To What Degree is Chronic Inflammation the Cause of Thymic Involution with Age?
The thymus is vital to the function of the adaptive immune system. It is where T cells mature after their creation as thymocytes in the bone marrow, acquiring the necessary tolerance and function to venture forth into the body and defend it against pathogens, cancerous cells, and senescent cells. Unfortunately the thymus declines in size with age, its active tissue replaced with fat, in a process known as thymic involution. The consequence of this is an ever smaller supply of new T cells, ready to tackle threats. The adaptive immune system becomes ever less functional as a result, its limited set of cells uselessly specialized to threats such as cytomegalovirus, and otherwise ever more damaged and dysfunctional, lacking replacements.
A broad spectrum of efforts in the research community are focused on reversing the loss of thymus tissue with age. Even just considering companies actively involved in development: Lygenesis is building thymus organoids to insert into patient lymph nodes; Intervene Immune is trying human trials with a mix of hormones that have had some effect in animal studies; and Repair Biotechnologies, founded by Bill Cherman and I, is working on FOXN1 upregulation via gene therapy. Looking back into the research community, there have been past efforts with recombinant KGF, which unfortunately doesn't seem to work in humans, interest in upregulation of BMP4, and more.
Which mechanisms are most important in the age-related portion of thymic involution? This appears quite different in cause and trajectory from the rapid, regulated loss of thymus tissue that occurs in the transition from child to adult. In today's open access paper, the authors suggest that the chronic inflammation of aging causes a quite specific disruption in processes essential to tissue maintenance in the thymus. In fact the thymus, by virtue of its comparative simplicity in structure, might be a good starting point for understanding in general how inflammation disrupts tissue maintenance throughout the body, accelerating the onset of degenerative aging and loss of function.
Cell-type-specific role of lamin-B1 in thymus development and its inflammation-driven reduction in thymus aging
Elevated proinflammatory cytokines in aging animals, including humans, have been shown to contribute to various organ dysfunctions and human diseases. Indeed, extensive studies in vitro have shown that proinflammatory cytokines can induce senescence of a number of tissue culture cells. For example, either overexpression of CXCR2 in human primary fibroblasts or treatment of these cells with IL-1α or TNF-α induces cellular senescence. These proinflammatory cytokines can also reinforce cellular senescence in other primary tissue culture cells triggered by forced oncogene expression. Despite these studies, however, the cell/tissue source of age-associated inflammation and whether such inflammation disrupts structural proteins and thus contributes to organ aging remain unclear in any organism.
Considering the varied environments different tissues/organs reside in and the different functions they perform, it is highly likely that the inflammatory causes and consequences are different in different tissues and organisms. Cellular senescence triggered by inflammation has been implicated in aging and organ degeneration in mammals. The multitudes of senescence-associated cellular changes have, however, made it difficult to pinpoint which of these changes makes a key contribution toward age-associated organ dysfunction. Additionally, vertebrate organs often contain complex cell types, which makes it challenging to identify the cell sources and targets of inflammation that contribute to organ aging. Among many organs, the vertebrate thymus has a relatively simple stromal cell population called thymic epithelial cells (TECs) that are essential for thymic development, organization, and function. The TECs can thus serve as a relatively simple model to understand how inflammation and cellular senescence could influence structural proteins and in turn contribute to organ aging.
As a primary lymphoid organ, the thymus produces naïve T cells essential for adaptive immunity. Differentiated from the Foxn1-positive progenitors, the TECs consist of cortical TECs (cTECs) and medullary TECs (mTECs) that make up the cortical and medullary compartments of the thymus, respectively. The age-associated thymic involution or size reduction is known to contribute to the dysfunction of the immune system. Studies in mice have shown that thymic involution can be separated into two phases. The first phase occurs within ~6 weeks after birth and is characterized by a rapid reduction of thymic size. This phase is referred to as the developmentally related involution and it does not negatively affect the immune system. The second phase of thymic involution occurs during the process of organism aging and is manifested as a gradual reduction of thymic size and naïve T-cell production. Foxn1 reduction in TECs soon after birth appears to contribute to the first developmental phase of thymic involution, but the cause of the second age-associated phase of involution is unknown.
Among the structural proteins, lamins, the major component of the nuclear lamina that forms a filamentous meshwork in the nucleus has been implicated in proper organogenesis. Interestingly, reduction of lamin-B1 is found in the aging human skins, Alzheimer's disease patient brains, and various Drosophila organs, but the cause of such reduction and its impact on organ function, especially in mammals, remain poorly understood. We show that of the three lamins, only lamin-B1 is required in TECs for the development and maintenance of the spatially segregated cortical and medulla compartments critical for proper thymic function. We identify several proinflammatory cytokines in the aging thymus that trigger TEC senescence and TEC lamin-B1 reduction. Importantly, we report the identification of 17 adult TEC subsets and show that lamin-B1 reduction in postnatal TECs contributes to the age-associated TEC composition change, thymic involution, reduced naïve T-cell production, and lymphopenia.
Reason, off topic Thymus question. Can not mature Bone Marrow do everything that the Thymus does? It would seem to me we only have a Thymus when young because young people do not have adequate bone marrow for adaptive immunity, but mature bones have sufficient marrow for adaptive immunity.
@Reason - I think this is actually the first time that you have stated public ally that Repair Biotechnologies is working on a FOXN1 gene therapy, which is good to hear. I was afraid you guys were working on steroid injections or something else that might only have a weak effect.
IMO lifetime accumulation of microbial burden and wacky blood lipid profiles are the reason. Fix those things and you likely fix thymic atrophy.
"Low density lipoprotein or cholesterol reduces the expression of the thymus transcription factor Foxn1 via low density lipoprotein receptors (LDLR) on the membrane surface and low density lipoprotein receptor-related proteins on the cell surface, which cause the thymus function decline or degradation"
"The Pivotal Role of Thymus in Atherosclerosis Mediated by Immune and Inflammatory Response"
I missed that you posted that paper in November, sorry.
To my layman eyes FOXN1 has been something of an open goal since the original demonstration of thymic regeneration in mice, and yet it has required the investment of a near zealot like Reason to actually try and bring it to the clinic.
How is this possible? It seems like a lot of the technological unknowns have already been answered? You can use plasmids rather than an integrating gene vector. The organ is fairly easily accessible by injection. You could use electroporation to deliver the plasmids.
The only big remaining known unknown is whether fibrosis of the lymph nodes will mean that a rejuvenated thymus doesn't do much?
But if it does do something the payoff could be enormous. How come no one else has computed an expected value of this investment and concluded that the large upside means it is worthy of investment?
In a way we are in uncharted territory. There a lot of potential approaches. The mainstream researchers stick with the less risky and less rewarding paths. And yet if you go host a few steps beyond you could potentially find "gold" of the amazing discoveries . Or nothing interesting...