senescence of mesenchymal stem cells via modulating telomere shelterin // Front. Aging Neurosci. 2014. V. 6. https://doi.org/10.3389/fnagi.2014.00103
  90. Loganathan C., Kannan A., Panneerselvam A. et al. The possible role of sirtuins in male reproduction // Mol. and Cell. Biochemistry. 2021. V. 476. P. 2857–2867. https://doi.org/10.1007/s11010-021-04116-2
  91. Zhang X., Ameer F.S., Azhar G., Wei J.Y. Alternative splicing increases sirtuin gene family diversity and modulates their subcellular localization and function // Int. J. Mol. Sci. 2021. V. 22. № 2. https://doi.org/10.3390/ijms22020473
  92. Matsushima S., Sadoshima J. The role of sirtuins in cardiac disease // Am. J. Physiology-Heart and Circulatory Physiol. 2015. V. 309. № 9. P. H1375–H1389. https://doi.org/10.1152/ajpheart.00053.2015
  93. Chen C., Zhou M., Ge Y. et al. SIRT1 and aging related signaling pathways // Mechanisms Ageing and Development. 2020. V. 187. https://doi.org/10.1016/j.mad.2020.111215
  94. Van der Horst A., Tertoolen L.G., de Vries-Smits L.M. et al. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2SIRT1 // J. Biol. Chem. 2004. V. 279. № 28. P. 28873–28879. https://doi.org/10.1074/jbc.M401138200
  95. Jablonska B., Gierdalski M., Chew L.J. et al. Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury // Nat. Communications. 2016. V. 7. № 1. https://doi.org/10.1038/ncomms13866
  96. Zhao K., Zhang H., Yang D. SIRT1 exerts protective effects by inhibiting endoplasmic reticulum stress and NF-κB signaling pathways // Front. in Cell and Development. Biol. 2024. V. 12. https://doi.org/10.3389/fcell.2024.1405546
  97. Yu X., Li Y., Mu X. Effect of quercetin on PC12 alzheimer’s disease cell model induced by Aβ25-35 and its mechanism based on Sirtuin1/Nrf2/HO‐1 pathway // BioMed Res. Int. 2020. V. 2020. № 1. https://doi.org/10.1155/2020/8210578
  98. Zhao Y., Jiang Q., Zhang X. et al. l-Arginine alleviates LPS-induced oxidative stress and apoptosis via activating SIRT1-AKT-nrf2 and SIRT1-FOXO3a signaling pathways in C2C12 myotube cells // Antioxidants. 2021. V. 10. № 12. P. 1957.
  99. Jin D., Zhao Y., Sun Y. et al. Jiedu tongluo baoshen formula enhances renal tubular epithelial cell autophagy to prevent renal fibrosis by activating SIRT1/LKB1/AMPK pathway // Biomedicine & Pharmacotherapy. 2023. V. 160. https://doi.org/10.1016/j.biopha.2023.114340
  100. Zhu L., Duan W., Wu G. et al. Protective effect of hydrogen sulfide on endothelial cells through Sirt1-FoxO1-mediated autophagy // Ann. Translational Med. 2020. V. 8. № 23. https://doi.org/10.21037/atm-20-3647
  101. Yan D., Yang Y., Lang J. et al. SIRT1/FOXO3-mediated autophagy signaling involved in manganese-induced neuroinflammation in microglia // Ecotoxicology and Environmental Safety. 2023. V. 256. https://doi.org/10.1016/j.ecoenv.2023.114872
  102. Qi X., Zheng S., Ma M. et al. Curcumol suppresses CCF-mediated hepatocyte senescence through blocking LC3B–lamin B1 interaction in alcoholic fatty liver disease // Front. in Pharmacology. 2022. V. 13. https://doi.org/10.3389/fphar.2022.912825
  103. Meng F., Qian M., Peng B. et al. Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice // eLife. 2020. V. 9. https://doi.org/10.7554/eLife.55828
  104. Guo Z., Li P., Ge J., Li H. SIRT6 in aging, metabolism, inflammation and cardiovascular diseases // Aging and Disease. 2022. V. 13. № 6. P. 1787. https://doi.org/10.14336/AD.2022.0413
  105. Dong X.C. Sirtuin 6A key regulator of hepatic lipid metabolism and liver Health // Cells. 2023. V. 12. № 4. https://doi.org/10.3390/cells12040663
