Rare Genetic Variant Linked to Healthy Aging Discovered in Long-Lived Families
Researchers at Leiden University Medical Center analyzed genomes of long-lived families and identified a rare variant in the CGAS gene that may reduce inflammation and contribute to a longer healthspan.
People age differently. Some remain free of major diseases well into old age, while others develop serious health problems much earlier. Although life expectancy has risen dramatically over the past 200 years, the number of years spent in good health has not increased at the same pace. Researchers have long known that exceptional longevity often runs in families and is linked to a later onset of chronic illnesses, but the genetic factors that help protect these families remain poorly understood.
New research being presented at the annual conference of the European Society of Human Genetics in Gothenburg suggests that studying entire long-lived families may provide a clearer picture of the biological mechanisms that support a longer healthspan. The study, led by Pasquale Putter, a PhD student in Prof. Eline Slagboom's group at Leiden University Medical Center, analyzed the genomes of 212 groups of long-lived siblings from the Leiden Longevity Study. The team identified four genomic regions likely to contain longevity-related genes, and further analysis narrowed the search to 12 rare protein-altering genetic variants.
One of those variants was found in the CGAS (cyclic GMP-AMP synthase) gene, previously linked to aging. This variant appeared in two long-lived families. CGAS helps trigger inflammation when DNA is detected in the wrong place inside a cell, such as during viral infections or cell damage. The researchers believe that members of these families likely have only one active copy of the CGAS gene, reducing the inflammatory response while still being sufficient to clear infections and repair damage, thereby contributing to protective mechanisms that enable extended healthspan and survival.
The scientists caution that much more work is needed before implications for human health can be determined. Completely shutting down the CGAS pathway could make people more vulnerable to infections and cancer, while excessive activation can lead to chronic inflammation and long-term tissue damage. To better understand the mutation's function in a living organism, the researchers plan to introduce the CGAS mutation into killifish at the Max Planck Institute for the Biology of Ageing in Germany. Killifish are the shortest-lived vertebrates, with a natural lifespan of three to nine months, allowing the team to test whether the mutation increases lifespan and affects tissue health.
Professor Alexandre Reymond, chair of the conference and not involved in the research, said the findings help scientists zoom in on factors tied to longevity and point to key elements that may extend the healthspan of all people.
