IMMClock Reveals Immune Aging and T Cell Function at Single-Cell Resolution

The aging of the immune system substantially impacts individual immune responses, yet accurately quantifying immune age remains a complex challenge. Here we developed IMMClock, a novel immune aging clock that uses gene expression data to predict the biological age of individual CD8⁺ T cells, CD4⁺ T cells, and NK cells. The accuracy of IMMClock is first validated across multiple independent datasets, demonstrating its robustness. Second, utilizing the IMMClock, we find that intrinsic cellular aging processes are more strongly altered during immune aging than differentiation processes. Thirdly, our analysis confirms the strong associations between immune aging and established processes such as cellular senescence, exhaustion, and telomere length at the single cell level. Furthermore, immune aging is accelerated under several disease conditions such as type 2 diabetes, heart disease, and cancer. Finally, we apply IMMClock to analyze a perturb-seq gene activation screen of T cell functionality. We find that the post-perturbation immune age of individual T cells is strongly correlated with their pre-perturbation immune age. Furthermore, the immune age at resting state of individual T cells is strongly predictive of their post-stimulation activation state. Overall, IMMClock advances our understanding of immune aging by providing precise, single-cell level age estimations. Its future applications hold promise for identifying interventions that concomitantly rejuvenate and activate T cells, potentially enhancing efforts to counteract age-related immune decline. ### Competing Interest Statement E.R. is a co-founder of Medaware Ltd, Metabomed Ltd, and Pangea Biomed Ltd (divested from the latter). E.R. serves as a non-paid scientific consultant to Pangea Biomed Ltd and on the Scientific Advisory Board of GlaxoSmithKline (GSK) oncology. N.P.R. receives compensation and holds equity in Marble Therapeutics, Boston, MA, and in IMEL Biotherapeutics, Waltham, MA. The other authors declare that they have no potential competing interests.