Despite this reaction to her hallucinations, she was calm and alert during her physical exam, with normal vital signs other than high blood pressure. She reported a history of high blood pressure, diabetes, heart failure and chronic back pain but no prior psychiatric history.

What happened next: Since the woman had no past psychiatric history, doctors opted for a medical assessment before consulting a psychiatrist. A blood test revealed mild metabolic acidosis, meaning her blood was too acidic. A toxicology screen detected high levels of salicylates, a class of compound that includes acetylsalicylic acid, better known as aspirin.

The diagnosis: When questioned, the woman acknowledged that she had been taking over 15 aspirin pills a day for multiple weeks. Each of these pills, marketed for back and body pain, contained 500 milligrams of aspirin.

Upon further questioning, the woman confirmed that she had tinnitus (ringing in her ears), which is a classic symptom of salicylate toxicity. In other words, she'd overdosed on aspirin.

The treatment: Doctors consulted experts at Michigan's poison control center, who recommended intravenous (IV) treatment with sodium bicarbonate (the chemical name for baking soda). This treatment alkalinizes blood and urine, meaning it makes them less acidic. This enables more salicylate to be excreted through the kidneys, allowing the drug to be eliminated through the urine.

After 11 hours of the IV treatment, the woman's blood salicylate levels dropped from 28.8 milligrams per deciliter (mg/dL) to 18.3 mg/dL. Her hallucinations ceased and the tinnitus improved within 48 hours of her arrival at the hospital. She was discharged without having seen a psychiatrist.

What makes the case unique: Aspirin is generally safe when used in doses indicated on the bottle or advised by a person's doctors. However, taking too much aspirin can irritate the gastrointestinal tract, as well as disrupt the activity of parts of the nervous system.

At high enough doses, salicylates can stimulate part of the brain called the medulla, which regulates breathing. This results in hyperventilation that causes the body to lose too much carbon dioxide, and at first, the blood becomes more alkaline. This process is known as respiratory alkalinosis.

However, salicylates also disrupt metabolism, leading to metabolic acidosis from a buildup of lactic acid in the body, as the woman experienced. When metabolic acidosis overwhelms the respiratory alkalinosis and causes the blood to acidify, organ damage can occur. These metabolic effects may also explain the tinnitus, as it drives increases in arachidonic acid that stimulate receptors in the inner ear.

The woman's daily intake of roughly 75 milligrams of aspirin per kilogram of body weight was about half the typical dose associated with acute salicylate poisoning. However, it was still a large amount to take every day for weeks, and older age is also a risk factor for severe outcomes of acute salicylate toxicity.

The authors of the case report noted that although she had tinnitus, she lacked many other hallmark symptoms of salicylate overdose, such as nausea and fever.

To the clinicians, the woman's case served as a reminder that long-term aspirin toxicity may result in different symptoms than acute poisoning does. In past case reports, other patients with chronic salicylate toxicity have also reported visual hallucinations. But that potential symptom is not as well understood as more common symptoms like tinnitus.

The case report authors added that longer-term exposure to aspirin may be associated with more neurological symptoms because chronic exposure increases the odds of the drug crossing the blood-brain barrier — a gatekeeper that allows only certain substances from the blood into the brain. They added that doctors should consider poisoning, including salicylate toxicity, for patients with psychotic symptoms with no clear cause.

For more intriguing medical cases, check out our Diagnostic Dilemma archives.

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

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"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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