We all know that aging can take quite a toll on our bodies, but why do older individuals seem to be more susceptible to the flu? New research at the University of Michigan (U-M) has the answers.

In the almost-forgotten world before the COVID-19 pandemic, influenza was the most widely-circulating respiratory virus in the developed world. Just like the coronavirus, it was especially dangerous for and had better odds of infecting older individuals (those over roughly 65 years of age) compared to younger ones.

New research at the University of Michigan is piecing together why this is. According to their findings, the main reason seems to be that alveolar macrophages, immune cells which make up the first line of defense in our lungs, start becoming compromised with age. As an individual gets older, the densities of these cells in their lungs dramatically decrease, leaving the tissues vulnerable to infection.

Old defenses

The current study is based on previous research which found that, when macrophages from old mice are transferred into younger ones, the cells were rejuvenated — they looked and behaved like their younger counterparts again. According to Judy Chen, a Ph.D. candidate at the U-M Michigan Medicine school and lead author of the paper, this suggests that something in the lungs themselves is controlling the apparent age of macrophages. So, the team set out to find exactly what that something was.

They focused their research on a substance known as prostaglandin E2 (PGE2), a previously-identified compound of interest in this regard. PGE2 is a lipid immune modulator with a wide range of effects inside the body, from labor induction in pregnancy to inflammation with arthritis, and also present in the lungs. The team found that levels of PGE2 increase in the lungs with age.

Such a build-up is likely a mark of senescence; although there is quite some overlap between the concepts of aging and senescence, they are not one-to-one. Aging is understood to be the product of wear and tear on our bodies, a build-up of degradation over time that our bodies cannot repair. Senescence is a natural process of programmed cellular death. As cells age, they gradually incur damage, including in the genetic material that guides their functions. This could lead to ‘rogue’ cells being spawned. So, senescence is there to make old cells lose their ability to divide and multiply. It is commonly seen as our bodies’ insurance policy against runaway cellular multiplication which could lead to issues such as tumors or cancers.

The team suspects that the buildup of PGE2 in the lungs acts on macrophages here as well, progressively limiting their ability to perform immune functions. Their experiments confirmed that, as we age, the cellular linings of alveoli — the air sacs in our lungs — become senescent, increase the production of PGE2, and show suppressed immune responses.

“One of the interesting things about these cells is they secrete a lot of inflammatory factors,” says first author Judy Chen, a Ph.D. candidate at U-M.

In order to test the link between PGE2 and a patient’s increased susceptibility to influenza, they treated older mice with a drug that blocks PGE2 production. These mice “ended up having more alveolar macrophages and had better survival rates” against influenza than untreated mice, Chen adds.

Going forward, the team wants to investigate the mechanism through which PGE2 affects macrophages in the lungs and determine whether it plays a role in inflammation elsewhere in the body. This is due to the fact that, as we age, we become more susceptible to a whole host of other infections and conditions beyond influenza, and the team is curious to see whether the same mechanism they uncovered here could be to blame.

The paper “Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection” has been published in the journal Nature Communications.