The remote south Atlantic island of St. Helena boasts an international celebrity: the tortoise Jonathan, the oldest living land animal. At 194 years old, he has outlasted the expected lifespan for an Aldabra giant tortoise (Aldabrachelys gigantea) by about a century. Now, scientists have identified a range of unique genetic and epigenetic traits that may hold the key to this longevity.

The new research zoomed in on Jonathan's genes, as well as the chemical tags that sit on top of DNA molecules, known as "epigenetic markers." These markers help control which genes are activated and to what degree. The analysis finds that Jonathan's genes associated with mitochondrial function are in great shape, epigenetically speaking, which suggests that they've played a big role in the tortoise's success.

While mitochondrial function has long been linked to longevity and mitochondrial dysfunction has been tied to disease, Jonathan offers fresh insight into that dynamic, said study co-author Stephen Clark, chief scientist of the Kallel Foundation, a nonprofit in Nashville researching drug targets to promote human longevity.

Clark and colleagues published their findings Wednesday (Oct. 7) in the journal Science Advances.

Decoding Jonathan's secrets to long life

Nearly a decade ago, the researchers enlisted Joe Hollins, the vet tasked with Jonathan's care, to collect samples from the record-setting animal. Island authorities forbade the vet from drawing the tortoise's blood, fearing the risk of an infection.

"I didn't want to be the doctor that killed Jonathan," Clark told Live Science. Hollins collected samples via cheek swab instead.

When the samples arrived in the U.S., the researchers sequenced them, but when their computers kept crashing, they discovered that the DNA had been isolated from bacteria in Jonathan's mouth rather than the tortoise's own cells.

Clark "had to go back and beg" for permission to collect more data, he said. The vet then sent cheek scrape samples, which are collected with a slightly different tool than cheek swabs. This time, the DNA was in fact from Jonathan.

The DNA isolated from those cheek tissue samples was more fragmented than it would have been in a blood sample, so the researchers filled in the gaps using an existing reference genome from a 36-year-old Aldabra tortoise named Tank. They also compared Jonathan's DNA to that of a Galápagos tortoise (Chelonoidis abingdoni) named Lonesome George, who was believed to be over 100 years old at the time of his death in 2012.

The team found that, compared to Tank and Lonesome George, Jonathan carried 287 unique variants of genes that had previously been linked to aging-related pathways. These included genes involved in DNA repair and the function of telomeres — the protective tips at the end of chromosomes that tend to shorten with age.

These pathways are also related to aging processes in humans, highlighting a "broader signature of aging" across species, Greer Dolby, an assistant professor of biology at The University of Alabama at Birmingham, who was not involved with the study, told Live Science.

The researchers also looked at epigenetic changes, including DNA methylation, which is when a chemical tag called a methyl group binds the DNA. Certain patterns of DNA methylation can function as a "clock" in that they reflect an organism's biological age; scientists have recently harnessed these patterns in the study of human aging. In this case, the team compared the DNA methylation across Jonathan's genome to that of young and old Aldabra tortoises.

The methylation patterns were more disordered in the older tortoises, reflecting random changes acquired over time, the researchers found. Scientists call this phenomenon "methylation entropy." For most genes, Jonathan's DNA methylation patterns were more disordered than those of the young tortoises. But in a suite of genes tied to mitochondrial function — specifically the bits of those genes that switch them "on" — Jonathan had more organized methylation patterns. That might keep expression of these genes consistent over time, the researchers theorized.

Mitochondria produce energy that cells need to function properly, repair themselves and reduce further damage to DNA. "Keeping the entropy low in these mitochondrial genes, or keeping pristine mitochondria, is likely to be a contributor to longevity," Clark said.

However, the authors couldn't determine a causal relationship — they didn't run any tests that could definitively prove that Jonathon's lack of entropy in these genes explains his long life. Clark argued that additional experiments on a blood sample from Jonathan could offer a more comprehensive view of his genome.

Jonathan's full genetic profile can't be known until after the tortoise's death, when researchers can collect DNA from more tissues, said Vincent Lynch, a professor of biology at the University at Buffalo, who was not involved with the study.

"Some organs are more susceptible to different diseases of old age than other ones, and that happens because mutations accumulate over time," he told Live Science. "We would ideally like to know what those mutations are in those specific tissues."

Furthermore, Lynch questioned whether entropy was a useful characterization of age-related DNA methylation patterns, as methylation can be unpredictable. That said, he agreed that the genes flagged in the study offer helpful data for future work on longevity.

More experiments are needed to determine whether these mitochondrial genes actually play a role in longevity across all Aldabra tortoises, let alone in other animals, or if Jonathan is just an outlier.

"Maybe Jonathan is just really good at being old," Lynch said.

The patient: A 65-year-old woman in Michigan

The symptoms: The woman arrived at the emergency room via ambulance and asked to see a psychiatrist for her visual hallucinations. "I'm seeing dead people," she told clinicians, adding that she'd even fired a gun at her hallucinations in one instance, according to a report of her case. (The report does not describe what the hallucinations looked like.)

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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