Understanding why some people stay healthy without developing disease until late in life (have an increased healthspan), whereas others become infirm at a much younger age has important implications for the health of today's ageing population. Life expectancy has significantly increased in the last two centuries, but healthspan has not kept pace. Survival into extremely old age (longevity) runs in families and is associated with a delayed onset of multiple chronic health conditions, yet its protective genetic basis remains largely unclear. Most studies to date have looked at the particular genetics of healthy long-lived individuals rather than those of families. However, new research to be presented today (Tuesday) at the annual conference of the European Society of Human Genetics in Gothenburg has revealed that studying long-lived family members can help to identify some of the mechanisms that enable them to have a significantly longer healthspan.
The problem with studying individuals 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 behavioural 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. Presenting the results of the intergenerational ageing study today (Tuesday), Mr Pasquale Putter, a final-year PhD student in Prof. Eline Slagboom's group at Leiden University Medical Center, Leiden, The Netherlands, explains that their 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. "This made it clear that their longer healthspan was passed down to subsequent generations," he says.
The researchers scanned the genomes of 212 groups of long-lived sibships (offspring with the same two parents) from the Leiden Longevity Study. They identified four genomic regions at which longevity genes were likely to be found. "This meant that we could restrict our focus to 350 genes rather than around 20 000," says Mr Putter. After performing further analysis, they found 12 rare protein-altering genetic variants in these regions that might influence longevity.
Previous research has suggested that the CGAS (cyclic GMP-AMP synthase) gene plays a role in the ageing process, and one of these 12 genetic variants mapped to this gene and was identified in two long-lived families. This 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. "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," Mr Putter says.
"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 direct implications of this research for human health have to be explored further, the researchers say, because the role of CGAS depends highly on context. 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 Cologne, Germany.
"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," says Mr Putter. "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."
Chair of the conference, Professor 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."
The growing role of NIR-II imaging in preclinical research