An international collaboration led by a neurologist and experts in advanced genomics at Vanderbilt Health has coaxed one of the secrets of extreme longevity from a 194-year-old giant tortoise named Jonathan.
Jonathan’s secret involves entropy, the tendency of biological systems to become disordered over time.
One of the hallmarks of aging is mitochondrial dysfunction. It results from increasing entropy, or disorder, in “promoters,” the genetic on-and-off switches that regulate the efficiency of mitochondria, the energy-producing organelles in most animal cells. A reliable supply of cellular energy is essential for many biological processes.
Despite his many years, Jonathan somehow had avoided the toll of entropy. By painstakingly piecing together his genome, the researchers discovered that the promoters of genes involved in mitochondrial energy production retained a remarkably youthful “orderliness.” In this respect, it was as if he had hardly aged at all.
These findings, published Oct. 7 in the journal Science Advances , suggest that it might be possible to protect mitochondria from the aging-related consequences of disordered gene expression, thereby extending a healthy human lifespan — the “healthspan,” according to the paper’s senior and corresponding author, Stephen (Wes) Clark, MD, PhD, MSCI.
For decades, animal studies have hinted at the antiaging potential of certain generic drugs, such as rapamycin , which was developed in 1999 to prevent the rejection of transplanted organs, said Clark, President and Chief Scientist of the Kallel Foundation ( www.kallel.org ), a Nashville-based nonprofit organization focused on longevity research.
Pharmaceutical companies have little financial incentive to conduct clinical trials of these drugs because they no longer have patent protection. Kallel was established, in part, to bypass this commercial bottleneck.
“As a nonprofit, we want to do clinical trials that no drug company wants to do,” Clark said. With sufficient funding, “we could start next year.”
A neuro-oncologist and former Vanderbilt University faculty member, Clark had long wondered why the incidence of tumors of the brain and central nervous system increases until the mid-80s, then stops. Neuroblastomas, for example, rarely occur in people in their 90s. Are extremely elderly people somehow protected from these tumors?
Next-generation sequencing (NGS) technologies, developed about 20 years ago, make it possible to look for answers. These methods can rapidly sequence a body’s entire DNA (the genome) or specific genomic sites with attached, gene-regulating methyl groups.
Methyl groups (-CH3, one carbon atom bonded to three hydrogen atoms) attached to the DNA work like “on-and-off switches” for genes, Clark explained. Genes that are “methylated” are turned off, while those without methyl groups are turned on. Could methylation have something to do with entropy — and aging?
Clark’s scientific odyssey began the moment he heard about Jonathan , widely considered to be the oldest living land animal.
Before this study, Clark said, no one had tried to determine the entropy, or disorder, in the methylation pattern of an animal as old as Jonathan by sequencing its “epigenome,” the body of chemical compounds that regulate gene expression without altering the DNA.
Hatched in about 1832 in the Seychelles (pronounced Say-SHELZ), an Indian Ocean archipelago, Jonathan was brought to St. Helena, a remote volcanic tropical island in the South Atlantic about 1,200 miles west of Angola, in 1882.
The approximately 450-pound tortoise lives with other giant tortoises on the grounds of the Plantation House, the governor’s official residence on the island, which is a British Overseas Territory. Blind from cataracts but retaining excellent hearing, Jonathan has been visited by generations of British royalty, including Queen Elizabeth II.
In 2017, Clark asked St. Helena veterinarian Joe Hollins if he could obtain a blood sample for sequencing. The blood draw request was denied due to concerns about Jonathan’s health, but Hollins was allowed to scrape a small tissue sample from inside the animal’s cheek.
Now Clark had to assemble a team to analyze the tissue and pay for the research. He did that by establishing the Kallel Foundation, which he named for the Swedish-Norse word for spring, as in “eternal spring.”
The Stephen Voland Research Fund, which supports research in neuro-oncology at the Vanderbilt-Ingram Cancer Center, provided $50,000 to finance the study. Voland, an Army veteran and East Tennessee businessman, established the fund with his wife, Terri, before his death in 2012 from a rare form of glioblastoma.
The analysis of Jonathan’s genome and epigenome was led by Benjamin Vaisvil, a scientist affiliated with Kallel, and Daniel Schmitt, of Igenbio Inc., a Chicago-based genomics and bioinformatics company.
Vaisvil and Schmitt are first authors of the Science Advances paper, along with 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 for the study. “Angela, Madison, and the whole team at VANTAGE were key (to) us finishing this paper,” Clark said.
Aided by an international team of experts, including UCLA’s Steve Horvath, PhD, known for developing a methylation-based aging “clock,” the researchers determined that promoters involved in mitochondrial function and RNA processing had “low methylation entropy.”
The resulting “high-fidelity gene expression” in critical pathways partially protected Jonathan from age-related decline, they concluded, mirroring a 2025 study that found “exceptionally efficient mitochondrial function” in a 117-year-old woman.
Additional studies using blood, which yields a more complete and “pristine” DNA sequence, will be needed to validate Jonathan’s “secret.” Clark said the foundation also plans to expand its investigations into other long-lived species and other pathways associated with aging.
Clark has not yet been to St. Helena but is looking forward to meeting Jonathan and perhaps continuing their research collaboration. So far, he said, “It’s been a really amazing journey.”
Science Advances
7-Oct-2026