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.