An epigenetic profile defining the DNA methylation age (DNAm age) of an individual has been suggested to be a biomarker of aging, and thus possibly providing a tool for assessment of health and mortality. In this study, we estimated the DNAm age of 378 Danish twins, age 30–82 years, and furthermore included a 10‐year longitudinal study of the 86 oldest‐old twins (mean age of 86.1 at follow‐up), which subsequently were followed for mortality for 8 years. We found that the DNAm age is highly correlated with chronological age across all age groups (r = 0.97), but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4–77%) increased mortality risk for each 5‐year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more‐than‐double mortality risk for the DNAm oldest twin compared to the co‐twin and a ‘dose–response pattern’ with the odds of dying first increasing 3.2 (1.05–10.1) times per 5‐year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest‐old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging.

Summary: Telomerase is of key importance for telomere maintenance, and variants of the genes encoding its major subunits, telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), are candidates for interindividual variation in telomere length. Recently, the two SNPs rs3772190 and rs12696304 in the TERC locus were reported to be associated with leukocyte telomere length (LTL) in two genome‐wide association studies, while one haplotype of TERT (rs2853669, rs2736098, rs33954691, and rs2853691) has been reported to be associated with both LTL and longevity in a candidate gene study. In this study, we investigated the two TERC and four TERT SNPs in middle‐aged, old, and oldest‐old Danes (58–100 years) and their association with LTL (n = 864) and longevity (n = 1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest‐old and 736 middle‐aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross‐sectional and a longitudinal approach. Applying an additive model, we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coefficient = −0.08, P = 0.011) and in male rs12696304 G carriers (regression coefficient = −0.13, P = 0.014). No TERT variations showed association. Moreover, the A allele of rs3772190 (TERC) was found to be associated with longevity [hazard rate (AG + AA) = 1.31, P = 0.006]. No associations with longevity were observed for the TERT SNPs or haplotypes. Our study, thus, indicates that TERC is associated with both LTL and longevity in humans.

Background: Epigenetic changes may result from the interplay of environmental exposures and genetic influences and contribute to differences in age‐related disease, disability, and mortality risk. However, the etiologies contributing to stability and change in DNA methylation have rarely been examined longitudinally.Methods: We considered DNA methylation in whole blood leukocyte DNA across a 10‐year span in two samples of same‐sex aging twins: (a) Swedish Adoption Twin Study of Aging (SATSA; N = 53 pairs, 53% female; 62.9 and 72.5 years, SD = 7.2 years); (b) Longitudinal Study of Aging Danish Twins (LSADT; N = 43 pairs, 72% female, 76.2 and 86.1 years, SD=1.8 years). Joint biometrical analyses were conducted on 358,836 methylation probes in common. Bivariate twin models were fitted, adjusting for age, sex, and country.Results: Overall, results suggest genetic contributions to DNA methylation across 358,836 sites tended to be small and lessen across 10 years (broad heritability M = 23.8% and 18.0%) but contributed to stability across time while person‐specific factors explained emergent influences across the decade. Aging‐specific sites identified from prior EWAS and methylation age clocks were more heritable than background sites. The 5037 sites that showed the greatest heritable/familial–environmental influences (p < 1E−07) were enriched for immune and inflammation pathways while 2020 low stability sites showed enrichment in stress‐related pathways.Conclusions: Across time, stability in methylation is primarily due to genetic contributions, while novel experiences and exposures contribute to methylation differences. Elevated genetic contributions at age‐related methylation sites suggest that adaptions to aging and senescence may be differentially impacted by genetic background.

Every year thousands of blood samples are drawn from patients admitted to Danish hospitals for diagnostic and treatment purposes. Traditionally, the leftover blood will be discarded after the required laboratory analyses are completed. However, such residual blood samples can be highly valuable for biomedical research, given the vast amount of clinical information these samples are often accompanied by—directly from the electronic patient record or through linkage to medical registers. To this end the Copenhagen Hospital Biobank (CHB) was established, with the overall aim to facilitate research in health and disease by enabling researchers’ access to a large resource of well-defined patient samples.