Fight Aging!

I periodically publish thoughts on self-experiments that seem interesting and relevant to aging. Despite the influence of the quantified self movement, the broader self-experimentation community is largely terrible on matters of research, rigor, reporting, and safety. My motivation is to do something to raise the bar on all of these items.

For every discussion I've published on a particular self-experiment, there are half a dozen others sitting at some stage of research and interest. Over the past year or so, I've been on and off looking into sex steroid ablation as a mechanism for thymus regrowth. Since my company, Repair Biotechnologies, works on thymus regrowth as a way to reverse immune system aging, I have read up on most of the ways in which that has been attempted or achieved in animals and humans. The thymus is responsible for the maturation of T cells, a complicated process in which the cells are educated to attack pathogens and dangerous cells, but not normal tissue. The thymus atrophies with age, and by age 50 there is usually little active tissue left. Lacking a robust supply of new T cells, the immune system slowly declines into immunosenescence.

In humans, only two approaches to thymus regeneration have produced positive results. The small Intervene Immune trial used lengthy treatment with growth hormone alongside a few other substances to try to offset the negative effects of growth hormone. More impressive results, at least in the metrics measured, have been obtained from the use of sex steroid ablation in prostate cancer patients. For this approach, thymic growth has only been assessed in animal models. In human patients, the metrics have been naive T cell and recent thymic emigrant populations.

One has to ask the question: is it plausible for a 50-plus-year-old male to undergo a short period of sex steroid ablation in order to regrow the atrophied thymus, and rebuild the naive T cell population? Well, yes and no. Can it be done, yes. The evidence is pretty good. A fresh naive T cell population will last a decade or more without further reinforcement before it starts to become problematic - the normal course of aging, and people who have had the thymus surgically removed, tells us that. Many animal studies of castration and sex steroid ablation show thymic regrowth and revitalized production of T cells, for at least a short period of time. Based on trials of hematopoietic stem cell transplantation carried out in conjunction with sex steroid ablation, it is reasonable to think that three to six months would be required for a human naive T cell population to be reconstituted. Lesser duration of upregulated production of T cells would produce lesser benefits.

There is an interesting sidebar on what happens to the thymus in castrated mice. It doesn't grow in the sense of producing new cells. The cortical thymic epithelial cells grow in size. Then a few weeks later they shrink again. But this does produce upregulation of T cell production, and to a certain degree we don't really care that much about how the upregulation occurs so long as the T cells are of the right types and behavior. In human prostate cancer patients, increased T cell production is observed after months following sex steroid ablation, so the mechanisms are clearly distinct.

So why not conduct this self-experiment? Because the challenges and unknowns are not insignificant. Firstly, all human data and near all mouse data is in males - obviously necessarily the case in the prostate cancer studies. We have no good idea as to how to apply this sort of approach to females of either species. Secondly, while sex steroid ablation can be carried out very effectively using more modern drugs such as degarelix, a majority of the older prostate cancer patients it is used with do not recover the testosterone levels they exhibited prior to treatment. This is true even for the shortest treatment duration of 3-6 months, and appears to become worse the longer the treatment is continuously applied. There is really no established way of producing sex steroid ablation and very low testosterone levels with both rapid onset and rapid recovery, to get the overall duration to be any shorter than this.

Degarelix is an interesting drug. It causes very rapid sex steroid ablation, within a day or two, unlike other approaches that require a month or more to reach the desired point. When delivered intravenously, it leaves the system within a couple of days. But delivered subcutaneously, it forms a bolus that releases slowly over months. This is great for its intended use, but not so helpful if one wants a rapid recovery from sex steroid ablation. A single injection of degarelix is a 4-6 month commitment from start to (hopefully) final recovery - and the data indicates that the largely older prostate cancer patients do not tend to fully recover prior testosterone levels. Whether this is also true of younger individuals in the 40-50 age range is an interesting question with an unknown answer. Is the incomplete recovery inherent to age, or inherent to the usual secondary effects of sex steroid ablation on the systems of sex steroid regulation?

In principle one could inject degarelix intravenously every few days for a month to obtain a month of sharp onset and sharp recovery of testosterone levels. Then repeat every six months or so for a few years. One might expect that to greatly diminish side-effects, while still causing some degree of thymus regrowth. While the data exists for a single intravenous injection in humans, no-one knows what effects this might have if repeated extensively, or nor the proper calibration of dose and timing. Intravenous injection will produce spikes of much higher levels of the drug than occur for subcutaneous injection, and there is no data on what this does over time. That would all have to be discovered.

So while this might be an interesting project for someone with a high tolerance for personal risk, and an interest in conducting many trial runs with many blood tests along the way, it doesn't seem all that practical. Meanwhile, the practical approach of using degarelix in the well-established and well-characterized way it is used with prostate cancer patients, for the shortest period possible, produces lasting side-effects that most men might be somewhat unhappy to experience.

Setting aside that conclusion for a moment, if one was going to do this, how to measure outcomes? That should always be the question, regardless of whether or not a potential project is ever undertaken. Inability to come up with good metrics is a very compelling reason, in and of itself, not to carry out a self-experiment. In this case, there are good, well-established measures, however, and they will be applicable to any approach to restoration of thymic activity. Firstly, one can look at the Intervene Immune paper for some simpler approaches. In bloodwork to assess immune populations, the lymphocyte to monocyte ratio, CD4+ and CD8+ naive T cell counts, and recent thymic emigrants are all tests that exist and are to varying degrees easily accessed. One of course has to measure testosterone levels in order to prove that sex steroid ablation is taking place. For the thymus itself, careful CT scans have to be performed. The trick is to ensure that exactly the same location in cross-section is imaged at each assessment. There are papers covering how to do that, such as by taking increments in distance from the sternal notch as an anchor point. Assessing the cellularity of the thymus (it is unlikely to change in size) emerge from an examination of before and after images.

So on the whole, sex steroid ablation as an approach to regrowing the thymus and repopulating the naive T cell pool in older adults has good human evidence for efficacy in males, but is also risky and comparatively costly, and the existing tools are adapted to a use case that doesn't match well with this goal. Better approaches are needed, but developing them is likely beyond the means and interest of most self-experimenters.