The study, published October 7 in the journal Science Advances, was led by Stephen (Wes) Clark, MD, PhD, MSCI, a neuro-oncologist and former Vanderbilt University faculty member who now serves as President and Chief Scientist of the Kallel Foundation, a Nashville-based nonprofit focused on longevity research. Working with experts in advanced genomics at Vanderbilt Health and collaborators around the world, the team set out to answer a deceptively simple question: what does the genome of an animal that has lived nearly two centuries look like, and can it reveal why some organisms resist the ravages of time while others do not?

The answer, according to the researchers, lies in one of the most fundamental concepts in physics and biology: entropy. Entropy is the tendency of ordered systems to drift toward disorder over time, and living organisms are not exempt from this drift. One of the hallmarks of aging is mitochondrial dysfunction, a breakdown in the efficiency of mitochondria, the tiny energy-producing organelles found in most animal cells. A reliable supply of cellular energy is essential for virtually every biological process, so when mitochondria falter, tissues and organs falter with them.

The Vanderbilt-led team focused on a specific mechanism by which entropy invades the aging cell. Promoters, the genetic on-and-off switches that regulate how efficiently mitochondria operate, accumulate disorder as an animal ages. This disorder manifests in methylation patterns, the chemical tags attached to DNA that act like switches for gene expression. Methyl groups, each consisting of one carbon atom bonded to three hydrogen atoms, silence genes when attached, while genes lacking these tags remain active. Over decades, the precise placement of these molecular switches degrades, and gene regulation becomes increasingly noisy and unreliable.

By painstakingly piecing together Jonathan’s genome and epigenome, the researchers discovered something remarkable. Despite his many years, the promoters of genes involved in mitochondrial energy production had retained a strikingly youthful orderliness. In technical terms, these promoters displayed low methylation entropy, meaning the chemical switches governing critical energy-production pathways had not degraded into the chaotic patterns typically seen in aged animals. The result, the team concluded, was high-fidelity gene expression in pathways essential to life, which partially protected Jonathan from the age-related decline that afflicts other organisms. In this respect, it was as if he had hardly aged at all.

The findings echo a 2025 study that documented exceptionally efficient mitochondrial function in a 117-year-old woman, suggesting that the preservation of orderly gene regulation in energy pathways may be a shared signature of extreme longevity across very different species. According to Clark, the senior and corresponding author of the new paper, the results suggest it might one day be possible to protect human mitochondria from the aging-related consequences of disordered gene expression, thereby extending the healthspan, the portion of life spent in good health rather than merely adding years.

Clark’s scientific odyssey began the moment he heard about Jonathan, but his curiosity about the biology of extreme old age had deeper roots. As a neuro-oncologist, he had long wondered why the incidence of tumors of the brain and central nervous system rises steadily until the mid-80s and then abruptly stops. Neuroblastomas, for example, rarely occur in people in their 90s. He asked whether extremely elderly people might somehow be protected from these tumors, and whether the answer could be found in the epigenome, the body of chemical compounds that regulates gene expression without altering the underlying DNA sequence. Before this study, no one had attempted to measure the entropy of methylation patterns in an animal as old as Jonathan by sequencing its epigenome.

Getting a sample from a 194-year-old national treasure was no small feat. In 2017, Clark asked St. Helena veterinarian Joe Hollins whether a blood sample could be obtained for sequencing. The blood draw was denied out of concern for Jonathan’s health, but Hollins was permitted to scrape a small tissue sample from inside the animal’s cheek. That modest specimen became the foundation of the entire project. To analyze it and fund the work, Clark established the Kallel Foundation, named for the Swedish-Norse word for spring, as in eternal spring. The Stephen Voland Research Fund, which supports neuro-oncology research at the Vanderbilt-Ingram Cancer Center and was created by Army veteran and East Tennessee businessman Stephen Voland and his wife Terri before his death in 2012 from a rare form of glioblastoma, provided $50,000 to finance the study.

The genomic and epigenomic analysis was led by Benjamin Vaisvil, a scientist affiliated with Kallel, and Daniel Schmitt of Igenbio Inc., a Chicago-based genomics and bioinformatics company, who served as first authors alongside Angela Jones, Core Manager for NGS Services at VANTAGE, Vanderbilt Technologies for Advanced Genomics, Vanderbilt Health’s shared resource for genomic investigation. Jones and her colleague Madison Taylor led the DNA and epigenetic sequencing. Aided by an international team of experts, including Steve Horvath, PhD, of UCLA, renowned for developing a methylation-based aging clock, the researchers determined that promoters involved not only in mitochondrial function but also in RNA processing showed low methylation entropy, preserving the fidelity of gene expression in multiple critical pathways.

The research also carries a practical ambition. For decades, animal studies have hinted at the antiaging potential of generic drugs such as rapamycin, which was developed in 1999 to prevent the rejection of transplanted organs. But pharmaceutical companies have little financial incentive to run clinical trials of drugs that no longer enjoy patent protection. Kallel was established in part to bypass this commercial bottleneck. As a nonprofit, Clark said, the foundation wants to conduct the clinical trials that no drug company wants to do, and with sufficient funding, those trials could begin as early as next year. Additional studies using blood, which yields a more complete and pristine DNA sequence than cheek tissue, will be needed to fully validate Jonathan’s secret, and the foundation plans to expand its investigations into other long-lived species and other aging-related pathways. Clark, who has not yet visited St. Helena, looks forward to meeting the ancient tortoise in person and perhaps continuing their collaboration. So far, he said, it has been a really amazing journey, one that began with a cheek scraping from a blind but sharp-eared tortoise who has been visited by generations of British royalty, including Queen Elizabeth II, and who may yet teach humanity how to grow old without falling apart.

Subject of Research: Epigenomic analysis of methylation entropy in the world's oldest living land animal, a 194-year-old giant tortoise, to understand mitochondrial aging and extreme longevity

Article Title: An extremely old giant tortoise named Jonathan May hold the secret to a long, healthy life: Study

Article References: An extremely old giant tortoise named Jonathan May hold the secret to a long, healthy life: Study. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: Jonathan the tortoise, longevity, aging, epigenetics, methylation entropy, mitochondria, gene expression, healthspan, genomics, Science Advances, Vanderbilt University Medical Center, rapamycin