The sirtuin family in health and disease

Abstract

Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.

Fig. 1

The historical timeline on milestones in SIRT family members

Fig. 2

Overview of the roles of SIRTs in inflammation. a SIRTs mainly play an anti-inflammatory effect by regulating inflammatory mediators, however, early inhibition of SIRT2 may prevent neuroinflammation evidenced by reduced levels of GFAP, IL-β, IL-6, and TNF-α; (b) SIRTs could negatively regulate several pro-inflammatory cytokines; (c) SIRTs are involved in the regulation of NF-κB signaling pathway. https://biorender.com. ABCA1 ATP‑binding cassette A1, ABCG1 ATP‑binding cassette G1, Arf alternative reading frame, CaMKKβ Ca(2 + )/calmodulin-dependent protein kinase kinase β, CCR7 C‑C chemokine receptor type 7, CRIF1 CR6-interacting factor1, CTLA4 cytotoxic T lymphocyte–associated antigen 4, CTRP1 C1q/tumor necrosis factor-related protein 1, DBC1 deleted in breast cancer 1, DEPTOR DEP-domain containing mTOR-interacting protein, DMP1 dentin matrix protein-1, Ebi3 Epstein-Barr virus–induced gene 3, FGF21 fibroblast growth factor 21, FXR farnesoid X receptor, GFAP glial fibrillary acidic protein, HIF-α hypoxia-inducible factor-alpha, HMGB1 high-mobility group box 1, HNF4α hepatocyte nuclear factor 4α, HO1 heme oxygenase-1, ICOS inducible T cell co-stimulator, IFN-γ interferon-γ, IKKβ inhibitor kappa B kinaseβ, IRAK interleukin-1 receptor-associated kinase, IRF9 interferon regulatory factor 9, LXR liver X receptor, MCP monocyte chemotactic protein, MCPIP1 MCP-1 induced protein, MIP-2 macrophage inflammatory protein-2, MKP-1 mitogen-activated protein kinase phosphatase-1, NT5C3A pyrimidine 5'-nucleotidase, PAI-1 plasminogen activator inhibitor-1, PARP-1 peroxisome proliferator-activated receptor 1, PGRN progranulin, RORγt RAR-related orphan receptor γ-t, TAK1 transforming growth factor β activated kinase-1, TM thrombomodulin, VCAM-1 vascular cell adhesion molecule-1, XBP1 X-box binding protein 1

Fig. 3

Overview of the roles of SIRTs in cell metabolism. SIRTs participate in glucose metabolism, lipid metabolism, and other metabolisms via interacting with metabolism-related genes and enzymes. (i) In the nuclear, SIRT1 and SIRT6 activate the transcription factors HIF2α and HIF1α respectively through different manners and subsequently improve glycolysis. Besides, SIRT1 regulates gluconeogenesis by activating PGC1α and inhabiting FOXO1, thereby affecting the transcriptional activation of their target genes. SIRT1 also promotes fatty acid oxidation by activating PGC1α and promoting the expression of target genes. Besides the positive regulation, SIRT1 and SIRT6 suppress SREBP1 and transcriptionally represses lipogenesis. (ii) In cytoplasm, SIRT2 deacetylates and activates the rate-limiting enzyme PEPCK and promotes gluconeogenesis during low nutrient condition. Moreover, SIRT2 inhabits ACLY and deters lipid synthesis. (iii) Regarding SIRTs in mitochondria, SIRT4 and SIRT5 reduces PDH activity which converts pyruvate to acetyl CoA. Both SIRT3 and SIRT4 target GDH, but their enzymatic activities are opposite. Besides GDH, SIRT3 also improves IDH2 and LCAD activity, thus enhancing cellular respiration and stimulating β-oxidation of fatty acids. Moreover, SIRT5 represses IDH2 activity and may disrupt glutamine metabolism through GLS. Activation and inhibition effects are displayed in “arrows” and “inhibitors”, respectively. https://biorender.com. ACC acetyl-CoA carboxylase, ACLY ATP citrate lyase, ANT2 adenine nucleotide translocase 2, Bmal1 brain-muscle-Arnt-like protein-1, CDK2 cyclin-dependent kinase 2, ChREBP carbohydrate response element-binding protein, CPS1 carbamoyl phosphate synthetase 1, CPT1 carnitine palmitoyl transferase 1 A, eIF5A eukaryotic initiation factor 5A, GDH glutamate dehydrogenase, GLUT glucose transporter, HIF1/2α hypoxia-Inducible Factor-1/2α, HK2 hexokinase 2, HSF1 heat shock factor 1, IDH2 isocitrate dehydrogenase 2, LCAD long chain acyl CoA dehydrogenase, MCD malonyl CoA decarboxylase, MBD1 methyl-CpG-binding domain protein 1, MDH1 malate dehydrogenases 1, m-TORc1/2 mTOR complex 1/2, MyoD myogenic differentiation factor, NNMT nicotinamide N-methyl transferase, PARP poly (ADP-ribose) polymerase, PDH pyruvate dehydrogenase, PEPCK1 phosphoenolpyruvate carboxykinase, PFK phosphofructokinase-1, PK pyruvate kinase, PTP1B protein-tyrosine phosphatase 1B, RIPK1/3 receptor interacting protein kinases 1/3, SLC1A5 solute carrier family 1 member 5, SREBP1 sterol regulatory element binding protein 1, TRAP1 tumor necrosis factor receptor-associated protein 1, Tsc2 tuberous sclerosis complex 2, ZEB1 zinc finger E-box binding homeobox 1

