Epigenetic biomarkers as indicator and predictor of late-life mortality in older individuals

Tan, Q. (Supervisor)

Activity: ExaminationInternal examination


DNA methylation is an key epigenetic processmechanism in which methyl groups attach to the DNA molecules, and thereby, regulates gene activity through blocked transcription by attaching methyl groups to the DNA molecules without changing the underlying genetic sequence. DNA methylation is deeplyfurthermore one of the main contributors to involved in the aging process and is a strong predictor of age-related outcomes. With recent advancements in high-throughput moleculargenomic profiling, large cohorts have been unearthed, accompanied bycollected for DNA methylation samplesprofiling, which have enabled researchers to investigate molecular events in previously unseen resolutions. However, as our population is aging more rapidlygrowing older, the need to investigate how we age and how the aging process contributes to age-related outcomes, such a sincluding mortality, is as essential as ever. This thesis features a collection of novel studies manuscripts all in tunder the theme of DNA methylation-based analysis of aging studies and age-related methylome pattern on older individuals, especially with a focus on all-cause mortality.
The first studymanuscript introduces an epigenome-wide association study of all-cause mortality, with a comparison to findings from a how the agingDNA methylome profiling of agingevolves based on the findings from another study on the same samples. The results suggesthint that the aging-related variations ion the DNA methylome, most profoundly, have a shielding effect against all-cause mortality and thus appear to be an active processregulation in maintaining homeostasis and survival regulation in the elderlyold age.
The second studymanuscript introduces a systems biologyrevolves around the published framework weighted- gene-expression correlation network analysis (WGCNA), to investigate promoter DNA methylation and their associations to all-cause mortality in a network-based fashion. The study identifies result shows that clusters of genes are significantly associated with the risk of death and further explain our findings through using bioinformatics tools for functional annotationsmeta-analyses, such as pathway enrichment analysis. The findings suggest that co-regulatory epigenetic mechanisms are significantly involved in modulatingfurther increase the risk of death, as compared to singular epigenetic events.
The third manuscript study explores the unknown ageing patterns of DNA methylation on the Y-chromosome in four cohorts of older males and their association with mortality. These findings revealport a highly accelerated methylation gain on the Y-chromosome in terms of methylation gain that has a stronger effect with increasing age, validated across all four cohorts. Interestingly, these general pattern of increased methylation with age on the Y-chromosome findings are the is opposite ofto what has previously been reported on the autosomes. By testing the associations of all-cause mortality for the age-related CpG markers, we furthermore reveal a predominantly beneficial effectlowered hazard ratio on survival by age-related methylation changes on the Y-chromosome in the direction of the methylation gain coefficientssuggesting an active epigenetic remodelling in response to the aging process, which hint that the markers support longevity during aging.
The final studymanuscript investigates the sex-specific age-patterns of DNA methylationaging coefficients ofn the X-chromosome and compareshow these differ them between sexes. The results show that age-related DNA methylation patterns are again dominated by increased methylation with age, similar as the Y-chromosome. The study inferred four methylation patterns in relation to X-chromosome inactivation (XCI) which are differentially implicated in the aging process with CpGs under XCI in females least involved in the age-related methylation changes while CpGs escaping XCI actively implicated in aging. specific CpG sites have highly determinable patterns that are profoundly shared across unrelated subjects with a strong signal. Additionally, a large proportion of the female X-chromosome is inactivated, and further becomes more inactivated during aging. Interestingly, this strong pattern has not previously been described and seems to explain some of the shared factors regarding the X-chromosome inactivation phenomenon, in the proportion of hypermethylated CpG sites. The age-dependent age patterns are further annotated for functional interpretation concerning aging-related diseases and functional impairments.
In conclusion, we analysed and tested age-dependent several DNA methylation-based patterns in the elderly and their association with all-cause mortality features in human subjects of old age, including aging-trajectories, all-cause mortality, X-chromosome inactivation and a using statistical models and bioinformatics tools moreincluding the advanced systems biology method for all-cause mortalityapproach. Our results show that the aging methylome demonstrates an active response to the aging process that is beneficial for survival through epigenetic remodelling especially on the sex chromosomes. supports homeostasis throughout life. In contrast, irregularities in this process might explain all-cause mortality from an age-related perspective.
Period1. Apr 201730. Mar 2020