Epigenetic signature of human immune aging in the GESTALT study

• DOI: 10.7554/elife.86136
• Publication Date: 2023-08-17T10:15:17Z
• Authors: Roshni Roy; Pei-Lun Kuo; Julián Candia; Dimitra Sarantopo...; Ceereena Ubaida-M...; Dena Hernandez; Mary Kaileh; Sampath Arepalli; Amit Singh; Arsun Bektas; Jaekwan Kim; Ann Z Moore; Toshiko Tanaka; Julia McKelvey; Linda Zukley; Cuong Nguyen; Tonya Wallace; Christopher Dunn; William Wood; Yulan Piao; Christopher Coletta; Supriyo De; Jyoti Sen; Nan-ping Weng; Ranjan Sen; Luigi Ferrucci
• Keywords: 0301 basic medicine; Aging; DNA methylation; hypoxia; QH301-705.5; Science; Q; R; Genetics and Genomics; CD8-Positive T-Lymphocytes; DNA Methylation; 3. Good health; Epigenesis, Genetic; 03 medical and health sciences; immune cells; healthy aging; Medicine; Humans; Biology (General); Complement Activation

Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood-borne immune cell types (naive B, naive CD4+ and CD8+ T cells, granulocytes, monocytes, and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousands of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1β) and REST transcription factor (TF) motifs, respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to TF motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.