Two people born on the exact same day can age in totally different ways ‪—‬ one in relative health and the other with chronic disease. Now, scientists have found a key difference in the immune systems of people who are more prone to age-related conditions, and it could help explain why some people remain healthier longer.

In young people, the immune system contains many naive T cells, a type of white blood cell. Over time, exposure to pathogens and vaccinations transforms some of these T cells into memory cells, which can respond quickly to defend the body against germs.

These memory cells make different types of characteristic proteins, called granzymes, which kill infected cells. They come in different "flavors," including granzyme K and granzyme B.

In a new study, published Friday (Oct. 9) in the journal Immunity, scientists found that individuals with more memory cells that make granzyme K than cells that make granzyme B tend to have healthier aging.

In the future, the balance of cells making granzyme K and granzyme B in a person's blood could be used as a test to determine "whether you're on the right trajectory of aging or not," study co-author Maxim Artyomov, an immunologist at Washington University in St. Louis, told Live Science.

Hunting for a signature of healthy aging

In earlier research, the same team found that, in old lab mice, granzyme K-making cells accumulated in several tissues and were linked to inflammation. They also observed the same increase in granzyme K cells in blood samples from older adults.

In the new study, they uncovered another piece of the puzzle: a dynamic with granzyme B-producing cells.

They began by analyzing immune cells sampled from over 2,600 people ages 18 to 97, looking at the balance of granzyme K- and granzyme B-making cells. They found that people with a lower ratio of granzyme K to granzyme B cell populations were more likely to have autoimmune diseases or other chronic immune conditions.

In a second analysis, they looked at both immune cells and blood-borne proteins sampled from 329 people, using the data to pinpoint a "protein signature" linked to an abundance of granzyme B-making cells.

They went on to hunt for this protein signature in around 48,000 participants who'd provided data to the UK Biobank, a large database of health data from U.K.-based adults. People who were predicted to have higher levels of granzyme B-making cells based on their blood proteins had worse health outcomes in the following 17 years, with a higher risk of death and of conditions like diabetes, high blood pressure, and liver and kidney disease.

The findings might point to an aspect of immune aging that wasn't previously understood.

"I think that's really exciting," Claire Gustafson, an immunologist at the Allen Institute, said of the results. "It highlights there's potentially some novel biology that we haven't really observed before," Gustafson, who was not involved in the research, told Live Science.

However, while there's a strong association between the balance of these cell populations and disease risks, Artyomov emphasized that the study does not prove that this ratio directly causes the poor health outcomes. Further studies would be needed to understand why having more granzyme B cells is linked with poorer health.

"This observation might be just a consequence, not a cause of the disease," Artyomov noted.

It's also important to note that granzyme K-making cells in mice are not the same as granzyme K-making cells in humans. In mice, they represent a more mature, specialized stage of immune cell development, whereas in humans, granzyme B cells better fit that description, he told Live Science.

That points to a key way that immunity in mice and humans is different, which was "underappreciated" before, Gustafson said. So when we're comparing these cells in mice and humans, "we're not looking at apples to apples," she said. Scientists now specifically "need to look more into humans, as it's not reflected in animal models."

In people, immune cells' features can also vary across diverse human populations, Gustafson added. We need more data across different populations to get a "true understanding of universal immune health," she said. The K-to-B ratio may be a "novel" clue that can help scientists understand healthy aging, but more data is needed to unpack why and how that ratio is linked to healthy or unhealthy aging.

"This is kind of like the first step to be able to get there," she told Live Science.

This article is for informational purposes only and is not meant to offer medical advice.

Emerging treatments aim to reverse or stall signs of aging in the body and thus cut the risk of age-related diseases. One of those signs is an accumulation of "zombie cells" — damaged cells that spew harmful substances rather than dying off and getting cleared away by the immune system.

Some scientists are designing treatments aimed at killing those zombies directly. But what if we instead helped the body's cleanup crew get rid of them?

"I think rejuvenating the immune system could rectify a lot of problems," said Roel de Maeyer, an immunologist at the University of Oxford. "We know hospitals are full of older people suffering from infections that younger people don't need to go to [the] hospital for."

The aim of these rejuvenating therapies would be to help people live healthier for longer, he told Live Science.

How do cells turn into zombies?

The immune system constantly gets rid of old, dysfunctional and dead cells to keep tissues healthy, but that cleanup gets less effective with age.

When cells die, they display proteins on their surfaces that act as "eat me" signals for immune cells, called macrophages, to engulf and destroy them. However, some cells refuse to die and instead become senescent. These zombified cells can lurk in tissues for years, releasing chemicals that drive inflammation and damage.

Senescent cells can form due to DNA damage from oxidative stress, radiation, or even normal cell division. Cells lose bits of DNA each time they make copies of themselves, and they have intricate mechanisms to decide when it becomes a "bit too dangerous to keep dividing," de Maeyer said. If a cell can no longer divide, it usually undergoes a process called programmed cell death or becomes senescent, he said.

Senescence can be beneficial in some contexts; it helps heal wounds, for example. But an accumulation of senescent cells is linked to damaging inflammation and impaired organ function.

"If there are many senescent cells in a tissue, that's usually a bad sign," de Maeyer said. The number of senescent cells goes up with age and is linked to many age-related conditions, such as heart disease and dementia.

Slaying zombies

Studies in mice have shown that using drugs to kill senescent cells can reverse inflammation and some signs of cellular aging. These drugs, called senolytics, force senescent cells to enter programmed cell death, thus reducing their numbers, said Jure Povsin, a biochemist at the Max Planck Institute of Biochemistry in Germany. This ultimately reduces inflammation and improves tissue function, he told Live Science.

