Pickering Andrew M, Lehr Marcus, Miller Richard A
J Clin Invest. 2015 May;125(5):2059-68. doi: 10.1172/JCI80514. Epub 2015 Apr 13.
There is large variation in lifespan among different species, and there is evidence that modulation of proteasome function may contribute to longevity determination. Comparative biology provides a powerful tool for identifying genes and pathways that control the rate of aging. Here, we evaluated skin-derived fibroblasts and demonstrate that among primate species, longevity correlated with an elevation in proteasomal activity as well as immunoproteasome expression at both the mRNA and protein levels. Immunoproteasome enhancement occurred with a concurrent increase in other elements involved in MHC class I antigen presentation, including β-2 microglobulin, (TAP1), and TAP2. Fibroblasts from long-lived primates also appeared more responsive to IFN-γ than cells from short-lived primate species, and this increase in IFN-γ responsiveness correlated with elevated expression of the IFN-γ receptor protein IFNGR2. Elevation of immunoproteasome and proteasome activity was also observed in the livers of long-lived Snell dwarf mice and in mice exposed to drugs that have been shown to extend lifespan, including rapamycin, 17-α-estradiol, and nordihydroguaiaretic acid. This work suggests that augmented immunoproteasome function may contribute to lifespan differences in mice and among primate species.
不同物种之间的寿命存在很大差异，并且有证据表明蛋白酶体功能的调节可能有助于确定寿命。比较生物学为识别控制衰老速率的基因和途径提供了一个强大的工具。在这里，我们评估了皮肤来源的成纤维细胞，并证明在灵长类物种中，寿命与蛋白酶体活性的升高以及免疫蛋白酶体在mRNA和蛋白质水平上的表达相关。免疫蛋白酶体增强伴随着参与MHC I类抗原呈递的其他元件的同时增加，包括β-2微球蛋白、（TAP1）和TAP2。长寿灵长类动物的成纤维细胞对IFN-γ的反应也比短寿灵长类物种的细胞更敏感，并且这种IFN-γ反应性的增加与IFN-γ受体蛋白IFNGR2的表达升高相关。在长寿的斯内尔侏儒小鼠的肝脏以及暴露于已被证明可延长寿命的药物（包括雷帕霉素、17-α-雌二醇和去甲二氢愈创木酸）的小鼠肝脏中也观察到免疫蛋白酶体和蛋白酶体活性的升高。这项工作表明，增强的免疫蛋白酶体功能可能导致小鼠和灵长类物种之间的寿命差异。
