In addition to lung damage, another way that senescent cells may exacerbate COVID-19 involves the SASP cocktail of inflammatory factors and proteins that degrade the network of proteins that support the organs in which they’re embedded. Some specialists in the researchers have begun arguing that inflammatory factors in the SASP may also suppress the immune response to the virus underlying COVID-19 (SARS-CoV-2). This hypothesis is based on a number of previous studies showing that chronic inflammation caused by numerous different conditions interferes with the immune response to multiple other viruses, including blunting the immune system’s response to vaccines against influenza, yellow fever, and hepatitis B. Moreover, inflammation driven by macrophages in the lesions of patients with atherosclerosis suppress the activation of T-cells, and this is associated with the failure of T-cells from these patients to mount an effective T-cell response against the virus that causes chickenpox in children and shingles (herpes zoster) in older adults. In one study, damping down the release of inflammatory factors in the skin before administering a shingles vaccine virus boosted the T-cell response to the vaccine.
Inflammation is complicated, however: acute inflammatory responses to injury or infection are essential to wound repair and successful immune response, respectively, whereas the chronic inflammation of aging impairs both, drowning out the local ramp-up when immune cells are actually needed and instead dispersing those cells all over the body to sites riddled with aging damage, futilely trying to repair microscopic injuries they cannot resolve. This is why drugs and antibody therapies that simply force down the inflammatory response lead to vulnerability to infection.
The solution here is not to attack the inflammation, but to remove and repair the underlying aging damage, thereby eliminating the source of chronic inflammatory stimulus while freeing up the rejuvenated tissues’ ability to mount an effective inflammatory response to acute threats.
A surprising example of this has emerged in the context of aging and COVID-19. As a result of the pandemic, people worldwide have become familiar with the “cytokine storm” — a severe inflammatory response that leads to immune derangement and the deadly acute respiratory distress syndrome (ARDS) that directly kills so many COVID infectees. Cytokine storms are also involved in many other viral fatalities, and the fact that young people can mount aggressive cytokine storms is thought by many scientists to be the reason why so many middle-aged people were killed by the 1918 influenza epidemic, which normally stalks the elderly and extremely young infants and children while leaving middle-aged people alone.
But there’s a wrinkle on cytokine storms and aging in COVID-19. Chinese researchers have found that a delayed immune response to the virus, as much as the strength of it, predicts death from COVID-19, accompanied by higher levels of inflammatory factors at death and depleted levels of multiple immune cell types. A study in aging monkeys suggests reasons why. The researchers found young monkeys infected with SARS-CoV-2 quickly mounted a savage immune response, complete with extensive attack of macrophages and T-cells and high levels of inflammatory factors within the first week of infection, but were quickly able to recover after that. By contrast, the immune response was delayed in old monkeys — and this seemed to have cost them. Having gotten started late, the old animals’ immune systems seem to have attempted to make up for lost time, mounting a more severe cytokine storm that recruited even higher levels of infiltrating macrophages and drove a more persistent T-cell attack. Yet those aged T-cells were also less effective at actually fighting the virus, making the inflammation and immune cell attack on the tissues purely self-destructive — a story we have seen play too often in our hospitals in recent days.
One important component of the SASP is an inflammatory factor called IL-6, which rises with age and predicts the risk of frailty and death even without SARS-CoV-2 infection. Now a new report indicates that a hospitalized COVID-19 patient’s IL-6 level is a strong risk factor for going on to require a ventilator, suggesting that senescent cells make aging people more vulnerable to the disease, and that senescent cell ablation could shore up this vulnerability. These findings are so compelling that some clinical centers treating critically ill COVID-19 patients are making experimental use of monoclonal antibody therapies such as tocilizumab and sarilumab, which block IL-6’s access to its receptors. But if we restore NK cells’ ability to eliminate senescent cells, people infected with SARS-CoV-2 would start off with lower IL-6 levels more characteristic of a young person, and thus better prepared for the fight.
In addition to IL-6, it’s recently been discovered that there is a network of factors emitted in the SASP that trigger the formation of blood clots and impede the countervailing factors that dissolve them. It’s long been known that an imbalance in these factors becomes increasingly common as people age, especially if they have risk factors for cardiovascular disease. The discovery that the SASP could tip the balance toward excessive coagulability, combined with the fact that aging people’s tissues become increasingly riddled with senescent cells over time, suggests that senescent cells and their SASP may be a key driver of this process.
Senescent cells’ possible culpability in the pro-clotting bias in aging people’s blood was already an important avenue for research before the rise of COVID-19, since the excessive tendency to form and maintain clots puts them at greater risk of heart attack, stroke, and venous thromboembolism (VTE) — abnormal clots forming in the veins. But it becomes a matter of acute focus in the face of multiple reports that high levels of markers of excessive clotting are common in COVID-19 patients at hospitalization, and foreshadow admission to the ICU and death from or with COVID-19 (in Holland and in Wuhan). Indeed, despite receiving prophylactic anti-clotting medication, nearly a third of Dutch patients with COVID-19 suffered from dangerous blood clots, including very commonly VTE that work their way up to cut off the lung tissue’s own blood supply, starving the lung itself of oxygen even as it is under attack by the virus and the patient’s own immune system.
Medical researchers have suggested a number of possible causes of excessive clotting specific to COVID-19, but as usual, the role of aging itself has been almost entirely ignored, despite the powerful influence of age in one’s risk of dying of the disease. Older people’s burden of senescent cells, the recent research suggests, may be predisposing them to a clotting crisis if infected by SARS-CoV-2.
Fortunately, the same research that originally identified the pro-clotting cocktail in the SASP also suggests that rejuvenation biotechnology could eliminate the associated risk of dangerous blood clots. Mice, like people, suffer a rise in senescent cell burden when given the chemotherapy drug doxorubicin, which then release SASP factors that favor the formation and stability of blood clots. In response, the mice produce higher levels of clot-initiating platelets, and those platelets are placed on a hair trigger. Activating a senescent-cell-destroying suicide gene prevented all of these things from happening, suggesting that purging aging cells from aging people could also leave them better prepared to survive an infection with SARS-CoV-2. Conversely, researchers at the Mayo Clinic have discovered that proteins from the SARS-CoV-2 virus exacerbate the SASP in human senescent cells, creating a vicious cycle of inflammation consistent with the ravages of the virus in older people.