DNAmTL (DNA methylation telomere length)

DNAmTL is an epigenetic estimator of telomere length derived from the methylation levels of 140 CpG sites in blood DNA, trained via elastic net regression against Southern-blot-measured leukocyte telomere length in 2,256 participants from the Women's Health Initiative and Jackson Heart Study. Unlike qPCR or flow-FISH, it does not measure telomere sequence directly; instead it captures a methylation signature co-varying with telomere attrition across the replicative history of the leukocyte compartment. DNAmTL correlates with chronological age at r ≈ −0.62 to −0.80, substantially exceeding measured leukocyte telomere length (r ≈ −0.30 to −0.40). Lu, Horvath et al. (2019, Aging) validated the estimator in 9,044 methylation arrays across seven cohorts including Framingham Heart Study and TwinsUK (mean follow-up 11.8 years): each kilobase increase in age-adjusted DNAmTL associated with HR = 0.37 for all-cause mortality (p = 2.5×10⁻²⁰), HR = 0.51 for coronary heart disease (p = 6.6×10⁻⁵), and HR = 0.27 for congestive heart failure (p = 3.6×10⁻⁶) — all stronger than measured-LTL associations. Wang et al. (2024, Clinical Epigenetics; NHANES 1999–2002) confirmed the predictive advantage over qPCR-based telomere length. Liang et al. (2024, Aging Cell; n = 2,398) showed a one-kilobase decrease in DNAmTL associates with 40% higher mortality risk (HR = 0.60) and that HIV infection links to shorter DNAmTL (β = −0.25, p = 1.5×10⁻¹²). DNAmTL requires Illumina EPIC or 450k array data; causal direction remains unresolved.