  106. Zhang N., Li Z., Mu W. et al. Calorie restriction-induced SIRT6 activation delays aging by suppressing NF-κB signaling // Cell Cycle (Georgetown, Tex.). 2016. V. 15. № 7. P. 1009–1018. https://doi.org/10.1080/15384101.2016.1152427
  107. Zhang P., Tu B., Wang H. et al. Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion // Proc. Natl Acad. Sci. USA. 2014. V. 111. № 29. P. 10684–10689. https://doi.org/10.1073/pnas.1411026111
  108. Li X., Liu L., Jiang W. et al. SIRT6 protects against myocardial ischemia–reperfusion injury by attenuating aging-related CHMP2B accumulation // J. Cardiovascular Translational Res. 2022. V. 15. № 4. P. 740–753. https://doi.org/10.1007/s12265-021-10184-y
  109. Lu J., Sun D., Liu Z. et al. SIRT6 suppresses isoproterenol-induced cardiac hypertrophy through activation of autophagy // Translational Res. 2016. V. 172. P. 96–112. https://doi.org/10.1016/j.trsl.2016.03.002
  110. Cao Y., Peng T., Ai C. et al. Inhibition of SIRT6 aggravates p53-mediated ferroptosis in acute lung injury in mice // Heliyon. 2023. V. 9. № 11. https://doi.org/10.1016/j.heliyon.2023.e22272
  111. Li L., Zhang H., Chen B. et al. BaZiBuShen alleviates cognitive deficits and regulates Sirt6/NRF2/HO-1 and Sirt6/P53-PGC-1α-TERT signaling pathways in aging mice // J. Ethnopharmacology. 2022. V. 282. https://doi.org/10.1016/j.jep.2021.114653
  112. Tarighi S., Kumari P., Vaquero A. et al. The SIRT7-nucleolus connection in cancer: ARF enters the fray // Mol. & Cell. Oncology. 2024. V. 11. № 1. https://doi.org/10.1080/23723556.2024.2381287
  113. Ford E., Voit R., Liszt G. et al. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription // Genes & Development. 2006. V. 20. № 9. P. 1075–1080. https://doi.org/10.1101/gad.1399706
  114. Kasselimi E., Pefani D.E., Taraviras S., Lygerou Z. Ribosomal DNA and the nucleolus at the heart of aging // Trends in Biochem. Sci. 2022. V. 47. № 4. P. 328–341. https://doi.org/10.1016/j.tibs.2021.12.007
  115. Kumari P., Tarighi S., Braun T., Ianni A. SIRT7 acts as a guardian of cellular integrity by controlling nucleolar and extra-nucleolar functions // Genes. 2021. V. 12. № 9. https://doi.org/10.3390/genes12091361
  116. Raza U., Tang X., Liu Z., Liu B. SIRT7: The seventh key to unlocking the mystery of aging // Physiol. Reviews. 2024. V. 104. № 1. P. 253–280. https://doi.org/10.1152/physrev.00044.2022
  117. Kiran S., Chatterjee N., Singh S. et al. Intracellular distribution of human SIRT 7 and mapping of the nuclear/nucleolar localization signal // FEBS J. 2013. V. 280. № 14. P. 3451–3466. https://doi.org/10.1111/febs.12346
  118. Sun L., Fan G., Shan P. et al. Regulation of energy homeostasis by the ubiquitin-independent REGγ proteasome // Nat. Communications. 2016. V. 7. № 1. https://doi.org/10.1038/ncomms12497
  119. Mohrin M., Shin J., Liu Y. et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging // Science. 2015. V. 347. № 6228. P. 1374–1377. https://doi.org/10.1126/science.aaa2361
  120. Liu J.P., Chen R. Stressed SIRT7: Facing a crossroad of senescence and immortality // Clin. Experim. Pharmacol. and Physiol. 2015. V. 42. № 6. P. 567–569. https://doi.org/10.1111/1440-1681.12423
  121. Shin J., He M., Liu Y. et al. SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease // Cell Reports. 2013. V. 5. № 3. P. 654–665. https://doi.org/10.1016/j.celrep.2013.10.007
  122. Ianni A., Kumari P., Tarighi S. et al. SIRT7-dependent deacetylation of NPM promotes p53 stabilization following UV-induced genotoxic stress // Proc. Natl Acad. Sci. USA. 2021. V. 118. № 5. https://doi.org/10.1073/pnas.2015339118
