Influenza vaccination as a modulator of inflammaging: Trained tolerance as a mechanistic lens on heterologous effects in age-related diseases

Influenza vaccination may confer benefits that extend well beyond seasonal protection against respiratory infection: reduced cardiovascular morbidity and mortality, lower dementia incidence, fewer cardio-renal complications, improved survival in the very old, and emerging signals in oncology and diabetes. Although vulnerable to confounding and evidence in adults aged ≥ 75-80 years and in frail populations remains scarce, their magnitude, cross-organ consistency and apparent dose-response suggest that protection is not explained solely by prevention of infection, but points to a shared upstream mechanism: modulation of chronic inflammation. Recent single-cell multiomic studies provide a plausible substrate: inactivated influenza vaccine induces persistent epigenetic remodelling in monocytes and myeloid dendritic cells, lasting up to six months,and, consistent with a regulatory recalibration of innate reactivity, termed trained tolerance. This myeloid axis is also central to inflammaging, whose clinical expression in older people is frailty. We review multiomic, preclinical and epidemiological evidence supporting a framework in which influenza vaccination may exert effects beyond pathogen-specific protection. Murine models provide causal evidence that vaccination can modify vascular, neurodegenerative and tumour pathology through systemic immune mechanisms. We position these findings alongside heterologous effects of other vaccines and examine their relevance to chronic inflammation. Although innate immune reprogramming involves pathways shared with inflammaging, a direct effect on chronic low-grade inflammation remains unproven. Key uncertainties including healthy-vaccinee bias, the absence of frailty stratification and the age discordance between mechanistic and clinical evidence are discussed.