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Aging and disease    2020, Vol. 11 Issue (4) : 927-945     DOI: 10.14336/AD.2019.0820
Review |
Sirtuins and their Biological Relevance in Aging and Age-Related Diseases
Zhao Lijun1, Cao Jianzhong2, Hu Kexin1, He Xiaodong2, Yun Dou1, Tong Tanjun1,*, Han Limin1,*
1Peking University Research Center on Aging, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Beijing, China
2Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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Abstract  

Sirtuins, initially described as histone deacetylases and gene silencers in yeast, are now known to have many more functions and to be much more abundant in living organisms. The increasing evidence of sirtuins in the field of ageing and age-related diseases indicates that they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. Here, we summarize some of the recent discoveries in sirtuin biology that clearly implicate the functions of sirtuins in the regulation of aging and age-related diseases. Furthermore, human sirtuins are considered promising therapeutic targets for anti-aging and ageing-related diseases and have attracted interest in scientific communities to develop small molecule activators or drugs to ameliorate a wide range of ageing disorders. In this review, we also summarize the discovery and development status of sirtuin-targeted drug and further discuss the potential medical strategies of sirtuins in delaying aging and treating age-related diseases.

Keywords sirtuins      aging      age-related diseases      cancer     
Corresponding Authors: Tong Tanjun,Han Limin   
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These authors contributed equally to this work.

