DNA Methylation Changes with Aging in Younger Individuals

The measurement of changing patterns of DNA methylation is developing into a promising biomarker of aging. The study linked below provides confirming evidence to show that this approach works for a wide range of ages in humans, but can still be discerning over a fairly narrow age range, even at younger ages, those at which people are likely to first start using future rejuvenation treatments. DNA methylation is a form of epigenetic marker that alters protein production: decorations attached to DNA that change constantly in response to circumstances. Some of those circumstances involve the accumulating cell and tissue damage that causes aging, processes that are the same in every individual, and so we should expect to find characteristic changes in DNA methylation patterns that reflect the state of aging.

Biomarkers of aging of this sort are important as an independent measure of the degree to which a putative rejuvenation therapy is actually working, a test that can be carried out much more rapidly and cheaply than the only currently viable approach of life span studies. By "actually working" I mean not just clearing senescent cells, or breaking cross-links, or replacing stem cells, all of which are simple enough to verify in and of themselves given the technology to build the treatment in the first place, but that a successful implementation of such as therapy also has an impact on global measures that are (a) strongly associated with aging, and (b) sensitive enough to pick up a change in biological age corresponding to a few years of normal aging.

Chronological aging-associated changes in the human DNA methylome have been studied by multiple epigenome-wide association studies (EWASs). Certain CpG sites have been identified as aging-associated in multiple studies, and the majority of the sites identified in various studies show common features regarding location and direction of the methylation change. However, as a whole, the sets of aging-associated CpGs identified in different studies, even with similar tissues and age ranges, show only limited overlap. In this study, we further explore and characterize CpG sites that show close relationship between their DNA methylation level and chronological age during adulthood and which bear the relationship regardless of blood cell type heterogeneity.

In this study, with a multivariable regression model adjusted for cell type heterogeneity, we identified 1202 aging-associated CpG sites in whole blood in a population with an especially narrow age range (40 - 49 years). Repeatedly reported CpGs located in genes ELOVL2, FHL2, PENK and KLF14 were also identified. Regions with aging-associated hypermethylation were enriched regarding several gene ontology (GO) terms (especially in the cluster of developmental processes), whereas hypomethylated sites showed no enrichment. The genes with higher numbers of CpG hits were more often hypermethylated with advancing age. The comparison analysis revealed that of the 1202 CpGs identified in the present study, 987 were identified as differentially methylated also between nonagenarians and young adults in a previous study (the Vitality 90+ study), and importantly, the directions of changes were identical in the previous and in the present study.

Here we report that aging-associated DNA methylation changes can be identified in a middle-aged population with a narrow age range of 9 years. A great majority of these sites have been previously reported as aging-associated in a population aged 19 to 90 years. Aging-associated DNA methylation changes are not uniform, but occur due to different reasons, at different rates and directions in different parts of the genome and are not alike in all cell types. Thus, due to this diverse nature of aging-associated DNA methylation changes, all confounding factors should be accounted for in the analysis, in order to obtain comparable results. Our results support the notion that cell type heterogeneity should be adjusted for when analyzing tissues consisting of mixed cell types. Moreover, our results imply that considerable proportion of DNA methylation changes show clock-like behavior throughout adulthood.

Link: http://dx.doi.org/10.1186/s12864-016-2421-z


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