Leukocyte telomere length and epigenetic-based mortality risk score: associations with all-cause mortality among older adults

Abstract

Telomere length (TL) has been established as a biomarker of aging and aging-related health outcomes, but showed only a weak or inconsistent association with all-cause mortality in previous epidemiological studies. Recently, an epigenetic 'mortality risk score' (MS) based on whole blood DNA methylation at 10 mortality-related CpG sites has been demonstrated to be strongly related to all-cause mortality at the population level. This study aimed to address the association between TL and this MS, and to assess and compare their associations with all-cause mortality. The MS was derived from the DNA methylation profiles measured by Illumina Human Methylation450K Beadchip and TL was measured by quantitative PCR at baseline among 1517 participants aged 50-75 of the German ESTHER cohort study. In cross-sectional bi- and multivariable analyses, the MS was strongly associated and showed monotonic dose-response relationships with TL (p-values <0.05). However, only the MS but not TL was associated with all-cause mortality during a median follow-up of 12.5 years. After controlling for potential covariates and TL, hazard ratios (95% CI) for all-cause mortality for low, moderate and high levels of the MS defined by 1, 2-5 and >5 CpG sites with aberrant methylation were 2.24 (1.13-4.41), 3.31 (1.76-6.22) and 6.33 (3.22-12.41) compared to a MS of 0, respectively. Our investigation shows that the epigenetic-based MS is strongly associated with TL, a broadly accepted aging biomarker, and at the same time shows much stronger associations with all-cause mortality than the latter.

Epigenetic predictors of all-cause mortality are associated with objective measures of neighborhood disadvantage in an urban population

“…Using data from residents of Detroit, we find that a recently developed epigenetic biomarker of mortality [27] is associated with summary measures of neighborhood characteristics constructed from objective measures of neighborhood characteristics which are indicative of neighborhood advantage/disadvantage based primarily on the quality of the built environment (Supplemental Table 2). The continuous epigenetic mortality score developed by Zhang et al [27] is a strong predictor of mortality, and in an independent validation study, a one unit increase was associated with a 2.64-fold increase (95% confidence interval, 1.98-3.52) in all-cause mortality risk [31]. We found that PC7, a principal component driven by neighborhood characteristics such as the number of abandoned Fig.…”

“…Recent advances in DNA array technology and data availability have allowed researchers to develop DNA methylation-based biomarkers for outcomes such as accelerated aging [29], chronic disease risk [30], and mortality risk [27,31]. For aging, there has been substantial work showing that DNA methylation age is accelerated by adverse environmental exposures [17].…”

“…For other epigenetic biomarkers, there has been little research to evaluate their response to the external environment, in particular neighborhood characteristics. Here, we evaluate the degree to which objective measures of neighborhood quality/disadvantage, such as the condition of the street and buildings and lack of greenspace, are associated with a validated epigenetic mortality risk score (eMRS) [27,31]. We further do this in a predominantly African-American cohort, an understudied racial group in the field of epigenetics.…”

Association between telomere length in the DNA of peripheral blood leukocytes and the propofol dose in anesthesia induction

“…Hence, telomeres play a major part in cellular senescence [15] and might contribute signi cantly to the inherited background of human aging and longevity [16]. Aging results from a dynamic, complex, and multifactorial processes related to a decreased propofol dose by gradual accumulation of different types of cellular and molecular damage [17,18].TL demonstrated strong associations with propofol dose in our study, and be helpful for determining the propofol dose during aging as well as improving the safety of anesthesia.…”

Blood‐derived DNA methylation predictors of mortality discriminate tumor and healthy tissue in multiple organs

“…We first derived a 10-CpG-based mortality risk score (MRscore) from a whole blood epigenome-wide association study (EWAS) of mortality [12]. The MRscore was shown to strongly predict all-cause and causespecific mortality, and to strongly correlate with other well-established aging indicators (such as telomere length, oxidative stress, frailty index, and the epigenetic clock), while outperforming these indicators in survival prediction [13][14][15]. The MRscore was first derived and validated in two large German cohorts, and its strong association with mortality has subsequently been confirmed in multiple large cohort studies from the United States, such as the Framingham Heart Study, the Women's Health Initiative, and the Normative Aging Study [11,16,17].…”