Aging reflects which parts of DNA a cell protects as disorder spreads: Unity Biotechnology co-founder compares a long-lived tortoise with dogs and proposes a testable hypothesis about transposons

Aging reflects which parts of DNA a cell protects as disorder spreads: Unity Biotechnology co-founder compares a long-lived tortoise with dogs and proposes a testable hypothesis about transposons

In a thread on X on October 10, Nathaniel David, co-founder of Unity Biotechnology, a biotech company developing drugs to target cellular senescence, compared two recent findings: the stability of some genes in Jonathan, a 194-year-old tortoise, and the loss of control over mobile DNA sequences in large dog breeds. From this comparison, he proposed a general principle of aging and a testable hypothesis about the sequence of events in dogs.

Comparing a mouse with a whale tells us little: they differ in a million ways, making it difficult to identify which differences matter for aging. David instead compares nearly identical animals within a species whose lifespans differ sharply: dogs of different breeds, or Jonathan and other members of his species, which usually live less than a hundred years.

Jonathan’s epigenome is the pattern of chemical marks on DNA that switch genes on and off. An analysis of this pattern found that these marks become disorganized across the genome with age, except at the promoters of genes involved in mitochondrial function, RNA processing, and DNA repair. There, the patterns remain as well defined as in a five-year-old juvenile. Researchers also found extra copies of DNA repair genes in Jonathan, along with ten copies of the perforin gene, compared with seven in another giant tortoise, Lonesome George. Immune cells use perforin to punch holes in a target cell’s membrane; extra copies of the gene may improve the clearance of senescent and cancerous cells.

Dogs show the opposite pattern. An analysis of methylation in breeds of different sizes found that large breeds, which have shorter lifespans than small breeds, lose methylation fastest at transposons. These are DNA sequences that can copy themselves and insert those copies elsewhere in the genome. The loss is greatest at the evolutionarily “youngest” transposons.

David brings the two findings together in one proposition:

Aging is about choosing where to allow disorder, rather than avoiding it altogether.

The tortoise protects genes involved in mitochondrial function and DNA repair, while dogs lose control over transposons first. “Everything deteriorates. What matters is what you protect,” David writes.

Epigenetic clocks, which estimate biological age from methylation patterns, run faster in dogs when they are young than when they are old: a large breed appears epigenetically older than a small breed of the same chronological age. If accumulating damage were driving the clocks, they would be expected to accelerate toward the end of life. David interprets this as a developmental program that keeps running: “Aging looks more like growth that never stops than wear and tear.”

This also underlies his explanation for a longstanding paradox: larger individuals within a species live shorter lives, whereas larger species generally live longer. Within a species, greater size requires more growth with the same budget for tissue repair. Across species, evolution increases the repair budget along with body size, as illustrated by the tortoise’s extra copies of DNA repair genes and the perforin gene.

According to David, each year by which epigenetic age exceeds chronological age raises mortality risk by 2% in humans and 15% in dogs. But dogs live roughly six times shorter lives than humans, so when expressed as a fraction of lifespan, the two figures are equivalent.

David considers the dog study solid and the tortoise study a hypothesis: it compares one animal with four others, and, in his assessment, part of the tortoise paper’s genetic analysis does not support its conclusions. Together, the studies yield a testable prediction: if transposon reactivation causes aging rather than merely marking it, reactivation should precede inflammation and cancer in dogs, with a more pronounced pattern in larger breeds. David proposes that the authors of the same dog study test this prediction.