Researchers have recently proposed that the normal operation of DNA repair contributes to the epigenetic change that is observed to occur with age. This is an interesting concept, and we'll see how it progresses in the years ahead, particularly as therapies based on alteration of epigenetic markers emerge as an area of active medical research and development.
Epigenetic decorations to DNA are a part of the complex regulatory system controlling the amounts and timing of protein production carried out by a cell. Cells react to changing circumstances with changes to epigenetic markers such as DNA methylation. Some of the alterations in cells and tissues that take place with advancing age, such as rising levels of molecular damage, are very similar between individuals, and thus weighted combinations of the status of specific epigenetic markers can be used to measure age. But most epigenetic change is highly variable and highly individual, dependent on the circumstances that each cell finds itself in, communications with surrounding cells, the overall environment, diet, state of health, and so forth.
At the present time is far from clear as to why exactly most epigenetic changes occur; building the full map and understanding of epigenetic adjustments in response to circumstances will likely still be a going concern decades from now. Even those epigenetic markers used to build biomarkers of aging are not yet firmly connected to specific underlying causes, though work is proceeding towards that end. This uncertainty gives rise to academic and popular debate over where epigenetic change sits in the tangled web of cause and consequence in aging. Programmed aging theorists hold that epigenetic changes are a cause of aging, and reversing them is therefore rejuvenation. Aspects of this view are being voiced more loudly these days, now that certain entities with deep pockets and well-oiled hype machinery are putting venture funding into the development of clinical therapies based on reprogramming cells to have youthful epigenetic patterns.
It would be very surprising to find that epigenetic change is at the roots of aging. The most telling arguments against this are the numerous contributions to aging based on the accumulation of metabolic waste that our biochemistry cannot break down, even in youth. No approach to restoring youthful epigenetic patterns can address that. Epigenetic change can certainly be a proximate cause to all sorts of disarray in aging, however. Reprogramming cells has been shown to restore mitochondrial function, and the general malaise in mitochondria that takes place in all cells in aging tissue can be traced back through failing fission, failing mitophagy, to gene expression levels of specific proteins. Force a cell to produce those proteins at a youthful level, and mitochondria will function once again.
Yet how great a gain can be produced while ignoring the underlying causes? If the history of medicine teaches us anything, it is that efforts to treat age-related disease without addressing its causes have been a miserable failure. Will it really be that much better to take one or two steps closer to the cause, while still not addressing it? That is an important question, and one we are going to see tested in practice, sadly. Enthusiasm and funding for taking those one to two steps is far greater than that for addressing the known root causes of aging.
In this broader context, the work noted here is quite interesting, proposing that the normal ongoing processes of DNA damage and repair taking place in every cell can, over time, produce at least some of the epigenetic changes of aging. They use artificially raised levels of DNA damage and repair to produce accelerated epigenetic change in mice that is at least similar to that of aging.
Despite it long having been the consensus that DNA damage and the resulting epigenetic changes are drivers of aging, some recent studies have questioned the importance of mutations in aging. For example, the number of mutations present in aged yeast cells is fairly low, and some genetically engineered strains of mice with high levels of free radicals or mutation rates do not appear to age prematurely, nor do they have shorter lifespans than their wild-type counterparts.
This appears to suggest that mutational load may not have such a strong influence on aging as was once thought, and the researchers of this new study consider further evidence suggesting the same. They also suggest that epigenetic alterations are perhaps the most important driver of aging and that, far from being random in nature, these changes are predictable and reproducible.
Researchers suggest that DNA double-strand breaks (DSBs) are a possible reason for epigenetic changes and show that there are clues to be found in yeast. In yeast cells, DSBs trigger a DNA damage signal that summons epigenetic regulators and takes them away from gene promoters to the site of the DSB on the DNA, where they then facilitate the repair of the break. The researchers suggest that after these repairs, the regulators responsible for repairing the DSBs return to their original locations on the genome, thus turning off the DNA damage signal, but this does not always happen.
The researchers suggest that with each successive cycle of DNA damage response and repair, the epigenetic landscape begins to change and regulators gradually become displaced, reaching a point where the DNA damage response remains active, leaving cells in a chronic state of stress. This stressed state then causes them to become dysfunctional and ultimately alters their cellular identity.
There are numerous hallmarks of aging in mammals, but no unifying cause has been identified. In budding yeast, aging is associated with a loss of epigenetic information that occurs in response to genome instability, particularly DNA double-strand breaks (DSBs). Mammals also undergo predictable epigenetic changes with age, including alterations to DNA methylation patterns that serve as epigenetic "age" clocks, but what drives these changes is not known. Using a transgenic mouse system called "ICE" (for inducible changes to the epigenome), we show that a tissue's response to non-mutagenic DSBs reorganizes the epigenome and accelerates physiological, cognitive, and molecular changes normally seen in older mice, including advancement of the epigenetic clock. These findings implicate DSB-induced epigenetic drift as a conserved cause of aging from yeast to mammals.