Fig. 4

Overview of the roles of SIRTs in oxidative stress. a The overall roles of SIRTs in regulating cellular oxidative stress. The effect of SIRTs on oxidative stress is mainly via affecting the following proteins, mainly including Nrf2, FOXOs and SOD. SIRT1 and SIRT6 could indirectly affecting Nrf2 signaling, thereby regulating oxidative stress. SIRT3 activates FOXO3, which leads to increasement of MnSOD, allowing for the elimination of ROS. In addition, SIRT1, SIRT2, and SIRT6 could upregulate the expression of SOD, then reducing the ROS and inhibiting the oxidative stress; (b) The regulatory effects of SIRTs on main proteins in oxidative stress. SIRT1 downregulation by NF-κB leads to oxidative stress. Moreover, SIRT3 regulates ROS generation, causing suppression of NF-κB activation, and SIRT6 reduces NF-kB activation and represses oxidative stress. c The roles of SIRTs in regulation of transcription factors. SIRT1 increases the expression of FOXO1, reducing the production of ROS and oxidative stress. SIRT1 inhibits oxidative stress by deacetylating P53 protein. Besides, SIRT1 could activate PGC-1α and alleviate oxidative stress injury. d The proteins less studied that activate or inhibit SIRT1. Activation and inhibition effects are displayed in green and red arrows, respectively. https://biorender.com. AT1 angiotensin type 1, ATF6 activating transcription factor 6, Bach1 BTB domain and CNC homolog 1, BIP binding immunoglobulin protein, CD36 cluster of differentiation 36, CHOP C/EBP-homologous protein, CoQ10 coenzyme Q10, COX2 cyclooxygenase-2, CPEB-1 cytoplasmic polyadenylation element binding protein 1, DPP4 dipeptidyl peptidase-4, DRG2 GTP-binding protein 2, FASTK Fas-activated serine/threonine kinase, FNDC5 fibronectin type III domain-containing 5, GCN5 general control non-repressed protein 5, GDF11 Growth differentiation factor 11, Hcy homocysteine, hnRNP heterogeneous nuclear ribonucleoprotein F, HO-1 heme oxygenase 1, Keap-1 kelch-like ECH-associated protein 1, LDH lactate dehydrogenase, LOX-1 lectin-like oxidized low-density lipoprotein receptor-1, Lsd lysine-specific demethylase 1, MIF migration inhibitory factor, MPO myeloperoxidase, NEU1 neuraminidase 1, NRLP3 NOD-like receptor thermal protein domain associated protein 3, OGG-1 BER enzyme 8oxoG DNA glycosylase I, PDGFR-α platelet derived growth factor receptor α, PGAM2 glycolytic enzyme phosphoglycerate mutase 2, PRMT protein arginine methyltransferase, α-SMA smooth muscle alpha actin, TIGAR TP53-induced glycolysis and apoptosis regulator, timp-1 tissue inhibitor of metalloproteinase 1, TOPK T‑lymphokine‑activated killer cell‑originated protein kinase, UCP2 uncoupling protein 2, Wt1 Wilms' tumor 1, Wt2 Wilms' tumor 2

