The faltering quality of the immune system in later life is driven by several quite different factors, but the one that is perhaps most evident in the immune declines of middle age is the atrophy of the thymus. The thymus is a small organ located under the sternum and over the heart; it is where thymocytes produced in the bone marrow mature into T cells. As ever more of the active tissue of the thymus is replaced with fat, the ongoing supply of new T cells diminishes. The adaptive immune system becomes ever more a closed system and its cells become ever more dysfunctional: exhausted, senescent, misconfigured and overly focused on persistent viral infections such as cytomegalovirus, lacking the ability to respond to new threats. Thus older people have increased cancer risk, increased senescent cell burden, and reduced ability to defend themselves against infectious pathogens. This is why a number of research groups and biotech startups, including the company that I cofounded with Bill Cherman, Repair Biotechnologies, are working on ways to regenerate the thymus.

Why does the thymus atrophy? There are at least two stages. Initially thymic involution takes place in early life. By the end of teenage years, the thymus is much reduced from childhood. This is a developmental program. Afterwards, however, different mechanisms take over: evidence strongly suggests chronic inflammation to play an important role in reducing the ability of thymic progenitor cells to sustain thymic tissue. This may or may not be linked to cellular senescence. Senescent cells are highly inflammatory, but it seems unlikely that cellular senescence plays an important role prior to middle age. The senescent cell burden is thought to be very low up until that time - since the immune system plays an important role in culling senescent cells, it isn't until the immune system starts to decline in earnest that senescent cells really begin to play a significant role in aging. So the slow decline of the thymus from early adulthood to early middle age is more of a question mark, while for later declines we can point to the usual culprit of significantly increased inflammation and presence of senescent cells. There are no doubt other mechanisms at work as well, of course.

In this open access paper, researchers delve more deeply into the atrophy of the thymus and its regrowth via the mechanism of sex steroid ablation. They provide evidence for this to involve existing cells expanding their structure rather than generation of new thymic cells, at least for this method of thymic regrowth. It makes for interesting reading in the context noted above; it is worth thinking about the various processes noted here in relation to chronic inflammation. It is perhaps more interesting as a reminder that sex steroid ablation in mice has been shown by other research groups to only produce transient regrowth of the thymus (it is unclear as to whether this is also the case in humans, as long term data is lacking), and that this regrowth doesn't reproduce the youthful structure of the thymus, even while it certainly seems to boost the output of T cells.

Dynamic changes in epithelial cell morphology control thymic organ size during atrophy and regeneration