Research progress in the role of SIRT6 in aging and metabolism

doi:10.3969/j.issn.1674-8115.2024.11.011

Abstract

Abstract:

SIRT6, a member of the sirtuin family of histone deacetylases, belongs to the class Ⅲ longevity proteins and exhibits NAD⁺-dependent deacetylase and mono-ADP-ribosyltransferase activities. SIRT6 is primarily located in the cell nucleus and plays a pivotal role in regulating genomic stability and relative gene expression, participating in the control of key processes such as energy metabolism and aging. Given its crucial role in maintaining cellular homeostasis and organismal health, SIRT6 has emerged as a potential therapeutic target, sparking significant research interest in the development of targeted modulators. Activating the longevity protein with drugs may provide therapeutic strategies for age-associated diseases, including aging, metabolic syndrome, inflammation, and reproductive health issues. The review elaborates the structural characteristics, enzymatic activities, and biological functions of SIRT6, as well as the mechanisms of action, pharmacological activities, and clinical applications of various SIRT6 activators.

Key words: SIRT6, catalytic activity, aging, metabolism, inflammation, drug discovery

CLC Number:

R966

LIU Yonghui, TANG Li, LIANG Taigang, ZHANG Jian, FENG Li. Research progress in the role of SIRT6 in aging and metabolism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(11): 1439-1446.

