Mitochondrial sirtuins, key regulators of aging

Abstract

Mitochondrial dysfunction is a hallmark of aging, characterized by a decline in mitochondrial biogenesis and quality control, compromised membrane integrity, elevated ROS production, damaged mitochondrial DNA (mtDNA), impaired mitochondrial-nuclear crosstalk, and deregulated metabolic balance. Among the key longevity regulators, sirtuin family members SIRT3, SIRT4, and SIRT5 are predominantly localized to mitochondria and play crucial roles in maintaining mitochondrial function and homeostasis. This review explores how mitochondrial sirtuins mitigate aging-related mitochondrial dysfunctions and their broader implications in aging-related diseases. By elucidating the intricate interplay between mitochondrial dysfunction and mitochondrial sirtuins, we aim to provide insights into therapeutic strategies for promoting healthy aging and combating age-related pathologies.

Keywords

mitochondrial sirtuins / mitochondrial dysfunction / aging

References

[1] Liu GH , Ding Z , Izpisua Belmonte JC . iPSC technology to study human aging and aging-related disorders. Curr Opin Cell Biol 2012; 24: 765- 74.

[2] Yang Y , Lu X , Liu N , et al. Metformin decelerates aging clock in male monkeys. Cell 2024; 187: 6358- 78.e29.

[3] Lopez-Otin C , Blasco MA , Partridge L , et al. Hallmarks of aging:an expanding universe. Cell 2023; 186: 243- 78.

[4] Ma S , Ji Z , Zhang B , et al. Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging. Cell 2024; 187: 7025- 44.e34.

[5] Cai Y , Song W , Li J , et al. The landscape of aging. Sci China Life Sci 2022; 65: 2354- 454.

[6] Sun S , Li J , Wang S , et al. CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord. Nature 2023; 624: 611- 20.

[7] Aging Biomarker C , et al. Biomarkers of aging. Sci China Life Sci 2023; 66: 893- 1066.

[8] Huang D , Zuo Y , Zhang C , et al. A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis. Protein Cell 2023; 14: 888- 907.

[9] Liu B , Qu J , Zhang W , et al. A stem cell aging framework, from mechanisms to interventions. Cell Rep 2022; 41: 111451.

[10] Wang C , Yang K , Liu X , et al. MAVS antagonizes human stem cell senescence as a mitochondrial stabilizer. Research 2023; 6: 0192.

[11] Sun N , Youle RJ , Finkel T . The mitochondrial basis of aging. Mol Cell 2016; 61: 654- 66.

[12] Ren R , Deng L , Xue Y , et al. Visualization of aging-associated chromatin alterations with an engineered TALE system. Cell Res 2017; 27: 483- 504.

[13] Hu H , Ji Q , Song M , et al. ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin. Nucleic Acids Res 2020; 48: 6001- 18.

[14] Wu QJ , Zhang T-N , Chen H-H , et al. The sirtuin family in health and disease. Signal Transduct Target Ther 2022; 7: 402.

[15] Ji Z , Liu GH , Qu J . Mitochondrial sirtuins, metabolism, and aging. J Genet Genomics 2022; 49: 287- 98.

[16] Li H , Cai Z . SIRT3 regulates mitochondrial biogenesis in aging-related diseases. J Biomed Res 2022; 37: 77- 88.

[17] Samant SA , Zhang HJ , Hong Z , et al. SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 2014; 34: 807- 19.

[18] Zhang J , Xiang H , Liu J , et al. Mitochondrial sirtuin 3:new emerging biological function and therapeutic target. Theranostics 2020; 10: 8315- 42.

[19] Liu J , Li D , Zhang T , et al. SIRT3 protects hepatocytes from oxidative injury by enhancing ROS scavenging and mitochondrial integrity. Cell Death Dis 2017; 8: e3158.

[20] Lang A , Anand R , Altinoluk-Hambüchen S , et al. SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy. Aging (Albany NY) 2017; 9: 2163- 89.

[21] 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; 36: 2724- 36.

[22] Lang A , Grether-Beck S , Singh M , et al. MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4. Aging (Albany NY) 2016; 8: 484- 505.