Fig. 5

Overview of the roles of SIRTs in apoptosis. SIRT protein family has functions in both physiological conditions and diseases by regulating the acetylation modification and/or influencing various apoptosis-related proteins by crosstalk of pathways. Meanwhile, they can also be regulated by the molecules in the aforementioned process, such as microRNA, FoxO1, FoxO3a, TNF-α and NF-κB. a The roles of SIRT1 in regulating apoptosis by targeting apoptosis-related proteins and pathways; (b) The roles of SIRT3 in regulating apoptosis by targeting apoptosis-related proteins and pathways; (c) The roles of SIRT2, SIRT4 and SIRT5 in regulating apoptosis by targeting apoptosis-related proteins and pathways; (d) The roles of SIRT6 in regulating apoptosis by targeting apoptosis-related proteins and pathways; (e) The roles of SIRT7 in regulating apoptosis by targeting apoptosis-related proteins and pathways. https://biorender.com. ATM ataxia telangiectasia mutated, Cyt C cytochrome c, ELA elabela, GAPDH glyceraldehyde 3-phosphate dehydrogenase, HIC1 hypermethylated in cancer-1, HIPK2 homeodomain-interacting protein kinase-2, INZ inauhzin, JAK2 janus kinase 2, MALAT1 metastasis-associated lung adenocarcinoma transcript 1, Mcl-1 myeloid cell leukemia 1, MicRNA microRNA, MST1 mammalian sterile 20-like kinase 1, PLD2 phospholipase D2, RORA retinoid-related orphan receptor α, TSPYL2 testis-specific protein y-encoded-like 2, Yap yes-associated protein, ZMAT1 zinc finger matrin-type 1

Fig. 6

Overview of the roles of SIRTs in autophagy. SIRTs can regulate a series of substrates involved in the process of macroautophagy and mitophagy. Meanwhile, they can also be regulated by a series of molecules in the aforementioned process. SIRTs are all involved in the regulation of macroautophagy, of which AMPK/mTOR signaling is the most common pathway. In addition, SIRT1, SIRT3, SIRT4, and SIRT5 are also involved in PINK1/Parkin-mediated mitophagy or Bnip3-mediated mitophagy. https://biorender.com. ACE2 angiotensin-converting enzyme 2, ATGL adipose triglyceride lipase, Bnip3 BCL2 interacting protein 3, CERKL ceramide kinase-like protein; circ, circular RNA; CUL4B, cullin 4B, eEF2 eukaryotic elongation factor-2, eEF2K eukaryotic elongation factor-2 kinase, EGFR epidermal growth factor receptor, ESRRA estrogen-related receptor α, FBXW7 F-box and WD repeat domain-containing 7, FoxM1 forkhead box M1, G6Pase-α glucose-6-phosphatase-α, GAS5 growth arrest specific 5, Hes‑1 hairy and enhancer of split‑1, HIF1α hypoxia-inducible factor 1 α, HIST1H1C histone cluster 1 H1 family member c, IPMK inositol polyphosphate multikinase, LDHB lactate dehydrogenase B, lncR long non-coding RNA, miR miRNA, NAT10 nucleolar protein N-acetyltransferase 10, NMNAT1 nicotinamide mononucleotide adenylyltransferase 1, Notch‑1 Notch homolog 1, OPA1 optic atrophy 1, p53 tumor protein p53, PINK PTEN induced putative kinase, PLIN5 perilipin 5, PTEN phosphatase and tensin homolog, SQSTM1/p62 sequestosome 1, TFEB transcription factor EB, TUG1 taurine-upregulated gene 1, TyrRS tyrosyl transfer-RNA synthetase, Ube2v1 ubiquitin-conjugating E2 enzyme variant 1

Fig. 7

Overview of the roles of SIRTs in cell proliferation. (i) SIRTs participate in regulating cell proliferation by affecting a group of downstream proteins, including p53, p65, STAT3, FOXO1, AMPK, etc. (ii) SIRTs are also regulated by a series of ncRNAs and proteins, such as lncRNA PVT1, miR-34a, IFN-γ, MDM2, PRARα, eNOS, TCF3, etc, and subsequently promote or inhibit cell proliferation directly. (iii) In addition, SIRTs could activate or inhibit several signaling pathways, which perform important roles in cell proliferation, including JAK2/STAT3 signaling pathway, Wnt/β-catenin signaling pathway, PI3K/AKT signaling pathway, Notch signaling pathway, and ERK/STAT3 signaling pathway. Activation and inhibition effects are displayed in green and red arrows, respectively. https://biorender.com. ACAT1 acetyl coenzyme A acyltransferase1, Bmi-1 B-cell-specific Moloney murine leukemia virus integrationsite-1, CCAR2 cell cycle and apoptosis regulator protein 2, CDK9 cyclin-dependent kinase9, Drp1 dynamin-related protein 1, Erα estrogen receptor α, FASN fatty acid synthase, GLP-1 glucagon-like peptide-1, H1 histone1, HIF-2α hypoxia inducible factor-2α, K-Ras p21, MEF2D myocyte enhancer factor 2D, mitoCOX-2 mitochondria cyclooxygenase-2, MRP migration inhibitory-factor related protein, mTORC1 mTOR complex 1, Pcsk9 proprotein convertase subtilisin/kexin type 9, PD-L1 programmed death 1-ligand 1, POLD1 DNA polymerase delta 1, Pol-I DNA polymerase I, BBC3 Bcl-2 binding component 3, Rb retinoblastoma protein, SPEBP1 phosphatidylethanolamine binding protein 1, STAT1 signal transducer and activator of transcription 1, TCF3 transcription factor 3, Twist1 twist family bHLH transcription factor 1, ZEB2 zinc finger E-box binding homeobox 1