Figures/Tables 3

TrendMD

References 65

1	WU Q J, ZHANG T N, CHEN H H, et al. The sirtuin family in health and disease[J]. Signal Transduct Target Ther, 2022, 7(1): 402.
2	SHARMA A, MAHUR P, MUTHUKUMARAN J, et al. Shedding light on structure, function and regulation of human sirtuins: a comprehensive review[J]. 3 Biotech, 2023, 13(1): 29.
3	DZIDEK A, CZERWIŃSKA-LEDWIG O, ŻYCHOWSKA M, et al. The role of increased expression of sirtuin 6 in the prevention of premature aging pathomechanisms[J]. Int J Mol Sci, 2023, 24(11): 9655.
4	KLEIN M A, DENU J M. Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators[J]. J Biol Chem, 2020, 295(32): 11021-11041.
5	HOU T Y, TIAN Y, CAO Z Y, et al. Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation[J]. Mol Cell, 2022, 82(21): 4099-4115.e9.
6	PAN P W, FELDMAN J L, DEVRIES M K, et al. Structure and biochemical functions of SIRT6[J]. J Biol Chem, 2011, 286(16): 14575-14587.
7	YOU Y Z, LIANG W. SIRT1 and SIRT6: the role in aging-related diseases[J]. Biochim Biophys Acta Mol Basis Dis, 2023, 1869(7): 166815.
8	MAHLKNECHT U, HO A D, VOELTER-MAHLKNECHT S. Chromosomal organization and fluorescence in situ hybridization of the human Sirtuin 6 gene[J]. Int J Oncol, 2006, 28(2): 447-456.
9	TENNEN R I, BERBER E, CHUA K F. Functional dissection of SIRT6: identification of domains that regulate histone deacetylase activity and chromatin localization[J]. Mech Ageing Dev, 2010, 131(3): 185-192.
10	SMIRNOVA E, BIGNON E, SCHULTZ P, et al. Binding to nucleosome poises human SIRT6 for histone H3 deacetylation[J]. Elife, 2024, 12: RP87989.
11	WANG Z A, MARKERT J W, WHEDON S D, et al. Structural basis of sirtuin 6-catalyzed nucleosome deacetylation[J]. J Am Chem Soc, 2023, 145(12): 6811-6822.
12	KALOUS K S, WYNIA-SMITH S L, OLP M D, et al. Mechanism of Sirt1 NAD⁺-dependent protein deacetylase inhibition by cysteine S-nitrosation[J]. J Biol Chem, 2016, 291(49): 25398-25410.
13	SACCONNAY L, CARRUPT P A, NURISSO A. Human sirtuins: structures and flexibility[J]. J Struct Biol, 2016, 196(3): 534-542.
14	MIN J, LANDRY J, STERNGLANZ R, et al. Crystal structure of a SIR2 homolog-NAD complex[J]. Cell, 2001, 105(2): 269-279.
15	RONNEBAUM S M, WU Y X, MCDONOUGH H, et al. The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical ubiquitination[J]. Mol Cell Biol, 2013, 33(22): 4461-4472.
16	JIN L, WEI W T, JIANG Y B, et al. Crystal structures of human SIRT3 displaying substrate-induced conformational changes[J]. J Biol Chem, 2009, 284(36): 24394-24405.
17	BARAN M, MIZIAK P, STEPULAK A, et al. The role of sirtuin 6 in the deacetylation of histone proteins as a factor in the progression of neoplastic disease[J]. Int J Mol Sci, 2023, 25(1): 497.
18	QIU B Q, LI S, LI M T, et al. KAT8 acetylation-controlled lipolysis affects the invasive and migratory potential of colorectal cancer cells[J]. Cell Death Dis, 2023, 14(2): 164.
19	MOSTOSLAVSKY R, CHUA K F, LOMBARD D B, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6[J]. Cell, 2006, 124(2): 315-329.
20	LU Z Z, CHEN H J, WANG W Q, et al. Synthesized soliton crystals[J]. Nat Commun, 2021, 12(1): 3179.
21	TIAN X, FIRSANOV D, ZHANG Z H, et al. SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species[J]. Cell, 2019, 177(3): 622-638.e22.
22	MAO Z Y, HINE C, TIAN X, et al. SIRT6 promotes DNA repair under stress by activating PARP1[J]. Science, 2011, 332(6036): 1443-1446.
23	MICHISHITA E, MCCORD R A, BOXER L D, et al. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6[J]. Cell Cycle, 2009, 8(16): 2664-2666.
24	XIAO C Y, KIM H S, LAHUSEN T, et al. SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice[J]. J Biol Chem, 2010, 285(47): 36776-36784.
25	ROICHMAN A, ELHANATI S, AON M A, et al. Restoration of energy homeostasis by SIRT6 extends healthy lifespan[J]. Nat Commun, 2021, 12(1): 3208.
26	DONG X C. Sirtuin 6: a key regulator of hepatic lipid metabolism and liver health[J]. Cells, 2023, 12(4): 663.
27	ZHANG W Q, WAN H F, FENG G H, et al. SIRT6 deficiency results in developmental retardation in cynomolgus monkeys[J]. Nature, 2018, 560(7720): 661-665.
28	SIMON M, YANG J P, GIGAS J, et al. A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A[J]. EMBO J, 2022, 41(21): e110393.
29	FERRER C M, ALDERS M, POSTMA A V, et al. An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality[J]. Genes Dev, 2018, 32(5/6): 373-388.
30	KIM H S, XIAO C Y, WANG R H, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis[J]. Cell Metab, 2010, 12(3): 224-236.
31	NAIMAN S, HUYNH F K, GIL R, et al. SIRT6 promotes hepatic β-oxidation via activation of PPARα[J]. Cell Rep, 2019, 29(12): 4127-4143.e8.
32	TAO R Y, XIONG X W, DEPINHO R A, et al. FoxO3 transcription factor and Sirt6 deacetylase regulate low density lipoprotein (LDL)-cholesterol homeostasis via control of the proprotein convertase subtilisin/kexin type 9 (Pcsk9) gene expression[J]. J Biol Chem, 2013, 288(41): 29252-29259.
33	ELHANATI S, KANFI Y, VARVAK A, et al. Multiple regulatory layers of SREBP1/2 by SIRT6[J]. Cell Rep, 2013, 4(5): 905-912.
34	ZHONG L, D′URSO A, TOIBER D, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha[J]. Cell, 2010, 140(2): 280-293.
