Thymic Aging May Be Associated with COVID-19 Pathophysiology in the Elderly

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.

Immune system aging and the aging-related diseases in the COVID-19 era

“…Thus, aging of the immune system itself would both directly and indirectly affect the course of COVID-19. The first reason would be the decreased ability of the aging IS to recognize the new virus, SARS-CoV-2, due to greatly reduced output of new naïve T cells from involuted thymus [ 113 , 114 ]. Next, the immunosenescence - remodeled IS of the elderly individuals would reduce its ability to build effective response to the virus, which exists in significantly higher load in the elderly, especially burdened with advanced immunosenescence [ 41 , 115 ].…”

Innate and adaptive immune defects associated with lower SARS-CoV-2 BNT162b2 mRNA vaccine response in elderly people

“…Remarkably, it has been described that thymic function failure predicts all-cause mortality in healthy elderly people (Ferrando-Martínez et al, 2013) and has a relevant role in viral infections such as HIV-1 infection (Delgado et al, 2002; Douek et al, 1998; Ferrando-Martinez et al, 2017). Moreover, it has been suggested that thymic aging might have an important implication in COVID-19 disease severity (Kellogg and Equils, 2021; Wang et al, 2021). Importantly, we discovered that the thymic dysfunction, along with the memory inflation and a higher homeostatic T cell proliferation and activation found in old people, were correlated to a lower response to SARS-CoV-2 vaccination.…”

Thymus Degeneration and Regeneration

“…Similar observations were also shown in SARS-CoV-1 ( 102 ), MERS ( 103 ),and experimental models of SARS-CoV-2 infection ( 104 ). It is proposed that immunosenescence and inflammaging are high-risk factors for severe COVID-19 in the elderly, suggesting that the age-related clinical severity of COVID-19 is due to impaired antiviral immune function and excessive self-damaging immune reactions in the elderly ( 101 , 105 ). Others also posited that the advanced age population is highly prone to viral infection because of a lower functional capacity of phagocytes to eliminate pathogens and activate the adaptive immune response ( 106 , 107 ).…”