[23] Polletta L , Vernucci E , Carnevale I , et al. SIRT5 regulation of ammonia-induced autophagy and mitophagy. Autophagy 2015; 11: 253- 70.

[24] Guedouari H , Daigle T , Scorrano L , et al. Sirtuin 5 protects mitochondria from fragmentation and degradation during starvation. Biochim Biophys Acta Mol Cell Res 2017; 1864: 169- 76.

[25] Fabbrizi E , Fiorentino F , Carafa V , et al. Emerging roles of SIRT5 in metabolism, cancer, and SARS-CoV-2 infection. Cells 2023; 12: 852.

[26] Liu J , Yan W , Zhao X , et al. Sirt3 attenuates post-infarction cardiac injury via inhibiting mitochondrial fission and normalization of AMPK-Drp1 pathways. Cell Signal 2019; 53: 1- 13.

[27] Crane JD , Devries MC , Safdar A , et al. The effect of aging on human skeletal muscle mitochondrial and intramyocellular lipid ultrastructure. J Gerontol A Biol Sci Med Sci 2010; 65: 119- 28.

[28] Herbener GH . A morphometric study of age-dependent changes in mitochondrial population of mouse liver and heart. J Gerontol 1976; 31: 8- 12.

[29] Marzetti E , Calvani R , Coelho-Junior HJ , et al. Mitochondrial quantity and quality in age-related sarcopenia. Int J Mol Sci 2024; 25: 2052.

[30] Mozet C , Martin R , Welt K , et al. Cardioprotective effect of EGb 761 on myocardial ultrastructure of young and old rat heart and antioxidant status during acute hypoxia. Aging Clin Exp Res 2009; 21: 14- 21.

[31] Schmucker DL , Sachs HG . Age-dependent alterations in rat ventricular myocardium:a quantitative analysis. Mech Ageing Dev 1985; 31: 89- 101.

[32] Dawson NJ , Salmon P . Age-related increase in mitochondrial quantity may mitigate a decline in mitochondrial quality in red blood cells from zebra finches (Taeniopygia guttata). Exp Gerontol 2020; 133: 110883.

[33] Dorn GW , Vega RB , Kelly DP . Mitochondrial biogenesis and dynamics in the developing and diseased heart. Genes Dev 2015; 29: 1981- 91.. 2nd.

[34] Abu Shelbayeh O , Arroum T , Morris S , et al. PGC-1alpha Is a master regulator of mitochondrial lifecycle and ros stress response. Antioxidants (Basel) 2023; 12: 1075.

[35] Popov LD . Mitochondrial biogenesis:an update. J Cell Mol Med 2020; 24: 4892- 9.

[36] Sczelecki S , Besse-Patin A , Abboud A , et al. Loss of Pgc-1alpha expression in aging mouse muscle potentiates glucose intolerance and systemic inflammation. Am J Physiol Endocrinol Metab 2014; 306: E157- 167.

[37] Rakshe PS , Dutta BJ , Chib S , et al. Unveiling the interplay of AMPK/SIRT1/PGC-1alpha axis in brain health:promising targets against aging and NDDs. Ageing Res Rev 2024; 96: 102255.

[38] Meng H , Yan W-Y , Lei Y-H , et al. SIRT3 regulation of mitochondrial quality control in neurodegenerative diseases. Front Aging Neurosci 2019; 11: 313.

[39] Huang D , Liu M , Jiang Y . Mitochonic acid-5 attenuates TNFalpha-mediated neuronal inflammation via activating Parkinrelated mitophagy and augmenting the AMPK-Sirt3 pathways. J Cell Physiol 2019; 234: 22172- 82.

[40] Aging Atlas C . Aging atlas:a multi-omics database for aging biology. Nucleic Acids Res 2021; 49: D825- 30.

[41] Kao TY , Chiu Y-C , Fang W-C , et al. Mitochondrial lon regulates apoptosis through the association with Hsp60-mtHsp70 complex. Cell Death Dis 2015; 6: e1642.

[42] Han Y , Zhou S , Coetzee S , et al. SIRT4 and its roles in energy and redox metabolism in health, disease and during exercise. Front Physiol 2019; 10: 1006.

[43] Hong J , Raza SHA , Ma H , et al. Multiple omics analysis reveals the regulation of SIRT5 on mitochondrial function and lipid metabolism during the differentiation of bovine preadipocytes. Genomics 2024; 116: 110773.

