Fight Aging!

The majority of the research community sees aging as a consequence of damage, which leads to reactions in the form of changes in the operation of metabolism. Cells react with altered levels of gene expression, leading to different amounts of various proteins in circulation, and other more complex changes also take place. Not all of these reactions are a good thing, and many cause further harm. In the programmed aging viewpoint, the changes in protein levels are the fundamental cause of aging, an evolved system that causes aging and exists because it provided selection benefits in early life. Thus to one school of thought repair of damage is absolutely the best approach while to the other it is pointless, and vice versa for efforts to change protein levels directly in old tissues without repairing damage.

The strange thing about modern aging research, or the tragic thing depending on your viewpoint, is that despite the majority considering aging to be caused by damage, the research they undertake is actually far more suited to the programmed aging school of thought. The most common approach to research is to examine the end stage of a particular aspect of aging, and pick out proximate causes, or changes in protein levels and gene expression, and try to alter them. This is the path forced upon researchers by the regulatory structure they work within: commercialization of treatments is only permitted for named diseases, the late stages of age-related damage. So they must work from the end backwards, and thus the first things they find are always going to be proximate causes and reactions.

This must all change if we are to see effective treatments based on damage repair. Meanwhile the programmed aging theorists should be pretty pleased with the current state of affairs, since it is going in the direction they would recommend even though they are ostensibly having a tough time in winning over their colleagues to their hypotheses on aging. This is a slow moving debate that is only ever going to be settled by the establishment of rejuvenation treatments that actually work, and thereby demonstrate one view to be wrong. That goal is muddied by the fact that there are many layers of damage and reaction, and thus one can in fact achieve modest benefits in some cases by altering proximate causes.

It is my belief that the timing of development and aging is determined by chromatin state. The body knows how to be young, and it knows how to be old. The difference is coded in chromosomes, especially in telomere length of stem cells and epigenetic markers in endocrine cells. I am proposing that aging is, in large part, a matter of epigenetics. A different set of genes is turned on when we are young compared to when we are old, and that makes all the difference.

I believe that aging is controlled by several biological clocks. This is a strong claim, but I think it has good support, outlined in the references above. Biological clocks certainly control development, puberty and related schedules early in life. How the body knows its own age is yet incompletely understood. It's a good bet that the same clocks that control development have been re-purposed to control aging. There are three clocks we know something about. These are the epigenetic clock, shrinkage of the thymus, master gland of the immune system. A common way to construct a clock is with a feedback loop. A clock looks at itself to determine its next move. The body has a feedback loop between epigenetic state (at a cell level) and circulating hormones and RNAs (at a systemic level).

There is intriguing data from parabiosis that circulating factors may be able to reprogram the body's age state. (This is the "back end" of the feedback loop described above.) If we're looking for quick progress against aging, the circulating hormones are more accessible and make a more convenient target than trying to get inside the cell nucleus to reprogram epigenetic state directly. If we're lucky, then adding some factors to the blood while blocking others will have a long-lasting effect of re-programming epigenetics, and the body will take over by continuing to secrete a "young mix" into the blood stream. If we're not so lucky, it may be necessary to perform some epigenetic re-programming more invasively.

Link: http://joshmitteldorf.scienceblog.com/2014/10/29/open-letter-on-research-priorities-in-aging/