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

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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.

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作者简介

V. Markelov

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

Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

俄罗斯联邦, Ufa, 450054; Ufa, 450008

L. Akhmadishina

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

Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

俄罗斯联邦, Ufa, 450054; Ufa, 450064

O. Kochetova

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

Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

俄罗斯联邦, Ufa, 450054; Ufa, 450008

V. Erdman

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

Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

俄罗斯联邦, Ufa, 450054; Ufa, 450008

G. Korytina

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

编辑信件的主要联系方式.
Email: guly_kory@mail.ru

Institute of Biochemistry and Genetics

俄罗斯联邦, Ufa, 450054; Ufa, 450008

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2. Fig. 1. Molecular mechanisms of cellular aging.

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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.

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