By studying long-lived families, scientists have uncovered a rare genetic clue that may help explain why some people stay healthier and live longer than others.
Scientists are uncovering new clues about why some people remain healthy well into old age while others develop chronic illnesses much earlier. A new study suggests that looking at families with multiple long-lived members, rather than studying individuals alone, may reveal rare genetic changes that help extend healthspan, the years a person lives free from chronic disease and cognitive decline.
Life expectancy has risen dramatically over the past two centuries, but those extra years have not always been accompanied by better health. Researchers hope that identifying the genetic factors behind healthy aging could eventually lead to new ways to help more people stay healthier for longer.
The findings were presented at the annual conference of the European Society of Human Genetics in Gothenburg.
Why Long-Lived Families Offer Unique Insights
Studying individual people who live exceptionally long lives can make it difficult to separate the effects of genetics from lifestyle, income, education, and other environmental influences. Some people from families with average lifespans may still live to an advanced age, while others from long-lived families may not.
Researchers believe that examining families in which exceptional longevity spans multiple generations offers a better opportunity to identify inherited genetic factors.
Presenting results from the intergenerational aging study, Mr Pasquale Putter, a final-year PhD student in Prof. Eline Slagboom’s group at Leiden University Medical Center in Leiden, The Netherlands, pointed to earlier research showing that middle-aged adults with long-lived parents developed cardiometabolic disease 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,” he says.
Rare Gene Variants Linked to Longevity
To search for genetic clues, the team analyzed the genomes of 212 groups of long-lived sibships (offspring with the same two parents) enrolled in the Leiden Longevity Study.
The researchers narrowed their search to four regions of the genome where longevity-related genes were most likely to be located.
“This meant that we could restrict our focus to 350 genes rather than around 20,000,” says Mr. Putter.
Additional analysis uncovered 12 rare protein-altering genetic variants within those regions that could contribute to longer, healthier lives.
CGAS Gene Emerges as a Promising Candidate
One of the most intriguing discoveries involved the CGAS (cyclic GMP-AMP synthase) gene, which earlier research has already linked to aging.
The newly identified variant was found in two long-lived families. CGAS helps trigger the body’s inflammatory response when DNA appears where it should not inside a cell, such as during a viral infection or after cellular damage.
“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,” Mr. Putter says.
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 where rare mutations are involved. 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.”
Next Step Is Testing the Gene in Living Animals
The researchers caution that the findings are still at an early stage and that the health effects of CGAS depend heavily on context.
Completely blocking the CGAS pathway could leave the body more vulnerable to infections and cancer, while excessive activation of the pathway can drive chronic inflammation and tissue damage. Because of this balance, more research is needed before any medical applications can be considered.
The team is now 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 to see whether the changes observed in laboratory experiments also occur in a living organism.
“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,” says Mr. Putter.
“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, chair of the conference and not involved in the study, said the work could have broad implications for aging research.
“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.”
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