The core hypothesis of this paper is that epigenetic changes characteristic of aging are all adaptive, beneficial attempts by cells to resist damage and dysfunction. This seems dubious. Looking into the aging body, we can point to any number of maladaptive, harmful changes in function; reactions that would be beneficial in youth, or when operating only temporarily, but become harmful in the aged tissue environment, or when sustained over time. Think of the way the immune system reacts to the age-damaged environment to generate chronic inflammation, for example. Why should epigenetic regulation be exempt from such maladaptive change?
Methylation clocks have found their way into the community of aging research as a way to test anti-aging interventions without having to wait for mortality statistics. But methylation is a primary means of epigenetic control, and presumably has evolved under strong selection. Hence, if methylation patterns change consistently at late ages it must mean one of two things. Either (1) the body is evolved to destroy itself (with inflammation, autoimmunity, etc.), and the observed methylation changes are a means to this end; or (2) the body detects accumulated damage, and is ramping up repair mechanisms in a campaign to rescue itself.
My thesis herein is that both Type 1 and Type 2 changes are occurring, but that only Type 1 changes are useful in constructing methylation clocks to evaluate anti-aging interventions. This is because a therapy that sets back Type 1 changes to an earlier age state has stopped the body from destroying itself; but a therapy that sets back Type 2 changes has stopped the body from repairing itself. Thus, a major challenge before the community of epigenetic clock developers is to distinguish Type 2 from Type 1.
The existence of Type 1 epigenetic changes is in conflict with conventional Darwinian thinking, and this has prompted some researchers to explore the possibility that Type 1 changes might be a form of stochastic epigenetic drift. I argue herein that what seems like directed epigenetic change really is directed epigenetic change. Of five recent articles on "stochastic methylation clocks," only one is based on truly stochastic changes. Using the methodology from this paper and a methylation database, I construct a measure of true methylation drift, and show that its correlation with age is too low to be useful.
Link: https://doi.org/10.18632/aging.206245
View the full article at FightAging