  123. Lu Y.F., Xu X.P., Lu X.P. et al. SIRT7 activates p53 by enhancing PCAF-mediated MDM2 degradation to arrest the cell cycle // Oncogene. 2020. V. 39. № 24. P. 4650–4665. https://doi.org/10.1038/s41388-020-1305-5
  124. Zhao J., Wozniak A., Adams A. et al. SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway // J. Experim. & Clin. Cancer Res. 2019. V. 38. P. 1–16. https://doi.org/10.1186/s13046-019-1246-4
  125. Vazquez B.N., Thackray J.K., Simonet N.G. et al. SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair // EMBO J. 2016. V. 35. № 14. P. 1488–1503. https://doi.org/10.15252/embj.201593499
  126. Vazquez B.N., Thackray J.K., Simonet N.G. et al. SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina // Nucl. Acids. Res. 2019. V. 47. № 15. P. 7870–7885. https://doi.org/10.1093/nar/gkz519
  127. Bi S., Liu Z., Wu Z. et al. SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer // Protein & Cell. 2020. V. 11. № 7. P. 483–504. https://doi.org/10.1007/s13238-020-00728-4
  128. North B.J., Verdin E. Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis // PloS One. 2007. V. 2. № 8. https://doi.org/10.1371/journal.pone.0000784
  129. Rack J.G.M., VanLinden M.R., Lutter T. et al. Constitutive nuclear localization of an alternatively spliced sirtuin-2 isoform // J. Mol. Biol. 2014. V. 426. № 8. P. 1677–1691. https://doi.org/10.1016/j.jmb.2013.10.027
  130. Chen X., Lu W., Wu D. Sirtuin 2 (SIRT2): Confusing roles in the pathophysiology of neurological disorders // Front. in Neuroscience. 2021. V. 15. https://doi.org/10.3389/fnins.2021.614107
  131. Zhu C., Dong X., Wang X. et al. Multiple roles of SIRT2 in regulating physiological and pathological signal transduction // Genet. Research. 2022. V. 2022. P. e38. https://doi.org/10.1155/2022/9282484
  132. Serrano L., Martínez-Redondo P., Marazuela-Duque A. et al. The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation // Genes & Development. 2013. V. 27. № 6. P. 639–653. https://doi.org/10.1101/gad.211342.112
  133. Kim H.W., Kim S.A., Ahn S.G. Sirtuin inhibitors, EX527 and AGK2, suppress cell migration by inhibiting HSF1 protein stability // Oncology Reports. 2016. V. 35. № 1. P. 235–242. https://doi.org/10.3892/or.2015.4381
  134. Zhang H., Park S.H., Pantazides B.G. et al. SIRT2 directs the replication stress response through CDK9 deacetylation // Proc. the Nat. Acad. Sci. USA. 2013. V. 110. № 33. P. 13546–13551. https://doi.org/10.1073/pnas.1301463110
  135. Zhang X., Brachner A., Kukolj E. et al. SIRT2 deacetylates GRASP55 to facilitate post-mitotic Golgi assembly // J. Cell Sci. 2019. V. 132. № 21. https://doi.org/10.1242/jcs.232389
  136. Carmona B., Marinho H.S., Matos C.L. et al. Tubulin post-translational modifications: the elusive roles of acetylation // Biology. 2023. V. 12. № 4. https://doi.org/10.3390/biology12040561
  137. Moujaber O., Fishbein F., Omran N. et al. Cellular senescence is associated with reorganization of the microtubule cytoskeleton // Cell. and Mol. Life Sci. 2019. V. 76. P. 1169–1183. https://doi.org/10.1007/s00018-018-2999-1
  138. Park S.Y., Chung M.J., Son J.Y. et al. The role of sirtuin 2 in sustaining functional integrity of the liver // Life Sci. 2021. V. 285. https://doi.org/10.1016/j.lfs.2021.119997
  139. Kim S.B., Heo J.I., Kim H., Kim K.S. Acetylation of PGC1α by histone deacetylase 1 downregulation is implicated in radiation-induced senescence of brain endothelial cells // J. Gerontology. Series A. Biol. Sci. and Med. Sci. 2019. V. 74. № 6. P. 787–793. https://doi.org/10.1093/gerona/gly167
  140. Krishnan J., Danzer C., Simka T. et al. Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system // Genes & Development. 2012. V. 26. № 3. P. 259–270. https://doi.org/10.1101/gad.180406.111
