People age differently. Some remain free of major diseases well into old age, while others develop serious health problems much earlier. Understanding why this happens is increasingly important as populations age around the world.
Although life expectancy has increased dramatically over the past 200 years, the number of years people spend in good health has not increased at the same rate. Researchers have long known that exceptional longevity (longevity) is often hereditary and is linked to a later onset of chronic diseases. 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 presented at the European Society of Human Genetics’ annual conference in Gothenburg suggests that studying entire long-lived families may provide a clearer picture of the biological mechanisms that support longer lifespans. (A person’s life expectancy is the number of years they live free of chronic diseases and cognitive decline.)
Why family studies are important
Studying families offers an important advantage because longevity is influenced by many factors beyond genetics. Socioeconomic status, lifestyle, behavior, and environmental influences play important roles in determining both life expectancy and health. As a result, some people from families with an average life expectancy can live exceptionally long lives, while others from long-lived families cannot.
Presenting the results of the study on intergenerational aging, Pasquale Putter, a final-year doctoral student in Professor Eline Slagboom’s group at Leiden University Medical Center in Leiden, the Netherlands, explained that previous research by the team had already revealed a surprising pattern.
Middle-aged people with long-lived parents developed cardiometabolic diseases an average of 13 years later than their partners whose parents had a shorter life expectancy.
“This made it clear that their greater longevity was passed on to subsequent generations,” he says.
Searching for longevity genes
To investigate further, the researchers analyzed the genomes of 212 long-lived sib groups (descendants of the same two parents) that participated in the Leiden Longevity Study.
The team identified four regions of the genome that appeared to contain genes related to longevity.
“This meant we were able to narrow our focus to 350 genes rather than around 20,000,” says Mr Putter.
Additional analyzes further narrowed the search and revealed 12 rare protein-altering genetic variants that may contribute to a longer, healthier life.
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 within 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 may have reduced the inflammatory response in their bodies, while still being sufficient to clear infections and repair damage, thus contributing to protective mechanisms that allow for longer lifespans and survival,” says Mr Putter.
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 this family approach will help us separate some of the environmental factors from those that are truly genetic, particularly those involving rare mutations. 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: test the mutation in Killifish
Scientists warn that much more work is needed before the implications for human health can be determined. The effects of CGAS are highly context-dependent.
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 mutation works in a living organism, 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 Aging in Cologne, Germany.
“Killfishes are the shortest-lived vertebrates, with a natural lifespan of between three and nine months. Using them as a model will allow us to determine whether the mutation contributes to a longer lifespan compared to control groups, and also investigate its effects on tissue health,” says Mr Putter.
“We also intend to follow up 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 extend life expectancy
Professor Alexandre Reymond, chair of the conference and who was not involved in the research, said the findings could help scientists better understand the biology behind healthy ageing.
“These findings allow our community to focus on factors related to longevity and, more importantly, point to what are perhaps key elements in extending everyone’s lifespan.”