Could Rejuvenating the Immune System Help Clear “Zombie Cells” and Slow Aging?

Scientists are investigating treatments that could slow or reverse some effects of aging and reduce the risk of age-related diseases. One promising target is the buildup of “zombie cells”—damaged, dysfunctional cells that avoid being removed and release substances that promote inflammation.

Some researchers are developing drugs that directly kill these cells. Others are exploring a different strategy: helping the immune system recognize and remove them more effectively.

“I think if we rejuvenate the immune system, we can solve a lot of problems,” said Roel De Meyer, an immunologist at the University of Oxford. The goal of these rejuvenation treatments is to help people live longer, healthier lives, he told Live Science.

How do cells become “zombies”?

The immune system constantly removes old, dysfunctional and dead cells to keep tissues healthy. However, this cleansing process becomes less effective with age.

When a cell dies, proteins appear on its surface that act as an “eat me” signal to immune cells. Macrophages—immune cells that engulf and destroy cellular debris—then remove the dead cell.

Some cells, however, stop dividing without dying. These senescent cells can remain in tissues for years, releasing chemicals that cause inflammation and damage. Because of their behavior, they are sometimes called “zombie cells.”

Senescent cells can form because of DNA damage, oxidative stress, radiation or normal cell division. Cells lose some DNA each time they copy themselves, and they have mechanisms that determine when continued division becomes too dangerous.

When cells can no longer divide safely, they typically undergo programmed cell death or enter a senescent state. Senescence can be beneficial in some situations, including wound healing. But the accumulation of senescent cells can contribute to inflammation and impaired organ function.

“If you have a lot of senescent cells in a tissue, that’s usually a bad sign,” De Meyer said. The number of these cells increases with age and is associated with age-related conditions including heart disease and dementia.

Senolytics: drugs designed to kill zombie cells

Studies in mice have shown that drugs designed to kill senescent cells can reverse some signs of inflammation and cellular aging. These drugs, known as senolytics, force senescent cells into programmed cell death and reduce their numbers.

“This ultimately reduces inflammation and improves tissue function,” said Jure Povshin, a biochemist at the Max Planck Institute for Biochemistry in Germany.

However, scientists still do not fully understand why the aging immune system becomes less capable of eliminating senescent cells. To investigate, researchers have focused on macrophages, the immune cells responsible for engulfing dying cells.

How the EP2 receptor may interfere with immune cleanup

Research has identified a receptor called EP2 on macrophages. A study published in Science in July found that older macrophages have higher levels of this receptor and are less able to remove senescent cells effectively.

When scientists genetically deleted the EP2 receptor in laboratory mice, the macrophages regained some of their function and the mice had fewer senescent cells. Compared with normal mice of the same age, the genetically modified mice showed less cognitive decline, muscle weakness, cardiac dysfunction and systemic inflammation.

On some measures, including the ability to remember familiar objects, the modified mice performed similarly to younger mice.

“It takes a lot of energy to engulf cells.”

Dr. Katrin Andreasson, neurologist at Stanford University

Why aging macrophages run out of energy

Scientists believe EP2 may cause problems by disrupting how macrophages use energy.

A molecule called PGE2 binds to the EP2 receptor. PGE2 is a type of prostaglandin—a molecule involved in cell communication during stress or injury. Prostaglandins can contribute to fever, pain and swelling, while drugs such as ibuprofen reduce inflammation by blocking their production.

A large-scale study published in 2001 found a link between regular use of prostaglandin-inhibiting drugs and a lower risk of Alzheimer’s disease. People over age 55 who took the drugs regularly for at least two years had a lower risk of developing Alzheimer’s than people who did not. The study could not prove that the drugs directly prevented the disease, but it drew attention to the possible role of inflammation and EP2 activity.

“I thought, ‘Wow, this is interesting,’” said Dr. Katrin Andreasson, a neurologist at Stanford University and co-author of a later study.

Andreasson and her colleagues found that aged macrophages have high levels of EP2 receptors. Increased EP2 activity disrupted how the cells processed energy. Instead of burning glucose to generate energy like younger macrophages, the older cells stored it away.

As a result, the macrophages could not efficiently engulf dying cells. Blocking EP2 restored more normal energy use, while older mice with reduced EP2 activity showed less inflammation and better scores on cognitive tests.

Senescent cells may also send a “don’t eat me” signal

EP2 activity is only part of the problem. Some studies suggest that senescent cells actively suppress the ability of macrophages to engulf them using a protein called CD47.

CD47 acts as a “don’t eat me” signal that tells macrophages a cell is healthy and does not need to be destroyed. Researchers at the Max Planck Institute showed in a 2023 study that this signal is stronger in aging cells.

The amplified signal can impair macrophage function. After interacting with senescent cells, macrophages may even become less capable of engulfing other dying cells, allowing cellular debris to accumulate.

These findings suggest that reducing the “don’t eat me” signal in senescent cells could complement treatments that block EP2. However, CD47 is present on all living cells, so removing it throughout the body would not be safe or selective.

A specific enzyme modifies CD47 on senescent cells. A 2023 study found that blocking this enzyme could protect macrophages from CD47’s effects. Targeting the enzyme may therefore offer a more selective way to weaken the “don’t eat me” signal in aging cells, Povshin said.

The long road from mouse studies to human treatments

Turning these findings into anti-aging treatments for people would be a major advance, but significant challenges remain.

Although blocking EP2 produced consistent results in laboratory mice, those animals are genetically similar and live in controlled environments. Humans are much more biologically diverse and are exposed to different environmental factors, which can complicate clinical research, De Meyer said.

EP2 inhibitors have been studied in clinical trials as cancer treatments, but their potential use in aging remains understudied.

Drugs that target CD47 are at an even earlier stage. The Max Planck team’s 2023 study used both human and mouse macrophages, but the approach has not yet been tested as an anti-aging treatment in living mice or humans.

Another approach involves blocking a protein called p38, which is highly active in macrophages from older people. In a 2020 study, De Meyer’s team found that blocking p38 helped macrophages better recognize and remove dying cells in certain tests.

Researchers later administered an experimental p38-blocking drug called rosmapimod to adults aged 65 and older. Although the drug helped restore immune-cell function, it caused liver problems in subsequent trials, making it unsuitable for long-term use, De Meyer said.

Andreasson’s team blocked EP2 in mice without causing negative side effects. However, she emphasized that the results must be thoroughly tested in humans.

“The next logical step would be to figure out how to inhibit this receptor in a safe way,” she said.

Important: This article is for informational purposes only and does not provide medical advice.