  141. Ng F., Tang B.L. Sirtuins' modulation of autophagy // J. Cell. Physiol. 2013. V. 228. № 12. P. 2262–2270. https://doi.org/10.1002/jcp.24399
  142. Wang Z., Yu T., Huang P. Post-translational modifications of FOXO family proteins // Mol. Med. Rep. 2016. V. 14. № 6. P. 4931–4941. https://doi.org/10.3892/mmr.2016.5867
  143. Wang F., Nguyen M., Qin F.X., Tong Q. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction // Aging Cell. 2007. V. 6. № 4. P. 505–514. https://doi.org/10.1111/j.1474-9726.2007.00304.x
  144. Yu W., Dittenhafer-Reed K.E., Denu J.M. SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status // J. Biol. Chem. 2012. V. 287. № 17. P. 14078–14086. https://doi.org/10.1074/jbc.M112.355206
  145. Oppedisano F., Nesci S., Spagnoletta A. Mitochondrial sirtuin 3 and role of natural compounds: the effect of post-translational modifications on cellular metabolism // Crit. Rev. in Biochem. and Mol. Biol. 2024. V. 59. № 3–4. P. 1–22. https://doi.org/10.1080/10409238.2024.2377094
  146. Koentges C., Cimolai M.C., Pfeil K. et al. Impaired SIRT3 activity mediates cardiac dysfunction in endotoxemia by calpain-dependent disruption of ATP synthesis // J. Mol. and Cell. Cardiol. 2019. V. 133. P. 138–147. https://doi.org/10.1016/j.yjmcc.2019.06.008
  147. Silaghi C.N., Farcaș M., Crăciun A.M. Sirtuin 3 (SIRT3) pathways in age-related cardiovascular and neurodegenerative diseases // Biomedicines. 2021. V. 9. № 11. https://doi.org/10.3390/biomedicines9111574
  148. Xin T., Lu C. SirT3 activates AMPK-related mitochondrial biogenesis and ameliorates sepsis-induced myocardial injury // Aging (Albany NY). 2020. V. 12. № 16. P. 16224. https://doi.org/10.18632/aging.103644
  149. Sundaresan N.R., Samant S.A., Pillai V.B. et al. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70 // Mol. and Cell. Biol. 2008. V. 28. № 20. P. 6384–6401. https://doi.org/10.1128/MCB.00426-08
  150. Song C.L., Tang H., Ran L.K. et al. Sirtuin 3 inhibits hepatocellular carcinoma growth through the glycogen synthase kinase-3β/BCL2-associated X protein-dependent apoptotic pathway // Oncogene. 2016. V. 35. № 5. P. 631–641. https://doi.org/10.1038/onc.2015.121
  151. Cheng Y., Ren X., Gowda A.S. et al. Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress // Cell Death & Disease. 2013. V. 4. № 7. P. e731–e731. https://doi.org/10.1038/cddis.2013.254
  152. Rangarajan P., Karthikeyan A., Lu J. et al. Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia // Neuroscience. 2015. V. 311. P. 398–414. https://doi.org/10.1016/j.neuroscience.2015.10.048
  153. Zhang M., Deng Y.N., Zhang J.Y. et al. SIRT3 protects rotenone-induced injury in SH-SY5Y cells by promoting autophagy through the LKB1-AMPK-mTOR pathway // Aging and Disease. 2018. V. 9. № 2. P. 273. https://doi.org/10.14336/AD.2017.0517
  154. Li Y., Ma Y., Song L. et al. SIRT3 deficiency exacerbates p53/Parkin-mediated mitophagy inhibition and promotes mitochondrial dysfunction: Implication for aged hearts // Int. J. Mol. Med. 2018. V. 41. № 6. P. 3517–3526. https://doi.org/10.3892/ijmm.2018.3555
  155. Kumar S., Lombard D.B. Mitochondrial sirtuins and their relationships with metabolic disease and cancer // Antioxidants & Redox Signaling. 2015. V. 22. № 12. P. 1060–1077. https://doi.org/10.1089/ars.2014.6213
  156. Min Z., Gao J., Yu Y. The roles of mitochondrial SIRT4 in cellular metabolism // Front. in Endocrinology 2019. V. 9. https://doi.org/10.3389/fendo.2018.00783
  157. Haigis M.C., Mostoslavsky R., Haigis K.M. et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β cells // Cell. 2006. V. 126. № 5. P. 941–954. https://doi.org/10.1016/j.cell.2006.06.057
