Immune cells and inflammatory proteins are differentially associated with subsequent DNA methylation biological aging measures in the Framingham Heart Study Offspring Cohort

To gain a more comprehensive understanding of the relationships among immunoscenescence and inflammaging(definition), and subsequent epigenetic aging, we measured a panel of 43 immune cell phenotypes and 68 inflammatory proteins collected from blood samples provided by participants in the Framingham Heart Study Offspring Cohort at Exam 7 (1998-2001) and principal component-based DNA methylation (DNAm)-based biologic clocks measured at the subsequent exam (Exam 8 2005-2008), an average of 6 years later. A total of 24 of the 43 immune cell phenotypes and 55 of the 68 inflammatory proteins investigated were significantly associated with at least one of six DNAm aging metrics in age and sex adjusted models. The immune cell associations persisted after accounting for cardiovascular disease and its risk factors, but the protein associations were attenuated. The effects of the inflammatory proteins were larger in the subset of individuals who were < 60 at the protein measurement, compared to those ≥ 60. Immune cell measurements had more associations with age acceleration measures from the 1st generation DNAm clocks and the 2nd generation PhenoAge, while the inflammatory proteins were primarily associated with age acceleration measures based on PhenoAge, GrimAge, and the Dunedin Pace of Aging metric. This study is one of the first attempts to investigate prospective relationships between baseline immune cell composition measured via flow cytometry and inflammatory protein levels and DNAm age measured several years later and represents one of the most comprehensive mappings of immune and inflammatory contributions to DNAm-based age acceleration and pace of aging metrics to date.