Despite an enormous amount of effort, researchers have discovered very few human gene variants with reliable effects on longevity across multiple study populations, and even those effects are small. FOXO3 is one of these genes. The current consensus in the face of this data is that variants in thousands of genes contribute to natural differences in human longevity, interacting strongly with one another and with environmental differences, such that the picture is somewhat different in every individual. The usual situation is for any genetic study of longevity to find a few correlations, but those correlations then fail to appear in any other study, even of people in the same region and community. Researchers here suggest that even for FOXO3, the picture is more complicated than thought, and it has less influence on aging than thought.

People who live into their 90s or 100s - beyond the typical life expectancy near 80 for adults - can offer important lessons about healthy aging. Centenarians experience slower aging throughout their lives; live independently well into their 90s and spend only the last relatively few years of their exceptionally long lives with significant diseases or disabilities. Unlike average aging, in the case of people who live into their late 90s and even into their 100s, centenarians appear to benefit from combinations of longevity-enabling genes that likely protect against aging and age-related diseases and disability. FOXO3 could be playing such a role for people who live into their early to mid-90s. The gene had gained quite a bit of attention over the last 10 years as a possible contributor to longevity, but despite a lot of study, the mechanism by which FOXO3 helps people remains murky. The goal of the new study was to better understand the gene's role in survival to not just the 90s but beyond to even more exceptional ages.

The researchers examined genetic data from blood samples of 2,072 extremely old subjects from four centenarian studies: the New England Centenarian Study; the Southern Italian Centenarian Study; the Longevity Genes Project; and the Long Life Family Study. Researchers conducting centenarian studies such as these are working together to discover the biological mechanisms that enable remarkable aging. The researchers found that while FOXO3 did seem to play a role in longevity to a degree, that role did not generally affect living to ages 96 or older for men, or 100 for women - the oldest one percent of the population. "We attended presentations and read scientific papers claiming associations between FOXO3 variants and longevity, yet when we tested for these associations among centenarians, we were unable to reproduce the findings. We suspect that part of the reason may be because these earlier claims were coming from studies made up mostly of people in their 80s and 90s, and not those in their 100s."