Causal effects of immune cell populations on biological aging: a Mendelian randomization study

While immune system involvement in aging is increasingly recognized, causal relationships between specific immune cell populations and biological aging indicators remain unclear. We aimed to identify immune targets influencing aging trajectories to inform future immunomodulatory interventions. We conducted two-sample Mendelian randomization (MR) analysis using immunophenotype GWAS data (3,757 Sardinian participants) and aging phenotype statistics (PhenoAgeAccel: n = 107,460; BioAgeAccel: n = 98,446). Analysis employed IVW methodology with sensitivity analyses including weighted median estimation, MR-Egger regression, MR-PRESSO, and Cochran's Q statistic. Significance was determined using False Discovery Rate (FDR) correction (P_FDR < 0.05). After FDR correction, seventeen immune cell phenotypes showed significant associations with PhenoAgeAccel: two cDCs, one monocyte subtype, ten myeloid cells, three TBNK cells, and one Treg population. Key findings included protective effects of FSC-A on granulocyte (β = -0.24, 95% CI:-0.37 to -0.10, P_FDR = 1.81 × 10^-2) and risk associations of CD14⁺ CD16^- monocyte (β = 0.41, 95% CI:0.24-0.58, P_FDR = 6.84 × 10^-4). Among TBNK cells, CD8⁺ T cell (β = 0.32, 95% CI: 0.16-0.47, P_FDR = 6.44 × 10^-3) and CD28^- CD8⁺ T cell (β = 0.40, 95% CI: 0.23-0.58, P_FDR = 8.14 × 10^-4) emerged as risk factors. For BioAgeAccel, four phenotypes showed suggestive relationships, with Unswitched Memory B Cell showing the strongest protective effect (β =  - 0.32, 95% CI:-0.52 to-0.12, p = 1.75 × 10^-3). Our study revealed causal relationships between specific immune cell phenotypes and biological aging acceleration, identifying potential therapeutic targets for age-modulation and suggesting immune signatures as crucial regulators in aging-related processes.