[44] Jensen MB , Jasper H . Mitochondrial proteostasis in the control of aging and longevity. Cell Metab 2014; 20: 214- 25.

[45] Cilleros-Holgado P , Gómez-Fernández D , Piñero-Pérez R , et al. Mitochondrial quality control via mitochondrial unfolded protein response (mtUPR) in ageing and neurodegenerative diseases. Biomolecules 2023; 13: 1789.

[46] Lima T , Li TY , Mottis A , et al. Pleiotropic effects of mitochondria in aging. Nat Aging 2022; 2: 199- 213.

[47] Houtkooper RH , Mouchiroud L , Ryu D , et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 2013; 497: 451- 7.

[48] Owusu-Ansah E , Song W , Perrimon N . Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 2013; 155: 699- 712.

[49] Xu M , Xue R-Q , Lu Y , et al. Choline ameliorates cardiac hypertrophy by regulating metabolic remodelling and UPRmt through SIRT3-AMPK pathway. Cardiovasc Res 2019; 115: 530- 45.

[50] Chen H , Zhang DM , Zhang ZP , et al. SIRT3-mediated mitochondrial unfolded protein response weakens breast cancer sensitivity to cisplatin. Genes Genomics 2021; 43: 1433- 44.

[51] Shi H , Deng H-X , Gius D , et al. Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet 2017; 26: 1915- 26.

[52] Lu Z , Chen Y , Aponte AM , et al. Prolonged fasting identifies heat shock protein 10 as a Sirtuin 3 substrate:elucidating a new mechanism linking mitochondrial protein acetylation to fatty acid oxidation enzyme folding and function. J Biol Chem 2015; 290: 2466- 76.

[53] Gibellini L , Pinti M , Beretti F , et al. Sirtuin 3 interacts with Lon protease and regulates its acetylation status. Mitochondrion 2014; 18: 76- 81.

[54] Wang S , Long H , Hou L , et al. The mitophagy pathway and its implications in human diseases. Signal Transduct Target Ther 2023; 8: 2023.

[55] Valente EM , Abou-Sleiman PM , Caputo V , et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004; 304: 1158- 60.

[56] Harper JW , Ordureau A , Heo JM . Building and decoding ubiquitin chains for mitophagy. Nat Rev Mol Cell Biol 2018; 19: 93- 108.

[57] Ryu D , Mouchiroud L , Andreux PA , et al. Urolithin a induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med 2016; 22: 879- 88.

[58] Jain IH , Zazzeron L , Goli R , et al. Hypoxia as a therapy for mitochondrial disease. Science 2016; 352: 54- 61.

[59] Ribeiro MF , Genebra T , Rego AC , et al. Amyloid beta peptide compromises neural stem cell fate by irreversibly disturbing mitochondrial oxidative state and blocking mitochondrial biogenesis and dynamics. Mol Neurobiol 2019; 56: 3922- 36.

[60] Eisner V , Picard M , Hajnoczky G . Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol 2018; 20: 755- 65.

[61] Giacomello M , Pyakurel A , Glytsou C , et al. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol 2020; 21: 204- 24.

[62] Dulac M , Leduc-Gaudet J-P , Cefis M , et al. Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice. J Physiol 2021; 599: 4045- 63.

[63] Song M , Franco A , Fleischer JA , et al. 2nd. Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence. Cell Metab 2017; 26: 872- 83.e5.

[64] Deng Z , He M , Hu H , et al. Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3- mediated TFAM deacetylation. Autophagy 2024; 20: 151- 65.

[65] Carraro M , Carrer A , Urbani A , et al. Molecular nature and regulation of the mitochondrial permeability transition pore(s), drug target(s) in cardioprotection. J Mol Cell Cardiol 2020; 144: 76- 86.

[66] Rottenberg H , Hoek JB . The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore. Aging Cell 2017; 16: 943- 55.

[67] Rottenberg H . The reduction in the mitochondrial membrane potential in aging:the role of the mitochondrial permeability transition pore. Int J Mol Sci 2023; 24: 12295.

