The Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK.
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Mol Cell. 2019 Oct 3;76(1):110-125.e9. doi: 10.1016/j.molcel.2019.08.005. Epub 2019 Aug 29.
Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.
无法产生适应性免疫应答是衰老的一个标志。B 细胞功能的降低导致老年人疫苗接种效果不佳和感染高发。在这里，我们表明，自噬减少是免疫衰老的一个核心分子机制。自噬水平在成熟淋巴细胞中特异性降低，导致老年人记忆 B 细胞反应受损。亚精胺是一种内源性多胺代谢物，可在体内诱导自噬，并使记忆 B 细胞反应恢复活力。在机制上，亚精胺对翻译因子 eIF5A 进行翻译后修饰，而 eIF5A 对自噬转录因子 TFEB 的合成至关重要。衰老的人体内亚精胺耗竭，导致 TFEB 表达和自噬减少。亚精胺补充恢复了这一途径，并改善了老年人类 B 细胞的反应。总之，我们的研究结果揭示了一种意想不到的自噬调节机制，该机制由翻译水平上的 eIF5A 介导，可用于逆转人类的免疫衰老。
