Long-Lived Families Reveal Rare CGAS Gene Variant Linked to Extended Healthspan
Key Insights
Researchers analyzing genomes of 212 long-lived sibling groups in the Leiden Longevity Study identified 12 rare protein-altering genetic variants potentially linked to healthier aging.
One variant in the CGAS (search) gene, found in two long-lived families, may reduce inflammatory response while preserving immune defense, contributing to extended healthspan.
Middle-aged individuals with long-lived parents developed cardiometabolic diseases (search) an average of 13 years later than partners whose parents had shorter lifespans.
A new study from the Leiden University Medical Center (search) has identified a rare genetic variant in the CGAS (search) gene that may help explain why some families enjoy not just longer lives, but longer healthy lives. The findings, presented at the annual conference of the European Society of Human Genetics in Gothenburg, emerge from an intergenerational approach that examined entire families rather than isolated long-lived individuals.
The research builds on the Leiden Longevity Study, which has tracked families where exceptional longevity appears to cluster across generations. Pasquale Putter, a final-year PhD student in Professor Eline Slagboom's group, reported that middle-aged adults with long-lived parents developed cardiometabolic diseases (search) an average of 13 years later than their partners whose parents had shorter lifespans. "This made it clear that their longer healthspan was passed down to subsequent generations," Putter said.
Narrowing the Genetic Search
To identify the genetic underpinnings of this inherited protection, the team analyzed the genomes of 212 groups of long-lived siblings. This family-based approach allowed researchers to pinpoint four regions of the genome likely to contain genes associated with longevity.
"This meant that we could restrict our focus to 350 genes rather than around 20,000," Putter explained. Further analysis narrowed the search to 12 rare protein-altering genetic variants that may contribute to longer, healthier lives.
The CGAS (search) Variant and Inflammation
One variant, identified in two long-lived families, resides in the CGAS (search) (cyclic GMP-AMP synthase) gene, which has previously been linked to aging. CGAS plays a central role in inflammation by triggering the body's immune response when DNA is detected in the wrong location inside a cell — a scenario that can occur during viral infections or when cells sustain damage.
The researchers hypothesize that the variant reduces the inflammatory response without eliminating it entirely. "It is likely that members of these families had only one active copy of the CGAS (search) 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, thereby contributing to the protective mechanisms that enable extended healthspan and survival," Putter said.
This balance is critical. The scientists caution that completely blocking the CGAS (search) pathway could increase vulnerability to infections and cancer, while excessive activation may contribute to chronic inflammation and long-term tissue damage.
Why Family Studies Matter
Studying families offers a distinct advantage in longevity research. Aging is shaped by more than DNA — socioeconomic status, lifestyle, behavior, and environmental influences all play major roles in determining both lifespan and healthspan. As a result, some individuals from families with average life expectancy may still live exceptionally long lives, while others from long-lived families may not. The family-based approach helps researchers disentangle inherited genetic protection from the circumstances in which people live.
"We hope that taking this family approach will help us to untangle some of the environmental factors from those that are truly genetic, particularly those where rare mutations are involved," Putter said. "We have been surprised by the magnitude of the effect of the CGAS (search) mutation in the in vitro experiments we have carried out to date."
Next Steps: From Cells to Killifish
The research team is now moving from in vitro experiments to in vivo studies. They plan to introduce the CGAS (search) mutation into killifish at the Max Planck Institute for the Biology of Ageing in Cologne, Germany.
"Killifish are the shortest-lived vertebrates, with a natural lifespan of between three to nine months. Using them as a model will enable us to determine whether the mutation contributes to increased lifespan when compared with control groups, and also to investigate its health effects in tissues," Putter said.
The team also intends to investigate other promising candidate longevity variants identified in the Leiden Longevity Study through collaborations with other research groups.
Professor Alexandre Reymond, chair of the conference who was not involved in the research, underscored the broader significance of the work. "These findings allow our community to zoom in on factors tied to longevity and, more importantly, they point to what maybe are key elements to extend the healthspan of all," Reymond said.