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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.
Since T cells must be continuously produced throughout life, the accelerated atrophy of the thymus with age is enigmatic, especially given its latent regenerative potential. Age-associated atrophy is common to many tissues (for instance, muscle, central nervous system, skin, and testes), and can be a consequence of cell loss (death), but often is associated with the shrinkage (atrophy) of individual cells, collectively resulting in tissue atrophy. Likewise, regeneration may be attributed to proliferation of stem or end stage cells (hyperplasia), but can also result from growth of existing cells (hypertrophy) that is independent of proliferation. Despite the magnitude of atrophy and regeneration in the thymus, the underlying mechanisms for these processes have remained obscure, although our previous findings show that both are attributable to changes in cortical thymic epithelial cells (cTEC). Our non-presumptive analysis of global gene expression in young cTEC, aged cTEC, or aged cTEC in the regenerating thymus suggested that genes associated with cell size and shape dominated the dynamic landscape. However, the size and shape of individual cTEC has been difficult to discern using conventional methods, thus obscuring any changes that might occur during age atrophy or regeneration.
In other tissues, epithelial cells exhibit distinctive morphologies, and are polarized (with respect to a basement membrane) in either a single simple layer or in multiple stratified layers. In the thymus, with the exception of a small proportion of conventional epithelial cells lining the capsule and blood vessels, most TEC lack classical epithelial morphology. Instead, they are defined as epithelial mainly based on biochemical features, such as the appearance of desmosomes or keratin filaments. Various histochemical markers indicate that cTEC, in particular, form an extensive network of finely branched cell processes, but the morphology and number of individual cells in this network has been very difficult to define, due to this elaborate branching morphology and their relatively uniform staining with various antibody markers. Medullary thymic epithelial cells (mTEC) appear to be less dense, and therefore more easily defined as individual cells, but extensive heterogeneity among lineage markers has rendered the morphology of individual mTEC vague as well. Consequently, defining the size, shape, and interconnectivity of these essential cells has remained enigmatic.
Given the need for continuous T cell production during life, the thymus is paradoxically the most rapidly aging tissue in the body. It reaches peak tissue mass (in all species studied) prior to the onset of adolescence, and exhibits rapid and progressive atrophy afterwards, such that by mid-life most healthy mass is lost. Except at very late age, thymic lymphocytes are essentially unchanged in the atrophied thymus, while these age related changes are primarily manifest in stromal cells, particularly cortical. Niche availability provided by cTEC is the rate limiting feature for lymphoid cellularity and thymus size. Thus, as cTEC deteriorate during aging, the thymus becomes proportionally smaller. Since new T cells are produced proportionally to thymic mass, peripheral homeostasis thus becomes more dependent on homeostatic expansion of existing T cells, with the repertoire gradually drifting towards immunologic memory, with diminished broad spectrum immunity as a result.
Remarkably, the atrophied thymus retains potent regenerative capacity, and can be induced to attain its full peak size by stimuli such as androgen ablation. Quite logically, albeit without much evidence, thymic atrophy is assumed to result from senescence-associated cell death among TEC, while regeneration is believed to result from proliferative expansion from an epithelial stem cell or progenitor cell population. Consistent with these concepts, experimental loss of cTEC does result in decreased thymus size, while induction of cTEC proliferation results in a larger thymus. However, the fact that thymus size changes in response to TEC number (and resulting lymphoid capacity) does not mean that atrophy or regeneration, under physiologic conditions, necessarily involve changes in TEC number.
The present study stems from a large temporal database of stromal transcriptional profiles during aging and regeneration. Non-presumptive analysis indicates that dynamic changes in genes associated with cell size and cell morphology dominated the regeneration response. Here we use two different medullary stroma may play an important role in modulation of cTEC morphology via paracrine production of known morphogens and growth factors. Our findings reconcile diverse existing concepts, and provide a revised view of atrophy and regeneration based on structural remodeling of a novel cTEC morphology that is unique among metazoan tissues.
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