[68] Panov AV , Dikalov SI . Cardiolipin, perhydroxyl radicals, and lipid peroxidation in mitochondrial dysfunctions and aging. Oxid Med Cell Longev 2020; 2020: 1323028.

[69] Rottenberg H , Hoek JB . The mitochondrial permeability transition:nexus of aging, disease and longevity. Cells 2021; 10: 79.

[70] Hafner AV , Dai J , Gomes AP , et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY) 2010; 2: 914- 23.

[71] Yang W , Nagasawa K , Münch C , et al. Mitochondrial sirtuin network reveals dynamic SIRT3-dependent deacetylation in response to membrane depolarization. Cell 2016; 167: 985- 1000. e21.

[72] Tu LF , Cao L-F , Zhang Y-H , et al. Sirt3-dependent deacetylation of COX-1 counteracts oxidative stress-induced cell apoptosis. FASEB J 2019; 33: 14118- 28.

[73] Shi JX , Wang QJ , Li H , et al. SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis. Exp Ther Med 2017; 13: 342- 8.

[74] Haschler TN , Horsley H , Balys M , et al. Sirtuin 5 depletion impairs mitochondrial function in human proximal tubular epithelial cells. Sci Rep 2021; 11: 15510.

[75] Giorgi C , Marchi S , Simoes ICM , et al. Mitochondria and reactive Oxygen species in aging and age-related diseases. Int Rev Cell Mol Biol 2018; 340: 209- 344.

[76] Gomez J , Mota-Martorell N , Jove M , et al. Mitochondrial ROS production, oxidative stress and aging within and between species:evidences and recent advances on this aging effector. Exp Gerontol 2023; 174: 112134.

[77] Lee YH , Kuk MU , So MK , et al. Targeting mitochondrial oxidative stress as a strategy to treat aging and age-related diseases. Antioxidants (Basel) 2023; 12: 934.

[78] Qiu X , Brown K , Hirschey MD , et al. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 2010; 12: 662- 7.

[79] Tao R , Coleman MC , Pennington JD , et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 2010; 40: 893- 904.

[80] Ahn BH , Kim H-S , Song S , et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A 2008; 105: 14447- 52.

[81] Papa L , Germain D . SirT3 regulates the mitochondrial unfolded protein response. Mol Cell Biol 2014; 34: 699- 710.

[82] Braidy N , Poljak A , Grant R , et al. Differential expression of sirtuins in the aging rat brain. Front Cell Neurosci 2015; 9: 167.

[83] Zeng J , Jiang M , Wu X , et al. SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation. Aging Cell 2018; 17: e12789.

[84] Luo YX , Tang X , An X-Z , et al. SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity. Eur Heart J 2017; 38: 1389- 98.

[85] Zhou L , Wang F , Sun R , et al. SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense. EMBO Rep 2016; 17: 811- 22.

[86] Lin ZF , Xu H-B , Wang J-Y , et al. SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Biochem Biophys Res Commun 2013; 441: 191- 5.

[87] Liu L , Peritore C , Ginsberg J , et al. Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTPinduced mice model of Parkinson's disease. Behav Brain Res 2015; 281: 215- 21.

[88] Stewart JB , Chinnery PF . The dynamics of mitochondrial DNA heteroplasmy:implications for human health and disease. Nat Rev Genet 2015; 16: 530- 42.

[89] Kong M , Guo L , Xu W , et al. Aging-associated accumulation of mitochondrial DNA mutations in tumor origin. Life Med. 2022; 1: 149- 67.

[90] Sharpley MS , Marciniak C , Eckel-Mahan K , et al. Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition. Cell 2012; 151: 333- 43.

[91] Picca A , Guerra F , Calvani R , et al. The contribution of mitochondrial DNA alterations to aging, cancer, and neurodegeneration. Exp Gerontol 2023; 178: 112203.

[92] Quan Y , Xin Y , Tian G , et al. Mitochondrial ROS-Modulated mtDNA:a potential target for cardiac aging. Oxid Med Cell Longev 2020; 2020: 9423593.

[93] Pillai VB , Bindu S , Sharp W , et al. Sirt3 protects mitochondrial DNA damage and blocks the development of doxorubicininduced cardiomyopathy in mice. Am J Physiol Heart Circ Physiol 2016; 310: H962- 972.

