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

Jesper Lund

Publikation: AfhandlingPh.d.-afhandling

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Abstrakt

DNA methylation is a key epigenetic mechanism that regulates gene activity without changing the underlying genetic sequence. DNA methylation is deeply involved in the aging process and is a strong predictor of age-related outcomes. With recent advancements in high-throughput genomic profiling, large cohorts have been collected for DNA methylation profiling, which has enabled researchers to investigate molecular events in previously unseen resolutions. However, as our population is aging more rapidly, the need to investigate how we age and how the aging process contributes to age-related outcomes, including mortality, is as essential as ever. This thesis features a collection of novel studies all under the theme of DNA methylation-based analysis of aging, especially with a focus on all-cause mortality.


The first study introduces an epigenome-wide association study of all-cause mortality, with a comparison to findings from a DNA methylome profiling of aging on the same samples. The results suggest that the aging-related variations in the DNA methylome, most profoundly, have a shielding effect against all-cause mortality and thus appear to be an active regulation in maintaining homeostasis and survival in the elderly.


The second study introduces a systems biology framework weighted gene-expression correlation network analysis (WGCNA) to investigate promoter DNA methylation and their associations to all-cause mortality. The study identifies clusters of genes significantly associated with the risk of death and further explain our findings using bioinformatics tools for functional annotations, such as pathway enrichment analysis. The findings suggest that co-regulatory epigenetic mechanisms are significantly involved in modulating the risk of death.


The third study explores the age patterns of DNA methylation on the Y-chromosome in four cohorts of older males and their association with mortality. The findings reveal a highly accelerated methylation gain on the Y-chromosome with increasing age, validated across all four cohorts. Interestingly, the general pattern of increased methylation with age on the Y-chromosome is opposite to what has previously been reported on the autosomes. By testing the associations of all-cause mortality for the age-related CpG markers, we further reveal a predominantly beneficial effect on survival by age-related methylation changes on the Y-chromosome, suggesting an active epigenetic remodeling in response to the aging process.


The final study investigates sex-specific age-patterns of DNA methylation on the X-chromosome and compares them between sexes. The results show that age-related DNA methylation patterns are again dominated by increased methylation with age, similar to the Y-chromosome. The study inferred four methylation patterns in relation to X-chromosome inactivation (XCI), which are differentially implicated in the aging process. Here, CpGs under XCI in females are the least involved in the age-related methylation changes and CpGs escaping XCI are actively implicated in aging. The age-dependent age patterns are further annotated for functional interpretation concerning aging-related diseases and functional impairments.


In conclusion, we analyzed and tested age-dependent DNA methylation patterns in the elderly and their association with all-cause mortality using statistical models and bioinformatics tools, including the systems biology approach. Our results show that the aging methylome demonstrates an active response to the aging process that is beneficial for survival through epigenetic remodeling, especially on the sex chromosomes.
OriginalsprogEngelsk
Bevilgende institution
  • Syddansk Universitet
Vejledere/rådgivere
  • Tan, Qihua, Hovedvejleder
  • Baumbach, Jan, Bivejleder
  • Christensen, Kaare, Bivejleder
Udgiver
DOI
StatusUdgivet - apr. 2020

Bibliografisk note

The appendix has been removed from the Open Access file due to copyright.

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