Pasquale Putter was poring over genetic data from 212 sibling groups in Leiden when he spotted something extraordinary: a rare mutation in the CGAS gene, shared by two families whose members routinely lived into their 90s and beyond—healthy and free of chronic disease well past the age most people begin to decline. At Leiden University Medical Center, Putter and his team have uncovered compelling evidence that a longer healthspan—the period of life spent in good health—is not just a matter of luck or lifestyle, but can be inherited through rare genetic variants. With life expectancy rising globally but the quality of those extra years lagging, this research offers a powerful glimpse into how we might not only live longer, but stay healthier for longer.
The study focused on families from the Leiden Longevity Study, where earlier work had already shown that middle-aged children of long-lived parents developed cardiometabolic diseases like type 2 diabetes and heart disease a full 13 years later than their peers whose parents died younger. That striking delay pointed to a heritable shield against aging—one that couldn’t be explained by wealth, diet, or exercise alone. By zeroing in on families rather than individuals, the researchers could filter out environmental noise and isolate the genetic signals that truly matter. Scanning the genomes of long-lived siblings, they identified four key genomic regions likely to harbor longevity genes, narrowing their search from 20,000 genes down to just 350.
Within those regions, they found 12 rare protein-altering genetic variants, one of which landed squarely in the CGAS gene—a known player in inflammation and cellular aging. In two long-lived families, individuals carried only one functional copy of CGAS, suggesting a dampened inflammatory response. This may sound counterintuitive, but chronic inflammation is a major driver of age-related disease. A quieter CGAS response could mean less cellular damage over time, without compromising the body’s ability to fight infections. "It is likely that members of these families had only one active copy of the CGAS gene, rather than two, and that this will have reduced the inflammatory response in their bodies, while still being sufficient to clear infections and repair damage," Putter explains.
Now, the team is testing this hypothesis in killifish—tiny vertebrates with a lifespan of just three to nine months—at the Max Planck Institute for the Biology of Aging in Cologne. By introducing the CGAS mutation, they hope to see if the same protective effects observed in cells translate to whole organisms. If so, it could open new pathways for therapies that mimic this natural genetic advantage. While complete suppression of CGAS could be dangerous, fine-tuning its activity might offer a way to extend healthspan across the population. For a world where more of us are living longer, but not necessarily healthier, that balance could be everything.