[94] Chen LY , Wang Y , Terkeltaub R , et al. Activation of AMPKSIRT3 signaling is chondroprotective by preserving mitochondrial DNA integrity and function. Osteoarthritis Cartilage 2018; 26: 1539- 50.

[95] Cheresh P , Kim S-J , Jablonski R , et al. SIRT3 Overexpression ameliorates asbestos-induced pulmonary fibrosis, mt-DNA damage, and lung fibrogenic monocyte recruitment. Int J Mol Sci 2021; 22: 6856.

[96] Li GH , Li Y-H , Yu Q , et al. Unraveling the metabolic heterogeneity and commonality in senescent cells using systems modeling. Life Med. 2025; 4: lnaf003.

[97] Gonzalez-Freire M , Diaz-Ruiz A , Hauser D , et al. The road ahead for health and lifespan interventions. Ageing Res Rev 2020; 59: 101037.

[98] Wallace DC . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer:a dawn for evolutionary medicine. Annu Rev Genet 2005; 39: 359- 407.

[99] Amorim JA , Coppotelli G , Rolo AP , et al. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol 2022; 18: 243- 58.

[100] Guo M , Zhang J , Ma Y , et al. Bone morphogenetic protein 7 derived from DPP4(+) cells in beige fat ameliorates ageassociated metabolic dysfunction. Life Med. 2023; 2: lnad025.

[101] Wang CH , Wei YH . Roles of mitochondrial sirtuins in mitochondrial function, redox homeostasis, insulin resistance and type 2 diabetes. Int J Mol Sci. 2020; 21: 5266.

[102] Cimen H , Han M-J , Yang Y , et al. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 2010; 49: 304- 11.

[103] Jing E , O'Neill BT , Rardin MJ , et al. Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes 2013; 62: 3404- 17.

[104] Bharathi SS , Zhang Y , Mohsen A-W , et al. Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. J Biol Chem 2013; 288: 33837- 47.

[105] Hallows WC , Yu W , Smith BC , et al. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell 2011; 41: 139- 49.

[106] Kumar S , Lombard DB . Mitochondrial sirtuins and their relationships with metabolic disease and cancer. Antioxid Redox Signal 2015; 22: 1060- 77.

[107] Min Z , Gao J , Yu Y . The roles of mitochondrial SIRT4 in cellular metabolism. Front Endocrinol (Lausanne) 2018; 9: 783.

[108] Laurent G , German NJ , Saha AK , et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 2013; 50: 686- 98.

[109] Nakagawa T , Lomb DJ , Haigis MC , et al. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 2009; 137: 560- 70.

[110] Xiangyun Y , Xiaomin N , Linping G , et al. Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth. Oncotarget 2017; 8: 6984- 93.

[111] Sadhukhan S , Liu X , Ryu D , et al. Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. Proc Natl Acad Sci U S A 2016; 113: 4320- 5.

[112] Martin-Montalvo A , de Cabo R . Mitochondrial metabolic reprogramming induced by calorie restriction. Antioxid Redox Signal 2013; 19: 310- 20.

[113] Tong Y , Gao H , Qi Q , et al. High fat diet, gut microbiome and gastrointestinal cancer. Theranostics 2021; 11: 5889- 910.

[114] Quiros PM , Mottis A , Auwerx J . Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol 2016; 17: 213- 26.

[115] Walker BR , Moraes CT . Nuclear-Mitochondrial interactions. Biomolecules 2022; 12: 427.

[116] Sahin E , Colla S , Liesa M , et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 2011; 470: 359- 65.

[117] Kim SJ , Mehta HH , Wan J , et al. Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging (Albany NY) 2018; 10: 1239- 56.

[118] Zhang F , Pracheil T , Thornton J , et al. Adenosine Triphosphate (ATP) Is a candidate signaling molecule in the mitochondria-to-nucleus retrograde response pathway. Genes (Basel) 2013; 4: 86- 100.

[119] Shahbazian MD , Grunstein M . Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem 2007; 76: 75- 100.

[120] Hallows WC , Lee S , Denu JM . Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A 2006; 103: 10230- 5.

[121] Zhao L , Su H , Liu X , et al. mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A. Cell Biosci 2022; 12: 183.

