A Programmed Aging View of Epigenetic Clock Challenges
The author of this paper is an advocate for programmed aging. This is the view that degenerative aging is actively selected by evolutionary processes, perhaps because it helps to reduce the risk of runaway population growth, or perhaps because aging species better adapt to ecological change, rather than being a side-effect of selection effects focused on early life reproductive success that tend to produce systems that accumulate damage to fail over time. In some programmed aging views, epigenetic change is close to being the root cause of aging, being the implementation of an evolutionarily selected program. It is interesting to see an outline of perceived challenges in epigenetic clock development from the programmed aging viewpoint, to contrast with the challenges seen by other researchers, which are focused on the lack of understanding of how specific epigenetic changes reflect underlying damage and dysfunction.
Late in life, the body is at war with itself. There is a program of self-destruction (phenoptosis) implemented via epigenetic and other changes. I refer to these as type (1) epigenetic changes. But the body retains a deep instinct for survival, and other epigenetic changes unfold in response to a perception of accumulated damage (type (2)).
In the past decade, epigenetic clocks have promised to accelerate the search for anti-aging interventions by permitting prompt, reliable, and convenient measurement of their effects on lifespan without having to wait for trial results on mortality and morbidity. However, extant clocks do not distinguish between type (1) and type (2). Reversing type (1) changes extends lifespan, but reversing type (2) shortens lifespan. This is why all extant epigenetic clocks may be misleading.
Separation of type (1) and type (2) epigenetic changes will lead to more reliable clock algorithms, but this cannot be done with statistics alone. New experiments are proposed. Epigenetic changes are the means by which the body implements phenoptosis, but they do not embody a clock mechanism, so they cannot be the body's primary timekeeper. The timekeeping mechanism is not yet understood, though there are hints that it may be (partially) located in the hypothalamus. For the future, we expect that the most fundamental measurement of biological age will observe this clock directly, and the most profound anti-aging interventions will manipulate it.