Leukocyte telomere length, T cell composition and DNA methylation age

Both leukocyte telomere length (LTL) and DNA methylation age are strongly associated with chronological age. One measure of DNA methylation age─ the extrinsic epigenetic age acceleration (EEAA)─ is highly predictive of all-cause mortality. We examined the relation between LTL and EEAA. LTL was measured by Southern blots and leukocyte DNA methylation was determined using Illumina Infinium HumanMethylation450 BeadChip in participants in the Women's Health Initiative (WHI; n=804), the Framingham Heart Study (FHS; n=909) and the Bogalusa Heart study (BHS; n=826). EEAA was computed using 71 DNA methylation sites, further weighted by proportions of naïve CD8⁺ T cells, memory CD8⁺ T cells, and plasmablasts. Shorter LTL was associated with increased EEAA in participants from the WHI (r=-0.16, p=3.1x10^-6). This finding was replicated in the FHS (r=-0.09, p=6.5x10^-3) and the BHS (r=-0.07, p=3.8x 10^-2). LTL was also inversely related to proportions of memory CD8⁺ T cells (p=4.04x10^-16) and positively related to proportions of naive CD8⁺ T cells (p=3.57x10^-14). These findings suggest that for a given age, an individual whose blood contains comparatively more memory CD8⁺ T cells and less naive CD8⁺ T cells would display a relatively shorter LTL and an older DNA methylation age, which jointly explain the striking ability of EEAA to predict mortality.