Nutritional Programming of Lifespan by FOXO Inhibition on Sugar-Rich Diets

Dobson, A.; Ezcurra, Marina; Flanagan, Charlotte E.; Summerfield, Adam C.; Piper, Matthew D. W.; Gems, David; Alic, Nazif

doi:10.1016/j.celrep.2016.12.029

Cited by 59 publications

(82 citation statements)

References 48 publications

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“…This effect could be ascribed to the sugar-rich diet-mediated induction of insulin-like signaling, which in turn inhibits dFoxO activity and suppresses dFoxO target genes encoding epigenetic regulators in the fat body. Their data underscore the importance of dFoxO in linking overnutrition to lifespan attenuation in Drosophila melanogaster (Dobson et al 2017). …”

Section: Foxo6 In Longevitymentioning

confidence: 89%

“…Indeed, there is evidence that dFoxO is not required for dietary restriction-induced lifespan extension in Drosophila melanogaster , although dFoxO modulates this process (Giannakou et al 2008; Hwangbo et al 2004; Min et al 2008). In a recent study, Dobson and colleagues took an opposite approach to address whether dFoxO is liable for the overnutrition-elicited reduction of lifespan in Drosophila melanogaster (Dobson et al 2017). They demonstrate that even transient feeding with a sugar-rich diet in early adulthood could produce a long-lasting detrimental effect on subsequent survival in female flies.…”

Section: Foxo6 In Longevitymentioning

confidence: 99%

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FoxO integration of insulin signaling with glucose and lipid metabolism

Lee

Dong

2017

Journal of Endocrinology

254

177

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The forkhead box O family consists of FoxO1, FoxO3, FoxO4 and FoxO6 proteins in mammals. Expressed ubiquitously in the body, the four FoxO isoforms share in common the amino DNA binding domain, known as “forkhead box” domain. They mediate the inhibitory action of insulin or insulin-like growth factor on key functions involved in cell metabolism, growth, differentiation, oxidative stress, senescence, autophagy and aging. Genetic mutations in FoxO genes or abnormal expression of FoxO proteins are associated with metabolic disease, cancer or altered lifespan in humans and animals. Of the FoxO family, FoxO6 is the least characterized member and is shown to play pivotal roles in the liver, skeletal muscle and brain. Altered FoxO6 expression is associated with the pathogenesis of insulin resistance, dietary obesity and type 2 diabetes, and risk of neurodegeneration disease. FoxO6 is evolutionally divergent from other FoxO isoforms. FoxO6 mediates insulin action on target genes in a mechanism that is fundamentally different from other FoxO members. Here we focus our review on the role of FoxO6, in contrast with other FoxO isoforms, in health and disease. We review the distinctive mechanism by which FoxO6 integrates insulin signaling to hepatic glucose and lipid metabolism. We highlight the importance of FoxO6 dysregulation in the dual pathogenesis of fasting hyperglycemia and hyperlipidemia in diabetes. We review the role of FoxO6 in memory consolidation and its contribution to neurodegeneration disease and aging. We discuss the potential therapeutic option of pharmacological FoxO6 inhibition for improving glucose and lipid metabolism in diabetes.

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Section: Foxo6 In Longevitymentioning

confidence: 89%

Section: Foxo6 In Longevitymentioning

confidence: 99%

FoxO integration of insulin signaling with glucose and lipid metabolism

Lee

Dong

2017

Journal of Endocrinology

254

177

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“…Thus, it is possible for expression measures to trend in the same direction in DR and HS. Further, Dobson et al [70] found that excess sugar diets in young adult flies inhibited foxo and reduced survival in middle and old age. While we did not measure lifespan and fecundity here, our data showed mixed pattern of foxo activation in across diet tissue combinations, and these mapped to many coexpression modules (Table S5) which may be due to the relatively young age (i.e.…”

Section: Discussionmentioning

confidence: 99%

Diverse biological processes coordinate the transcriptional response to nutritional changes in aDrosophila melanogastermultiparent population

