Leicester experts uncover secrets of healthy ageing from the world’s oldest person

Scientists have studied the genetics and lifestyle factors that enabled María Branyas, officially the oldest person in the world until she died last year, to reach 117 years old.

Researchers funded by the NIHR Leicester BRC at the University of Leicester’s van Geest Multi-Omics Facility carried out an analysis of thousands of proteins circulating in the blood of this exceptionally long-lived individual.  By comparing her protein profile with those of other women across different age groups, the Leicester researchers could see what was unique about her biology.

Between 17 January 2023 and 19 August 2024, María Branyas, of Spain, was officially the world’s oldest person, until she died aged 117 years and 168 days. To uncover the secrets of her extraordinary longevity, a team of researchers has done a deep dive into her genetics, proteomics, epigenetics, microbiome and lifestyle. The findings have now been published in Cell Reports Medicine.

When María was 116 years old, the team collected samples of her blood, saliva and stool, to analyse her genetics.

“She had an exceptional genome enriched in variants in genes that are associated with enhanced lifespan in other species, such as dogs, worms and flies,” says team leader Manel Esteller at the Josep Carreras Leukaemia Research Institute in Barcelona, Spain.

María, who showed no sign of dementia, also had many gene variants that keep blood lipid levels low, protecting the heart and cognition, says Esteller.

“At the same time, she was devoid of gene variants associated with the risk of pathologies such as cancer, Alzheimer’s and metabolic disorders.”

Blood test results also revealed that her lipid metabolism was among the most efficient ever reported, according to the researchers.

“Her lipid profile was amazing, with very low cholesterol,” says Esteller.

“This was related to her frugal diet and genes that quickly metabolised damaging molecules.”

Esteller says María didn’t drink alcohol or smoke, and adhered to a Mediterranean diet, made up of lots of vegetables, fruits, legumes and olive oil. She also ate three servings of plain, sugar-free yoghurt every day.

The team’s tests also suggest that María retained an efficient immune system into old age and a gut microbiome characteristic of a much younger individual.

The collaboration with Leicester began when Professor Esteller approached Professor Salvador Macip, from Leicester’s Division of Molecular and Cell Biology, to contribute to the multiomics study.

Julia Bonet, a PhD student from Professor Macip’s group spent six months training and working in the mass spectrometry laboratory at the University of Leicester’s van Geest Multi-Omics Facility.   

Afterwards, Leicester’s Dr Thong Cao was contacted to work on the rare plasma samples from a 116-year-old woman (one of the oldest people ever documented).

Dr Cao said: "Because of our established expertise, we were asked to carry out the proteomics analysis. I then met with the first author, Dr Eloy Santos, to plan the work, and the samples were sent to us for detailed analysis using mass spectrometry at the Leicester van Geest Multi-Omics Facility.

"Our role was to use advanced mass spectrometry to study thousands of proteins circulating in the blood of this exceptionally long-lived individual. Proteins are the molecular ‘workhorses’ of the body and provide important clues about health and disease. By comparing her protein profile with those of other women across different age groups, we could see what was unique about her biology.

 The Leicester analyses helped uncover that: 

• Her blood proteins suggested a very low level of inflammation, which is unusual at such an advanced age and is often linked to healthier ageing

• Observed signs of strong lipid and cholesterol transport systems: essentially, her body was very efficient at handling fats, which may have protected her cardiovascular health

• The data also revealed enhanced detoxification and antioxidant responses that suggest her body had powerful mechanisms to counteract cellular stress

• Altogether, these patterns pointed towards biological pathways that could help explain why she remained healthy into extreme old age

Dr Cao added: "It was a privilege for Leicester to be part of this unique international study. Using our state-of-the-art proteomics facility, we were able to uncover biological signatures in the blood of one of the world’s oldest women that pointed to unusually low inflammation and strong protective mechanisms. These findings highlight how Leicester’s expertise in mass spectrometry can contribute to understanding the biology of healthy ageing.”

Further findings

Researchers also discovered high levels of Actinobacteriota bacteria in María's gut, including the well-known probiotic Bifidobacterium. This typically declines with age, but is elevated in centenarians and supercentenarians, and it is thought to have multiple anti-ageing benefits, such as reducing inflammation.

The team suspects her yoghurt consumption helped continuously replenish her Bifidobacterium levels. 

“It shows that maybe a dietary intervention can be associated not only with avoiding obesity and other pathologies, but also with prolonged life, acting through the microbiome gut landscape,” says Esteller.

Finally, the scientists tried to gauge whether María biological age differed substantially from her chronological age. This was done by creating an epigenetic clock based on her DNA methylation – the process in which DNA adds or removes chemical tags that help switch various genes on and off. 

“Her biological age was an average 23 years younger than her chronological age, one of the reasons that she was alive,” says Esteller.

Previous research suggests that supercentenarians can have genetic variants associated with various medical conditions, such as Alzheimer’s disease or heart problems, but somehow have the means to endure them, leading to a long life.

“Very few studies are available for supercentenarians. In these [previous ones], only one dimension is studied - the microbiome,” says Esteller.

“Our study shows that overcoming such diseases is a combination of good genes plus the other factors: [a] beneficial microbiome, slowed-down biological age shown by a younger epigenome and an efficient immune system, plus the behaviour part – no smoking, no alcohol, low-fat diet.”

Richard Faragher at the University of Brighton in the UK says the study demonstrates how many tests are now available to longevity researchers, but cautions that this is a case report of one individual and there is a “danger that a slightly unusual variant in, for example, a gene can be turned into a scientific ‘just-so story’ about its relevance to ageing."

Instead, he says there are two main explanations for the survival of very long-lived individuals.

“Firstly, that there is something special about them, for example genetically, and secondly, survivorship bias, aka they got lucky,” says Faragher.

To offer proof against her longevity just being luck, there would need to be evidence that María is part of a family in which people are known to be long lived, which isn’t presented in this study, he says.