[122] Shuai L , Zhang L-N , Li B-H , et al. SIRT5 regulates brown adipocyte differentiation and browning of subcutaneous white adipose tissue. Diabetes 2019; 68: 1449- 61.

[123] Jeong SM , Xiao C , Finley LWS , et al. SIRT4 has tumorsuppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 2013; 23: 450- 63.

[124] Zeng G , Liu H , Wang H . Amelioration of myocardial ischemia-reperfusion injury by SIRT4 involves mitochondrial protection and reduced apoptosis. Biochem Biophys Res Commun 2018; 502: 15- 21.

[125] Fan Z , Liu Z , Zhang N , et al. Identification of SIRT3 as an eraser of H4K16la. iScience 2023; 26: 107757.

[126] Sengupta A , Haldar D . Human sirtuin 3 (SIRT3) deacetylates histone H3 lysine 56 to promote nonhomologous end joining repair. DNA Repair (Amst) 2018; 61: 1- 16.

[127] Scher MB , Vaquero A , Reinberg D . SirT3 is a nuclear NAD+- dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev 2007; 21: 920- 8.

[128] Bao X , Wang Y , Li X , et al. Identification of ‘erasers' for lysine crotonylated histone marks using a chemical proteomics approach. Elife 2014; 3: e02999.

[129] Sundaresan NR , Samant SA , Pillai VB , et al. SIRT3 is a stressresponsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol 2008; 28: 6384- 401.

[130] Sundaresan NR , Gupta M , Kim G , et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 2009; 119: 2758- 71.

[131] Diao Z , Ji Q , Wu Z , et al. SIRT3 consolidates heterochromatin and counteracts senescence. Nucleic Acids Res 2021; 49: 4203- 19.

[132] Matsushita N , Yonashiro R , Ogata Y , et al. Distinct regulation of mitochondrial localization and stability of two human Sirt5 isoforms. Genes Cells 2011; 16: 190- 202.

[133] Ramadani-Muja J , Gottschalk B , Pfeil K , et al. Visualization of Sirtuin 4 distribution between mitochondria and the nucleus, based on bimolecular fluorescence self-complementation. Cells 2019; 8: 1583.

[134] Bergmann L , Lang A , Bross C , et al. Subcellular localization and mitotic interactome analyses identify SIRT4 as a centrosomally localized and microtubule associated protein. Cells 2020; 9: 1950.

[135] Giblin W , Bringman-Rodenbarger L , Guo AH , et al. The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics. J Clin Invest 2021; 131: e138926.

[136] Sidorova-Darmos E , Sommer R , Eubanks JH . The role of SIRT3 in the brain under physiological and pathological conditions. Front Cell Neurosci 2018; 12: 196.

[137] Anderson KA , Huynh FK , Fisher-Wellman K , et al. SIRT4 Is a lysine deacylase that controls leucine metabolism and insulin secretion. Cell Metab 2017; 25: 838- 55.e15.

[138] Xie Y , Cai N , Liu X , et al. SIRT5:a potential target for discovering bioactive natural products. J Nat Med 2025; 79: 441- 64.

[139] Jing E , Emanuelli B , Hirschey MD , et al. Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci U S A 2011; 108: 14608- 13.

[140] Noone J , Rochfort KD , O'Sullivan F , et al. SIRT4 is a regulator of human skeletal muscle fatty acid metabolism influencing inner and outer mitochondrial membrane-mediated fusion. Cell Signal 2023; 112: 110931.

[141] Haigis MC , Mostoslavsky R , Haigis KM , et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006; 126: 941- 54.

[142] Murugasamy K , Munjal A , Sundaresan NR . Emerging roles of SIRT3 in cardiac metabolism. Front Cardiovasc Med 2022; 9: 850340.

[143] Peng X , Ni H , Kuang B , et al. Sirtuin 3 in renal diseases and aging:from mechanisms to potential therapies. Pharmacol Res 2024; 206: 107261.

[144] Yang S , Liu C , Jiang M , et al. A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes. Protein Cell 2024; 15: 98- 120.

[145] Wang X , Liu Z , Zhang L , et al. Mitochondrial transplantation for the treatment of cardiac and noncardiac diseases:mechanisms, prospective, and challenges. Life Med. 2024; 3: lnae017.

