An Interview with Morgan Levine on the Epigenetic Clock

The Life Extension Advocacy Foundation staff regularly publish interviews with scientists and other figures in the aging research community. In this interview they talk with one of the researchers presently working on the development of biomarkers of aging, specific those based on epigenetic markers such as DNA methylation. These epigenetic decorations to the genome determine the pace at which proteins are produced from their blueprint genes. They shift constantly in response to circumstances, one among myriad feedback loops determining cell behaviors. Eight years ago, researchers started to find that weighted algorithms combining the DNA methylation status of certain sites on the genome produced a score that correlated quite closely with chronological age. The first such algorithm was termed the epigenetic clock, and the name has stuck.

Later it was found that people with a higher score than their chronological age tended to exhibit a greater risk of age-related disease and mortality, and vice versa. Thus epigenetic clocks appear to measure physiological age rather than chronological age, and are an assessment of the burden of cell and tissue damage. Or rather they are measuring certain characteristic changes in cell behavior that take place in response to that underlying damage and its consequences. At this point it remains uncertain as to which of the changes of aging it is that various different epigenetic clocks measure; which mechanisms contribute to the clock, and to what degree. For example, epigenetic clocks seem insensitive to physical fitness, which is odd, given that exercise certainly affects risk of age-related disease.

The research community is very interested in the production of viable biomarkers of aging, as success will greatly speed up the development of rejuvenation therapies. Presently the only way to find out whether a treatment actually slows or reverses aging, or extends healthy life span, is to run a life span study. Those are expensive and time consuming in mice, and impractical in humans. If a potential therapy can be quickly assessed with a biomarker test that runs before and after treatment, then that is a whole different picture, however. It would open the door to the cost-effective exploration and assessment of many more therapies than are presently being tested. It would hopefully also shut the door on many present projects that are most likely a waste of time, but continue to obtain sizable amounts of funding regardless.

Interview with Prof. Morgan Levine

Why do epigenetic changes matter for longevity?

We are finding that age-related epigenetic changes are associated with mortality risk and, perhaps more importantly, with disease incidence. For instance, we have different algorithms that represent levels of DNA methylation that we expect to see for someone of a given age. Individuals who have methylation profiles indicative of someone older than they are have increased risk of morbidity and mortality. For instance, if you compare two 40-year olds and one has the methylation profile of someone who is 45, while the other has the methylation profile of someone who is 35, the former will, on average, live for fewer years and develop disease earlier.

What is the theory/mechanism behind the various epigenetic clocks now available?

This is ongoing work that we are actively pursuing. There are about a dozen epigenetic clocks in the literature - perhaps the most famous being the Horvath clock (although it wasn't the first). However, even though these clocks are all intended to capture the same latent concept (biological aging), they differ in their predictions of age and age-adjusted death and disease risk. Using transcriptomic and proteomic data from both blood and brain, we have found that accelerated aging measured using the most widely known epigenetic clocks seem to relate to mitochondrial dysfunction, PI3K/Akt signaling, and immunosenesence.

There is also some evidence coming out that they may reflect cellular senescence to some degree. That being said, our theory is that the clocks - because they are composites of hundreds of CpGs, cytosine separated from a guanine by one phosphate - represent a grab bag of mechanisms. We are currently working on decomposing the various clocks and are finding that they differ in their proportions of various "types" of methylation changes, each of which may have their own distinct mechanisms. Our hypothesis that breaking the clocks down into constituent parts may facilitate our understanding of the underlying biology that is either driving these age-related changes, and/or the functional implications of such changes.

How far are we from understanding epigenetic changes well enough to be able to turn back the clock by changing the epigenetics in individual organisms?

I think we are quite a long way from that. The epigenome is a complex system, and we are not at the point where we can model these changes very well - there is a lot of room for improvement when it comes to the clocks. That being said, we are even further away from understanding what these changes represent or if they are even causal. I hypothesize that many of these changes are actually reactions to something going wrong in some system. Thus, altering DNA methylation directly will not be beneficial and could, in fact, be harmful if this isn't accompanied by changes to the system/extracellular environment. If some of these changes are effects (read-outs) of aging, then they are not the correct points of intervention. Further, many of the changes may be compensatory, and thus making an old cell epigenetically young but leaving it in an aged organismal environment could be detrimental and possibly contribute to neoplastic transformations.

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