Date Published: March 06, 2018
Publisher: Impact Journals
Author(s): Yan Zhang, Kai-Uwe Saum, Ben Schöttker, Bernd Holleczek, Hermann Brenner.
Survival predictors are of potential use for informing on biological age and targeting prevention of aging-related morbidity. We assessed associations of 2 novel methylomic survival indicators, a methylation-based mortality risk score (MRscore) and the epigenetic clock-derived age acceleration (AA), with a well-known survival predictor, frailty index (FI), and compared the 3 indicators in mortality prediction. In a large population-based cohort with 14-year follow-up, we found both MRscore and AA to be independently associated with FI, but the association was much stronger for MRscore than for AA. Although all 3 indicators were individually associated with all-cause mortality, robust associations only persisted for MRscore and FI when simultaneously including the 3 indicators in regression models, with hazard ratios (95% CI) of 1.91 (1.63–2.22), 1.37 (1.25–1.51), and 1.05 (0.90–1.22), respectively, per standard deviation increase of MRscore, FI, and AA. Prediction error curves, Harrell’s C-statistics, and time-dependent AUCs all showed higher predictive accuracy for MRscore than for FI and AA. These findings were validated in independent samples. Our study demonstrates the ability of the MRscore to strongly enhance survival prediction beyond established markers of biological age, such as FI and AA, and it thus bears potential of a surrogate endpoint for clinical research and intervention.
With the population aging worldwide , preservation of good health at older ages has become one of the most important public health challenges and development of interventions that can counteract aging-related morbidity and mortality is emerging as major area of research. This necessitates a good measure of individual’s biological age to assess the benefits from interventions. Frailty indices (FI), based on the accumulation of declines in health and function ability, which are typically expressed as proportion of age-related health deficits presented from a list of such deficits, are regarded as one of best characterized measures of biological age [2, 3]. They are closely related to chronological age and other aging-related phenotypes [4-6], and predict longevity better than chronological age . Another attractive indicator of biological age is the recently established epigenetic clock, also known as DNA methylation (DNAm) age, which was trained to be highly correlated to chronological age but estimates the biological age of a tissue, cell or organ based on DNAm of multiple CpGs across the genome . The deviation of thus derived DNAm age, i.e. the epigenetic clock, from the chronological age is termed epigenetic age acceleration (AA). The AA was found to be predictive for mortality, independent from chronological age [9-11]. A growing body of evidence also indicates associations between the AA and various aging-related diseases [12-15], as well as FI . However, a recent study comparing the FI and AA side by side for survival prediction demonstrated that the FI outperformed the AA, and the AA was not a significant predictor in the presence of FI 
Altogether 993, 858, and 470 subjects with available data on MRscore, DNAm age and frailty were included in the analyses of subset I, II, and III, respectively. Table 1 shows the participants’ characteristics and average levels of the 3 survival indicators in the three subsets. Due to over-sampling of deceased participants in subset II and of participants with cancer diagnosis during follow-up in subset III, mean age, DNAm age, AA, and MRscore were higher in subset II and III than in subset I, while essentially no difference in FI was observed between the three subsets. The proportions of current smokers were also higher in subset II and III than in subset I. During follow-up, 264 participants included in subset I died, subset II included 435 deaths, of which 120 were from the subcohort (N=543), and 199 participants in subset III died (Supplementary Figure S1).
In this study of more than 2300 community-dwelling older adults with 14 years of follow-up, we demonstrated that our newly derived MRscore was strongly associated with frailty estimated by accumulation of 34 health deficits. The association was much stronger compared to that between frailty and the other methylomic survival predictor, the epigenetic clock-derived AA. The MRscore predicted all-cause mortality better than FI, a well-established measure of frailty. Survival prediction was improved by combining MRscore and FI, whereas the epigenetic AA had no independent predictive value in models containing MRscore and FI. These findings were validated in samples that did not overlap with samples from which the MRscore was derived, and demonstrated the ability of the MRscore to strongly enhance survival prediction beyond established markers of biological age, such as FI and AA.