Variations in Innate Immune Cell Subtypes Correlate with Epigenetic Clocks, Inflammaging and Health Outcomes

This study uses a high‐resolution DNA methylation reference panel for 19 immune cell‐types, as well as transcriptomic, metabolomic, and large population cohort data to show that age‐related epigenetic heterogeneity within monocytes correlates with inflammaging, biological age, and all‐causemortality, and does so more strongly than existing monocyte classifications. The same panel also identifies an erythroblast‐like component that correlates with dysfunctional erythropoiesis and all‐cause mortality. This heterogeneity drives another component of epigenetic clocks, yet biological aging clocks remain independently associated with cause‐specific and all‐cause mortality. Abstract Epigenetic clocks in blood have shown promise as tools to quantify biological age, displaying robust associations with morbidity and all‐cause mortality. Whilst the effect of cell‐type heterogeneity on epigenetic clock estimates has been explored, such studies have been limited to studying heterogeneity within the adaptive immune system. Much less is known about whether heterogeneity within the innate immune system can impact epigenetic clock estimates and their associations with health outcomes. Here, we apply a high‐resolution DNAm reference panel of 19 immune cell‐types, including young and adult monocyte, natural killer, and neutrophil subsets, demonstrating how shifts within these innate subtypes display associations with epigenetic clock acceleration, inflammaging, and all‐cause mortality. The associations of monocyte heterogeneity with inflammation are further validated using transcriptomic and metabolomic data. Additionally, a non‐negligible fraction of nucleated red blood cell‐like cells in circulation is found to associate with inflammaging, markers of dysfunctional erythropoiesis, and is a major risk factor for all‐cause mortality. These results extend findings obtained within the adaptive immune system to innate immune and erythrocyte‐like cells, demonstrating how heterogeneity within these other blood cell compartments is also associated with inflammaging, epigenetic clocks, and health outcomes. This study uses a high-resolution DNA methylation reference panel for 19 immune cell-types, as well as transcriptomic, metabolomic, and large population cohort data to show that age-related epigenetic heterogeneity within monocytes correlates with inflammaging, biological age, and all-causemortality, and does so more strongly than existing monocyte classifications. The same panel also identifies an erythroblast-like component that correlates with dysfunctional erythropoiesis and all-cause mortality. This heterogeneity drives another component of epigenetic clocks, yet biological aging clocks remain independently associated with cause-specific and all-cause mortality. Abstract Epigenetic clocks in blood have shown promise as tools to quantify biological age, displaying robust associations with morbidity and all-cause mortality. Whilst the effect of cell-type heterogeneity on epigenetic clock estimates has been explored, such studies have been limited to studying heterogeneity within the adaptive immune system. Much less is known about whether heterogeneity within the innate immune system can impact epigenetic clock estimates and their associations with health outcomes. Here, we apply a high-resolution DNAm reference panel of 19 immune cell-types, including young and adult monocyte, natural killer, and neutrophil subsets, demonstrating how shifts within these innate subtypes display associations with epigenetic clock acceleration, inflammaging, and all-cause mortality. The associations of monocyte heterogeneity with inflammation are further validated using transcriptomic and metabolomic data. Additionally, a non-negligible fraction of nucleated red blood cell-like cells in circulation is found to associate with inflammaging, markers of dysfunctional erythropoiesis, and is a major risk factor for all-cause mortality. These results extend findings obtained within the adaptive immune system to innate immune and erythrocyte-like cells, demonstrating how heterogeneity within these other blood cell compartments is also associated with inflammaging, epigenetic clocks, and health outcomes. Advanced Science, Volume 12, Issue 43, November 20, 2025.