Summary: A new study reevaluates the role of the FOXO3 gene in human longevity. Researchers report that certain FOXO3 variants moderately influence survival into the 90s, but these common variants do not appear to drive truly exceptional longevity—surviving to ages 96+ in men or 100+ in women.
Source: Oregon State University
Gene variants in FOXO3 are associated with reaching the 90s but do not appear to determine survival into the oldest ages, according to new research.
New research led by Harold Bae, an assistant professor in the College of Public Health and Human Sciences at Oregon State University, challenges earlier reports that linked specific FOXO3 variants with exceptional longevity. The study finds that while some FOXO3 polymorphisms modestly influence reaching advanced ages, they do not significantly predict survival past the most extreme thresholds of human lifespan.
“These variants seem to contribute to living into the early to mid-90s,” said Bae, a biostatistician who focuses on statistical genetics and genetic epidemiology in healthy aging. “However, they do not appear to be major determinants of the truly exceptional longevity seen in the oldest one percent of the population.”
The study, published in the Journals of Gerontology: Biological Sciences, involved an international team of researchers: Anastasia Gurinovich, Stacy L. Andersen, Thomas T. Perls and Paola Sebastiani of Boston University; Gil Atzmon and Nir Barzila of Albert Einstein College of Medicine; and Alberto Malovini, Francesco Villa and Annibale Puca of the University of Salerno, Italy. Their analysis aimed to clarify whether FOXO3 variants influence survival beyond typical advanced ages and into the most extreme longevity categories.
Centenarians and other extremely old individuals provide valuable insight into healthy aging. People who reach 100 and beyond often exhibit slower physiological aging, greater independence late in life, and compressed periods of serious disease or disability at the end of life. Understanding the genetic and biological factors that support such outcomes could reveal mechanisms of resilience and protection against age-related disease.
Previous work highlighted FOXO3 as a candidate longevity gene, but its precise role has remained unclear. The new study sought to determine whether FOXO3 single nucleotide polymorphisms (SNPs) associated with living to old age also affect the probability of surviving to the most extreme ages—defined in this analysis as the oldest one percentile of survival for a given birth cohort (96+ years for white males and 100+ years for white females in the 1900 birth cohort).
To address this question, the team examined genetic data from multiple centenarian cohorts. They analyzed blood-derived genotypes from 2,072 extremely old participants drawn from four centenarian studies: the New England Centenarian Study; the Southern Italian Centenarian Study; the Longevity Genes Project at Albert Einstein College of Medicine; and the National Institutes of Health-funded Long Life Family Study. In a broader gene-wide analysis that included additional participants from these and related datasets, the total sample size used for analysis of relevant variants reached 8,266 individuals with case ages ranging from 96 to 119 years.
The researchers replicated previously reported associations for a subset of FOXO3 variants that correlate with older age. Several of these replicated variants also act as expression quantitative trait loci (eQTLs) for FOXO3, influencing the gene’s expression in brain tissue; rs6911407 and rs2253310 showed notable effects on expression. Despite these replications, none of the common published variants examined showed a significant effect on mortality risk beyond the extreme age thresholds that define the oldest one percentile.
One uncommon homozygous genotype at rs9384680 displayed a statistically notable association with mortality risk in a small female subgroup, a result that had not been previously reported. However, this association was observed in only 11 females and requires cautious interpretation and further validation in independent samples.
“We reviewed claims of FOXO3’s association with longevity and tested those findings specifically among centenarians,” said Thomas T. Perls, director of the New England Centenarian Study. “Many earlier studies relied largely on participants in their 80s and 90s rather than those reaching 100 and beyond, which may explain differences between prior reports and our centenarian-based analyses.”
The study’s conclusions underscore that while FOXO3 contributes to human aging, common FOXO3 variants are not sufficient to explain survival into the most exceptional age ranges. The researchers emphasize that exceptional longevity likely arises from complex combinations of genetic factors, environmental influences, and lifestyle, and that further research is needed to identify the genetic architectures and biological pathways that promote extreme longevity.
Funding: Research funding was provided by the National Institute on Aging, The William M. Wood Foundation, and the Paulette and Marty Samowitz Family Foundation.
Source: Harold Bae, Oregon State University
Original research: Effects of FOXO3 polymorphisms on survival to extreme longevity in four centenarian studies. Published in Journals of Gerontology: Biological Sciences. DOI: 10.1093/gerona/glx124
Abstract
Effects of FOXO3 polymorphisms on survival to extreme longevity in four centenarian studies
Previous studies reported FOXO3 single nucleotide polymorphisms (SNPs) associated with human longevity. It remains unclear whether those SNPs influence mortality risk beyond the oldest one percentile of survival. Using data from four longevity studies (total n = 8,266, case ages 96–119 years), the authors tested 107 SNPs across the FOXO3 gene for association with survival to at least the oldest one percentile for the 1900 birth cohort (≥96 years for white males; ≥100 years for white females). Seventeen previously published variants were replicated; several act as expression quantitative trait loci for FOXO3, with rs6911407 and rs2253310 notably affecting expression in brain tissue. Survival analysis showed that none of the 17 common published variants significantly modified mortality risk beyond the extreme age threshold. An uncommon homozygote genotype at rs9384680 exhibited the strongest association with mortality risk (p = 2.68E-04) in a small female subgroup (n = 11), a novel finding that requires confirmation. In summary, common FOXO3 variants are associated with older age but do not appear to alter mortality risk at the most extreme ages of human survival.