Greg Fahy is currently wrapping up a trial of one of the simpler methods that might produce some degree of rejuvenation in the the thymus, turning back a little of the process of thymic involution, the withering of functional tissue in this organ. The thymus atrophies quite early in adult life, and further with later aging. As the thymus provides an environment for processes that are necessary in the creation of the immune cells called T cells, this decline limits the immune system. A faster pace of creation for T cells should help with some of the age-related deterioration of the immune system, which arises in part because too many of the existing cells become dysfunctional, and because the pace of replacement is too slow to keep up.
I think that this trial is unlikely to be enormously effective at addressing the problem, and will probably only produce modest effects, but the point of the exercise is to prove in humans that any degree of thymic restoration can produce a commensurate level of benefits. If that can be accomplished via this approach, then hopefully funds can be found to bring one of the more effective methods demonstrated in mice into human medicine: FOXN1 gene therapy, tissue engineering and transplant of replacement thymic tissue, some form of cell therapy to spur regeneration of new thymus tissue, and so forth.
So from around age 20 (or younger) the thymus begins to shrink and loses the ability to produce T cells, why does this happen?
Nobody knows why thymic atrophy, or involution, occurs, but it happens in all vertebrates, starting really at the age of puberty. Some have suggested that it happens to save energy, since the production of properly qualified T cells is very energy intensive and inefficient, and of course, at puberty, the body begins to devote more energy to reproduction, which might require a tradeoff against using energy for immune maintenance. This could be adaptive since, in nature, humans would not have lived long enough for immune system collapse to set in, even though today, the situation is different. Regardless of the evolutionary reason for it, the most immediate biochemical cause of involution seems to be mostly a drop in thymic FOXN1 expression, although some have pointed to a decline in intra-thymic IL-7 and the negative influence of circulating sex hormones, for example.
You recently ran a human clinical trial to regrow the thymus gland. Can you please tell us what is the main goal of the project and what is the progress?
The trial was conducted under an FDA-approved IND and with review from multiple scientific and ethics committees. It consisted of a 12-month treatment course for 9 men divided into two cohorts, with the first cohort starting in October of 2015 and the second ending in April of this year. Our goal was to gather preliminary evidence indicating that it is possible to safely regenerate the normal aging human thymus and restore its functions, essentially reversing the process of age-related immunological deterioration. We chose to work with healthy men in part because this was a small trial, which required a reasonably uniform population, and in part because more information was available for men than for women. We chose an age range of 50 to 65 years because this range extends from several years before to a few years after the threshold age at which the immune system tends to collapse. Success would therefore suggest the possibility of preventing or even reversing the early stages of immune collapse. In future trials, we intend to enroll both women and older men.
The outcome measures included MRI evaluation of thymic density before and after treatment, simple and sophisticated assessment of T cell population distributions, measurements of many serum factors related to immune system function and general health, lymphocyte telomere length distributions and telomerase activity, and biological age based on the Horvath epigenetic clock. Regarding our results, first of all, when you're working with human beings, safety has to be the top priority, so I'm glad to be able to say that we met or exceeded all of our safety targets. Regarding thymic imaging results, preliminary analyses indicate that there was a consistent and substantial increase in thymic density, which indicates replacement of thymic fat with more water-rich material, and in previous studies on human immunodeficiency patients, this coincided with improved thymic function. Superficial tests of immune system aging showed improvements in 8 out of 9 men, and we were able to identify a possible correctable reason for the failure of the 9th volunteer. Men of all ages were able to respond positively and to avoid side effects. However, the most definitive endpoints of our study are still being analyzed at four different locations around the world, so we won't really know the final results of our study for probably another month or two.
Are we going to see a publication anytime soon?
I'm not sure about soon, but certainly, as soon as we can. This will be a complicated paper with lots of authors and lots of data to present, but also with top-tier academic co-authors who can help us go through the scientific review process quickly. In any case, we certainly want to make sure that any novel results are shared with the broader medical and scientific communities.