  158. Jeong S.M., Xiao C., Finley L.W. et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism // Cancer Cell. 2013. V. 23. № 4. P. 450–463. https://doi.org/10.1016/j.ccr.2013.02.024
  159. Sun X., Li Q., Tang Y. et al. Epigenetic activation of secretory phenotypes in senescence by the FOXQ1-SIRT4-GDH signaling // Cell Death & Disease. 2023. V. 14. № 7. P. 481. https://doi.org/10.1038/s41419-023-06002-9
  160. Luo Y.X., Tang X., An X.Z. et al. SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity // Europ. Heart J. 2017. V. 38. № 18. P. 1389–1398. https://doi.org/10.1093/eurheartj/ehw138
  161. Lin S., Wu B., Hu X., Lu H. Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction // Int. J. Biol. Sci. 2024. V. 20. № 4. P. 1256. https://doi.org/10.7150/ijbs.85585
  162. Lang A., Anand R., Altinoluk-Hambüchen S. et al. SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy // Aging (Albany NY). 2017. V. 9. № 10. P. 2163. https://doi.org/10.18632/aging.101307
  163. Fu L., Dong Q., He J. et al. SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway // Oncogene. 2017. V. 36. № 19. P. 2724–2736. https://doi.org/10.1038/onc.2016.425
  164. Du J., Zhou Y., Su X. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase // Science. 2011. V. 334. № 6057. P. 806–809. https://doi.org/10.1126/science.1207861
  165. Kumar S., Lombard D.B. Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology // Crit. Rev. in Biochem. and Mol. Biol. 2018. V. 53. № 3. P. 311–334. https://doi.org/10.1080/10409238.2018.1458071
  166. Bhatt D.P., Mills C.A., Anderson K.A. et al. Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice // J. Biol. Chem. 2022. V. 298. № 4. https://doi.org/10.1016/j.jbc.2022.101723
  167. Wang Y., Zhu Y., Xing S. et al. SIRT5 prevents cigarette smoke extract-induced apoptosis in lung epithelial cells via deacetylation of FOXO3 // Cell Stress and Chaperones. 2015. V. 20. № 5. P. 805–810. https://doi.org/10.1007/s12192-015-0599-7
  168. Zhang W.G., Bai X.J., Chen X.M. SIRT1 variants are associated with aging in a healthy Han Chinese population // Clin. Chim. Acta. Int. J. Clin. Chem. 2010. V. 411. № 21–22. P. 1679–1683. https://doi.org/10.1016/j.cca.2010.06.030
  169. Kim S., Bi X., Czarny-Ratajczak M. et al. Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity // Biogerontology. 2012. V. 13. № 2. P. 119–131. https://doi.org/10.1007/s10522-011-9360-5
  170. Crocco P., Montesanto A., Passarino G., Rose G. Polymorphisms falling within putative miRNA target sites in the 3′ UTR region of SIRT2 and DRD2 genes are correlated with human longevity // J. Gerontology. Series A: Biol. Sci. and Med. Sci. 2016. V. 71. № 5. P. 586–592. https://doi.org/10.1093/gerona/glv058
  171. Joseph A.M., Adhihetty P.J., Buford T.W. et al. The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high-and low-functioning elderly individuals // Aging Cell. 2012. V. 11. № 5. P. 801–809. https://doi.org/10.1111/j.1474-9726.2012.00844.x
  172. Donlon T.A., Morris B.J., Chen R. et al. Analysis of polymorphisms in 59 potential candidate genes for association with human longevity // J. Gerontology. Series A. Biol. Sci. and Med. Sci. 2018. V. 73. № 11. P. 1459–1464. https://doi.org/10.1093/gerona/glx247
  173. Hirvonen K., Laivuori H., Lahti J. et al. SIRT6 polymorphism rs117385980 is associated with longevity and healthy aging in Finnish men // BMC Med. Genet. 2017. V. 18. P. 1–5. https://doi.org/10.1186/s12881-017-0401-z
  174. You L.I., Qin J., Wei X. et al. Association of SIRT6 gene polymorphisms with human longevity // Iranian J. Public Health. 2016. V. 45. № 11. P. 1420.
