Although life expectancy has risen dramatically over the past 200 years, the number of years people spend in good health has not increased at the same pace. Researchers have long known that exceptional longevity (longevity) often runs in families and is linked to a later onset of chronic illnesses. However, the genetic factors that help protect these families remain poorly understood.

Most previous studies have focused on the genetics of individual people who live long lives. 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. (A person's healthspan is the number of years they live free from chronic disease and cognitive decline).

Why Family Studies Matter

Studying families offers an important advantage because longevity is influenced by many factors beyond genetics. Socioeconomic status, lifestyle, behavior, and environmental influences all play major roles in determining both lifespan and healthspan. As a result, some people from families with average life expectancy may still live exceptionally long lives, while others from long-lived families may not.

Presenting findings 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, explained that previous research from the team had already revealed a striking pattern.

Middle-aged individuals with long-lived parents developed cardiometabolic diseases 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.

Searching for Longevity Genes

To investigate further, researchers analyzed the genomes of 212 groups of long-lived sibships (offspring with the same two parents) participating in the Leiden Longevity Study.

The team identified four regions of the genome that appeared likely to contain genes linked to longevity.

"This meant that we could restrict our focus to 350 genes rather than around 20,000," says Mr. Putter.

Additional analysis narrowed the search even further, revealing 12 rare protein-altering genetic variants that may contribute to longer and healthier lives.

A Promising Role for the CGAS Gene

One of those variants was found in the CGAS (cyclic GMP-AMP synthase) gene, which has previously been linked to aging. The variant appeared in two long-lived families included in the study.

CGAS helps trigger inflammation when DNA is detected where it does not belong inside a cell. This can happen during viral infections or when cells are damaged.

"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.

The researchers believe this reduced inflammatory response may help protect against some of the damaging effects associated with aging while preserving the body's ability to defend itself.

"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: Testing the Mutation in Killifish

The scientists caution that much more work is needed before any implications for human health can be determined. The effects of CGAS depend heavily on context.

Completely shutting down the CGAS pathway could make people more vulnerable to infections and cancer. On the other hand, excessive activation of the pathway can lead to chronic inflammation and long-term tissue damage.

To better understand how the mutation functions in a living organism, the researchers are moving from in vitro experiments to in vivo studies. They plan to introduce the CGAS 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," 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."

New Clues to Extending Healthspan

Professor Alexandre Reymond, chair of the conference and not involved in the research, said the findings could help scientists better understand the biology behind healthy aging.

"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."