GOTHENBURG — Researchers from Leiden University Medical Center presented findings from an intergenerational aging study at the annual conference of the European Society of Human Genetics in Gothenburg. The research connected rare CGAS gene variants with an extended healthspan.

Life expectancy has increased over the last two centuries, but healthspan has not risen at the same pace. Survival into extremely old age is hereditary and correlates with a delayed onset of chronic health conditions. Middle-aged family members with long-lived parents experienced cardiometabolic disease onset 13 years later compared to partners whose parents lived shorter lives.

Pasquale Putter, a final-year doctoral student in Professor Eline Slagboom's research group at Leiden University Medical Center, stated, "This made it clear that their longer healthspan was passed down to subsequent generations." Researchers scanned the genomes of 212 groups of long-lived sibling pairs from the Leiden Longevity Study. This genomic analysis identified four regions that likely contain longevity genes.

He said, "This meant that we could restrict our focus to 350 genes rather than around 20,000." Researchers identified 12 rare protein-altering genetic variants within those genomic regions that may influence longevity. One of these 12 variants mapped to the CGAS gene and was found in two long-lived families. The CGAS gene produces an inflammatory response when DNA from a viral infection or cellular damage is detected inside a cell.

Putter stated, "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, thereby contributing to the protective mechanisms that enable extended healthspan and survival." Complete suppression of the CGAS pathway may increase susceptibility to infections and cancers, while chronic over-activation of the pathway can lead to sustained tissue damage from inflammation.

Researchers plan to conduct in vivo studies by introducing the CGAS mutation into killifish at the Max Planck Institute for the Biology of Ageing. Putter said, "Killifish are the shortest-lived vertebrates, with a natural lifespan of between three to nine months." He added that using killifish as a model would enable researchers to determine whether the mutation contributes to increased lifespan when compared with control groups, and also to investigate its health effects in tissues.

He said, "We also intend to follow up on our research by investigating other promising candidate longevity variants that we identified in the Leiden Longevity Study through collaborations with other groups." Professor Alexandre Reymond, who chairs the European Society of Human Genetics conference, said, "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."