Wear and tear on our bodies is inevitable as we get older, but what if we could slow it down?
It might mean better health for a greater proportion of our lives, and a lower risk of age-related diseases such as dementia.
Now, a new mouse study has identified what could be a crucial factor in biological aging: the gradual accumulation of this wear and tear. It seems it might not only involve cells getting damaged, but also certain troublesome cells not being properly cleared away.
Those troublesome cells are neutrophils, first-responder white blood cells that kill pathogens as part of the body’s immune system.
Neutrophils are very short-lived, and if they’re not cleared properly as they age, they can start to become harmful to organs.
Led by a team from Stanford University, the study has been published in Science, and shows that, in older mice, tissue-resident macrophages become less effective at clearing senescent (aging) neutrophils, contributing to decline across multiple organs.
“Senescent neutrophils are killing our tissues,” says neurologist Katrin Andreasson, from Stanford University.
“Clearance of these cells is essential for preventing chronic inflammation.”
In tests on young and old mice, the researchers reduced signaling through a cell receptor called EP2, using both drugs and genetic editing. This receptor sits on macrophages, immune cells that are tasked with cleaning up waste in the body, including neutrophils.
The researchers had previously shown that over time, macrophages become less efficient and can start to cause inflammation themselves – partly due to the pro-inflammatory EP2 receptor getting more active in later years.
When EP2 was disabled or blocked, the changes in older mice were notable. They showed more youthful patterns of inflammation, as well as improvements in memory, frailty, muscle loss, and heart function.
Reducing the effects of EP2 signaling seems to halt a slow decay in the energy metabolism of macrophage cells.
“Once that starts, there’s a steady decline in a macrophage’s performance,” says Andreasson.
“We’ve shown that when tissue-resident macrophages don’t have EP2 on their surfaces anymore or when that receptor is plugged up by a drug, this decline doesn’t happen.”
The researchers confirmed that reducing EP2 activity meant senescent neutrophils were once again being properly cleared out, limiting the damage they could do.
There was another discovery along the way as well: The researchers were able to identify 71 proteins that changed in older mice. Removing EP2 from TRMs restored 59 of these proteins toward youthful levels, and analysis of their likely cellular sources pointed to the liver as a major contributor.
“The liver is one of the body’s most tissue-resident-macrophage-enriched organs and a major contributor to aging-related changes in blood chemistry,” says Andreasson.
“It’s the central organ determining the body’s metabolic rate.”
It’s worth emphasizing that this is largely a mouse study, though the researchers also reanalyzed published data from human liver and heart tissue.
They found the same pattern in older human livers: fewer TRMs, more neutrophils, higher expression of the EP2 gene in TRMs, and reduced macrophage function. Older human hearts also showed fewer TRMs and higher EP2 expression, but not an increase in neutrophils.
Our bodies produce around 100 billion neutrophils a day, so it’s a big cleanup job to get rid of them, and the mouse experiments suggest keeping that clearance process working efficiently may be crucial for healthier aging.
Related: Your Body Doesn’t Age Steadily – It Ages in Two Big Bursts, Study Finds
There’s still lots more to do here – not least a proper analysis of the potential mechanisms in humans – but the researchers suggest that a drug targeting EP2 might eventually help limit age-related decline, if the findings translate to humans.
That will be quite the challenge – there are no approved drugs that selectively block EP2, and any treatment would need to do so safely without disrupting other beneficial effects.
“We’ve been trying to figure out why we age,” says Andreasson.
“Now we know at least one big reason for it.”
The research has been published in Science.
This article was fact-checked by Rebecca Dyer and edited by Rebecca Dyer. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.