35	DOMINY J E Jr, LEE Y, JEDRYCHOWSKI M P, et al. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis[J]. Mol Cell, 2012, 48(6): 900-913.
36	BIAN C, ZHANG R J, WANG Y X, et al. Sirtuin 6 affects glucose reabsorption and gluconeogenesis in type 1 diabetes via FoxO1[J]. Mol Cell Endocrinol, 2022, 547: 111597.
37	GUO Z Y, LI P, GE J B, et al. SIRT6 in aging, metabolism, inflammation and cardiovascular diseases[J]. Aging Dis, 2022, 13(6): 1787-1822.
38	GROOTAERT M O J, BENNETT M R. Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets[J]. Nat Rev Cardiol, 2022, 19(10): 668-683.
39	ROE K. An inflammation classification system using cytokine parameters[J]. Scand J Immunol, 2021, 93(2): e12970.
40	SUN H L, WU Y R, FU D J, et al. SIRT6 regulates osteogenic differentiation of rat bone marrow mesenchymal stem cells partially via suppressing the nuclear factor-κB signaling pathway[J]. Stem Cells, 2014, 32(7): 1943-1955.
41	CASPER E. The crosstalk between Nrf2 and NF-κB pathways in coronary artery disease: can it be regulated by SIRT6?[J]. Life Sci, 2023, 330: 122007.
42	XU S W, YIN M M, KOROLEVA M, et al. SIRT6 protects against endothelial dysfunction and atherosclerosis in mice[J]. Aging, 2016, 8(5): 1064-1082.
43	LEE Y, KA S O, CHA H N, et al. Myeloid sirtuin 6 deficiency causes insulin resistance in high-fat diet-fed mice by eliciting macrophage polarization toward an M1 phenotype[J]. Diabetes, 2017, 66(10): 2659-2668.
44	DING Y N, WANG T T, LV S J, et al. SIRT6 is an epigenetic repressor of thoracic aortic aneurysms via inhibiting inflammation and senescence[J]. Signal Transduct Target Ther, 2023, 8(1): 255.
45	TATONE C, EMIDIO G D, BARBONETTI A, et al. Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility[J]. Hum Reprod Update, 2018, 24(3): 267-289.
46	HAN L S, GE J, ZHANG L, et al. Sirt6 depletion causes spindle defects and chromosome misalignment during meiosis of mouse oocyte[J]. Sci Rep, 2015, 5: 15366.
47	LIU W J, ZHANG X M, WANG N, et al. Calorie restriction inhibits ovarian follicle development and follicle loss through activating SIRT1 signaling in mice[J]. Eur J Med Res, 2015, 20(1): 22.
48	LI L Y, HUA R, HU K Q, et al. SIRT6 deficiency causes ovarian hypoplasia by affecting Plod1-related collagen formation[J]. Aging Cell, 2024, 23(2): e14031.
49	BARTOSCH C, MONTEIRO-REIS S, ALMEIDA-RIOS D, et al. Assessing sirtuin expression in endometrial carcinoma and non-neoplastic endometrium[J]. Oncotarget, 2016, 7(2): 1144-1154.
50	DROBINTSEVA A O, MEDVEDEV D S, MAKARENKO S V, et al. Implication of sirtuins and kisspeptin in ovarian aging[J]. Usp Gerontol, 2021, 34(1): 18-23.
51	MICHISHITA E, PARK J Y, BURNESKIS J M, et al. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins[J]. Mol Biol Cell, 2005, 16(10): 4623-4635.
52	PASCOAL G F L, GERALDI M V, MARÓSTICA M R Jr, et al. Effect of paternal diet on spermatogenesis and offspring health: focus on epigenetics and interventions with food bioactive compounds[J]. Nutrients, 2022, 14(10): 2150.
53	WU Y F, YING J H, ZHU X Y, et al. Pachymic acid suppresses the inflammatory response of chondrocytes and alleviates the progression of osteoarthritis via regulating the Sirtuin 6/NF-κB signal axis[J]. Int Immunopharmacol, 2023, 124(Pt A): 110854.
54	LEE A, GU H, GWON M H, et al. Hesperetin suppresses LPS/high glucose-induced inflammatory responses via TLR/MyD88/NF-κB signaling pathways in THP-1 cells[J]. Nutr Res Pract, 2021, 15(5): 591-603.
55	PAN Z S, GUO J Y, TANG K J, et al. Ginsenoside Rc modulates SIRT6-NRF2 interaction to alleviate alcoholic liver disease[J]. J Agric Food Chem, 2022, 70(44): 14220-14234.
56	WU R Y, JIAN T, DING X Q, et al. Total sesquiterpene glycosides from loquat leaves ameliorate HFD-induced insulin resistance by modulating IRS-1/GLUT4, TRPV1, and SIRT6/Nrf2 signaling pathways[J]. Oxid Med Cell Longev, 2021, 2021: 4706410.
57	LOMBARDO G E, RUSSO C, MAUGERI A, et al. Sirtuins as players in the signal transduction of Citrus flavonoids[J]. Int J Mol Sci, 2024, 25(4): 1956.
58	IACHETTINI S, TRISCIUOGLIO D, ROTILI D, et al. Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells[J]. Cell Death Dis, 2018, 9(10): 996.
59	JIAO F Z, ZHANG Z W, HU H T, et al. SIRT6 activator UBCS039 inhibits thioacetamide-induced hepatic injury in vitro and in vivo[J]. Front Pharmacol, 2022, 13: 837544.
60	HUANG Z M, ZHAO J X, DENG W, et al. Identification of a cellularly active SIRT6 allosteric activator[J]. Nat Chem Biol, 2018, 14(12): 1118-1126.
61	HUANG Z M, ZHAO J X, DENG W, et al. Reply to: binding site for MDL-801 on SIRT6[J]. Nat Chem Biol, 2021, 17(5): 522-523.
62	YOU W J, STEEGBORN C. Binding site for activator MDL-801 on SIRT6[J]. Nat Chem Biol, 2021, 17(5): 519-521.
63	WU X, LIU H, BROOKS A, et al. SIRT6 mitigates heart failure with preserved ejection fraction in diabetes[J]. Circ Res, 2022, 131(11): 926-943.
64	ZHANG J H, LI Y P, LIU Q H, et al. Sirt6 alleviated liver fibrosis by deacetylating conserved lysine 54 on Smad2 in hepatic stellate cells[J]. Hepatology, 2021, 73(3): 1140-1157.
65	CHEN Y, CHEN J Y, SUN X X, et al. The SIRT6 activator MDL-800 improves genomic stability and pluripotency of old murine-derived iPS cells[J]. Aging Cell, 2020, 19(8): e13185.

