Aging and cancer epigenetics: Where do the paths fork?

Aging and cancer are clearly associated processes, at both the epidemiological and molecular level. Epigenetic mechanisms are good candidates to explain the molecular links between the two phenomena, but recent reports have also revealed considerable differences, particularly regarding the loss of DNA methylation in the two processes. The large-scale generation and availability of genome-wide epigenetic data now permits systematic studies to be undertaken which may help clarify the similarities and differences between aging and cancer epigenetic alterations. In addition, the development of epigenetic clocks provides a new dimension in which to investigate diseases at the molecular level. Here, we examine current and future questions about the roles of DNA methylation mechanisms as causal factors in the processes of aging and cancer so that we may better understand if and how aging-associated epigenetic alterations lead to tumorigenesis. It seems certain that comprehending the molecular mechanisms underlying epigenetic clocks, especially with regard to somatic stem cell aging, combined with applying single-cell epigenetic-age profiling technologies to aging and cancer cohorts, and the integration of existing and upcoming epigenetic evidence within the genetic damage models of aging will prove to be crucial to improving understanding of these two interrelated phenomena.

Blood DNA Methylation Patterns in Older Adults With Evolving Dementia.

Dementia and cognitive disorders are major aging-associated pathologies. The prevalence and severity of these conditions are influenced by both genetic and environmental factors. Reflecting this, epigenetic alterations have been associated with each of these processes, especially at the level of DNA methylation, and such changes may help explain the observed interindividual variability in the development of the 2 pathologies. However, the importance of epigenetic alterations in explaining their etiology is unclear because little is known about the timing of when they appear. Here, using Illumina MethylationEPIC arrays, we have longitudinally analyzed the peripheral blood methylomes of cognitively healthy older adults (>70 year), some of whom went on to develop dementia while others stayed healthy. We have characterized 34 individuals at the prediagnosis stage and at a 4-year follow-up in the postdiagnosis stage (total n = 68). Our results show multiple DNA methylation alterations linked to dementia status, particularly at the level of differentially methylated regions. These loci are associated with several dementia-related genes, including PON1, AP2A2, MAGI2, POT1, ITGAX, PACSIN1, SLC2A8, and EIF4E. We also provide validation of the previously reported epigenetic alteration of HOXB6 and PM20D1. Importantly, we show that most of these regions are already altered in the prediagnosis stage of individuals who go on to develop dementia. In conclusion, our observations suggest that dementia-associated epigenetic patterns that have specific biological features are already present before diagnosis, and thus may be important in the design of epigenetic biomarkers for disease detection based on peripheral tissues.