Summary: A new study challenges previous research into the role of the FOXO3 gene in super-aging. Researchers found the gene did, to a degree, play a role in longevity, but did not affect living to ages 96+ in men or 100+ in women.
Source: Oregon State University.
Variants of a gene thought to be linked to longevity appear to influence aging into the 90s, but do not appear to affect exceptional longevity, or aging over 100, a new study has found.
The research challenges previous findings that indicated some variants of the gene, FOXO3, played a role in exceptional longevity, said Harold Bae, an assistant professor in the College of Public Health and Human Sciences at Oregon State University and the lead author of the study.
“These variants did seem to have some impact, but they do not appear to be as influential toward truly exceptional longevity as previously thought,” said Bae, a biostatistician who studies statistical genetics and genetic epidemiology, particularly in relation to healthy aging research. “These variants will help you live to a certain age – the early to mid-90s — but won’t get you to exceptional longevity.”
The findings have been published in the Journals of Gerontology: Biological Sciences. Co-authors are Anastasia Gurinovich, Stacy L. Andersen, Thomas T. Perls and Paola Sebastiani of Boston University Schools of Medicine and Public Health; Gil Atzmon and Nir Barzila of Albert Einstein College of Medicine in New York; and Alberto Malovini, Francesco Villa and Annibale Puca of the University of Salerno, Italy.
People who live into their 90s or 100s — beyond the typical life expectancy near 80 for adults — can offer important lessons about healthy aging, Bae said. 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, said Sebastiani, the article’s senior author.
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 at Albert Einstein College of Medicine; and the National Institutes on Aging-funded 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 who published the Journals of Gerontology: Biological Sciences paper 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,” said Perls, the director of the New England Centenarian Study, Boston Medical Center, and co-author of the paper. “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.”
The researchers’ findings will likely prompt new areas of research as scientists continue to look for answers about genetic components of longevity and exceptional longevity, Bae said.
“There’s still more to learn about this gene,” he said. “We know for sure it influences aging, but what we show is that it may not be a key player in achieving truly exceptional age.”
Funding: The research was supported by grants from the National Institute on Aging; The William M. Wood Foundation; and the Paulette and Marty Samowitz Family Foundation.
Source: Harold Bae – Oregon State University
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Original Research: Full open access research for “Effects of FOXO3 polymorphisms on survival to extreme longevity in four centenarian studies” by Harold Bae, Anastasia Gurinovich, Alberto Malovini, Gil Atzmon, Stacy L. Andersen, Francesco Villa, Nir Barzilai, Annibale Puca, Thomas T. Perls, and Paola Sebastiani in Journals of Gerontology: Biological Sciences. Published online June 20 2017 doi:10.1093/gerona/glx124
Effects of FOXO3 polymorphisms on survival to extreme longevity in four centenarian studies
Previous studies note specific FOXO3 single nucleotide polymorphisms (SNPs) associated with human longevity. However, it is not clear if these SNPs influence mortality risk beyond the oldest 1 percentile of survival. Using data from four longevity studies (total n=8266, age range 96–119 years for cases), we tested gene-wide association between 107 SNPs and survival to at least the oldest 1 percentile of survival for the 1900 birth cohort (≥96, white males; ≥100 white females). This analysis replicated 17 previously published variants, several of which are significant expression quantitative trait loci of FOXO3; rs6911407 and rs2253310 have the most significant effect on FOXO3 expressions in brain tissue. We then performed a survival analysis to determine if any of these 107 SNPs impact upon mortality risk beyond the oldest 1 percentile. While none of the 17 published variants was significantly associated with mortality risk beyond this extreme age, an uncommon homozygote genotype of rs9384680 exhibited the strongest association with mortality risk (p=2.68E-04) in only 11 females, a heretofore unreported association. These analyses replicate the previous association of common variants of FOXO3 with older age but these common variants do not modify risk for mortality at ages beyond the oldest 1 percentile age of survival.
“Effects of FOXO3 polymorphisms on survival to extreme longevity in four centenarian studies” by Harold Bae, Anastasia Gurinovich, Alberto Malovini, Gil Atzmon, Stacy L. Andersen, Francesco Villa, Nir Barzilai, Annibale Puca, Thomas T. Perls, and Paola Sebastiani in Journals of Gerontology: Biological Sciences. Published online June 20 2017 doi:10.1093/gerona/glx124