Fig. 8

Overview of the roles of SIRTs in cell migration and invasion. SIRTs coordinate a multi-faceted regimen to control cell migration and invasion. In the nucleus, SIRT1, SIRT6, and SIRT7 may affect many key proteins, which also contain transcription factors, mainly involved in EMT process, TGF-β signaling, PI3K/Akt signaling, MMPs signaling, and AMPK signaling pathways, etc, thereby regulating cell migration and invasion. In the cytosol, SIRT2 could suppress cell migration and invasion by deacetylating target proteins such as AKR1C1 and IDH1. In mitochondria, SIRT3, SIRT4, and SIRT5 could participate in regulating cell migration and invasion via influencing various molecular mechanisms such as integrin adhesion and EMT. Activation and inhibition effects are displayed in green and red arrows, respectively. https://biorender.com. α7nAChR alpha7 subtype of nicotinic acetylcholine receptors, ISRE IFN-stimulated response element

Fig. 9

The roles of SIRTs in cancers. SIRTs are involved in a series of malignancies, including BC, LC, liver cancer, GC, PC, colorectal cancer, OC, EC, CC, malignant glioma, and leukemia. SIRTs act as tumor promoters (marked in red color), tumor suppressors (marked in green color), or both suppressor and promoter (marked in blue color). Major events in solid tumor development consist of tumor initiation, tumor proliferation, and tumor metastasis. Between these events, processes including cell proliferation, oxidative stress, apoptosis, angiogenesis, EMT, migration and invasion are promoted or inhibited. Depending on the tumor location, the metastasis site also varies, including lymph nodes, distant organs, liver, adjacent organs, etc. https://biorender.com

Fig. 10

The roles of SIRTs in circulatory system. SIRT1, SIRT3 and SIRT6 play protective roles in CVDs, such as cardiac fibrosis, heart failure, atherosclerosis, and MI/R injury. In addition, the protective effect of SIRT2 is observed in cardiac hypertrophy, cardiac fibrosis, as well as atherosclerosis. Furthermore, SIRT4 has a protective effect on atherosclerosis and MI/R injury. However, SIRT4 may have an adverse effect on cardiac hypertrophy and fibrosis. In contrast, SIRT5 plays protective role in cardiac hypertrophy and fibrosis, and similar protective effect is also observed in MI/R injury. Finally, the protective effect of SIRT7 is observed in cardiac hypertrophy and atherosclerosis. https://biorender.com

Fig. 11

The roles of SIRTs in respiratory system. SIRTs are involved in common respiratory diseases including COPD, asthma, lung fibrosis, COVID-19, and other lung injured diseases. SIRT1, SIRT3 and SIRT6 play protective effects in COPD, and these three members also have a positive effect on asthma. However, SIRT2 and SIRT7 could aggravate the occurrence of asthma. In lung fibrosis, the positive effects of SIRT1, SIRT3, SIRT6 and SIRT7 have been demonstrated. Besides, SIRT3 and SIRT6 contribute to the remission of lung injury, whereas SIRT1 play dual effects on the disease. Moreover, the activation of SIRT1 can effectively alleviate ventilator or paraquat-induced lung injury. Finally, SIRTs are also associated with COVID-19. https://biorender.com

