COVID-19, why are the elderly most affected?

Article by Mario Clerici Professore Ordinario di Immunologia e Immunopatologia, Università degli Studi di Milano
The COVID-19 epidemic has pinpointed  an aging problem known to all of us, but underestimated so far: the loss of strength of our immune system that increases the risk of contracting infectious diseases. To understand how this happens, we need to delve into the complexity of the immune system, understand its mechanisms of action and why they fail.The immune system: an army of cells and molecules The immune system is a complex set of cells and molecules that defends us from external aggression. It matures progressively after birth and accumulates defects and alterations in senility. This explains why in the elderly we observe the highest incidence of pathologies, including those caused by viral infections.The most important cellular components of the system are B lymphocytes, the cells that produce antibodies, and T lymphocytes, the cells that coordinate activities and intervene directly when it comes to eliminating a “foreign” agent from the body, for example a virus or even a tumor cell.

The immune system matures progressively after birth and accumulates defects and alterations in senility.

There are 2 types of T lymphocytes: T-CD4 and T-CD8. The former are the coordinators of all immune responses, because they help other lymphocytes to become operational when the body is exposed to external aggression. The latter are the direct interceptors of the immune response, because they are capable of directly eliminating cells infected with viruses and other aggressors.How the immune system ages An apparent paradox of the aging of the immune system is that it is characterized by two opposite phenomena: lymphocytes, on the one hand, loose their ability to react to external aggressions and undergo a process called immunosenescence, on the other hand they are constantly active in a process called inflammaging, which generates a state of latent chronic inflammation that damages tissues and is considered one of the main causes of age-related diseases.

The aging of the immune system is an apparent paradox: on the one hand lymphocytes are less efficient, on the other hand they are always active.

To understand how these processes affect the body’s ability to respond to infection, let’s look at them one by one.Immunosenescence Immunosenescence is characterized by quantitative and qualitative defects. The best known is the alteration of thymus function. The thymus is a gland that has a very important functional role in the maturation of the immune system and its maintenance. T lymphocytes (CD4 and CD8) mature in the thymus, from which they are then introduced into the bloodstream. With time, the thymus undergoes a gradual atrophy which diminuishes its ability to release lymphocytes into the bloodstream.Another immune system alteration concerns the T lymphocytes composition. Let’s take a step back. T lymphocytes can recognize a pathogen (virus, bacteria, etc.) using a specific receptor for the pathogen in question (called antigen). Those lymphocytes that circulate in the blood and have not yet encountered their antigen are called “naives“. Those that have already encountered it are called “memory“, because they “remember” that encounter.Memory lymphocytes are the cornerstones of immune memory, the one for which a close encounter with the antigen is enough to generate thousands of identical memory lymphocytes, some of which then remain in circulation for years and, at the moment of the second encounter, they proliferate again and eliminate it very quickly.

Vaccines are based on the principle of immune memory: whereby a new exposure to the pathogen (a virus in some cases) is sufficient to trigger quickly a very efficient response that eliminates the pathogen.

This is the working principle of the vaccines that expose T lymphocytes to antigen (properly inactivated and rendered harmless) and generate the immune memory that will defend us from future attacks and that can last for our entire life.While in the youngest the majority of T lymphocytes are naïve, because they have not met the target, in the elderly there is a strong accumulation of memory lymphocytes and a decrease in the number of the naïve ones. In other words, with time, we accumulate cells that remember previous encounters (memory) but we lose the young ones (naive) that serve to defend us from new antigens never met before.This is one of the causes of the weakening of immune defences against new viruses and bacteria that make the elderly more susceptible to infections with agents that have not circulated in humans before.

Over the years, we accumulate cells that remember previous encounters (memory) but we lose the young ones (naive) that serve to defend us from new antigens that we have never met before.

Another mechanism that also plays an important role in the loss of function of the immune system is cellular senescence, a phenomenon for which cells lose the ability to self-eliminate when they reach the end of their life cycle, accumulate and become zombie cells. Senescent lymphocytes damage other cells by producing inflammatory cytokines thus contributing to the other typical phenomenon of immune aging: inflammaging.Chronic inflammation predisposes the body to acute inflammatory reactions that can be devastating, as is probably the case in most elderly patients with COVID-19.Typically inflammation has the ability to self-suspend when it is no longer needed, but if the immune system is confronted with repeated aggression, the inflammatory process can become chronic and latent (symptom-free and difficult to detect), damaging all tissues. In other words, it is as if the immune system looses the energy needed to defend ourselves while trying to maintain a chronic inflammatory state that damages us.Chronic inflammation predisposes the body to acute inflammatory reactions that can be devastating. This is what happens in some patients, and probably also in some elderly people infected with the new coronavirus SARS-CoV-2: infection of the alveolar epithelial cells of the lung stimulates an exaggerated inflammatory response, called “cytokine storm“, which can lead to death.

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