Age progresses differently depending on the person. Some people don’t get seriously ill as they get older, but others develop serious health problems much earlier. As populations around the world continue to age, understanding why this happens becomes increasingly important.
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 pace. Researchers have long known that abnormal longevity (longevity) often runs in families and is associated with later onset of chronic diseases. However, the genetic factors that help protect these families are still poorly understood.
Most of the research to date has focused on the genetics of individual people who live longer. New research 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 underpin longer healthy lifespans. (A person’s healthy lifespan is the number of years they can live without chronic disease or cognitive decline).
Why is family research important?
Because longevity is influenced by many factors beyond genetics, there are important benefits to studying families. Socioeconomic status, lifestyle, behavior, and environmental influences all play a major role in determining both lifespan and healthspan. As a result, some members of families with average lifespans may still live very long lives, while others in long-lived families may not.
Pasquale Pater, a final year doctoral student in Professor Elaine Slagboom’s group at Leiden University Medical Center in Leiden, the Netherlands, explained while presenting the results of the intergenerational aging study that the team’s previous work had already revealed a striking pattern.
Middle-aged people with long-lived parents developed cardiometabolic disease on average 13 years later than their partners whose parents lived shorter lives.
“This shows that their longer healthy lifespans are passed on to later generations,” he says.
Search for longevity genes
To investigate further, the researchers analyzed the genomes of 212 groups of long-lived siblings (offspring of the same two parents) participating in the Leiden Longevity Study.
The research team identified four regions of the genome that are likely to contain genes associated with longevity.
“This meant we could limit our focus to 350 genes instead of about 20,000 genes,” Putter says.
Additional analysis further narrowed the search and revealed 12 rare gene mutations that alter proteins that may contribute to longer, healthier lives.
Promising role of CGAS genes
One of those variants was found in the CGAS (cyclic GMP-AMP synthase) gene, which was previously thought to be associated with aging. This variant appeared in two long-lived families included in the study.
CGAS helps trigger inflammation when non-existent DNA is detected inside cells. This can occur during viral infection or when cells are damaged.
“Members of these families likely had only one active copy of the CGAS gene instead of two, which is sufficient to reduce the body’s inflammatory response while clearing infections and repairing damage, thereby contributing to a defense mechanism that allows for healthy lifespan and extended survival,” Pater says.
Researchers believe that this reduced inflammatory response may help protect against some of the harmful effects of aging, while preserving the body’s defenses.
“We hope that taking this familial approach will help us disentangle some of the environmental factors that play a role that is truly genetic, especially rare mutations. We have been surprised by the magnitude of the impact of CGAS mutations in the in vitro experiments we have performed so far.”
Next step: Test mutations in medaka
Scientists warn that more research is needed to determine the effects on human health. The effectiveness of CGAS is highly context-dependent.
Completely blocking the CGAS pathway could make people more vulnerable to infections and cancer. On the other hand, overactivation of this pathway can lead to chronic inflammation and long-term tissue damage.
To better understand how mutations function in vivo, researchers are moving from in vitro experiments to in vivo studies. They plan to introduce the CGAS mutation into medaka fish at the Max Planck Institute for the Biology of Aging in Cologne, Germany.
“Medaka fish are the shortest-lived vertebrates, with a natural lifespan of 3 to 9 months. Using medaka as a model allows us to determine whether mutations contribute to longer lifespans compared to controls, and to investigate health effects in tissues,” Pater says.
“We also intend to follow up our research by investigating other promising longevity candidate variants identified in the Leiden Longevity Study through collaboration with other groups.”
New clues to extend your healthy lifespan
Conference chair Professor Alexandre Raymond, who was not involved in the research, said the findings could help scientists better understand the biology behind healthy aging.
“These findings allow our community to focus on factors associated with longevity and, more importantly, show that they may be important factors in extending healthy lifespans for all.”