  175. TenNapel M.J., Lynch C.F., Burns T.L. SIRT6 minor allele genotype is associated with > 5-year decrease in lifespan in an aged cohort // PLoS One. 2014. V. 9. № 12. https://doi.org/10.1371/journal.pone.0115616
  176. Kilic U., Gok O., Erenberk U. et al. A remarkable age-related increase in SIRT1 protein expression against oxidative stress in elderly: SIRT1 gene variants and longevity in human // PloS One. 2015. V. 10. № 3. https://doi.org/10.1371/journal.pone.0117954
  177. Song X., Wang H., Wang C. et al. Association of sirtuin gene polymorphisms with susceptibility to coronary artery disease in a North Chinese population // BioMed. Res. Int. 2022. V. 2022. № 1. https://doi.org/10.1155/2022/4294008
  178. Nasiri M., Rauf M., Kamfiroozie H. et al. SIRT1 gene polymorphisms associated with decreased risk of atherosclerotic coronary artery disease // Gene. 2018. V. 672. P. 16–20. https://doi.org/10.1016/j.gene.2018.05.117
  179. Camporez D., Belcavello L., Almeida J.F.F. et al. Positive association of a Sirt1 variant and parameters of oxidative stress on Alzheimer’s disease // Neurological Sci. 2021. V. 42. № 5. P. 1843–1851. https://doi.org/10.1007/s10072-020-04704-y
  180. Wei W., Xu X., Li H. et al. The SIRT2 polymorphism rs10410544 and risk of Alzheimer’s disease: a meta-analysis // Neuromolecular Med. 2014. V. 16. P. 448–456. https://doi.org/10.1007/s12017-014-8291-0
  181. Figarska S.M., Vonk J.M., Boezen H.M. SIRT1 polymorphism, long-term survival and glucose tolerance in the general population // PLoS One. 2013. V. 8. № 3. https://doi.org/10.1371/journal.pone.0058636
  182. Zillikens M.C., van Meurs J.B., Rivadeneira F. et al. SIRT1 genetic variation is related to BMI and risk of obesity // Diabetes. 2009. V. 58. № 12. P. 2828–2834. https://doi.org/10.2337/db09-0536
  183. Liu T., Yang W., Pang S. et al. Functional genetic variants within the SIRT2 gene promoter in type 2 diabetes mellitus // Diabetes Res. and Clin. Practice. 2018. V. 137. P. 200–207. https://doi.org/10.1016/j.diabres.2018.01.012
  184. Zheng X., Li J., Sheng J. et al. Haplotypes of the mutated SIRT2 promoter contributing to transcription factor binding and type 2 diabetes susceptibility // Genes. 2020. V. 11. № 5. https://doi.org/10.3390/genes11050569
  185. Kurylowicz A. In search of new therapeutic targets in obesity treatment: sirtuins // Int. J. Mol. Sci. 2016. V. 17. № 4. https://doi.org/10.3390/ijms17040572
  186. Kalemci S., Edgunlu T.G., Kara M. et al. Sirtuin gene polymorphisms are associated with chronic obstructive pulmonary disease in patients in Muğla province // Kardiochirurgia i torakochirurgia polska = Po-lish J. Cardio-Thoracic Surgery. 2014. V. 11. № 3. P. 306. https://doi.org/10.5114/kitp.2014.45682
  187. Korytina G.F., Akhmadishina L.Z., Markelov V.A. et al. Role of PI3K/AKT/mTOR signaling pathway and sirtuin genes in chronic obstructive pulmonary disease development // Vavilov J. Genet. and Breeding. 2023. V. 27. № 5. P. 512. https://doi.org/10.18699/VJGB-23-62
  188. Korytina G.F., Akhmadishina L.Z., Aznabaeva Y.G. et al. Associations of the NRF2/KEAP1 pathway and antioxidant defense gene polymorphisms with chronic obstructive pulmonary disease // Gene. 2019. V. 692. P. 102–112. https://doi.org/10.1016/j.gene.2018.12.061
  189. Kovanen L., Donner K., Partonen T. SIRT1 polymorphisms associate with seasonal weight variation, depressive disorders, and diastolic blood pressure in the general population // PloS One. 2015. V. 10. № 10. https://doi.org/10.1371/journal.pone.0141001
  190. Song Z.P., Li J.R., Gao R. et al. Association between single nucleotide polymorphism in promoter region of SIRT1 gene and senile degenerative heart valvular disease // Zhonghua Yi Xue Za Zhi. 2020. V. 100. № 13. P. 991–996. https://doi.org/10.3760/cma.j.cn112137-20190716-01575
  191. Huang J., Sun L., Liu M. et al. Association between SIRT1 gene polymorphisms and longevity of populations from Yongfu region of Guangxi // Chinese J. Med. Genet. 2013. V. 30. № 1. P. 55–59. https://doi.org/10.3760/cma.j.issn.1003-9406.2013.01.013
