Spermidine mitigates immune cell senescence, enhances autophagy, and boosts vaccine responses in healthy older adults

Older adults are particularly vulnerable to infectious diseases, and vaccines are often less effective in this population due to immunosenescence, which is characterized by diminished B and T memory responses. Autophagy is believed to underlie many facets of cellular aging, including immunosenescence. It is crucial for maintaining memory T and B cell functions but declines with age, along with the endogenous metabolite spermidine that helps maintain autophagy levels. We conducted a double-blind, randomized, placebo-controlled study in 40 volunteers over 65, administering oral spermidine after their third SARS-CoV-2 vaccine dose. Spermidine reduced immune cell senescence, evidenced by decreased p16 expression in lymphocytes. Following spermidine treatment, autophagic ux, TFEB targets, and autophagy-related genes detected by scRNA-seq were highly enriched in B cells. Spermidine signi cantly increased spike-speci c IgG secretion and memory B cells, and neutralizing antibody activity against SARS-CoV-2 strains, in vaccine non-responders that also presented with high immune cell senescence. Targeting immune senescence using spermidine may offer a practical approach to improve immune responses in vaccine non-responders, as a post- or pre-vaccination intervention. Additionally, it highlights the utility of immune senescence markers as predictive biomarkers for identifying vaccine non-responders, addressing a key challenge in vaccine development for an aging population.