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SUMMARY Failure to make adaptive immune responses is a hallmark of aging. In particular reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. However, the molecular mechanism underlying immune senescence is largely unknown. Here we show that autophagy levels are specifically reduced in mature lymphoid cells, leading to compromised memory B cell responses in old individuals. Spermidine, a naturally occurring polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses in an autophagy-dependent manner. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which assists the synthesis of TFEB, a key transcription factor of autophagy. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Replenishing spermidine 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, and this pathway can be harnessed to rejuvenate immune senescence in humans.

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