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Mol Cell. 2019 Oct 3;76(1):110-125.e9. doi: 10.1016/j.molcel.2019.08.005. Epub 2019 Aug 29.

Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence.

Author information

1
The Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK.
2
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
3
Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131, Naples, Italy.
4
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK; Target Discovery Institute, University of Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK.
5
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
6
Target Discovery Institute, University of Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK.
7
Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131, Naples, Italy; Department of Molecular and Human Genetics and Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
8
Division of Haematology, University Hospital and University of Zürich, 8091, Zürich, Switzerland.
9
The Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK. Electronic address: katja.simon@kennedy.ox.ac.uk.

Abstract

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.

KEYWORDS:

B cell; TFEB; aging; autophagy; eIF5A; spermidine

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