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Upregulation of Autophagy Reverses Age-Related Decline of Memory B Cell Function


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Posted 11 September 2019 - 10:22 AM


Memory B cells undertake some of the more important tasks in coordination of an effective immune response, circulating in the body to accelerate the deployment of other resources in the immune system to tackle a specific threat. Dysfunction in B cells is a significant component of the onset of age-related immunosenescence, the progressively greater incapacity of the immune system. Selectively removing and replacing B cells has been shown to improve matters, but here researchers identify failing autophagy as an important factor. B cells are long-lived, and long-lived cells tend to build up metabolic waste that is resilient to the enzymes available to break it down. This gums up the structures and systems used in autophagy, causing it to fail, and the cells to thus become ever more cluttered with damaged protein machinery and other harmful waste. This in turn degrades function.

During a regular influenza season, about 90% of the deaths occur in people older than 65 years. Immune responses to vaccines are known to be particularly ineffective in the elderly population. A major correlate of protection for vaccinations is the specific antibody titer generated by long-lived plasma B cells. With a lifespan of several decades, long-lived lymphocytes are particularly prone to accumulation of intracellular waste. Autophagy recycles unwanted cytoplasmic material. Autophagy-deficient lymphocytes are unable to generate adequate responses, in particular long-lived lymphocytes, memory T cells, memory B cells, and plasma B cells.

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.

Link: https://doi.org/10.1...cel.2019.08.005


View the full article at FightAging




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