María Branyas Morera was born on March 4, 1907, in San Francisco, less than a year after the earthquake that destroyed the city. When World War I broke out in 1914, her father died of tuberculosis on the ship bringing the family back to Spain. As a child, she witnessed the 1918 flu pandemic. During the Spanish Civil War, she worked as a nurse on the Republican front alongside her husband, a doctor. She witnessed World War II, the moon landing in 1968, the fall of the Berlin Wall in 1989, the turn of the millennium, and in 2020, she overcame a Covid infection. Over all those years, she lost her parents, her siblings, and even — the cross that most painfully affected her — her son. In 2023, she became the oldest living person on the planet. During the final years of her life, and until shortly before her death in August of last year, a group of scientists took several samples from her. Their results, recently published in Cell Reports Medicine, reveal the keys to her longevity.
“Study me, learn from me,” Manel Esteller recounts María telling him shortly after meeting her. Head of the Cancer Epigenetics group at the Josep Carreras Leukemia Research Institute, Esteller is the senior author of this research, in which some 40 scientists participated. He learned from the press that María lived near his laboratory, so he insisted on meeting her and studying her. “She said that when she reached 100, 105, or 108 years old, God had forgotten about her,” he recalls. But she soon regained her optimism. “She said to herself, ‘Look, since I’m here, I’ll do what I can, enjoying my family for as long as I have left,’” Esteller adds, concluding by emphasizing that María was “a very generous, very kind person, always with a smile.”
What the team led by Esteller has done is study the biological basis of María’s longevity and its possible connection to her habits and attitude toward life. On several occasions in recent years, they took samples of her saliva, blood, urine, and stool to perform a multi-omic analysis. The neologism refers to a set of molecular biology tools. The best known is the analysis of her genome; also popular is the study of her microbiome. Less well-known are the transcriptome (the specific expression of genes), the review of her metabolome (the metabolites resulting from cellular function), proteomics (the field dedicated to proteins), and epigenomics, the field in which Esteller’s team excels. The biology of such an elderly person has never been studied in such depth.
“María had a very mild case of Covid, and we may now know some of the reasons for that mildness with this study,” says Esteller. One is that she had “a very powerful immune system, very good defense cells,” he explains. They had a very long memory, recalling all the infections she had in her 117 years. “They were still very efficient at attacking microorganisms, but at the same time, they didn’t attack her own tissues, that is, they didn’t induce the inflammation so typical of autoimmune diseases,” he explains. Aside from the deafness in one ear she lived with from a young age, María aged with the typical mobility issues of the elderly, but in the absence of heart problems, tumors, or neurodegenerative diseases.
And yet the first results of this multi-omic analysis of María revealed that the dark side of old age was lurking. One of the markers most closely linked to aging is the length of telomeres, the caps that protect the ends of chromosomes. María’s telomeres were up to 40% shorter compared to a sample of people of all ages. “They were like the tip of a worn-out pencil, with almost nothing left. But despite that, her health was good. This allows us to deduce that telomeres indicate the passage of time, but not the poor health associated with the passage of time,” Esteller emphasizes. This work doesn’t invalidate the connection between telomeres and aging, but it does clarify it. “They’re a stopwatch; they indicate chronological age, that is, she was born in a certain year. But not biological age,” Esteller concludes. Epigenomics is responsible for this.
As can be seen in the photograph below, María didn’t look her age. And this isn’t a subjective impression. “If you give me your DNA, I can determine your age thanks to some chemical markers on it.” This is how Eloy Santos, a researcher at the Josep Carreras Leukemia Research Institute and lead author of the study, explains what epigenetic clocks are. Already used in forensic science to determine the age of a victim or their killer, in María’s case they used half a dozen of them. “None of the epigenetic clocks, regardless of the tissue, matched her age. None could in any way predict that this woman was 116 years old,” comments Santos, the member of Esteller’s group who visited María the most. The average obtained from these markers indicated that her biological age was 23 years younger than what her Spanish ID card indicated.
The study of her microbiome confirms this biological youth. By comparing the profile of her gut microbiota, now known to be closely linked to physical and mental health, with that of a sample of hundreds of people up to 91 years old, the researchers found it comparable to that of a young person, almost an adolescent. They also found that she maintained a very efficient cholesterol and lipid metabolism. “She had no alterations in her arteries; her pipes were very clean,” Esteller adds. To complete the profile, they detected that she had exceptional mitochondrial function. Mitochondria are responsible for cellular respiration and “in María’s case, they were very good machines for eliminating free radicals and oxidation,” they concluded.
Iñaki Martin-Subero, a researcher at the Catalan Institution for Research and Advanced Studies and head of the Biomedical Epigenomics group at IDIBAPS in Barcelona, was not involved in the study of María Branyas’ samples. However, he was familiar with the work of Esteller and his team, which involved scientists from around 20 institutions. “It’s an extremely comprehensive study,” he acknowledges. “With problems like such short telomeres or such accelerated DNA methylation, she wouldn’t have reached 117 years of age if she didn’t have a strong immune system or a microbiome to compensate for the other factors,” he adds. Martín-Subero also highlights elements that aren’t so easily read in genes, proteins, or mitochondria. With the healthy lifestyle she led or all the emotions she must have gone through losing so many relatives, “she had to be a very balanced person, stress-free; it’s not so much what you experience, but how you cope with it.”
Martín-Subero sees a limitation to the work, one that the authors already acknowledge, but essential nonetheless: “The sample is N=1, meaning it sheds light on how María lived so long, but we can’t say that about other centenarians; for that, we would have to study more and from the same environment.” The problem is that there aren’t enough supercentenarians to study. “Cases like María’s are so extraordinary that each of them could have reached such an advanced age through their own path,” he adds, as several other studies have pointed out. The researcher notes another limitation: “Despite being very comprehensive, the study includes data from four types of samples, but not others.” Martín-Subero is referring to María’s tissues or organs. Here, ethics prevailed over scientific interest.
“During her lifetime, we extracted samples that would cause the least possible disturbance to her, including saliva, blood, urine, and feces. We didn’t study anything that would cause excessive disturbance, because it’s one thing for her to be generous and lend her samples for study, and another thing to take advantage,” Santos clarifies. He agrees that the work would have gone further if they had analyzed María’s samples after she passed away in her sleep, on August 19, 2024, for example, from the neurons in her brain free of neurodegenerative disorders. “If we didn’t want to disturb her further while she was alive, how could we do it afterward? We didn’t do it out of respect for María and the family,” Santos adds.
Researchers agree on the extraordinary nature of María’s case. Not only because of her biology, but also because of her lack of harmful habits and her great sociability. But Santos doesn’t see this as a limitation; “being so special makes her even more useful to science,” he comments. This usefulness is what led María to allow them to visit and study her. “We have the concept that aging is equivalent to illness and that one thing necessarily goes hand in hand with the other. But this woman has shown us that, to a certain extent, this doesn’t have to be the case.”
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