Transmission electron micrograph of human neutrophils, immune cells that can turn rogue with age

ROSSANA MELO/SCIENCE PHOTO LIBRARY

As we age, our body loses its ability to clear out zombie-like cells that have stopped dividing, instead dripping out poison and turning other cells rogue. Restoring the ability to remove these “senescent” cells prevented signs of cognitive decline and frailty in older mice, with hints that the same outcomes could occur in people.

“What’s attractive about this study is that it is not trying to kill [senescent] cells directly,” says Derek Gilroy at University College London, who wasn’t involved in the research. “It is repairing the body’s own waste-disposal system that should have removed them in the first place.”

To better understand why this system goes awry, Katrin Andreasson at Stanford University, California, and her colleagues compared mice aged 6 to 8 months (roughly equivalent to people in their 20s) with mice aged 23 to 25 months (equivalent to people in their late 60s or 70s). They found that the older mice had more of these senescent cells in their organs, including the liver and spleen, as well as in their bone marrow.

Specifically, the senescent cells were neutrophils, immune cells that are normally the body’s first line of defence against infection. These would normally be cleared away by macrophages residing in tissue, which remove damaged cells and debris, but this ability declines with age.

Andreasson and her colleagues traced this decline to prostaglandin E2, a signalling molecule that increases with age. They found that higher prostaglandin E2 activity overstimulates a receptor called EP2 on tissue-resident macrophages, which leaves them less able to remove senescent cells.

Next, the team tested whether blocking this overstimulation could improve signs of ageing by genetically modifying the EP2 gene from tissue-resident macrophages in older mice. These animals went on to clear more senescent neutrophils and showed signs of healthier ageing, including lower levels of inflammation, reduced muscle loss, less visceral fat and better mobility, compared with unmodified mice of the same age. They also performed almost as well as young mice in memory tests.

“We were very surprised at the magnitude of the effect,” says Andreasson. “The paradox is that we had only reduced the level of [the receptor protein] EP2 by 50 per cent.”

The researchers also tested an experimental drug that blocks the EP2 receptor protein. When given orally to older mice for two months, this caused similar age-related improvements to those experienced by the genetically modified mice.

“This is a very promising study, but we need to be careful,” says Gilroy. “[The EP2 receptor] is part of a normal signalling system, and blocking it throughout the body could have unwanted effects.” The mice experienced no known side effects, but Gilroy says it may be safer to target the EP2 receptor in ageing macrophages specifically.

Finally, the team found similar patterns in human tissue, with liver samples from older people showing higher EP2 receptor activity and more senescent neutrophils. “The human data are supportive, but still correlative,” says Gilroy. “We haven’t yet shown that blocking [the EP2 receptor] can restore neutrophil clearance in aged human tissue.” 

The researchers are now planning to study whether this process affects the onset of conditions such as Alzheimer’s disease.