Epigenetics and the Programmed Aging View
The present vocal but minority view in the aging research mainstream is that aging is an evolved program with a strong epigenetic component. In this view, epigenetic changes are keyed to age, occur first, and cause the cell and tissue damage associated with aging. In the majority view of aging as a consequence of damage accumulation, the damage occurs first, and epigenetic changes are then a reaction to this damage, causing secondary and later issues. There is so much work yet to do in mapping out the detailed molecular biology of the progression of aging, and the blank spots on the map so large, that these two entirely opposing viewpoints, each with many variations, can continue to theorize and thrive.
For the damage accumulation view of aging, we fortunately don't need the full map of the molecular details of aging, an explanation of exactly how damage causes each and every age-related disease, in order to make solid progress towards the defeat of aging. All researchers need to do is to repair the root causes of aging, the forms of fundamental damage that distinguish old and young tissues, and these are well known and well cataloged. The fastest way to figure out what they are linked to in terms age-relate decline is to fix them and see what happens - which is also the fastest path to meaningful therapies. So, for example, life extension in mice has been robustly demonstrated in the case of clearing senescent cells, and clearance therapies are on their way to the clinic despite the vast amount of data yet to be gathered on how exactly aging progresses without this contribution.
The programmed aging school does need the molecular map of aging for significant progress, however. In this view, researchers should be working to list and revert epigenetic changes, and that should then either stop further damage or allow damage to be repaired by natural processes. Some such initial reversions, such as increased GDF11 levels, have been shown to produce benefits by restoring stem cell activity in old individuals - but is entirely possible for an epigenetic alteration to produce some level of benefits even if aging is caused by damage, and without addressing underlying damage, by reducing secondary issues or by forcing systems into action where they are normally in decline as a reaction to damage. Perhaps there will be consequences, such as a raised risk of cancer, but so far in the case of stem cells it is all working out better than expected. These results have boosted the confidence of the programmed aging side of the field, but I think they still overstate their case given the varying weights of evidence.
For readers who know me less well, I should introduce my perspective: I believe that aging is an evolved epigenetic program. When we are young and growing, particular genes are turned on and off with exquisite timing to determine the growth and development of bones, muscles, and organs. When we are old, the program continues, more slowly and more diffusely, but inexorably nonetheless. Genes are turned on that destroy us with inflammation and cell senescence and auto-immunity and programmed cell death, while the systems that protect us from pathogens and from free radical damage are gradually shut down. Evolution has left nothing to chance. Epigenetics is a new science in the 21st century. All the cells in one body have the same DNA (pretty much), but different genes are "expressed" (translated into proteins) in different tissues and at different times, and this is what controls the body's metabolism. In fact, only 2% of our DNA is genes, and 98% determines how the DNA is folded and spooled, opened and closed at particular times and places, and this in turn controls gene expression. We are 2% genetic and 98% epigenetic. The part of the epigenetic code on which we have the best handle at present is called "methylation of CpG islands". Long stretches of DNA have CGCGCGCG... on one strand, complemented by GCGCGCGC... on the other. Often the C's in this region get an extra methyl group, turning from cytosine to 5-methylcytosine. Then this stretch becomes a "repressor region," a signal to NOT express the adjacent gene.
DNA methylation can be persistent, turning a gene off for decades at a time. When a cell divides and its DNA is copied, the methylation pattern can be copied with it. This accounts for some of the persistence of epigenetics, and the way gene expression can be inherited across generations. DNA methylation has been appreciated for 30 years, but two recent developments make the subject attractive and accessible to research. (1) There is now a simple lab/computer technique for reading the methylation pattern from DNA. It relies on commercially available, automated machinery for PCR to sequence a full genome before and after chemical modification of the methylated C's. (2) There is now a simple lab/computer technique for changing the methylation state of any chosen target site in the DNA. It is based on CRISPR technology that is taking genetics labs by storm the last two years.
The correlation between aging and epigenetic status is established beyond dispute. But what does it mean? This is the big question. Most researchers think of the body as programmed by evolution to be as strong and healthy as possible. So, when different genes are expressed in old age, they find it natural to assume that the body is protecting itself in response to damage that it has suffered over the years. We express different genes when we are older because we need different genes when we are older. The other possible interpretation is my own, and it has become common among those who are closest to the field of epigenetics. It is that epigenetic changes with age are means of self-destruction. The body is programmed to die, and its suicide plan is laid out in the form of transcribing an unhealthy combination of genes. This idea flies in the face of traditional evolutionary theory. (How could natural selection prefer a genome that destroys itself and cuts off its own reproduction?) Nevertheless, the evidence for this hypothesis is robust. The genes that are turned on don't protect the body - quite the opposite. Genes for inflammation are dialed up. Genes for the body's defense against free radicals are dialed down. Cell turnover is dialed down. DNA repair is dialed down. The mechanisms of programmed cell death (apoptosis) are strengthened in healthy cells, at the same time that they are perversely weakened in cells that are a threat to the body, like infected cells and cancer cells.
In my opinion, the existing evidence heavily favors the hypothesis that aging is caused by epigenetic changes, rather than the other way around. When we look at the kinds of changes that occur, they seem to be pouring fuel on the fire, not putting it out. Protective genes are turned off and inflammatory genes are turned up. I also think that parabiosis experiments provide a strong clue. Three research groups have shown that injecting blood plasma from a young mouse into an old mouse makes the old mouse healthier, and relieves some problems associated with age. The blood plasma contains no cells - only signal molecules that are the product of gene expression. This is powerful evidence that youthful gene expression is supporting a strong and youthful body, and (conversely) that the kind of gene expression that characterizes old age is not doing the body any good. But the ultimate experiment will be to re-program gene expression in an old mouse and see if there is a rejuvenating effect.