The role of FoxO3 in longevity may involve upregulation of target genes involved in stress resistance, metabolism, cell cycle arrest, and apoptosis. Effective control of FoxO3 in response to environmental stimuli is likely critical to prevent ageing and age-related diseases including cardiovascular disease, type 2 diabetes, cancer and neurodegenerative diseases. The diagram shows how the well-known longevity-associated intervention of caloric restriction helps to maintain the redox state of the cell by cycling calories through the mitochondria so as to restore NAD+. Caloric restriction results in activation of sirtuins, leading to activation of FoxOs, improved autophagy, amino acid recycling via inhibition of mTOR activity, and other mechanisms leading to a healthy ageing phenotype. On the other hand, excess calories, particularly from carbohydrates, increase the NADH/NAD+ ratio and leads to lipogenesis, overproduction of ROS by mitochondria, poor autophagy and activation of mTOR as a result of an excess of protein intake. AKT1 is a term derived from the ‘Ak’ mouse strain that develops spontaneous thymic lymphomas (AKT1 is also known as protein kinase B). CAD = Coronary artery disease; HNF4a = hepatocyte nuclear factor 4α; GCN1l1 = general control of amino acid synthesis 1-like 1; O-GlcNAc = O-linked N-acetylglucosamine; OXPHOS = oxidative phosphorylation; PPARγC1α = peroxisome proliferator-activated receptor-γ coactivator 1α; TCA = tricarboxylic acid.
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.
Bae, a biostatistician who studies statistical genetics and genetic epidemiology said: “These variants will help you live to a certain age – the early to mid-90s – but won’t get you to exceptional longevity.” 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 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 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.
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 1% 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 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.” http://oregonstate.edu/ua/ncs/archives/2017/jul/new-findings-suggest-genetic-influence-aging-90s-not-beyondÂ
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