Epigenetics and Aging
New acquaintances would often ask what I did for a living before I retired. I would have to confess that in my former life I was a Professor of Genetics. What would follow would be a prolonged and uncomfortable pause in the conversation. “That’s a fascinating field”, would come the response after the delay. Surprisingly, a frequent question that might follow would be, “What’s all this I hear about epigenetics?”
Apparently epigenetics is becoming a subject of public discourse. I’m never sure what to answer. It’s not a subject I’ve studied over the years, but a recent paper caught my attention and inspired me to learn a little more about it.
Epigenetics is the study of heritable changes to cells and organisms that don’t involve alterations in DNA sequence. As a geneticist, that doesn’t seem like a reasonable definition because ultimately, all heredity can be traced back to the sequence of bases in DNA. But DNA can specify heritable secondary phenomena and agents that can modify how it is expressed. And that is what epigenetics is all about.
Let me offer an example. When a cell becomes committed to a specific differentiated state, its progeny usually continue to have the same fate. For instance, when a liver cell first forms, it will subsequently divide forming more liver cells, not nerve or kidney cells. The inheritance of a specific differentiated state is due to the action of proteins that bind to DNA (transcription factors) that direct transcription of various liver-specific genes. These proteins continue to be synthesized and to do their job over subsequent cell divisions.
While the maintenance of the differentiated state fits the definition of epigenetics, most scientists associate epigenetics with a heritable chemical change in either DNA or its accompanying proteins that doesn’t change the sequence of DNA but effects its expression. For example, the most common modification of DNA is the addition of a methyl group (CH3) to the base “C” preceding the base “G”, a change that occurs in a few percent of all the CG sequences in the human genome. It is catalyzed by a family of enzymes, DNA methylases, and is generally inherited from one cell generation to the next.
Most often methylation of DNA is associated with the repression of transcription, but that’s not a universal rule. The phenomenon plays an important role in development and in carcinogenesis. But in this post, I’m going to focus on it as a marker for aging.
My mother would often ask guests at parties that she threw to guess her age. She looked young and would glow when the estimates she was given were off by five or ten years. Her guests would take her word for her true age, but could they be sure? Is there some biological clock that can reveal the true chronological age of a person?
The answer is yes, and it’s a remarkably accurate one when read correctly. The clock makes use of the pattern of DNA methylation; that is, the changes at specific sites in the genome that gain or lose methyl groups with time (see 1 for a recent review). Not all sites demonstrate age-specific changes, but if an appropriate set of positions are monitored, they can be used as an “epigenetic clock” to accurately predict the chronological age of a subject.
The first accurate clocks were generated by a group of researchers at UCLA in 2011. They assayed the state of DNA methylation at two locations in the genome and used the results to predict the age of the subjects that they were studying. Samples were obtained from people ranging in age from their late teens to their early 70’s. Remarkably, the correlation between the state of methylation and age was incredibly good, with an average difference between actual age and predicted age of 5.2 years. Two other clocks that examined 71 and 353 sites, displayed accuracies of between 3 and 4 years respectively.
No one knows why certain DNA locations change their state of methylation in an orderly manner with time. The most likely possibility is that it may represent some byproduct of the aging process. Or, more intriguingly, it may be a process that actually is causal to aging. If so, by changing the methylation of some sites it may be possible to control the aging process. That’s exciting, but unlikely.
Aside from being a good party trick, what’s the practical value of being to tell the chronological age of someone from a sample taken from their blood or some other tissue? One use could be in forensics where determining the age of a possible perpetrator of a crime by analyzing tissue left at a crime scene might be a way of identifying a suspect. Another possibility derives from the observation that some people, as judged by their methylation numbers, seem to have aged faster or slower than others. The epigenetic clock might enable physicians to identify the environmental or hereditary factors that play a role in changing the rate of aging, one that either slow or hasten it, by studying such people.
There’s a nice non-technical article about Steve Horvath, one of the early builders of the epigenetic clock, that appeared in Nature several years ago (2) some of these matters.
1. “Dynamic DNA Methylation During Aging: A ‘Prophet’ of Age-Related Outcomes”, Xiao et al., Front. Genet. 18 (2019).
2. “Biomarkers and ageing: The clock-watcher” Nature 508:169-170 (2014).