Oxidative Stress and Cellular Senescence in Age-Related Thymic Involution

The thymus is where T cells of the adaptive immune system mature. Thymocytes are created by hematopoietic stem cells in the bone marrow and migrate to the thymus, where they undergo a process of change and selection to become T cells capable of deploying an immune response against pathogens and harmful cells, but not against healthy cells. Unfortunately, the active thymic tissue that guides this process atrophies with age in process known as involution. By the age of 50 most people have little functional thymic tissue left, and as a consequence the production of new T cells is greatly reduced. This loss of reinforcements is a major contribution to the age-related decline of the adaptive immune system. Without replacements, it becomes a cluttered mess of exhausted, senescent, and misconfigured cells. The overall number of T cells stays much the same, but their quality and behavior declines precipitously.

Given this, regrowth of active thymic tissue is an important goal for the rejuvenation research community. Several approaches have been demonstrated to achieve this goal in older mice, resulting in a restored production of T cells - with the caveat that if lymph nodes are too damaged by age, these new cells cannot sufficiently coordinate to improve immune function. Castration, sex-steroid ablation, delivery of recombinant KGF, delivery of growth hormone, and upregulation of FOXN1 are among the methods of thymic regrowth that work to varying degrees and with varying reliability in animal studies. Of those, sex-steroid ablation and growth hormone have interesting human data, while a human trial of KGF failed to produce results, probably because the dose was too low.

Of late, researchers have suggested that the age-related atrophy of the thymus is driven by chronic inflammation, a mirror of some infectious disease processes in which the thymus is damaged and reduced by the inflammation associated with persistent pathogens. Since the chronic inflammation of aging results to a large degree from rising levels of senescent cells in tissues, this suggests that senolytic therapies - or other means to control the inflammation of aging - might slow thymic involution to a sizable enough degree to be interesting.

Implications of Oxidative Stress and Cellular Senescence in Age-Related Thymus Involution

Despite the fundamental requirement for lifelong establishment and maintenance of an overall effective and adequate defense against pathogens, the function of the immune system deteriorates with age, affecting both innate and adaptive immune responses (immunosenescence). The thymus, which reaches its maximal size and T cell output during early postnatal life, exhibits early thymic involution, a phenomenon that becomes even more prominent with advancing age. Although the size of the human thymus seems to remain unchanged throughout life under normal conditions, in other vertebrates, it declines during aging. Nevertheless, in almost all vertebrates having a thymus, thymic cellularity is progressively decreased and replaced by adipose tissue over time, resulting in perturbation of the normal tissue architecture. Since T cell production is proportional to thymic epithelial tissue mass, thymic involution results in significant loss of its capability for de novo generation of immunocompetent T cells. The net outcome is a decline in frequency and function of naïve T cells, leading to a restricted T cell repertoire in the periphery.

Even though age-associated thymic regression represents one of the most recognizable features of the aging immune system, the underlying mechanisms are not well understood. Several candidates have been proposed, suggesting that thymic regression involves the interplay of various and different mechanisms; interestingly, there are lines of evidence that in this complex process, the thymic stroma and especially the TECS are the most sensitive compartment. A number of studies reported that sex steroid hormones, and especially androgens, contribute to age-associated thymic involution. This notion was based on the observations (a) that thymic involution, although beginning in early postnatal life, is more pronounced with the onset of puberty when sex steroid levels increase and (b) that high doses of sex steroid administration cause degeneration of the thymus.

Numerous studies have also implicated the growth hormone- (GH-) insulin-like growth factor- (IGF-) I axis in thymus regression. Both hormones promote thymic growth, and lately, GH has been used as an alternative strategy to rejuvenate the thymus in certain immunodeficiency disorders associated with thymic atrophy. GH and IGF-I have been also considered as regulators of age-associated thymic involution, since GH production declines with age. However, the effects of hormone treatment on thymus size in older mice are limited, implying that there are other factors that prevent thymic atrophy.

The phenomenon of infection-induced inflammation and consequently thymus regression has also been reported; in human studies as well as in animal experimental models, infections with pathogens led to thymic atrophy, although the underlying mechanisms have not been extensively studied. Lately, a new player suggested to be involved in accelerated thymus involution and dysfunction with age is oxidative stress. Notwithstanding that the generation of reactive oxygen metabolites is an integral feature of normal cellular metabolism, the accumulation of such genotoxic and proteotoxic oxygen-derived by-products seems to exert detrimental effects on thymic tissue. Contrariwise, genetic or biochemical enhancement of antioxidant activity has been proven to ameliorate thymic atrophy.

Similarly, oxidative damage is also a well-documented inducer of cellular senescence, a state of permanent cell cycle arrest. The accumulation of senescent cells maintains an inflammatory milieu (inflammaging) that causes tissue remodeling, affects the regenerative potential and proper function of tissues/organs due to exhaustion of progenitor and stem cells, and, ultimately, promotes aging and age-related pathologies. Considering that (1st) oxidative stress has been linked to both the induction of cellular senescence and thymic involution and (2nd) aging is characterized by accumulation of senescent cells as well as a decline in thymus function, it is not unreasonable to assume that cellular senescence may exert a critical role in the induction of thymic involution, with oxidative stress being the common denominator. Indeed, recent evidence, from human and animal studies, supports this notion.


If we can boost the immunity system of the aging (over 50?) that would be extremely helpful and a paradyn shift in the perception of people realizing we have some degree of controlling aging. Yes, getting senolytics out there would also be a huge boost for us older people.

I very much hope that Reason's company will be hugely successful and they see spectacular results inside of a decade.

Posted by: Robert at March 4th, 2020 3:11 PM

If thymic involution is complete by 50, while senescent burden is small before that age with senolysis being deemed so far as useless before 50+, would we need earlier senolytic treatments than envisioned until now?

I also wonder how longer-lived mammal species deal with thymic involution.

Posted by: Hervé Musseau at March 5th, 2020 2:02 AM

I really hope Repair Bio succeeds. I wonder how far they are away from demonstration in an animal model?

Posted by: jimofoz at March 5th, 2020 2:15 AM
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