Tweaking a Macrophage Receptor Staves Off Aging in Mice

Macrophages are the jack of all trades of the immune system. If a troublesome cell needs to be removed, they become biological bouncers, and when diseases invade our body, they become frontline soldiers.

A new study, published in Science, suggests that they might have another occupation: keeping organs looking youthful and healthy.¹ Research led by a team from Stanford University, suggests macrophages losing their ability to efficiently devour neutrophils could kickstart some aging processes. Blocking a molecular receptor on the macrophage’s surface resulted in older mice resisting other features of aging, like frailty and weight gain.

The Cells That Pile Up in The Body’s Landfills

Out of all the jobs macrophages do, there is one that is essential for the body’s day-to-day functions. “They’re the body’s garbage collection crew. A lot of that garbage is defunct cells,” said Katrin Andreasson, a neurologist at Stanford University and study coauthor, in a statement.

One of the biggest components of this cellular landfill is a type of white blood cell called neutrophil. These cells are critical for fighting off opportunistic infections in the bloodstream, but most live for less than a day in the body before being dispatched to the liver or spleen for clearance.

Removing these cells is important. Many of these cells, upon failing to encounter a threat in their patrols through our bloodstream, enter a cellular phase called senescence. Refusing to die, the cells inflame nearby tissue and generally cause havoc in the body. “Senescent neutrophils are killing our tissues,” Andreasson said. “Clearance of these cells is essential for preventing chronic inflammation.”

A subtype of macrophages, called tissue-resident macrophages, are on the case. But after a long life of swallowing dysfunctional cells, some macrophages lose their appetite and become less efficient at clearing neutrophils, letting inflammation run wild.

Andreasson’s team previously showed that a receptor called EP2 on macrophages’ surfaces is key to their reduced taste for neutrophils that becomes pronounced in old age.²

In the current study, the team removed this receptor from macrophages. “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 [in macrophage performance] doesn’t happen.”

Staving Off Aging in Mice

The team worked on mice, showing that older mice, aged between 23 and 25 months (equivalent to humans in their 60s or 70s), were different from younger mice at the molecular level. These animals showed changes in 71 different blood proteins. But in older mice that were genetically engineered to lack EP2 from their “teenage” years, the majority of these proteins stayed at “youthful” levels.

These mice also looked younger, had greater muscle mass, and had better functioning organs than unmodified older mice and even had memory performance that almost matched young, mentally sharp mice.

The team gave older mice a new, experimental drug that specifically inhibited EP2. This drug reduced their neutrophil counts toward more youthful levels. The team also showed that similar changes happen at a cellular level in humans, suggesting some of the findings could be translational.

But mass genetic modification is not a viable strategy for human therapies and there are no approved drugs that target EP2. While non-steroidal anti-inflammatory painkillers work by blocking related processes, they are non-specific and get in the way of other, important immune signals.

Moreover, EP2 will be a difficult target to hit precisely. It’s at the heart of a metabolic pathway that potential drugs will need to work around, said Andreasson, warranting further work before clinical translation.