A Review of DNA Methylation as a Tool For Measuring Age

DNA methylation, the decoration of DNA with methyl groups, is one of the mechanisms involved in epigenetic control over production of proteins from their blueprint genes. A cell is a factory packed with levers, dials, and feedback loops, most of which involve the amounts of specific proteins present in the cell and its surrounding environment. Cell behavior changes from moment to moment in reaction to circumstances, and epigenetic alterations such as DNA methylation regulate these changes by altering rates of protein production.

Over the past five or six years a number of researchers have made inroads in the use of patterns of DNA methylation as a measure of either biological age or chronological age. If we consider aging to be caused by an accumulation of damage to cells and tissue structures, then we should expect certain characteristic patterns of epigenetic alterations to emerge in response. Everyone ages due to the actions of the same underlying processes, and while most DNA methylation appears to be highly individual, patterns nonetheless emerge.

All of this is of interest to the aging research community because there is a great need for accurate ways to measure biological age. Testing proposed treatments that might slow or reverse aging takes far too long at the present time, requiring animal studies that last for years and cost millions to gain even a vague idea as to how effective any given treatment might be. If there was an agreed upon way to reliably measure the systematic reaction to higher levels of damage in an aged individual, then new therapies could be rapidly filtered for those that actually make a difference. To my eyes that should mean therapies that repair the forms of damage known to cause aging. I see a good marker for biological age as something that could bring an end to much of the debate over causes of aging, which causes are more important, and which strategy for the development of treatments should be pursued. A great deal of the present diversity of opinion and theory would evaporate in the face of better data.

On this topic, here is a very readable open access review paper that covers the recent history of work on DNA methylation as a measure of aging. As it makes clear, finding DNA methylation patterns that look promising is only the start of the process of producing an acceptable standard of measurement for aging:

DNA methylation and healthy human aging

The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor.

DNA methylation changes that are associated with age can be considered part of two related phenomena, epigenetic drift and the epigenetic clock. We have defined epigenetic drift as the global tendency toward median DNA methylation caused by stochastic and environmental individual-specific changes over the lifetime. The epigenetic clock, on the other hand, refers to specific sites in the genome that have been shown to undergo age-related change across individuals and, in some cases, across tissues.

A number of aspects of age-related DNA methylation remain, which should be further scrutinized. First, it is expected that certain life periods, such as early childhood, puberty, and advanced age, result in accelerated epigenetic changes. Most studies of DNA methylation and age have examined changes within specific periods of life - the first few years of life or adulthood to old age, for example. Moving forward, it will be important to determine what periods during the lifespan are the most changeable, which highlights the need for more rigorous studies. Moreover, work on the effects of environmental stimuli on the rates of epigenetic aging would contribute insight into how or why specific environmental exposures result in increased mortality. It could be hypothesized that people who are exposed to factors that affect mortality show advanced epigenetic compared to chronological age, although these effects may be tissue specific.

Several recent cross-sectional studies have published epigenetic clocks. Comparison of these sites across longitudinal studies, while controlling for confounders in DNA methylation such as tissue type, cellular composition, ethnicity, and environment, is necessary to confirm a consistent, reliable, and independent signature of DNA methylation and aging. This type of age predictor could be of use in a number of areas. In health, epigenetic age could be used to target or assess interventions or treatments. However, the health-related potential of epigenetic age still waits on an assessment of concordance between epigenetic and chronological age across a large population with longitudinal tracking of health during the aging process. This field has immense potential to inform human populations and will undoubtedly continue to develop in the near future.

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