Immune aging captures complementary aging biology beyond epigenetic clocks

Abstract

Biological aging clocks are typically evaluated through competitive benchmarking, implicitly assuming that a single metric can sufficiently capture the complexities of aging1-6. Here, we tested an alternative hypothesis: that distinct clock types capture orthogonal dimensions of aging and therefore yield greater value when integrated. Using the Framingham Heart Study, we compared the immune-aging metric, IMM-AGE, with established DNA methylation clocks and found that integrated models consistently outperformed single-clock approaches. To investigate the basis of this complementarity, we derived IMMAGE-Epi, a 22-CpG methylation surrogate of IMM-AGE which exhibited minimal overlap with canonical epigenetic clock CpGs, suggesting that immune aging is associated with a distinct methylomic feature and pathway space rather than representing a reformulation of existing clock architectures. Together, our findings support an emerging multidimensional model of biological aging in which integrating orthogonal biological clocks may offer greater translational utility than competitive single-clock optimization.