Researchers are writing a great many papers these days to point out the obvious regarding COVID-19, that the vast majority of SARS-CoV-2 coronavirus mortality occurs in older individuals, particularly those who already suffer age-related disease and thus a high burden of tissue and immune system dysfunction. This process of repeating the obvious seems necessary, given that the public discourse on the topic of the present pandemic presents it as a condition that affects all members of society more or less equally. In fact it is a condition that does little more than inconvenience near all younger people who are infected, while being quite dangerous for the old - along the same lines as influenza and many other common infectious diseases. This is entirely due to the fact that old people have damaged, dysfunctional immune systems. A range of research programs aim at rejuvenation of the immune system, and in a better world they would be receiving a great deal more attention than is presently the case.
Older subjects, men, and those with pre-existing conditions such as hypertension, diabetes, cancer, heart failure, and chronic obstructive pulmonary disease are more prevalent among hospitalized COVID-19 patients. Clinical risk factors for COVID-19-related deaths have been identified using a very large cohort. The most common comorbidities have age as a risk factor and have been described in recent years as age-related diseases. The COVID-19 case fatality rate (CFR), that is, the quotient of deaths to confirmed infections, was shown to be lower in patients below 60 years old (1.4%) compared to those who were 60 years or older (4.5%). The severity of the respiratory illness might be related to age-associated changes in the physical properties of the lung and the decline of the immune function, known as immunosenescence.
In general, the idea that older people are more susceptible to infections is not new. In fact, it has been reported that up to one third of deaths in the elderly is a result of infectious diseases. Persistent viral infections may also trigger monoclonal expansion of T cells, which over the lifetime results in poor variability of memory T cells. In turn, this eventually drives immune exhaustion due to the decline in T-cell diversity, a critical problem when facing novel threats such as SARS-CoV-2.
An additional feature that characterizes the severe cases of COVID-19 is the elevated levels of inflammation that can compromise lung tissue integrity and function, leading to pneumonia. Remarkably, accumulated and exhausted T cells secrete preferentially pro-inflammatory cytokines such as IFN and TNF. These cytokines can contribute, along with the innate immune system, to the low-grade pro-inflammatory background observed in elderly individuals, which may worsen COVID-19 outcomes and explain the elevated levels of inflammation. It is also possible that age-associated clonal hematopoiesis may contribute to the increased inflammation due to hematopoietic stem cell myeloid generation bias of pro-inflammatory macrophages and mast cells, and reduction of lymphoid differentiation.
Moreover, decreased T-cell capacity to properly activate antibody-secreting cells to further elicit effective immune responses may be compromised. Yet, another possible explanation is thymus involution. During aging, the thymus becomes atrophic and is gradually replaced by fibrotic tissue. This results in a reduced number, or even complete abrogation, of exiting naive T cells. Together, all these features may result in the decreased ability of older people to fight viral infections, leading to age-related inflammation and higher susceptibility of the lung, and eventually other organs, to the COVID-19-inflicted damage.
In this work, we revealed a strong link between COVID-19 fatality rate and aging. Based on our analysis, we propose that COVID-19, and more generally deadly respiratory diseases, should be considered as novel and emergent diseases of aging. Understanding that age is a major factor for fatality of COVID-19 may help to design approaches against this disease that target the aging process, along with specific antiviral approaches and those that boost more efficiently the human immune system of the elderly.