[146] Aging Biomarker C , et al. A framework of biomarkers for vascular aging:a consensus statement by the aging biomarker consortium. Life Med. 2023; 2: lnad033.

[147] Benigni A , Cassis P , Conti S , et al. Sirt3 deficiency shortens life span and impairs cardiac mitochondrial function rescued by opa1 gene transfer. Antioxid Redox Signal 2019; 31: 1255- 71.

[148] Kuznetsov AV , Troppmair J , Sucher R , et al. Mitochondrial subpopulations and heterogeneity revealed by confocal imaging:possible physiological role? Biochim Biophys Acta 2006; 1757: 686- 91.

[149] Martin-Fernandez B , Gredilla R . Mitochondria and oxidative stress in heart aging. Age (Dordr) 2016; 38: 225- 38.

[150] Torrealba N , Aranguiz P , Alonso C , et al. Mitochondria in structural and functional cardiac remodeling. Adv Exp Med Biol 2017; 982: 277- 306.

[151] Zeng Z , Xu P , He Y , et al. Acetylation of Atp5f1c mediates cardiomyocyte senescence via metabolic dysfunction in radiation-induced heart damage. Oxid Med Cell Longev 2022; 2022: 4155565.

[152] Guo AH , Baliira R , Skinner ME , et al. Sirtuin 5 levels are limiting in preserving cardiac function and suppressing fibrosis in response to pressure overload. Sci Rep 2022; 12: 12258.

[153] Chang Y , Wang C , Zhu J , et al. SIRT3 ameliorates diabetesassociated cognitive dysfunction via regulating mitochondriaassociated ER membranes. J Transl Med 2023; 21: 494.

[154] Csibi A , Fendt S-M , Li C , et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 2021; 184: 2256.

[155] Zaganjor E , Vyas S , Haigis MC . SIRT4 Is a regulator of insulin secretion. Cell Chem Biol 2017; 24: 656- 8.

[156] Ma Y , Fei X . SIRT5 regulates pancreatic beta-cell proliferation and insulin secretion in type 2 diabetes. Exp Ther Med 2018; 16: 1417- 25.

[157] Li J , Cui J , Tian Y . Neuron-periphery mitochondrial stress communication in aging and diseases. Life Med. 2022; 1: 168- 78.

[158] Aging Biomarker C et al. A framework of biomarkers for brain aging:a consensus statement by the aging biomarker consortium. Life Med. 2023; 2: lnad017.

[159] Zhang H , Li J , Ren J , et al. Single-nucleus transcriptomic landscape of primate hippocampal aging. Protein Cell 2021; 12: 695- 716.

[160] Yin J , Han P , Song M , et al. Amyloid-beta increases Tau by Mediating Sirtuin 3 in Alzheimer's disease. Mol Neurobiol 2018; 55: 8592- 601.

[161] Liu M , Zhang X , Wang Y . Curcumin alleviates Abeta(42)- induced neuronal metabolic dysfunction via the Thrb/SIRT3 axis and improves cognition in APP(TG) mice. Neurochem Res 2021; 46: 3166- 78.

[162] Gleave JA , Arathoon LR , Trinh D , et al. Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant alpha-synuclein rat model of parkinsonism. Neurobiol Dis 2017; 106: 133- 46.

[163] Duan WJ , Liang L , Pan M-H , et al. Theacrine, a purine alkaloid from kucha, protects against Parkinson's disease through SIRT3 activation. Phytomedicine 2020; 77: 153281.

[164] Liu L , Peritore C , Ginsberg J , et al. SIRT3 attenuates MPTPinduced nigrostriatal degeneration via enhancing mitochondrial antioxidant capacity. Neurochem Res 2015; 40: 600- 8.

[165] Yalcin GD , Colak M . SIRT4 prevents excitotoxicity via modulating glutamate metabolism in glioma cells. Hum Exp Toxicol 2020; 39: 938- 47.

[166] Wu S , Wei Y , Li J , et al. SIRT5 represses neurotrophic pathways and abeta production in Alzheimer's disease by targeting autophagy. ACS Chem Neurosci 2021; 12: 4428- 37.

