DNA methylation-based estimator of telomere length

Abstract

Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.

The Effect of Tobacco Smoking Differs across Indices of DNA Methylation-Based Aging in an African American Sample: DNA Methylation-Based Indices of Smoking Capture These Effects

“…Lu e al. (2019) developed a DNA methylation-based index of telomere length (mTL), i.e., the number of repetitive nucleotide sequences at the end of each chromosome that shortens with increasing number of replications [38]. Correlations between telomere length (TL) and age range between r = −0.513 for women and r = −0.552 for men [39].…”

“…Telomere length has long been of interest with regard to aging, but it has been considered problematic by some researchers due to difficulties in obtaining reliable measurement [40]. The DNA methylation-based index developed by Lu and colleagues (2019) [38] attempts to address this problem. Although it was developed to predict criterion measures of TL, mTL demonstrated superior prediction of health outcomes as well as stronger associations with health behaviors including smoking.…”

“…Lu and colleagues (2019) identified 140 CpG sites to estimate telomere length in Kb. Similar to accelerated aging [38], adjusting DNA methylation-based telomere length (mTLadjAge) was measured using the residual from regressing DNA methylation-based telomere length (mTL) on chronological age. A positive value would indicate mTL that is longer than expected based on chronological age.…”

“…A positive value would indicate mTL that is longer than expected based on chronological age. We used the (https://dnamage.genetics.ucla.edu/) website to calculate the mTL index [38].…”

Epigenetic clocks predict prevalence and incidence of leading causes of death and disease burden

“…Furthermore, telomere length is associated with cardiovascular disease, cancer risk and all-cause mortality (15)(16)(17). Lu et al proposed a DNAm-based estimator of telomere length termed 'DNAm Telomere Length' (DNAm TL) which exhibits stronger associations with lifespan, smoking history and body mass index when compared to phenotypic telomere length as measured by quantitative polymerase chain reaction or Southern blotting (18).…”