  192. Nasiri M., Rauf M., Kamfiroozie H. et al. SIRT1 gene polymorphisms associated with decreased risk of atherosclerotic coronary artery disease // Gene. 2018. V. 672. P. 16–20. https://doi.org/10.1016/j.gene.2018.05.117
  193. Helisalmi S., Vepsäläinen S., Hiltunen M. et al. Genetic study between SIRT1, PPARD, PGC-1alpha genes and Alzheimer's disease // J. Neurology. 2008. V. 255. № 5. P. 668–673. https://doi.org/10.1007/s00415-008-0774-1
  194. Maszlag-Török R., Boros F.A., Vécsei L., Klivényi P. Gene variants and expression changes of SIRT1 and SIRT6 in peripheral blood are associated with Parkinson's disease // Sci. Reports. 2021. V. 11. № 1. P. 10677. https://doi.org/10.1038/s41598-021-90059-z
  195. Kuningas M., Putters M., Westendorp R.G. et al. SIRT1 gene, age-related diseases, and mortality: the Leiden 85-plus study // J. Gerontology. Series A: Biol. Sci. and Med. Sci. 2007. V. 62. № 9. P. 960–965. https://doi.org/10.1093/gerona/62.9.960
  196. Wang Y., Tong L., Gu N. et al. Association of sirtuin 1 gene polymorphisms with the risk of coronary heart disease in Chinese Han patients with type 2 diabetes mellitus // J. Diabetes Res. 2022. V. 2022. https://doi.org/10.1155/2022/8494502
  197. Cheng J., Cho M., Cen J.M. et al. A tagSNP in SIRT1 gene confers susceptibility to myocardial infarction in a Chinese Han population // PloS One. 2015. V. 10. № 2. P. e0115339. https://doi.org/10.1371/journal.pone.0115339
  198. Yamac A.H., Uysal O., Ismailoglu Z. et al. Premature myocardial infarction: genetic variations in SIRT1 affect disease susceptibility // Cardiol. Res. and Practice. 2019. V. 2019. № 1. https://doi.org/10.1155/2019/8921806
  199. Dardano A., Lucchesi D., Garofolo M. et al. SIRT1 rs7896005 polymorphism affects major vascular outcomes, not all-cause mortality, in Caucasians with type 2 diabetes: A 13-year observational study // Diabetes/Metabolism Res. and Reviews. 2022. V. 38. № 4. https://doi.org/10.1002/dmrr.3523
  200. Kim S., Bi X., Czarny-Ratajczak M. et al. Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity // Biogerontology. 2012. V. 13. № 2. P. 119–131. https://doi.org/10.1007/s10522-011-9360-5
  201. Chen X., Mai H., Chen X. et al. Rs2015 polymorphism in miRNA target site of sirtuin2 gene is associated with the risk of Parkinson's disease in Chinese Han population // BioMed Res. Int. 2019. V. 2019. https://doi.org/10.1155/2019/1498034
  202. Albani D., Mazzuco S., Chierchia A. et al. The SIRT1 promoter polymorphic site rs12778366 increases IL-6 related human mortality in the prospective study «Treviso Longeva (TRELONG)» // Int. J. Mol. Epidemiol. and Genet. 2015. V. 6. № 1. P. 20–26.
  203. Shen Y., Chen L., Zhang S., Xie L. Correlation between SIRT2 3'UTR gene polymorphism and the susceptibility to Alzheimer's disease // J. Mol. Neuroscience: MN. 2020. V. 70. № 6. P. 878–886. https://doi.org/10.1007/s12031-020-01513-y
  204. Wang Y., Cai Y., Huang H. et al. MiR-486-3p influences the neurotoxicity of a-synuclein by targeting the SIRT2 gene and the polymorphisms at target sites contributing to Parkinson's disease // Cell.r Physiol. and Biochem. Int. J. Experim. Cell. Physiol., Biochem., and Pharmacol. 2018. V. 51. № 6. P. 2732–2745. https://doi.org/10.1159/000495963
  205. Cacabelos R., Carril J.C., Cacabelos N. et al. Sirtuins in Alzheimer's disease: SIRT2-related genophenotypes and implications for pharmacoepigenetics // Int. J. Mol. Sci. 2019. V. 20. № 5. https://doi.org/10.3390/ijms20051249
  206. Wei W., Xu X., Li H. et al. The SIRT2 polymorphism rs10410544 and risk of Alzheimer’s disease: A meta-analysis // Neuromol. Med. 2014. V. 16. P. 448–456. https://doi.org/10.1007/s12017-014-8291-0
  207. Crocco P., Montesanto A., Passarino G., Rose G. Polymorphisms falling within putative miRNA target sites in the 3′ UTR region of SIRT2 and DRD2 genes are correlated with human longevity // J. Gerontology Series A: Biol. Sci. and Med. Sci. 2016. V. 71. № 5. P. 586–592. https://doi.org/10.1093/gerona/glv058