[167] Yao X , Xia X , Hay DC , et al. Tuning mitochondrial dynamics for aging intervention. Life Med. 2024; 3: lnae008.

[168] Shen Y , Wu Q , Shi J , et al. Regulation of SIRT3 on mitochondrial functions and oxidative stress in Parkinson's disease. Biomed Pharmacother 2020; 132: 110928.

[169] You Y , Liang W . SIRT1 and SIRT6:the role in agingrelated diseases. Biochim Biophys Acta Mol Basis Dis 2023; 1869: 166815.

[170] Wu Y , Liu Y , Hao Z , et al. NAD(+) is critical for maintaining acetyl-CoA and H3K27ac in embryonic stem cells by Sirt1- dependent deacetylation of AceCS1. Life Med. 2022; 1: 401- 5.

[171] Liao G , Xie Y , Peng H , et al. Advancements in NMN biotherapy and research updates in the field of digestive system diseases. J Transl Med 2024; 22: 805.

[172] Peng F , Liao M , Jin W , et al. 2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis. Signal Transduct Target Ther 2024; 9: 133.

[173] Lu J , Zhang H , Chen X , et al. A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase. Free Radic Biol Med 2017; 112: 287- 97.

[174] Mori M , Cazzaniga G , Meneghetti F , et al. Insights on the modulation of SIRT5 activity:a challenging balance. Molecules 2022; 27: 4449.

[175] Dong C . Innovating medicine:the path forward. hLife 2024; 2: 147.

[176] Yu J , Li T , Zhu J . Gene therapy strategies targeting aging-related diseases. Aging Dis 2023; 14: 398- 417.

[177] Sun S , Qin W , Tang X , et al. Vascular endothelium-targeted Sirt7 gene therapy rejuvenates blood vessels and extends life span in a Hutchinson-Gilford progeria model. Sci Adv 2020; 6: eaay5556.

[178] Chen C , Liu J , Yu W . Unlocking heart anti-aging potential:the SIRT2-STAT3-CDKN2B pathway as a bridge between fiction and reality. Life Med. 2024; 3: lnae020.

[179] Ye Y , Yang K , Liu H , et al. SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B. Nat Aging 2023; 3: 1269- 87.

[180] Zhao Q , Jing Y , Jiang X , et al. SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1. Nat Metab 2025; 7: 556- 73.

[181] Cai Y , Ji Z , Wang S , et al. Genetic enhancement:an avenue to combat aging-related diseases. Life Med. 2022; 1: 307- 18.

[182] Yi F , Liu GH , Izpisua Belmonte JC . Human induced pluripotent stem cells derived hepatocytes:rising promise for disease modeling, drug development and cell therapy. Protein Cell 2012; 3: 246- 50.

[183] Brown K , Xie S , Qiu X , et al. SIRT3 reverses aging-associated degeneration. Cell Rep 2013; 3: 319- 27.

[184] Wang F , Zhang W , Yang Q , et al. Generation of a HutchinsonGilford progeria syndrome monkey model by base editing. Protein Cell 2020; 11: 809- 24.

[185] Yan P , Li Q , Wang L , et al. FOXO3-Engineered Human ESCDerived Vascular Cells Promote Vascular Protection and Regeneration. Cell Stem Cell 2019; 24: 447- 61.e8.

[186] Lei J , Wang S , Kang W , et al. FOXO3-engineered human mesenchymal progenitor cells efficiently promote cardiac repair after myocardial infarction. Protein Cell 2021; 12: 145- 51.

[187] Bi S , Liu Z , Wu Z , et al. SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer. Protein Cell 2020; 11: 483- 504.

[188] Ryu KW , Fung TS , Baker DC , et al. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria. Nature 2024; 635: 746- 54.

[189] Headley CA , Gautam S , Olmo-Fontanez A , et al. Extracellular delivery of functional mitochondria rescues the dysfunction of CD4(+) T cells in aging. Adv Sci (Weinh) 2024; 11: e2303664.

[190] Lei J , Xin Z , Liu N , et al. Senescence-resistant human mesenchymal progenitor cells counter aging in primates. Cell. Published online June 13, 2025.

RIGHTS & PERMISSIONS

The Author(s). Published by Oxford University Press on behalf of Higher Education Press.