Ng’oma

Williams-Simon

Rahman

et al. 2019

Preprint

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BackgroundEnvironmental variation in the amount of resources available to populations challenge individuals to optimize the allocation of those resources to key fitness functions. This coordination of resource allocation relative to resource availability is commonly attributed to key nutrient sensing gene pathways in laboratory model organisms, chiefly the insulin/TOR signaling pathway. However, the genetic basis of diet-induced variation in gene expression is less clear.ResultsTo describe the natural genetic variation underlying nutrient-dependent differences, we used an outbred panel derived from a multiparental population, the Drosophila Synthetic Population Resource. We analyzed RNA sequence data from multiple female tissue samples dissected from flies reared in three nutritional conditions: high sugar (HS), dietary restriction (DR), and control (C) diets. A large proportion of genes in the experiment (19.6% or 2,471 genes) were significantly differentially expressed for the effect of diet, 7.8% (978 genes) for the effect of the interaction between diet and tissue type (LRT, Padj. < 0.05). Interestingly, we observed similar patterns of gene expression relative to the C diet, in the DR and HS treated flies, a response likely reflecting diet component ratios. Hierarchical clustering identified 21 robust gene modules showing intra-modularly similar patterns of expression across diets, all of which were highly significant for diet or diet-tissue interaction effects (false discovery rate, FDR Padj. < 0.05). Gene set enrichment analysis for different diet-tissue combinations revealed a diverse set of pathways and gene ontology (GO) terms (two-sample t-test, FDR < 0.05). GO analysis on individual co-expressed modules likewise showed a large number of terms encompassing a large number of cellular and nuclear processes (Fisher exact test, Padj. < 0.01). Although a handful of genes in the IIS/TOR pathway including Ilp5, Rheb, and Sirt2 showed significant elevation in expression, known key genes such as InR, chico, insulin peptide genes, and the nutrient-sensing pathways were not observed.ConclusionsOur results suggest that a more diverse network of pathways and gene networks mediate the diet response in our population. These results have important implications for future studies focusing on diet responses in natural populations.

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“…Major nutrient-sensing pathways, such as insulin and TOR signaling, are highly conserved between flies and mammals and techniques for studying aging in flies are well-established (Piper & Partridge 2017). High-sucrose treatment (1.0 M compared to 0.15 M controls) reduces Drosophila lifespan (Na et al 2013), even with transient exposure (1.2 M compared to 0.15 M controls) in young adults (Dobson et al 2017). The type of sugar is important, as sucrose is more detrimental than glucose or fructose (Lushchak et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Glucose extends lifespan through enhanced intestinal barrier integrity inDrosophila

Galenza

Foley

2020

Preprint

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Dietary intervention has received considerable attention as an approach to extend lifespan and improve aging. However, questions remain regarding optimal dietary regime and underlying mechanism of lifespan extension. Here, we asked how glucose-enriched food extends the lifespan of Drosophila. We showed that glucose-dependent lifespan extension is independent of caloric restriction, or insulin activity, two established mechanisms of lifespan extension. Instead, we found that flies raised on glucoseenriched food increased the expression of cell junction proteins, and extended intestinal barrier integrity with age. Furthermore, chemical disruption of the intestinal barrier removed the lifespan extension associated with glucose-treatment, suggesting that glucose-enriched food prolongs adult viability by enhancing the intestinal barrier. We believe our data contribute to our understanding of intestinal health and may help efforts to develop preventative measures to limit the effects of aging and disease.

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Nutritional Programming of Lifespan by FOXO Inhibition on Sugar-Rich Diets

Cited by 59 publications

References 48 publications

FoxO integration of insulin signaling with glucose and lipid metabolism

FoxO integration of insulin signaling with glucose and lipid metabolism

Diverse biological processes coordinate the transcriptional response to nutritional changes in aDrosophila melanogastermultiparent population

Glucose extends lifespan through enhanced intestinal barrier integrity inDrosophila

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