Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?

Abstract

Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.

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

“…Immunosenescence and inflammaging are high risk factors for severe COVID-19 in the elderly [ 1 , 2 , 17 , 18 ]. As age-related thymic involution contributes to immunosenescence and inflammaging ( Figure 1 A, Table 1 third column) [ 16 ], thymic function should also be considered as a potential player in aged populations versus young [ 19 , 20 ], and may also impact vaccination efficiency in the elderly.…”

The Role of Immunogenetics in COVID-19

“…Another prominent feature of COVID-19 severity is the association with advanced age [ 1 , 2 , 66 , 67 ]. Below the role of comorbidities, which tend to become more frequent during the aging process, a potential contributor to COVID-19 severity in older people may be represented by the subtle chronic inflammatory status called inflammaging (one of the three hallmarks of immunosenescence—an increase in serum cytokines impairing the effectivity of immune responses) and by the age-related progressive reduction in the ability to trigger effective antibody and cellular responses against infections and vaccinations [ 66 , 68 , 69 , 70 , 71 ]. Thus, immunosenescence represents a further potential contributor to the insurgence of fatal complications in COVID-19 [ 8 , 62 , 63 ].…”

“…Thus, immunosenescence represents a further potential contributor to the insurgence of fatal complications in COVID-19 [ 8 , 62 , 63 ]. Lymphopenia and accumulation of immune cells showing immunophenotypic and functional signs of exhaustion were commonly documented in COVID-19 patients, correlating with age and severity [ 43 , 68 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. This strong resemblance to immunosenescence makes COVID-19 a possible scenario to deepen the knowledge about the molecular basis affecting normal immune cell metabolism/lifespan/turnover and to determine the importance of genetic variants and epigenetic modifications behind the appearance of inflammaging and immunosenescence [ 66 , 85 , 86 , 87 , 88 ].…”

“…This strong resemblance to immunosenescence makes COVID-19 a possible scenario to deepen the knowledge about the molecular basis affecting normal immune cell metabolism/lifespan/turnover and to determine the importance of genetic variants and epigenetic modifications behind the appearance of inflammaging and immunosenescence [ 66 , 85 , 86 , 87 , 88 ]. Furthermore, the improvement of our understanding of the relationship between immunogenetics and immunosenescence (including inflammaging) would be crucial in the design of a therapeutic strategy specifically for older COVID-19 patients [ 66 , 68 , 69 , 89 ].…”

Intersection between ageing-related Genes and SARS-CoV-2 Interactome: Is it higher than expected?

“…Among the other differences, we focus on the observation that the infection is significantly more lethal in elderly people [17,18,19,20]. Some studies have focused on the possible link between increased mortality rate and some characteristics of elderly people [21,22]. These studies suggested the potential effect of the virus as a trigger activating the decompensation of other chronic conditions [23,24,25,26].…”