The increased severity and mortality of COVID-19 observed in older individuals may be related to "inflammageing" — an age-associated phenomenon of higher levels of general inflammation throughout the body, which can inhibit immunity. Because the deadliest cases of COVID-19 have occurred mostly in older people — roughly 80% of the COVID-19 related deaths reported in the U.S. have been in those age 65 and older — researchers are wondering if the condition may serve as the trigger for the extreme inflammatory responses common in the lungs of severe COVID-19 patients.
In a Perspective published in the July 17 issue of Science, Arne Akbar and Derek Gilroy discuss the impact of inflammageing on immunity in aging individuals. They suggest that reducing inflammation using anti-inflammatory drugs in concert with vaccination efforts may provide a therapeutic strategy for enhancing immunity broadly and potentially improving COVID-19 outcomes in older patients.
"Aging has a profound impact on the immune system, and this may affect the way in which the immune system reacts to new infections like SARS-CoV-2," writes Akbar, the Perspective's lead author and researcher at University College London.
According to Akbar, any changes observed in the immune system of COVID-19 patients must be considered in the context of the natural age-associated changes in immunity.
Like so many other parts of the human body, our immune system tends to weaken with age. This general decline in immune function causes our bodily defense systems to respond more slowly to bacterial and viral threats, leaving the aged much more susceptible to infections. It's also why vaccination strategies for a number of different illnesses are often much less effective in older people.
In addition to the deterioration of immunity, another common condition of aging — and potential factor in vaccine ineffectiveness — is the development of inflammageing. Inflammageing is a systemic issue characterized by chronic low-grade inflammation, which occurs in the absence of infection.
Inflammation is an essential part of the immune response — it's the body's way of letting the immune system know that it needs healing or protection from foreign invaders. When the job is done, inflammation in tissues subsides. However, a growing body of evidence has shown that this smoldering state of elevated inflammation can instead worsen many age-related diseases and further inhibit the response from an already declining immune system.
Inflammageing is thought to be caused, at least partially, by cellular senescence — the deterioration of aged cells in the body's tissues. Some of the old "decrepit" cells that accumulate in the tissues of older people spontaneously release inflammatory molecules that trigger unwarranted inflammation responses. Researchers think the white blood cells that respond to the false alarms release a hormone-like molecule, which in turn directly inhibits the function of T-cells working to fight off legitimate threats like viruses, said Akbar.
While the natural, age-related elevation of inflammation may not be much of a danger on its own, Ackbar suggests that it could be the initial trigger that kicks off the hallmark extreme inflammatory responses seen in the worst COVID-19 cases studied around the world.
Although the majority of COVID-19 cases involve moderate symptoms in younger people, they are often devastating for elder individuals. Ackbar suggested the loss of inflammatory control in aged individuals may partly explain why the hyper-inflammation that causes severe respiratory damage so often occurs in older patients with severe COVID-19. However, it may not be the only source of the generalized increase in inflammation.
"Interestingly adipose tissue [body fat] is also inflammatory, which may explain, in part, why obesity is a risk factor for developing severe COVID-19," said Akbar.
Akbar noted that a key unknown in addressing COVID-19 is the relationship between elevated baseline inflammation and the massive inflammation that occurs in older patients with severe infections. However, reducing the numbers of senescent cells that accumulate during aging using a class of drugs called senolytics, or calming inflammageing with anti-inflammatory drugs, may be useful strategies for improving COVID-19 outcomes in this particularly susceptible group.
"The fact that the anti-inflammatory steroid dexamethasone has been shown to be effective in treating severe COVID-19 patients highlights that blocking inflammation is a promising strategy for treating COVID-19 patients," said Akbar.
As the efforts to produce a viable COVID-19 vaccine become more fruitful, ways to improve their effectiveness in the older population are paramount. Akbar said pre-conditioning with anti-inflammatory drugs or therapeutic elimination of senescent cells could be considered before a vaccine is administered. However, such approaches currently remain little more than hypotheses.
"There is an urgent need to understand what is happening in the infected and inflamed organs. More work needs to be done to show that senescent cells, especially in the lungs of older patients, are involved in amplifying inflammation during COVID-19 infection," said Akbar.
"However, if vaccines are effective in younger individuals, they would not spread the infection to others, and this would benefit older subjects indirectly."
[Credit for related image: Kathryn Harper/Flickr]