Department of Oncogene Research, Research for Microbial Disease, Osaka University, Suita, Osaka, Japan.
Department of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Commun Biol. 2021 Mar 19;4(1):357. doi: 10.1038/s42003-021-01879-8.
The naked mole-rat (NMR; Heterocephalus glaber) exhibits cancer resistance and an exceptionally long lifespan of approximately 30 years, but the mechanism(s) underlying increased longevity in NMRs remains unclear. In the present study, we report unique mechanisms underlying cholesterol metabolism in NMR cells, which may be responsible for their anti-senescent properties. NMR fibroblasts expressed β-catenin abundantly; this high expression was linked to increased accumulation of cholesterol-enriched lipid droplets. Ablation of β-catenin or inhibition of cholesterol synthesis abolished lipid droplet formation and induced senescence-like phenotypes accompanied by increased oxidative stress. β-catenin ablation downregulated apolipoprotein F and the LXR/RXR pathway, which are involved in cholesterol transport and biogenesis. Apolipoprotein F ablation also suppressed lipid droplet accumulation and promoted cellular senescence, indicating that apolipoprotein F mediates β-catenin signaling in NMR cells. Thus, we suggest that β-catenin in NMRs functions to offset senescence by regulating cholesterol metabolism, which may contribute to increased longevity in NMRs.
裸鼹鼠（NMR；Heterocephalus glaber）表现出对癌症的抵抗力和极长的寿命，大约 30 年，但 NMR 中寿命延长的机制尚不清楚。在本研究中，我们报道了 NMR 细胞中胆固醇代谢的独特机制，这可能是它们抗衰老特性的原因。NMR 成纤维细胞大量表达β-连环蛋白；这种高表达与富含胆固醇的脂滴的积累增加有关。β-连环蛋白的缺失或胆固醇合成的抑制会破坏脂滴的形成，并诱导衰老样表型，同时伴随着氧化应激的增加。β-连环蛋白的缺失下调了载脂蛋白 F 和 LXR/RXR 通路，这两个通路参与胆固醇的运输和生物合成。载脂蛋白 F 的缺失也抑制了脂滴的积累并促进了细胞衰老，表明载脂蛋白 F 在 NMR 细胞中介导β-连环蛋白信号。因此，我们认为 NMR 中的β-连环蛋白通过调节胆固醇代谢来抵消衰老，这可能有助于 NMR 寿命的延长。
