Amancherla, K.; Lin, P.; Perera, B. L. A.; Chow, N.; Sheng, Q.; Siddiqi, H. K.; Farber-Eger, E. H.; Wells, Q. S.; Freedman, J. E.; Schlendorf, K. H.; Shah, R.; Gamazon, E. R.

Solid-organ transplantation in aging recipients represents a unique opportunity to study how age-related immunity in the context of non-specific immunosuppression strategies balances infection, malignancy, and rejection. We sought to characterize the association between increasing recipient age at heart transplantation with acute allograft rejection and age-related cell-specific transcriptomic changes in circulating immune cells. This single-center retrospective cohort study evaluated individuals undergoing heart transplantation between July 2013 and December 2023 at Vanderbilt University Medical Center. Eligible participants were aged [≥]18 years. A subset of individuals underwent single-cell RNA-sequencing of circulating immune cells. The primary exposure was recipient age at the time of heart transplantation. The main outcome of the clinical-epidemiological portion of this study was acute rejection, inclusive of clinically relevant acute cellular or antibody-mediated rejection, within one-year post-transplant. Secondary outcomes included cell-specific compositional and transcriptomic changes with aging in circulating immune cells. Among 799 adults, each one standard deviation increase in recipient age was associated with a ~17% lower odds of allograft rejection (adjusted OR 0.83, 95% CI 0.71-0.98). In 40 individuals who underwent single-cell RNA-sequencing of circulating immune cells, increasing recipient age was associated with increases in CD4+ and CD8+ memory T cell subsets, monocytes, and NK cells. Furthermore, genes upregulated with increasing recipient age were associated with enrichment for pathways involved in immunosenescence and chronic low-grade inflammation while downregulated genes suggested decreased protein synthesis. These findings have clinical implications for an aging transplant population and support a more personalized approach to immunosuppression.