  208. Polito L., Kehoe P.G., Davin A. et al. The SIRT2 polymorphism rs10410544 and risk of Alzheimer's disease in two Caucasian case-control cohorts // Alzheimer's & Dementia: J. Alzheimer's Association. 2013. V. 9. № 4. P. 392–399. https://doi.org/10.1016/j.jalz.2012.02.003
  209. Dong C., Della-Morte D., Wang L. et al. Association of the sirtuin and mitochondrial uncoupling protein genes with carotid plaque // PloS One. 2011. V. 6. № 11. https://doi.org/10.1371/journal.pone.0027157
  210. Dong C., Della-Morte D., Cabral D. et al. Sirtuin/uncoupling protein gene variants and carotid plaque area and morphology // Int. J. Stroke: Official J. Int. Stroke Society. 2015. V. 10. № 8. P. 1247–1252. https://doi.org/10.1111/ijs.12623
  211. Albani D., Ateri E., Mazzuco S. et al. Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study «Treviso Longeva (TRELONG)» // Age (Dordrecht, Netherlands). 2014. V. 36. № 1. P. 469–478. https://doi.org/10.1007/s11357-013-9559-2
  212. Hirschey M.D., Shimazu T., Jing E. et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome // Mol. Cell. 2011. V. 44. № 2. P. 177–190. https://doi.org/10.1016/j.molcel.2011.07.019
  213. Zhong Y., Shen C., Peng Y. et al. Analysis of SIRT4 gene single-nucleotide polymorphisms in a Han Chinese population with dilated cardiomyopathy // Biomarkers in Medicine. 2022. V. 16. № 1. P. 11–21. https://doi.org/10.2217/bmm-2021-0363
  214. Sebastiani P., Riva A., Montano M. et al. Whole genome sequences of a male and female supercentenarian, ages greater than 114 years // Front. in Genetics. 2012. V. 2. https://doi.org/10.3389/fgene.2011.00090
  215. Tang S.S., Xu S., Cheng J. et al. Two tagSNPs rs352493 and rs3760908 within SIRT6 gene are associated with the severity of coronary artery disease in a Chinese Han population // Disease Markers. 2016. V. 2016. https://doi.org/10.1155/2016/1628041

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Molecular mechanisms of cellular aging.

Download (421KB)
Indexing metadata
3. Fig. 2. The main mechanisms of sirtuin-dependent modulation of cellular aging processes. IGF-1 – insulin-like growth factor; LKB1 – AMPK regulatory kinase; PPARγ – peroxisome proliferator-activated receptor gamma; GDH – glutamate dehydrogenase; FOXO3 – ForkheadboxO3 protein; p65 – subunit of NF-κB transcription factor; p-Akt – serine/threonine protein kinase; UCP2 – uncoupling protein 2; BAX – apoptosis regulator; S6K1 – ribosomal protein S6 kinase beta-1; TAK1 – TGF-beta-activated kinase 1; IDH2 – isocitrate dehydrogenase 2; CDK9 – cyclin-dependent kinase 9; NPM – nucleophosmin; NAD+ – nicotinamide adenine dinucleotide; RAPTOR – mTOR regulatory-associated protein; p-TSC1/2 – tuberous sclerosis proteins 1/2; PGC-1α – peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Ac – acetylated substrates for sirtuin deacetylase activity. Sirtuins (SIRT1–SIRT7) are key regulators of cellular aging, metabolic homeostasis, DNA repair, and stress responses. SIRT1 activates PGC-1α, enhancing mitochondrial biogenesis and fatty acid oxidation, and suppresses inflammation via modulation of NF-κB. SIRT3 and SIRT5 control the mitochondrial antioxidant response via activation of SOD2 and IDH2. SIRT6 regulates inflammation, DNA repair, and autophagy via modulation of NF-κB and CDK9. SIRT2 controls the cell cycle, cytoskeletal reorganization, and replicative stress. SIRT4 suppresses GDH and participates in mitochondrial repair, while SIRT7 maintains nuclear DNA homeostasis and regulates apoptosis via p53 and NPM factors. All sirtuins interact with key signaling pathways, including AMPK, mTOR, FOXO, insulin signaling, and DNA repair factors, providing a coordinated response to cellular stress and prolonging cell viability.

Download (558KB)
Indexing metadata

Copyright (c) 2025 Russian Academy of Sciences