Just Accepted Date: 22 August 2019   Issue Date: 30 July 2020
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Zhao Lijun
Cao Jianzhong
Hu Kexin
He Xiaodong
Yun Dou
Tong Tanjun
Han Limin
Cite this article:   
Zhao Lijun,Cao Jianzhong,Hu Kexin, et al. Sirtuins and their Biological Relevance in Aging and Age-Related Diseases[J]. Aging and disease, 2020, 11(4): 927-945.
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http://www.aginganddisease.org/EN/10.14336/AD.2019.0820     OR
SirtuinClasslocalizationEnzymatic activity
Sirt1INuclear/CytosolicDeacetylase,Deacylase
Sirt2INuclear/CytosolicDeacetylase, Deacylase
Sirt3IMitochondrial/ Nuclear/CytosolicDeacetylase, Decrotonylase
Sirt4IIMitochondrialDeacetylase, ADP-ribosyltransferase, Lipoamidase, Deacylase
Sirt5IIIMitochondrial/ Nuclear/CytosolicDeacetylase, Desuccinylase, Demalonylase, Deglutarylase
Sirt6IVNuclear/CytosolicDeacetylase,Demyristoylase, ADP-ribosyltransferase, Deacylase
Sirt7IVNucleolar/nuclearDeacetylase, Desuccinylase
Table 1  The location and enzymatic catalytic activity of sirtuins.
Substrates/targetsFunction
ModificationActivationInhiibition
SIRT1H3K9ac, H3K26ac, H3K16ac, H1K26, H1K9, H3K56, H3K14, H4K16, α-tubulin, p53Suv39h1, N-Myc, ER, Sirt6, ADAM-10, LKB1, AMPK, NBS1, XPA, MnSOD, WRN, Ku70, FOXO1/3, PGC-1a, PPARα, FXRNF-KB, p300, p66shc, mTOR, HIF-1a, TNF-1a, Histone acctylation, SREBP-1cGlucose metabolism, fatty-acid and cholesterol metabolism, differentiation, insulin secretion, and neuroprotection, stress responses, DNA repair, vascular protection and other cellular processes
SIRT2α-tubulin, H3K56ac, H4K16ac,FOXO, c-Myc, G6PD, PEPCKNF-KB, p53, FoxO1Cell-cycle control, carbohydrate and lipid metabolism, tubulin and transcription factors deacetylation and anti-inflammatory
SIRT3H3K9, H4K16, H3K56ac, H4K14ac,Ku70, Mn-SOD, FOXO3a, DH2, FAO, GDH, complexI/III, IDH2p53, HIF-1a, Ros, lipogcncasisregulation of mitochondrial enzymes deacetylation, ATP production, reactive oxygen species (ROS) management, b-oxidation, ketogenesis, cell death, and carbohydrate and lipid metabolism
SIRT4GDH, AMPK, ROS, PDHInsulin secretion, glutamine and fatty acid metabolism and regulate the ATP homeostasis
SIRT5CPS1SOD1GLSUrea cycle, regulation of ATP synthesis, metabolism, apoptosis and intracellular signaling, regulation of ammonia detoxification, fatty acid oxidation
SIRT6H2BK12, H3K9ac
H3K56ac, WRN
FOXO, PARP1, CtIP, P53, DNA-PKcs, CCNDBP1NF-KB, RELA, TNF-a, IGF-1, HIF-1a, Myc, c-Jun, PGC-1a, GCN5Telomeres and telomeric functions, DNA repair, metabolic homeostasis, inflammation, stress responses, and genomic stability
SIRT7H2A, H2B, H3 (H3K18)FOXORNA-POLY-merase, HIF-1a/2aregulates the transcription of rDNA and mediate histone desuccinylation
Table 2  The substrates/targets and functions of sirtuins.
SirtuinFunctions in agingRegulatory factor in signal pathway
PositiveNegative
YeastSir2Replicative lifespan extension Cell cycle arrestNAD+, mTOR, PKA, Sch9
C. eleganssir-2.1, sir-2.2, sir-2.3, sir-2.4Lifespan extension, Stress resistancemTOR, HLH-30, PHA-4, NHR-62, WWP-1, KLF-1, EGL-9, DAF-16, AAK-2, HSF-1, FOXA, DAF-2, IGF-1, SKN-1, SAMS-1, RAB-10, DRR-1, DRR-2UNC-51, ATG1, ULK1, BEC-1, ATG6, Beclin1, VPS-34, ATG-18, Wipi, ATG-7, ATG-8, IGG-1, HIF-1, TOR, RHEB-1, INS-7
DrosophiladSir2, Sirt4Lifespan extensionFOXO,4E-BPINR, p53, mTOR/S6K pathway
Mammalsirt1Lifespan extension, DNA repair, Cell cycle arrest, Cellular senescenceeNOS, Erβ, FOXO3PAI-1, p53, p16INK4a, NF-KB, p665hc, LKB1, Ciclin D1, mTOR/S6K pathway
sirt 2Cell cycle regulationBubR1, PPP, NAD+, FOXOs, Mn-SODWnt, AKT, NF-KB,
sirt 3Mitochondrial function, Oxidative stress, Centenarian-linked SNPsFOXO3A, Mn-SODNF-KB, MAPK/ERK, P13K/AKt
sirt 4Fatty acid oxidation, ApoptosisNF-KB, Bax, Caspase, GDH, AMPK
sirt 5Fatty acid oxidation, Oxidative stressBCL, GDH, PDH
sirt 6Lifespan extension, DNA repair, Genome stability, Telomere maintenanceNrf2, eNOS, IGF/AKt, p53P21Cip1/Waf1, NF-KB, ICM-1, PAI-1,
sirt 7Epigenetic regulation, Stress resistance, ApoptosisFOXO3Myc, HIF-1a/2a, p53,
Table 3  Functions and signaling pathway of sirtuins in aging.
Aging and age-related disease
Neurodegenerative diseasesPresbyophrenia, Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis
Cardiovascular and cerebrovascular diseasesHypertension, Coronary disease, Cardiomyopathies, Elder valvular heart disease, Arrhythmia, Cardiac failure, Cerebral infraction, Atherosclerosis
Metabolic related diseasesDiabetes, Metabolic syndrome, Osteoporosis, Hyperinsulinism-induced dyslipidaemia, Uarthritis, Non-alcoholic hepatic steatosis,
OthersScapulohumeral periarthritis, Chronic bronc, Chronic inflammation, Cancer
Table 4  Some age-related diseases in elderly population.
Oncogene/Tumor suppressorExpression in tumor tissue
Up-regulatedDown- regulated
SIRT1Bothlung cancer, prostatic cancer, colon cancer, breast cancer, ovarian cancer, leukemia, neuroblastomas, osteo-sarcomas, and non-melanoma skin carcinomasearly onset-mutant (BRCA1) breast cancer, beta-catenin-driven colon cancer model, sarcomas, lymphomas, teratomas, and carcinomas arising from deletion of p53, HFD-induced hepatocarcinomas, and age-associated spontaneous tumor development
SIRT2Bothacute myeloid leukemia, pancreatic cancer, neuroblastoma, high-grade human HCC and prostate cancerglioma, liver cancer, and esophageal and gastric adenocarcinomas
SIRT3Bothoral cancer40% of human breast and ovarian cancers
SIRT4Tumor suppressorsmall cell lung carcinoma, gastric cancer, breast cancer and leukemia
SIRT5Bothnon-small cell lung cancer, ovarian carcinomasquamous cell carcinoma, endometrial carcinoma
SIRT6Bothhuman skin squamous cell carcinoma and pancreatic, prostate and breast cancershead and neck squamous cell carcinoma, colon, pancreatic, liver and non-small cell lung cancers
SIRT7Oncogenethyroid cancer, hepatocellular carcinoma, bladder cancer and colorectal cancer
Table 5  The dual role of sirtuins in different cancer.
Activatorsinhibitors
SIRT1Piceatannol, Resveratrol, SRT1720. SRT2104, 1,4-DHP derivative, SRT1460, SRT2183Ex-527, ELT-11c
SIRT21,4-DHP derivativeAGK2, 3′-(3-fluoro-phenethyloxy)-2-anilino-benzamide, SirReal2, Compound 15e, UBCS0137, ELT-11c, Compound 28e, AEM2, TM, Chroman-4-one analogue, RK-9123016, NPD11033
SIRT3Piceatannol, Resveratrol, 1,4-DHP derivativeCompound 8, ELT-11c, SDX-437
SIRT4
SIRT5Piceatannol, Resveratrol, UBCS039
SIRT6UBCS039Compound 1
SIRT7
Table 6  Activators and inhibitors of sirtuins.
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