People age at different rates. Some reach very old age without serious illness, while others develop significant health problems much earlier. As the global population grows older, the need to understand why this happens is increasing.
Life expectancy has risen sharply over the past 200 years, but the number of years people live in good health has not increased at the same pace. Researchers have long known that exceptional longevity tends to run in families and is associated with later onset of chronic disease. Still, it is not fully clear which genetic factors protect these families.
Healthy aging is not measured only by how long a person lives. According to the World Health Organization, it is primarily defined by the ability to maintain function and well-being in older age, meaning the capacity to live actively, independently and meaningfully for as long as possible. As a result, the question driving aging research today is not only how to extend life, but how to extend the years in which the body and mind continue to function well.
So far, most studies have focused on identifying what is unique in the genetics of individuals who live to very old ages. A new study, presented this week at the annual meeting of the European Society of Human Genetics in Gothenburg, suggests taking a broader family-based approach: examining entire long-lived families may help better understand which biological factors allow some people to enjoy more “healthy years,” meaning years without chronic disease or cognitive decline.
Why does it run in families?
Longevity is not determined by genes alone. Socioeconomic status, lifestyle, behavior and environment all influence both lifespan and healthspan. As a result, some people from families with average life expectancy may live unusually long lives, while others from long-lived families may not.
Pascal Potter, a doctoral researcher in the group of Professor P. Eline Slagboom at the Leiden University Medical Center in the Netherlands, said previous research by the team has already shown a striking pattern: middle-aged individuals whose parents lived longer developed cardiometabolic diseases — conditions related to the heart and metabolism — on average 13 years later than their peers whose parents died younger. “It made clear to us that longer healthy years are also passed on to the next generation,” Potter said.
The mutations found in the study may shed light on the link between genetics and healthy aging
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To explore this further, researchers analyzed the DNA of 212 sibling groups from long-lived families. They identified four regions in the genome that likely contain genes associated with long life. “It meant we could narrow the search to just 350 genes instead of spreading it across about 20,000,” Potter explained. Further analysis reduced the list even more, revealing 12 rare genetic mutations that may contribute to longer and healthier lives.
The gene that activates the body’s alarm system
One of these mutations was found in a gene known as CGAS, which has previously been linked to aging processes. It appeared in two long-lived families included in the study. The gene helps trigger an inflammatory response when DNA is detected where it should not be inside a cell, a situation that can occur during viral infection or when a cell is damaged.
“It is likely that members of these families had only one active copy of the gene instead of two,” Potter added. “This reduced inflammation in their bodies, while still being sufficient to deal with infections and repair damage, and thus contributed to defense mechanisms that enable longer healthy years and extended lifespan.” According to the researchers, a reduced inflammatory response may help protect the body from some aging-related damage without undermining its natural ability to defend itself.
“We hope this family-based approach will help us separate environmental factors from those that are truly genetic, especially when it comes to rare mutations,” Potter said. “We were surprised by the strength of the effect of the CGAS gene mutation in the laboratory experiments we have conducted so far.”
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However, the researchers stress that much more work is needed before conclusions can be drawn about human health. The gene’s effects appear highly context-dependent: fully shutting down the CGAS pathway could make people more vulnerable to infections and cancer, while excessive activity could lead to chronic inflammation and long-term tissue damage.
To better understand how the mutation functions in a living organism, the researchers are now moving from lab experiments to in vivo studies. Next, they plan to introduce the mutation into killifish at the Max Planck Institute for Biology of Ageing in Cologne, Germany. “Killifish are the shortest-lived vertebrates, with a natural lifespan of only three to nine months. Using them will allow us to test whether the mutation truly contributes to extended lifespan compared with a control group, and to study its health effects across different tissues.”
In addition, the research team plans to continue investigating other promising mutations identified in the study, in collaboration with additional research groups. Professor Alexandre Reymond, chair of the conference, said the findings may help scientists better understand the biology behind healthy aging. “These discoveries allow the scientific community to focus on factors associated with longevity,” he said. “More importantly, they point to components that may be central to extending the healthy years of all of us.”