Infections remain a major cause of mortality and may threaten healthy aging. Previous studies have focused on isolated severe infections rather than longitudinal infection burden. We aimed to examine associations of infection trajectories with biological age acceleration (BAA) and assessed infection severity and genetic susceptibility. We included adults aged 20-74 years from the Shanghai Suburban Adult Cohort and Biobank, China, enrolled between 2016 and 2019 with valid biological age (BA) measurements at baseline and follow-up. Infection-related episodes were identified from linked local health information systems and summarized quarterly between baseline and first follow-up. Group-based trajectory modeling identified infection trajectories. BA was estimated using the Klemera-Doubal method and BAA was defined as the residual from regressing BA on chronological age. Linear mixed-effects models assessed associations with annual BAA change. Polygenic risk scores and Cox models evaluated genetic susceptibility and all-cause mortality. Among 7614 participants, four infection trajectories were identified: infrequent (71.15%), decreasing (18.72%), increasing (8.18%), and frequent (1.96%). Compared with the infrequent group, the frequent group showed the largest estimate in the age- and sex-adjusted model (β = 0.67, 95% CI: 0.04-1.31). A greater proportion of severe episodes was associated with faster BAA change. Associations persisted in long-term analyses and appeared stronger among individuals with higher polygenic susceptibility. Frequent infection trajectories were also associated with higher mortality and greater years of life lost. Longitudinal infection trajectories, particularly frequent and severe patterns, were associated with greater increases in BAA and higher mortality, supporting attention to cumulative infection burden in vulnerable populations.
