A Novel Role for the Longevity-Associated Protein SLC39A11 as a Manganese Transporter
Zhidan Xia,
Biyao Tang,
Xiaopeng Li,
Xinran Li,
Yangfan Jia,
Jianwei Jiang,
Jingyao Chen,
Jingshu Song,
Siyi Liu,
Junxia Min,
Fudi Wang
Affiliations
Zhidan Xia
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,
Zhejiang University School of Medicine, Hangzhou, China.
Biyao Tang
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,
Zhejiang University School of Medicine, Hangzhou, China.
Xiaopeng Li
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,
Zhejiang University School of Medicine, Hangzhou, China.
Xinran Li
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,
Zhejiang University School of Medicine, Hangzhou, China.
Yangfan Jia
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,
Zhejiang University School of Medicine, Hangzhou, China.
Jianwei Jiang
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,
Zhejiang University School of Medicine, Hangzhou, China.
Jingyao Chen
The Core Facilities,
Zhejiang University School of Medicine, Hangzhou, China.
Jingshu Song
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,
Zhejiang University School of Medicine, Hangzhou, China.
Siyi Liu
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,
Zhejiang University School of Medicine, Hangzhou, China.
Junxia Min
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,
Zhejiang University School of Medicine, Hangzhou, China.
Fudi Wang
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,
Zhejiang University School of Medicine, Hangzhou, China.
The identification of aging- and longevity-associated genes is important for promoting healthy aging. By analyzing a large cohort of Chinese centenarians, we previously found that single-nucleotide polymorphisms (SNPs) in the SLC39A11 gene (also known as ZIP11) are associated with longevity in males. However, the function of the SLC39A11 protein remains unclear. Here, we found that SLC39A11 expression is significantly reduced in patients with Hutchinson–Gilford progeria syndrome (HGPS). In addition, we found that zebrafish with a mutation in slc39a11 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 slc39a11 deficiency-induced phenotype in mutant zebrafish. Moreover, immunofluorescence showed significantly increased DNA damage and reactive oxygen species signaling in slc39a11 mutant zebrafish. Using inductively coupled plasma mass spectrometry (ICP-MS), we found that manganese significantly accumulates in slc39a11 mutant zebrafish, as well as in the serum of both global Slc39a11 knockout and hepatocyte-specific Slc39a11 knockout mice, suggesting that this metal transporter regulates systemic manganese levels. Finally, using cultured human fibroblasts, we found that both knocking down SLC39A11 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.