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Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double\u2010blind, randomised, placebo\u2010controlled pilot study in 40 adults over 65\u2009years of age following their third SARS\u2010CoV\u20102 vaccine dose to assess the safety of Spermidine and its effects on vaccine\u2010induced immunity. Daily oral supplementation (6\u2009mg, 13\u2009weeks) was well\u2010tolerated. Vaccine non\u2010responsiveness was common, and non\u2010responders exhibited a distinct immune\u2010senescence signature marked by elevated p16, mTOR signalling, and \u03b3\u2010H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike\u2010specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non\u2010responders. Single\u2010cell RNA\u2010seq after treatment revealed increased expression of TFEB targets and autophagy\u2010related genes in B cells, in line with elevated autophagic flux. These findings suggest that targeting immune cell senescence with Spermidine may improve vaccine responsiveness in older adults and highlight immune\u2010senescence markers as potential predictors of vaccine failure in ageing populations.<\/jats:p>","DOI":"10.1111\/acel.70545","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T07:37:08Z","timestamp":1779435428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults\u2014A Pilot Study"],"prefix":"10.1111","volume":"25","author":[{"given":"Ghada","family":"Alsaleh","sequence":"first","affiliation":[{"name":"Botnar Institute for Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences University of Oxford  Oxford UK"},{"name":"Kennedy Institute of Rheumatology University of Oxford  Oxford 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