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By Maria Azzurra Volpe
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A long life is not always the same as a healthy one. Many people now live far beyond the ages reached by previous generations, but those extra years can come with chronic illness, cognitive decline or frailty. That gap between lifespan and healthspan is one of the biggest questions facing aging research.
Now, scientists studying families with unusually long-lived members say the clues to healthier aging may be found not just in individuals, but across generations.
New research being presented at the annual conference of the European Society of Human Genetics in Gothenburg has focused on long-lived families taking part in the Leiden Longevity Study. Rather than looking only at people who reached exceptional ages, researchers examined groups of siblings from families where longevity appeared to cluster.
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The approach matters because aging is shaped by more than DNA. Lifestyle, socioeconomic background, behavior and environment can all influence whether someone develops disease earlier or remains healthy for longer. That makes it difficult to separate inherited protection from the circumstances people live in.
But family patterns can help researchers narrow the search.
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Pasquale Putter, a final-year PhD student in Professor Eline Slagboom’s group at Leiden University Medical Center in the Netherlands, said earlier work from the team showed a striking difference between people from long-lived families and their partners.
Middle-aged adults with long-lived parents developed cardiometabolic diseases an average of 13 years later than partners whose parents had shorter lifespans. “This made it clear that their longer healthspan was passed down to subsequent generations,” he said.
To look for possible genetic explanations, the researchers analyzed the genomes of 212 groups of long-lived siblings. That allowed them to identify four regions of the genome likely to contain genes associated with longer life.
“This meant that we could restrict our focus to 350 genes rather than around 20,000,” Putter said.
Further analysis pointed to 12 rare protein-altering genetic variants that may be involved in helping people live longer, healthier lives. One variant, found in two long-lived families, was in a gene called CGAS, which has previously been linked to aging.
CGAS plays a role in inflammation. It helps trigger the body’s response when DNA is detected in the wrong place inside a cell, something that can happen during infection or when cells are damaged. The researchers believe the variant may reduce the inflammatory response without shutting it down entirely.
“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,” Putter said.
That balance is important. The researchers caution that completely blocking the CGAS pathway could increase vulnerability to infections and cancer, while too much activation may contribute to chronic inflammation and tissue damage.
The next step is to test the mutation in killifish, short-lived vertebrates with natural lifespans of three to nine months.
“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,” Putter said.
Professor Alexandre Reymond, chair of the conference and not involved in the research, said the findings may help scientists focus on 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,” Reymond said.
For families who seem to age more slowly than others, the explanation is unlikely to be simple. But this research suggests that rare inherited changes may help reveal why some people not only live longer, but stay healthier for longer too.
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