Rare mutation tied to healthier aging in long-lived families
Researchers studying the Leiden Longevity Study found rare gene variants, including one in CGAS, that may help explain longer healthspan in some families.
By Lucas Ferreira · Science & Environment Writer
3 min read
Researchers studying families with exceptional longevity have identified rare genetic variants that may help some people avoid major disease for longer as they age. The findings, presented at the annual conference of the European Society of Human Genetics in Gothenburg, point to a mutation in the CGAS gene that may reduce damaging inflammation while preserving immune defenses.
The work comes as longer lives have not always translated into longer healthy lives. According to the European Society of Human Genetics, scientists have known that exceptional longevity can run in families and is often linked to later development of chronic illness, but the protective genetic factors have remained unclear.
Pasquale Putter, a final-year PhD student in Professor Eline Slagboom’s group at Leiden University Medical Center in the Netherlands, presented findings from an intergenerational aging study tied to the Leiden Longevity Study. Putter said earlier work by the team found that middle-aged people with long-lived parents developed cardiometabolic disease about 13 years later than their partners whose parents had shorter lifespans.
The researchers focused on families because lifespan and healthspan reflect more than DNA. The European Society of Human Genetics said income, lifestyle, behavior and environmental exposures can all affect how long people live and how long they remain free of chronic disease and cognitive decline.
Study narrowed search to rare variants
The team analyzed genomes from 212 groups of long-lived sibships, meaning offspring who shared the same two parents, in the Leiden Longevity Study. According to Putter, the analysis identified four genomic regions likely to contain longevity-related genes, allowing the researchers to narrow their search from about 20,000 genes to 350.
Further analysis pointed to 12 rare protein-altering variants that the researchers said may contribute to longer and healthier lives. One of the most notable variants was found in CGAS, short for cyclic GMP-AMP synthase, a gene already associated with aging research.
The CGAS variant appeared in two of the long-lived families in the study, according to the European Society of Human Genetics. CGAS helps activate inflammation when DNA is detected in the wrong place inside a cell, which can occur during infection or cellular damage.
Putter said members of the families likely had only one active copy of CGAS instead of two. He said that may have lowered their inflammatory response while still leaving enough activity to fight infections and repair damage, potentially supporting longer healthspan and survival.
Researchers plan animal tests
The team cautioned that the biology is context-dependent and that the finding does not yet point to a human treatment. According to the European Society of Human Genetics, fully blocking the CGAS pathway could increase vulnerability to infections and cancer, while too much activation can drive chronic inflammation and tissue damage.
To test the mutation in a living organism, the researchers plan to introduce it into killifish at the Max Planck Institute for the Biology of Ageing in Cologne, Germany. Putter said killifish, which have a natural lifespan of three to nine months, will let the team compare lifespan and tissue health against control groups.
Putter said the group also plans to study other candidate longevity variants identified in the Leiden Longevity Study through collaborations with other researchers. Professor Alexandre Reymond, chair of the conference and not involved in the work, said the findings could help scientists focus on biological factors tied to longevity and healthspan.
This story draws on original reporting from ScienceDaily.