As we age, the immune system begins to shift into a heightened state of alert, dialling up inflammation and running out of certain immune cells.
Covid-19 patients who are 80 or older are hundreds of times more likely to die than those under 40.
That's partly because they are more likely to have underlying conditions — like diabetes and lung disease — that seem to make the body more vulnerable to Covid-19.
But some scientists suggest another likely, if underappreciated, driver of this increased risk: the aging immune system.
The changes that ripple through our network of immune cells as the decades pass are complex, resulting in an overreaction here, a delayed response there and, overall, a strangely altered landscape of immunity.
Scientists who study the aging immune system say that understanding it may lead not only to a clearer sense of how age is tied to disease vulnerability, but to better strategies for Covid-19 vaccines and treatments.
"I felt like I was shouting at people, 'This is what's going on!' but no one was listening," said Arne Akbar, a professor of immunology at University College London who recently published an article in the journal Science explaining the state of research on the aging immune system.
When a virus infiltrates the body, cells in the first line of defense act swiftly and violently — sending out alerts and instructions to other cells, and provoking inflammation to start knocking down the virus.
The "innate" immune system, as it's called, also happens to be responsible for cleaning up damaged cells, misfolded proteins and other detritus in the body, even when there's no infection to fight.
In older people, such waste seems to outrun the immune system's ability to clear it, said Dr. Eric Verdin, the chief executive of the Buck Institute for Research on Aging in Novato, California. The innate immune system grows overwhelmed, and slides into a constant state of alert and inflammation.
At same time, elderly cells in tissues throughout the body are thought to change with age, releasing inflammatory substances of their own.
"They are not just benign, like old nice grandparents," Akbar said. "They're actually very cantankerous."
As a result, even perfectly healthy 65-year-olds usually have higher levels of immune proteins, like cytokines. This heightened state of chronic inflammation, sometimes called "inflammaging," is linked to frailty — older adults with higher levels of it may be more fragile and less mobile.
It also means that fighting off pathogens becomes more complicated: This inflammatory chaos in an aging body makes it harder for the messages sent out by the innate immune system to reach their targets.
On top of that, there's the danger that the innate immune system may overreact.
"We think that this is one of the reasons older individuals respond poorly to Covid-19," said Verdin.
Verdin and other experts said the aging immune system might be linked to reports of severe Covid-19 culminating in a cytokine storm, a reaction that causes high numbers of immune messengers to flood the body and can lead to organ failure.
This inflammation may also be part of why vaccines, whose effectiveness relies on a robust reaction from the immune system, don't work as well in older people — an effect that's likely to extend to Covid-19 vaccines. Akbar and his colleagues have found that people with high levels of inflammation tended to have weaker immune responses to the chickenpox virus, for example. And when they took an anti-inflammatory drug for four days before being injected, their immune responses improved.
A second wave
Several days after the innate immune response begins, the body starts a second wave of attacks against the viral invader. This adaptive immune system response is more targeted than the first, destroying cells infected by this specific virus.
But in older bodies, the adaptive response not only takes longer to get into gear, it arrives to find a scene of inflammatory pandemonium, said Amber Mueller, a postdoctoral researcher at Harvard Medical School who co-wrote a paper published in May about Covid-19 and aging. Think of firefighters coming to put out a house fire, she said.
"You have a whole neighbourhood of pedestrians or bystanders that are just hanging around, screaming their heads off, causing chaos," she said. "To the point that it makes it harder for the firefighters to find the fire — to find the infection — and then put it out effectively."
These delays mean that the pathogen has already made many copies of itself by the time the adaptive immune system gets to work and gains a foothold that might not have been available in a younger person. Additionally, older people have fewer fresh T cells, important players in the adaptive response that are trained to hunt down cells infected with a specific pathogen. When everything is working correctly, successful T cells make copies of themselves so that at the height of the infection, the body is swarming with them. Afterward, a few remain to prime us against return attacks from the same virus.
The supply of T cells that haven't already been assigned a pathogen dwindles over the decades. Those that remain may not be as good at copying themselves. And they may have trouble making the transition to patrolling the body against future attacks, said Dr. Shabnam Salimi, a professor of epidemiology and public health at the University of Maryland School of Medicine who wrote a recent paper about the interaction between aging and Covid-19.
"All these together make the immune system less functional during aging," Salimi said.
Research investigating Covid-19 treatments will have to take into account the specific cells and substances that go awry when the immune system ages, and drugs under investigation for fighting aging may be useful against the coronavirus, write Salimi and her colleague John Hamlyn in their article.
So far, little has been straightforward when it comes to treatments for Covid-19. Since it became clear that the virus sometimes provokes an out-of-control immune response, researchers have been testing whether reducing inflammation might help. Drugs that tamp down the levels of cytokines, like those used for treating rheumatoid arthritis and other autoimmune diseases, have not shown success in fighting the virus. What's more, chloroquine, which can help inhibit the aging of cells, caused increased mortality in Covid-19 clinical trials.
But the steroid dexamethasone, a potent anti-inflammatory, has been shown to reduce deaths from the virus. It resulted in one-third fewer deaths in people on ventilators and one-fifth fewer deaths in those on oxygen, according to a study published in June. (The drug may be ineffective, or even harmful, for patients in the early stages of the disease, however.)
At this point, it's important to design studies that take into account the special immune status of aging populations. Understanding these immune changes may help in finding treatments that work for older Covid-19 patients, but, Salimi said, it may also help younger people who may have some of the same problems without knowing it.
It's not just older people who have abnormally high levels of inflammation, or chinks in their immunological armour. It can happen to younger people as well.
In one recent study, for example, researchers found that young men with severe Covid-19 had mutations in the gene for a certain cell receptor. This receptor, some researchers suspect, grows scarcer as we age.
This particular immune alteration seems linked to why, in this case, the virus caused serious disease in young people with no pre existing conditions and in apparent good health.
"Even younger people may experience a similar pattern of severe disease as older people," Salimi said.
Written by: Veronique Greenwood
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