Fig. 12

The roles of SIRTs in digestive system, mainly including FLDs, liver and intestinal ischemia-reperfusion injury, HBV infection, pancreas diseases, and IBDs. In FLDs, SIRT1, SIRT2, SIRT3, and SIRT4 could provide protective effects, while the role of SIRT7 may be harmful. Notably, the effects of SIRT1, SIRT2, SIRT3, and SIRT4 may be dual effects; in different causes of liver injury, SIRT3 and SIRT6 are beneficial, while SIRT1 plays dual roles; in HBV infection, SIRT3, SIRT4, and SIRT6 can block viral replication, SIRT1, SIRT2, and SIRT5 may contribute to the HBV-induced pathomechanism in nontransformed hepatocytes, while the effect of SIRT7 could be dual; in liver ischemia-reperfusion injury and intestinal ischemia-reperfusion injury, SIRT1 and SIRT3 could reduce tissue damage, and SIRT6 could also protect intestinal ischemia/reperfusion injury, while SIRT2 augments liver ischemia-reperfusion injury; SIRT2, SIRT3, SIRT5, and SIRT7 have a protective role in inflammatory bowel diseases, however, SIRT1 may play opposite role; in other digestive diseases, SIRT1 acts inconsistently. https://biorender.com

Fig. 13

The role of SIRTs in nervous system, mainly including AD, HD, PD, brain injury, epilepsy, neuroinflammation, SCI, multiple sclerosis and ALS. SIRT1, SIRT3, and SIRT6 have protective effects on AD, multiple scierosis and amyotrophic lateral scierosis. SIRT1 plays a major protective role in HD. In PD, SIRT1 and SIRT3 provide protective effects. In addition, SIRT1, SIRT3, and SIRT5 are beneficial in both brain injury and epilepsy. SIRT1, SIRT2, and SIRT3 have roles in protecting against neuroinflammation. SIRT1 and SIRT6 could also protect SCI. Notably, the effects of SIRT2 may be harmful on AD, HD, PD, and brain injury. https://biorender.com

Fig. 14

The roles of SIRTs in diabetes and related target organs injury. a SIRT1, SIRT2, SIRT3, SIRT4, and SIRT6 are associated with pathological processes in the occurrence and development of DM. SIRT1 and SIRT2 have dual functions, including both improving insulin sensitivity and reducing insulin responsiveness. SIRT3, SIRT4, and SIRT6 mainly exert protective effect on DM. b SIRT1, SIRT3, SIRT4, and SIRT7 play protective roles in diabetic nephropathy. Low levels of SIRT1 and SIRT3 are associated with renal fibrosis and reduced expressions of SIRT1, SIRT4, and SIRT7 are related to podocyte apoptosis. c Increasing SIRT1 expression can exert protective effect during the development of neuropathy in sensory neuron of spinal cord. Moreover, SIRT1 could also reverse neuron damage in hippocampus. In addition, SIRT3 may inhibit neuropathy in sciatic nerve. d SIRT1, SIRT3, and SIRT6 are reduced in the pathological process of diabetic retinopathy. Additionally, SIRT1 is reduced during the damage of blood-retinal barrier. e SIRT1, SIRT3, and SIRT6 act protective roles in the development of diabetic cardiomyopathy, which consists of heart failure, cardiac fibrosis, cardiac hypertrophy, myocardial infarction, vascular injury and atherosclerosis. https://biorender.com. HOTAIR HOX transcript antisense RNA, Mff mitochondrial fission factor, SGLT2 sodium-dependent glucose transporters 2

Fig. 15

The roles of SIRTs in genitourinary system. SIRT protein family is involved in common of urogenital system including acute kidney disease, CKD (such as kidney fibrosis, kidney stone, aging-induced kidney injury, and vascular calcification in kidney), and genital system disease (mainly including erectile function, reproductive damage, male infertility, PCOS and endometriosis). SIRT1 play a protective effect in aforementioned disease. Moreover, the positive effects of SIRT3 and SIRT6 have been demonstrated in acute kidney disease, kidney fibrosis, vascular calcification in kidney, and male infertility. However, SIRT3 also play a protective role in kidney stone and PCOS, and SIRT6 is protectively associated aging-induced kidney injury. Besides, SIRT4-5 contribute to the remission of male infertility. Additionally, SIRT2 and SIRT7 can aggravate the occurrence of acute kidney disease, and SIRT2 also can aggravate the occurrence of kidney fibrosis. https://biorender.com

Fig. 16

Structures of most relevant SIRT activators

Fig. 17

Structures of most relevant SIRT inhibitors

Fig. 18

Characteristics of included randomized controlled trials by (a) regions; (b) condition of subject; (c) examination of tissue and samples; (d) years of recruitment and publication; (e) interventions