But while senolytics can help rid the body of zombie cells, it's not clear why the immune system fails to eliminate senescent cells in the first place. To find answers, scientists began looking at macrophages, the cells tasked with devouring dying cells.

Research pointed to a receptor on macrophages called EP2. One study, published in July in the journal Science, found that old macrophages have a greater number of these receptors and cannot eat senescent cells effectively.

Genetically deleting the EP2 receptor in lab mice restored the macrophages' function and reduced the number of senescent cells. Compared with normal mice of the same age, the genetically tweaked mice showed less cognitive decline, muscle loss, cardiac dysfunction and systemic inflammation.

On some of these metrics, such as the ability to remember familiar objects, the modified mice were comparable to younger mice.

A problem with energy

Why is the EP2 receptor at the root of this problem? Scientists found a clue in a huge study of older adults.

A molecule called PGE2 plugs into the EP2 receptor. It's a type of prostaglandin — a molecule that helps cells communicate during stress and injury and contributes to fever, pain and swelling. Drugs such as ibuprofen reduce inflammation by blocking prostaglandin production.

In 2001, a large study uncovered a connection between these prostaglandin-blocking drugs and Alzheimer's disease: People ages 55 and older who routinely took the drugs for at least two years had a lower risk of developing Alzheimer's than nonusers did. The study could not prove that the drugs directly prevented the disease, but it added to growing evidence that inflammation related to EP2 activity plays a role in Alzheimer's.

This caught the attention of Dr. Katrin Andreasson, a neurologist at Stanford University and co-author of the recent Science study.

"I thought, 'Wow, this is interesting,'" she told Live Science. "I wondered if there's a connection."

Andreasson and colleagues had an important breakthrough in 2021: They found that aging macrophages had higher levels of the EP2 receptor and that increased EP2 activity disrupted how the cells used their energy. Instead of burning glucose to produce energy like young macrophages do, these cells stashed it away.

As a result, the cells could not do their job properly, as "gobbling up cells requires a ton of energy," Andreasson said. Blocking the EP2 receptor restored normal energy use in the macrophages. In old mice, it also led to reduced inflammation and better scores on cognitive tests, compared with mice in which EP2 activity remained high.

Making senescent cells vulnerable

In their recent study, Andreasson's team uncovered another consequence of aging: Old mice accumulated many senescent neutrophils, a type of short-lived immune cell that acts as the body's first line of defense against germs. Neutrophils normally die within days and are then cleared away, but with age, they become more prone to senescence and accumulate.

"I think that's kind of an odd concept because they're [usually] very short-lived cells," said de Maeyer, who was not involved in the Science study. "Neutrophils are inherently quite inflammatory, so wanting to clear them from tissues is very valuable."

Old mice have too much EP2 activity in their macrophages, and that means they can't get rid of these neutrophils, Andreasson's team found. That may be why deleting EP2 seems to have anti-aging effects in multiple organs, they concluded.

But increased EP2 activity is just one side of the story; some studies suggest that zombie cells actively suppress macrophages' ability to eat them. They do this by using a tricky protein called CD47.

CD47 is a "don't eat me" signal that stops macrophages from destroying cells, Povsin said. "It signals that the cell is healthy, alive and doesn't need to be eaten."

However, that signal gets amplified in senescent cells, Max Planck researchers showed in a 2023 study. That means that, when macrophages interact with senescent cells, macrophages' function becomes impaired. Afterward, they even lose the ability to engulf dying, nonsenescent cells. This allows a ton of cellular debris to accumulate.

So, rather than just blocking EP2, it could also be beneficial to reduce that "don't eat me" signal in senescent cells, this research hints. But CD47 is found on all living cells, so scientists can't just deplete its numbers across the body.

A specific enzyme modifies CD47 on senescent cells, and in the 2023 study, blocking the enzyme helped spare macrophages from the effects of CD47. Therefore, blocking the enzyme could be a more selective approach to weaken the "don't eat me" signal on senescent cells, Povsin said.

A long road to treatments for people

Translating these ideas into anti-aging treatments for humans would be a major success in the science of aging, but experts say there are significant problems to overcome.

Although blocking EP2 had consistent results in lab mice, the rodents are genetically identical and bred in controlled environments. Humans are inherently more variable in their biology and the environmental factors they're exposed to, introducing confounding factors that would need to be addressed, de Maeyer said.

Additionally, in clinical trials, EP2-blocking drugs have so far been explored as cancer treatments, but they are "underexplored" in the context of aging, he added.

Drugs targeting CD47 are in an even earlier stage of development. In the 2023 research from Max Planck, the team used both human and mouse macrophages in their experiments, but the approach has not been tested as an anti-aging treatment in living mice or humans yet.

In 2020, de Maeyer's team used a different strategy to rejuvenate macrophages in older adults. They blocked a protein called p38, whose activity was high in the macrophages of older adults. Blocking the protein helped macrophages better recognize and eat dying cells in specific tests.

In that study, the team gave adults ages 65 and up an experimental drug called losmapimod to block p38. Although it helped restore their immune cell function, it was not suitable for long-term use because it caused liver problems in later trials, de Maeyer said.

In their mouse studies, Andreasson's team was able to block EP2 without causing any negative side effects. But she cautioned that we "really need to drill down on the research and confirm all this stuff in humans."

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

This article is for informational purposes only and is not meant to offer medical advice.

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