We use clocks to keep track of time. When it comes to the term ‘clock’, I think of the hour glass on my dresser, the pendulum clock in my living room, my first wristwatch that I was so excited to get or the display on the top of my smart phone. We use clocks to measure duration repeatedly, including the length of our lives, also known as our ‘age’.
One of the best known epigenetic clocks is the Horvath clock
However, some researchers working on aging are not satisfied with traditional clocks; instead they use ‘epigenetic clocks’ for the chronological age of our tissues.These clocks consist of hundreds of DNA methylation sites – sites at which DNA is chemically modified in the genome.
The idea is that changes in methylation occur stochastically at a roughly constant rate, such that the extent of changes in methylation reflects the age of the tissue. One of the best known epigenetic clocks is the Horvath clock, which has inspired many curious minds to look further into epigenetic aging.
A team from University of Southampton has recently found a new way to build an epigenetic clock to measure chronological aging. Age is a risk factor for multiple chronic diseases. Previous studies have applied association mapping, also known as linkage disequilibrium mapping, to age associated chronic diseases in the form of genome-wide association studies (GWAS) to understand human genetic susceptibility.
Built on linkage disequilibrium blocks from the GWAS catalog, Christopher Bell and colleagues analyzed DNA methylomes (DNA methylation across the whole genome) from more than two thousand people using an approach called methylated DNA immunoprecipitation-sequencing, or MeDIP-seq, to identify broad regional changes over age. This approach allows them to tie the epigenetic clock to diseases and incorporate epigenetic changes with age in disease models.
This clock differs from the Horvath clock in using DNA methylation blocks instead of individual sites. It consists of 71 of these blocks, which are known as age-related differentially methylated regions (aDMRs). Previous clocks have looked at hundreds of DNA methylation sites, but here, one DMR could cover multiple sites. To prove the design successful, the team finds that these building blocks have strong genetic associations with common diseases such as age-related bone loss. The work was recently published in Genome Biology.
DNA methylation becomes more variable as we age
While we may have several clocks to keep track of the chronological aging of our tissues, people appear to age at different rates. How can we measure this ‘biological aging’? It is known that DNA methylation becomes more variable as we age; in other words, we exhibit more variance in terms of whether or not there is a methyl group conjugated to particular positions in our DNA. However, the difference in the methylation level, rather than the variation of methylation in those sites, has gained the most attention so far.
New research published in Genome Biology looks at the methylation sites that become more variable over the aging process and find these sites can better reflect biological aging. The positions of methylation identified by the team led by Dr. Bas Heijmans are also found to be commonly associated with developmental or neurodevelopment genes.
These sites appear to correlate with RNA expression changes that occur while we age, and the affected pathways are known to be related to the aging process, including metabolism and DNA damage repair. Tumors, which are often found in people of advanced age, also accumulate DNA methylation changes at the exact sites the team identified.
These two studies are both efforts to find potential biomarkers of aging, which should accelerate mechanistic discoveries into the role of aging in disorders with advanced age. Future work to identify methylation profiles that mark health status and predict mortality should be even more exciting.