title: Nutritional Programming of Lifespan by FOXO Inhibition on Sugar-Rich Diets.
abstract: Consumption of unhealthy diets is exacerbating the burden of age-related ill health in aging populations. Such diets can program mammalian physiology to cause long-term, detrimental effects. Here, we show that, in Drosophila melanogaster, an unhealthy, high-sugar diet in early adulthood programs lifespan to curtail later-life survival despite subsequent dietary improvement. Excess dietary sugar promotes insulin-like signaling, inhibits dFOXO-the Drosophila homolog of forkhead box O (FOXO) transcription factors-and represses expression of dFOXO target genes encoding epigenetic regulators. Crucially, dfoxo is required both for transcriptional changes that mark the fly's dietary history and for nutritional programming of lifespan by excess dietary sugar, and this mechanism is conserved in Caenorhabditis elegans. Our study implicates FOXO factors, the evolutionarily conserved determinants of animal longevity, in the mechanisms of nutritional programming of animal lifespan.
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Gower Street, WC1E 6BT London, UK.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dobson
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Gower Street, WC1E 6BT London, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Ezcurra
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Gower Street, WC1E 6BT London, UK.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Flanagan
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Gower Street, WC1E 6BT London, UK.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Summerfield
authors.affiliation: School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Matthew D W
authors.initials: MDW
authors.lastname: Piper
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Gower Street, WC1E 6BT London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Gems
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Gower Street, WC1E 6BT London, UK. Electronic address: n.alic@ucl.ac.uk.
authors.forename: Nazif
authors.initials: N
authors.lastname: Alic
mesh_terms: D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D004032:Diet; D004040:Dietary Carbohydrates / Q000494:pharmacology*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008136:Longevity; D016019:Survival Analysis; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004040:Dietary Carbohydrates; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors
keywords: Drosophila; aging; diet; forkhead box O; nutritional programming of lifespan; transcriptional regulation