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By analyzing a large cohort of Chinese centenarians, we previously found that single-nucleotide polymorphisms (SNPs) in the\n            <jats:italic>SLC39A11<\/jats:italic>\n            gene (also known as\n            <jats:italic>ZIP11<\/jats:italic>\n            ) are associated with longevity in males. However, the function of the SLC39A11 protein remains unclear. Here, we found that\n            <jats:italic>SLC39A11<\/jats:italic>\n            expression is significantly reduced in patients with Hutchinson\u2013Gilford progeria syndrome (HGPS). In addition, we found that zebrafish with a mutation in\n            <jats:italic>slc39a11<\/jats:italic>\n            that significantly reduces its expression have an accelerated aging phenotype, including a shortened average lifespan, muscle atrophy and reduced swimming, impaired muscle regeneration, gut damage, and abnormal morphology in the reproductive system. Interestingly, these signs of premature aging were more pronounced in male zebrafish than in females. RNA-sequencing analysis revealed that cellular senescence may serve as a potential mechanism for driving this\n            <jats:italic>slc39a11<\/jats:italic>\n            deficiency-induced phenotype in mutant zebrafish. Moreover, immunofluorescence showed significantly increased DNA damage and reactive oxygen species signaling in\n            <jats:italic>slc39a11<\/jats:italic>\n            mutant zebrafish. Using inductively coupled plasma mass spectrometry (ICP-MS), we found that manganese significantly accumulates in\n            <jats:italic>slc39a11<\/jats:italic>\n            mutant zebrafish, as well as in the serum of both global\n            <jats:italic>Slc39a11<\/jats:italic>\n            knockout and hepatocyte-specific\n            <jats:italic>Slc39a11<\/jats:italic>\n            knockout mice, suggesting that this metal transporter regulates systemic manganese levels. Finally, using cultured human fibroblasts, we found that both knocking down\n            <jats:italic>SLC39A11<\/jats:italic>\n            and exposure to high extracellular manganese increased cellular senescence. These findings provide compelling evidence that SLC39A11 serves to protect against the aging process, at least in part by regulating cellular manganese homeostasis.\n          <\/jats:p>","DOI":"10.34133\/research.0440","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T06:41:59Z","timestamp":1720766519000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":13,"title":["A Novel Role for the Longevity-Associated Protein SLC39A11 as a Manganese Transporter"],"prefix":"10.34133","volume":"7","author":[{"given":"Zhidan","family":"Xia","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9059-0045","authenticated-orcid":false,"given":"Biyao","family":"Tang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."},{"name":"School of Public Health, Basic Medical Sciences, The First Affiliated Hospital, Hengyang Medical School, \rUniversity of South China, Hengyang, China."},{"name":"School of Public Health, School of Basic Medical Sciences, The First Affiliated Hospital, \rXinxiang Medical University, Xinxiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopeng","family":"Li","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinran","family":"Li","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangfan","family":"Jia","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Jiang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyao","family":"Chen","sequence":"additional","affiliation":[{"name":"The Core Facilities, \rZhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingshu","family":"Song","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyi","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8099-6327","authenticated-orcid":true,"given":"Junxia","family":"Min","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8730-0003","authenticated-orcid":true,"given":"Fudi","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang Provincial Key Laboratory of Bioelectromagnetics, State Key Laboratory of Experimental Hematology, \rZhejiang University School of Medicine, Hangzhou, China."},{"name":"School of Public Health, Basic Medical Sciences, The First Affiliated Hospital, Hengyang Medical School, \rUniversity of South China, Hengyang, China."},{"name":"School of Public Health, School of Basic Medical Sciences, The First Affiliated Hospital, \rXinxiang Medical University, Xinxiang, 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Manganese exposure and cognition across the lifespan: Contemporary review and argument for biphasic dose\u2013response health effects. Curr Environ Health Rep. 2016;3(4):392\u2013404.","journal-title":"Curr Environ Health Rep"},{"issue":"6","key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.ajhg.2015.11.002","article-title":"Autosomal-recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the manganese and zinc transporter gene SLC39A8","volume":"97","author":"Boycott Kym M","year":"2015","unstructured":"Boycott Kym M, Beaulieu Chandree L, Kernohan Kristin D, Gebril Ola H, Mhanni A, Chudley Albert E, Redl D, Qin W, Hampson S, K\u00fcry S, et al. Autosomal-recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the manganese and zinc transporter gene SLC39A8. Am J Hum Genet. 2015;97(6):886\u2013893.","journal-title":"Am J Hum Genet"},{"issue":"6","key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.ajhg.2015.11.003","article-title":"SLC39A8 deficiency: A disorder of manganese transport and glycosylation","volume":"97","author":"Park Julien H","year":"2015","unstructured":"Park Julien H, Hogrebe M, Gr\u00fcneberg M, DuChesne I, von der Heiden AL, Reunert J, Schlingmann Karl P, Boycott Kym M, Beaulieu Chandree L, Mhanni Aziz A, et al. SLC39A8 deficiency: A disorder of manganese transport and glycosylation. 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J Neurosci. 2017;37(25):5996\u20136006.","journal-title":"J Neurosci"},{"issue":"8","key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"E1769","DOI":"10.1073\/pnas.1720739115","article-title":"SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice","volume":"115","author":"Jenkitkasemwong S","year":"2018","unstructured":"Jenkitkasemwong S, Akinyode A, Paulus E, Weiskirchen R, Hojyo S, Fukada T, Giraldo G, Schrier J, Garcia A, Janus C, et al. SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice. 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J Clin Invest. 2019;129(12):5442\u20135461.","journal-title":"J Clin Invest"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00238-6"},{"issue":"9","key":"e_1_3_4_19_2","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22094646","article-title":"Molecular targets of manganese-induced neurotoxicity: A five-year update","volume":"22","author":"Tinkov AA","year":"2021","unstructured":"Tinkov AA, Paoliello MMB, Mazilina AN, Skalny AV, Martins AC, Voskresenskaya ON, Aaseth J, Santamaria A, Notova SV, Tsatsakis A, et al. Molecular targets of manganese-induced neurotoxicity: A five-year update. Int J Mol Sci. 2021;22(9): Article 4646.","journal-title":"Int J Mol Sci"},{"issue":"6","key":"e_1_3_4_20_2","first-page":"603","article-title":"Functional discoveries and mechanistic studies of manganese transporters","volume":"30","author":"Huang X","year":"2018","unstructured":"Huang X, Li L, Wang J, Min J, Wang F. 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