[1]	ZHU Zijun, QIAN Yife, LI Qianyu, LI Songling, QIN Wenli, LIU Yanfeng. Anaphase-promoting complex subunit 10 promotes hepatocellular carcinoma progression through regulation of the PI3K-AKT-mTOR signaling pathway [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1171-1182.
[2]	WANG Jingyi, DENG Jiali, ZHU Yi, DING Xinyi, GUO Jiajing, WANG Zhongling. Experimental study on novel pH-responsive manganese-based nanoprobes for ferroptosis and magnetic resonance imaging in breast cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1183-1193.
[3]	LI Siyu, CHEN Ya, HU Wentao, DAI Yongming, WU Yingwei. Using diffusion-relaxation correlation spectroscopic imaging to assess the heterogeneity of head and neck tumors and identify occult lymph node metastasis [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1202-1213.
[4]	WANG Rui, YUAN Ying, TAO Xiaofeng. Application value of synthetic magnetic resonance imaging in predicting cervical lymph node metastasis of oral cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(7): 900-909.
[5]	KERANMU Saitierguli, QIAN Lei, DING Siyi, MAHELIMUHAN Hanati, YANG Xueer, JIA Hao. Research progress of arginine metabolism in the regulation of mesenchymal stem cell function [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(7): 910-915.
[6]	ZHAO Xinyu, ZHANG Wenchao, CHEN Xuzhuo, SONG Jiaqi, HUANG Hui, ZHANG Shanyong. Study on the effects of spermidine on LPS-induced inflammatory osteolysis in mouse calvaria [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 673-683.
[7]	SUN Lei, DAI Shifeng, CHEN Yuhua, XU Xinyi, JIANG Kele, LI Xiaowen, LI Chengjing, WU Tingting. Quantitative analysis of the distance between articular disc and condyle in patients with temporomandibular disorders [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 684-692.
[8]	YANG Le, ZHOU Yi, WANG Keyun, LAI Yali. Research on the improvement of cognitive impairment, endoplasmic reticulum stress and neuroinflammation in Alzheimer's disease by emodin [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 727-734.
[9]	LI Zhuohang, YU Xindi, REN Jingya, SHEN Jia, DONG Suzhen, WANG Wei. Postoperative neurodevelopmental outcomes of end-to-side anastomosis for coarctation of the aorta [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 753-759.
[10]	GU Liangrui, YAN Bicong, FANG Tonglei, WU Jinliang. Correlation between brain imaging features and cognitive impairment in end-stage renal disease patients based on susceptibility-weighted imaging [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 760-765.
[11]	HUANG Yinghe, ZHAO Guanyu, SUN Yang, HOU Jianji, ZUO Yong. Research progress on macrophage metabolic regulation in wound healing of diabetes mellitus type 2 [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 792-799.
[12]	ZHANG Zhengjia, LI Xiaomin, ZHOU Xin, MA Hairong, AI Songtao. Preliminary study on the value of high-order functional magnetic resonance imaging in the evaluation of bone and soft tissue tumors [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(5): 585-596.
[13]	YU Kai, SHUAI Zhewei, HUANG Hongjun, LUO Yan. Research progress on the role and mechanisms of microglia in inflammatory diseases of central nervous system [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(5): 630-638.
[14]	CAO Mingming, WANG Hui, YIN Yafu. Current research status of imaging markers for cognitive impairment in Parkinson′s disease [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(5): 646-652.
[15]	ZHANG Huihua, GAN Jing, HOU Miaomiao, LU Na. Bidirectional Mendelian randomization study of the relationship between brain imaging-derived phenotypes and obstructive sleep apnea [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(4): 468-475.