An Aging Immune System May Explain Why Covid-19 Is So Harmful to the Elderly

Photo: Carlos Alvarez/Stringer/Getty Images

Much has been discovered about the novel coronavirus over the past six months. Statistical data has established that infection with the virus, SARS-CoV-2, is significantly more deadly in the elderly as compared to younger patients. If researchers can figure out why, it could lead to important advances in treatment.

The answer, it appears, may be due to the increased inflammation that occurs as humans age, a process scientists call inflammaging.

Recent data indicates adults over the age of 80 are hundreds of times more likely to die from Covid-19 as compared to those under the age of 40. As the body ages, so does its immune system. Thus, the prevailing thought is that our immune response to the virus becomes defective with increased age.

Why does this happen? Is it because the aging immune system is somehow weaker, or perhaps becomes hyperresponsive to viral intruders? Interestingly, the answer is likely both. To understand this concept we need to consider each branch of the army that comprises the body’s immune system.

When an elderly individual becomes infected with SARS-CoV-2, evidence is mounting that the innate immune response tends to become abnormally heightened.

Battle lines

The first branch is called the innate immune system. Cells of the innate immune system are the frontline foot soldiers in the defense against pathogens. They are able to attack foreign invaders quickly, but in a nonspecific fashion. The release of inflammatory particles by the innate immune system is akin to heaving grenades. While useful to respond to the initial assault, such a broad attempt to destroy the enemy virus can result in collateral damage to the body’s own organs and tissue.

Conversely, cells of the adaptive immune system are like snipers. These cells receive information about their adversary in the form of an antigen, a viral protein segment recognized as foreign by the adaptive immune cells. Although this process of intelligence gathering takes time, once activated, the adaptive immune system is able to systematically dismantle the enemy with efficiency and precision.

Inflammaging → Overactive innate system

Inflammaging results in a pro-inflammatory state that predisposes the innate immune system to overactivity. When an elderly individual becomes infected with SARS-CoV-2, evidence is mounting to suggest that the innate immune response tends to become abnormally heightened. Overactive innate immune cells release cell-signaling particles called cytokines which create a storm of inflammation that damages the body’s own tissue.

Inflammaging → Weakened adaptive system

At the same time, inflammaging blunts activation of the adaptive immune response. Weakened adaptive immune activity allows SARS-CoV-2 to multiply with less resistance, resulting in tissue damage directly from the virus itself. Vaccine studies with other viruses have revealed that increased inflammation dampens adaptive immunity by interfering with the process of antigen recognition, thereby reducing the vaccine’s effectiveness. This same concept applies when considering a pathogen rather than a vaccine.

When inflammation renders the adaptive immune system incapable of adequately recognizing antigen, the body can no longer properly defend against an invading virus. Interestingly, the opposite is also true. Reducing inflammation has been shown to improve antigen recognition and, in turn, the immune response to a vaccine.

Inflammaging is also caused by impaired removal of dead or dying (aka senescent) cells from the body.

Causes of inflammaging

Experts searching for causes of inflammaging describe multiple potential mechanisms. Inflammaging may be caused by misfolded proteins, a compromised gut barrier, or even the increased number of fat cells that come with obesity. This could, in part, explain why obesity, as well as other chronic conditions, increases the risk of adverse outcomes from Covid-19. Authors of a recently published article titled “Inflammaging: The missing link to Covid-19 age-related mortality?” remark that “inflammaging is associated with several diseases, including cardiovascular disease, insulin resistance, Type 2 diabetes, and cancer.” It should come as no surprise, then, that all of these conditions are associated with poor outcomes from Covid-19.

Inflammaging is also caused by impaired removal of dead or dying (aka senescent) cells from the body. As part of the natural aging process, senescent cells not only increase in number, but humans also become less effective at clearing them from the body. In their recently published perspective in the journal Science, professors of immunology Arne N. Akbar and Derek W. Gilroy hypothesize, “Because senescent cells secrete pro-inflammatory mediators and accumulate in every organ in the body during aging, another way to enhance immunity and reduce the inflammatory burden may be to eliminate these cells.”

A method to reduce inflammaging

Studies to explore the role of inflammaging are increasing in popularity. Research in mice has shown that removing senescent cells can reverse organ dysfunction associated with age. Now, investigations in humans are underway using drugs called senolytics to remove senescent cells from the body. Agents thought to have senolytic capability include metformin, a drug traditionally used to treat diabetes, as well as a host of other candidates.

Future aims

While the concept and study of inflammaging remains in its infancy, the premise has likely never been more universally applicable than during the Covid-19 pandemic. Given what has been discovered about how inflammaging affects the immune system, it’s no wonder that anti-inflammatory medications like dexamethasone as well as colchicine and anakinra, to a lesser extent, have demonstrated efficacy in treating Covid-19.

In fact, a study published on July 22 tracking over 1,800 hospitalized Covid-19 patients in New York City indicates treatment with systemic steroid medication improves outcomes in patients with elevated markers of inflammation but actually worsens the outcome for those without such elevated markers. Reducing inflammaging and its effects is an essential aspect to improving the treatment of Covid-19, a development many of us eagerly await.

Husband, Father, Health and science writer, Interpreter of medical jargon, Hospitalist physician, Board certified in internal medicine and pediatrics

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