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Naked mole rat cells are protected from cellular senescence via Wnt/β-catenin-promoted cholesterol metabolism

ABSTRACT: The naked mole rat (NMR; Heterocephalus glaber) exhibits cancer resistance and an exceptionally long lifespan of approximately 30 years. The longevity of the NMR is widely debated, as it poses challenges to theories associated with aging, cancer, and redox homeostasis. In the present study, we report unique mechanisms of cholesterol metabolism in NMR cells that could be responsible in part for their anti-senescent properties. We found that NMR fibroblasts abundantly express β-catenin, and that increased β-catenin activity is linked to increased accumulation of cholesterol-enriched lipid droplets. Either β-catenin knockdown or inhibition of cholesterol synthesis abolished lipid droplet formation, and enhanced induction of senescence-like phenotypes. Analysis of β-catenin-regulated genes revealed that β-catenin upregulated the LXR/RXR pathway and Apolipoprotein F, which are involved in cholesterol biogenesis and transport. Specifically, Apolipoprotein F is involved in the accumulation of lipid droplets, protecting NMR cells from cellular senescence. We thus suggest that increased β-catenin activity evolved in NMRs to offset senescence via the accumulation of cholesterol-enriched lipid droplets. Hence, the anti-senescence effects of the Wnt/β-catenin signaling in NMRs reveals new strategies for the development of anti-cancer and anti-aging treatments.

ORGANISM(S): Heterocephalus glaber

PROVIDER: GSE147871 | GEO | 2021/02/21

REPOSITORIES: GEO

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Project description:The immune system consists of a network of specialized cells and processes that protect the organism from diseases and regulates tissue repair. Natural killer (NK) cells and the αβ and γδ T cells comprise the cytotoxic arm of the immune system and have evolved to detect and eradicate cells infected with pathogens and affected by malignancies, in order to prevent their spread and subsequent tissue damage. The naked mole-rat (NMR; Heterocephalus glaber) exhibits an unusually long lifespan relative to its body size, remarkable cancer resistance, and a surprising absence of NK cells, likely lost during its evolution. So far, little is known about NMR T cells in terms of the subsets they comprise, the evolution of the genes that regulate their function, the diversity of their clonotypes, and the organ in which they mature – the thymus. Using single-cell RNA sequencing (scRNA-seq), we find that NMRs have a large population of circulating γδT cells, comprising two subsets, one with an activated cytotoxic profile. Using comparative genomics, we find that the NMR genome maintains a large diversity of γ and δ variable T-cell receptor (TCR) regions, relative to that in other mammalian genomes. We devise a novel TCR scRNA-seq approach, which reveals that the NMR cytotoxic γδT-cell subset harbors a dominant clonotype, and that, in contrast to mouse, the clonotypic diversity of NMR CD8 αβT cells is significantly lower than that of its CD4 αβT cells. The latter suggests that NMRs have evolved under a relaxed intracellular pathogenic selective pressure, consistent with the loss of their NK cells. We corroborate this by showing that the genomic diversity of NMR MHC-I genes, relative to that of MHC-II genes, is considerably smaller than in other mammalian genomes. In line with these findings, we further show that NMR thymi in early life are considerably smaller compared to mouse thymi, yet by middle age thymi of both species show equivalent signs of involution. Our study thus sheds significant light on NMR T cells and moves us one step closer towards understanding the contributions of the immune system to the remarkable longevity and cancer resistance of this species.

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Naked mole rat cells are protected from cellular senescence via Wnt/β-catenin-promoted cholesterol metabolism

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