Rare Genetic Variant in CGAS Gene Linked to Longer Healthspan in Families

Researchers have identified rare genetic variants in families with multiple long-lived members that may contribute to extended healthspan, the period of life free from chronic disease and cognitive decline. This approach focuses on familial longevity rather than individual cases to better isolate inherited genetic factors.

Life expectancy has increased significantly over the past two centuries, but these additional years have not always correlated with improved health. Scientists aim to pinpoint genetic contributors to healthy aging to eventually develop interventions that promote longer periods of good health.

Advantages of Studying Long-Lived Families

Examining individuals who live exceptionally long lives often complicates distinguishing genetic influence from environmental factors such as lifestyle, income, and education. Some individuals from families with average lifespans may reach advanced age, while others from long-lived families may not, making it difficult to separate inherited traits.

Researchers suggest that investigating families exhibiting exceptional longevity across generations offers a clearer opportunity to identify genetic components passed down through inheritance. Mr Pasquale Putter, a PhD student at Leiden University Medical Center, referenced prior research showing that middle-aged adults with long-lived parents developed cardiometabolic diseases 13 years later on average than their partners whose parents had shorter lifespans. He stated, “This made it clear that their longer healthspan was passed down to subsequent generations.”

Identification of Rare Genetic Variants

The research team analyzed genomes from 212 groups of siblings with long-lived parents enrolled in the Leiden Longevity Study. They concentrated on four genomic regions most likely to contain longevity-related genes, narrowing their focus to approximately 350 genes instead of the entire genome of around 20,000 genes, according to Mr. Putter.

This targeted analysis revealed 12 rare protein-altering genetic variants within those regions that could be linked to longer and healthier lives.

CGAS Gene Variant and Its Role in Longevity

Among the significant findings was a variant in the CGAS (cyclic GMP-AMP synthase) gene, previously associated with aging. This variant appeared in two long-lived families. CGAS plays a role in initiating the body's inflammatory response when DNA is detected inside a cell where it should not be, such as during viral infections or cellular damage.

Mr. Putter explained, “It is likely that members of these families had only one active copy of the CGAS gene, rather than two, which would have reduced their inflammatory response while still allowing sufficient clearance of infections and repair of damage. This mechanism may contribute to extended healthspan and survival.” He added, “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 involving rare mutations. We have been surprised by the magnitude of the effect of the CGAS mutation in the in vitro experiments we have carried out to date.”

Future Research on CGAS Mutation Effects

The researchers caution that these findings are preliminary and that the effects of CGAS depend heavily on biological context. Completely inhibiting the CGAS pathway could increase vulnerability to infections and cancer, while excessive activation may cause chronic inflammation and tissue damage. Therefore, further research is necessary before considering medical applications.

The team is preparing in vivo experiments at the Max Planck Institute for the Biology of Ageing in Cologne, Germany. They will introduce the CGAS mutation into killifish, the shortest-lived vertebrates with lifespans between three and nine months, to assess whether the mutation extends lifespan and affects tissue health compared to control groups. Mr. Putter said, “Using killifish as a model will enable us to determine whether the mutation contributes to increased lifespan and to investigate its health effects in tissues.”

Additionally, the researchers plan to pursue other candidate longevity variants identified in the Leiden Longevity Study through collaborations with other groups.

Implications for Aging Research

Professor Alexandre Reymond, chair of the European Society of Human Genetics conference and not involved in the study, remarked that the findings could have broad implications for aging research. He noted, “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.”