Study discovers longevity may be down to one particular gene

By Stephen Beech

Living to a ripe old age may be down to one particular gene, according to new research.

It was already known that a long, healthy lifespan runs from generation to generation in some families.

Now Dutch researchers have identified a gene in long-lived families that may be responsible for their longevity being passed on.

Scientists say that understanding why some people stay healthy without developing any illnesses until late in life while others become infirm at a much younger age has major implications for today's aging populations.

Life expectancy has significantly increased over the last two centuries, but "healthspan" — the number of years they live free from chronic disease and cognitive decline — has not kept pace.

Survival into extremely old age runs in families and is associated with a delayed onset of multiple chronic health conditions, but its protective genetic basis has remained largely unclear.

Most previous research has looked at the particular genetics of healthy long-lived individuals rather than those of families.

However, the new approach suggests that studying long-lived family members can help to identify some of the mechanisms that enable them to have a significantly longer healthspan.

The Dutch research team explained that the problem with studying individual people rather than families is that there are so many factors involved in having a long and healthy life.

Apart from genetics, socio-economic position, lifestyle, and other behavioral and social factors determine longevity and healthspan, with the result that individuals from a family with an average age at death may still become long-lived; and others may die at well under average age.

Study leader Pasquale Putter explained that the team's earlier research had shown that middle-aged family members with long-lived parents had a 13 years-later onset of cardiometabolic disease than did their partners with shorter-lived parents.

Putter, a final-year PhD student at Leiden University Medical Center, said: "This made it clear that their longer healthspan was passed down to subsequent generations."

The researchers scanned the genomes of 212 groups of long-lived sibships — offspring with the same two parents.

They identified four genomic regions at which longevity genes were likely to be found.

Putter said: "This meant that we could restrict our focus to 350 genes rather than around 20,000."

After further analysis, the team found 12 rare protein-altering genetic variants in these regions that might influence longevity.

Previous research has suggested that the cyclic GMP-AMP synthase (CGAS) gene plays a role in the aging process, and one of the 12 genetic variants mapped to the gene and was identified in two long-lived families.

The team explained that the gene is involved in producing an inflammatory response when DNA is detected within the cell where it does not belong, either in reaction to a viral infection, or when cellular damage has occurred.

Putter said: "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.

"We hope that taking this family approach will help us to untangle some of the environmental factors from those that are truly genetic, particularly those where rare mutations are involved.

"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."

The Dutch researchers say direct implications of the research for human health have to be explored further because the role of CGAS depends highly on context.

The team believe complete suppression of the CGAS pathway may increase susceptibility to infections and cancers, whereas chronic over-activation can lead to sustained damage caused by inflammation.

They are now moving towards in vivo studies to determine whether the changes seen in vitro will translate to similar changes in a whole organism by introducing the CGAS mutation into killifish at the Max Planck Institute for the Biology of Ageing in Germany.

Putter said: "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."

He added: "We also intend to follow up on our research by investigating other promising candidate longevity variants that we identified in the Leiden Longevity Study through collaborations with other groups."

The findings were presented June 16 at the annual conference of the European Society of Human Genetics in Gothenburg, Sweden.

Conference chair Alexandre Reymond, who was not involved in the research, said: "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."