Polyamines reverse immune senescence via the translational control of autophagy

Abstract

Organismal aging is associated with compromised cellular function, which can be partially attributed to accumulation of cellular damage. Being the major, if not only, cellular bulk-degradation mechanism, macroautophagy (hereafter autophagy) declines with age in multiple tissues and organisms. Spermidine is an endogenous polyamine metabolite that also declines with age. It prolongs lifespan and improves tissue functions of model organisms in an autophagy-dependent manner. We report that autophagic flux is significantly reduced in B cells from old mice. Spermidine induces autophagy and improves the function of both old mouse and old human B cells. Mechanistically, spermidine post-translationally modifies (hypusinates) the translation factor EIF5A. Hypusinated EIF5A specifically regulates the synthesis of the master autophagy and lysosome transcription factor, TFEB (transcription factor EB). This pathway declines with age in both mice and humans, which may eventually lead to declining autophagy and impaired tissue functions in old individuals.

Keywords: Aging; B cells; EIF5A; TFEB; autophagy; hypusine; spermidine; translation.

Figure 1.

Anabolism and catabolism are upregulated in activated B cells in a coordinated manner. MTOR integrates growth and nutrient signals to promote translation and cellular growth. Despite the high MTOR activity, autophagy is also upregulated in activated B cells via MTOR-independent signaling pathways. High autophagic flux relies on efficient protein synthesis. Specifically, spermidine sustains optimal translation via hypusinating EIF5A, which is required for maintaining high TFEB protein levels. Autophagy may in turn provide nutrients and degrade damaged organelles to assist the high growth rate and antibody production of activated B cells.