Thymic Involution Contributes to Immunosenescence and Inflammaging

The thymus is an underappreciated organ, responsible for the complex process of generating mature T cells of the adaptive immune system. Unfortunately it atrophies with age in a process called thymic involution. By age 50 most people have little active thymic tissue left. They must coast for the rest of their lives on the adaptive immune cells that they have at that point, replicating in the periphery of the body without a meaningful supply of new reinforcements. This inevitably leads to an immune system made up of damaged, overspecialized, and malfunctioning cells, incapable and inflammatory.

That part of the overall decline in immune function that is driven by thymic atrophy is a noteworthy component of aging, and this is why restoration of thymic tissue and activity is an important goal for the rejuvenation biotechnology research and development community. Since there are a number of us working on this, including Repair Biotechnologies, Lygenesis, and others, we might hope that a viable rejuvenation therapy for thymic function will arrive sooner rather than later in the years ahead.

The aged immune system has various characteristics. One of which is immunosenescence, which describes the vast and varied changes in the structure and function of the immune system as a result of age. Many of the early observations, such as reduced ability to fight new infections, diminished vaccine immunity, and reduced tumor clearance are generally categorized as immune insufficiencies. Immunosenescence is not due to the lack of immune cells, but due to reduced immune repertoire diversity, attributed to insufficient production of naïve immune cells and amplified oligo-clonal expansion of memory immune cells. Immunosenescence is therefore linked to the thymus. Natural aging causes the thymus to progressively atrophy, a process called thymic involution. This phenomenon is readily observed in most vertebrates and results in structural alterations, as well as functional decline, ultimately resulting in significantly decreased thymic output of naïve T cells that reduces the diversity of the T cell antigen receptor (TCR) repertoire, culminating in disrupted T cell homeostasis.

The second characteristic of aged immunity is termed inflammaging. Inflammaging describes the elevated self-reactivity in the elderly, resulting in the typical chronic, low-grade, but above baseline, systemic inflammatory phenotype observed in the absence of acute infection. Although immunosenescence and inflammaging appear to be opposing phenotypes, they comprise two sides of the same coin when attempting to holistically understand age-related immune dysfunction. It has been proposed that the basal inflammatory state in the elderly, defined by inflammaging, greatly contributes to many age-related degenerative diseases.

T lymphocyte (T cell) development and selection occurs in the thymus. Included in this process is central tolerance establishment. First is thymocyte negative selection, during which the majority of self (auto)-reactive T cells are depleted from the repertoire via apoptosis. Second is the generation of CD4 single positive FoxP3+ regulatory T (Treg) cells, whose primary function is to suppress T cell-mediated self-reactivity and preserve immune homeostasis in the periphery. These arms of central T cell tolerance work in tandem, and Treg cells most likely compensate for imperfections of negative selection, as some self-reactive T cells escape negative selection. With age, however, the atrophied thymus declines in its capacity to establish central tolerance, thereby, causing increased self-reactive T cells to escape to the periphery and participate in the process of inflammaging.

Link: https://doi.org/10.1186/s12979-020-0173-8

Comments

Given that the immune system is a distributed organ ie lymph nodes, bone marrow and tissue immune cells, is it actually necessary to reconstitute the atrophied thymus in order to rejuvenate the immune system ?
I suppose that, from first principles, the thymus must have evolved to be as and where it is for evolutionary reasons, so re- activating it is probably the right thing to do but beyond that I do not see why.
Re-activating the immune system per se is the thing and that must involve combating immunosenescence and in particular inappropriate oligoclonal expansion , mainly against Herpes viuses eg CMV.

A different aproach might be to, patially and serially, cause apoptosis of the immune system and then fill the vacant space with new primitive cells as with the latest treatments of graft versus host disease, after which allow time for the new cells to specialise including fresh new T cells.

Posted by: JLH at February 10th, 2020 6:42 AM

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