Drosophila lifespan control by dietary restriction independent of insulin-like signaling

Reduced insulin/insulin-like growth factor (IGF) signaling may be a natural way for the reduction of dietary nutrients to extend lifespan. While evidence challenging this hypothesis is accumulating with Caenorhabditis elegans, for Drosophila melanogaster it is still thought that insulin/IGF and the mechanisms of dietary restriction (DR) might as yet function through overlapping mechanisms. Here, we aim to understand this potential overlap. We found that over-expression of dFOXO in head fat body extends lifespan and reduces steady-state mRNA abundance of insulin-like peptide-2 under conditions of high dietary yeast, but not when yeast is limiting. In contrast, conditions of DR that increase lifespan change only insulin-like peptide-5 (ilp5) mRNA abundance. Thus, reduction of ilp5 mRNA is associated with longevity extension by DR, while reduction of insulin-like peptide-2 is associated with the diet-dependent effects of FOXO over-expression upon lifespan. To assess whether reduction of ilp5 is required for DR to extend lifespan, we blocked its diet-dependent change with RNAi. Loss of the ilp5 dietary response did not diminish the capacity of DR to extend lifespan. Finally, we assessed the capacity of DR to extend lifespan in the absence of dFOXO, the insulin/IGF-responsive transcription factor. As with the knockdown of ilp5 diet responsiveness, DR was equally effective among genotypes with and without dFOXO. It is clear from many Drosophila studies that insulin/IGF mediates growth and metabolic responses to nutrition, but we now find no evidence that this endocrine system mediates the interaction between dietary yeast and longevity extension

Juvenile hormone regulation of Drosophila aging

Background: Juvenile hormone (JH) has been demonstrated to control adult lifespan in a number of non-model insects where surgical removal of the corpora allata eliminates the hormone’s source. In contrast, little is known about how juvenile hormone affects adult Drosophila melanogaster. Previous work suggests that insulin signaling may modulate Drosophila aging in part through its impact on juvenile hormone titer, but no data yet address whether reduction of juvenile hormone is sufficient to control Drosophila life span. Here we adapt a genetic approach to knock out the corpora allata in adult Drosophila melanogaster and characterize adult life history phenotypes produced by reduction of juvenile hormone. With this system we test potential explanations for how juvenile hormone modulates aging. Results: A tissue specific driver inducing an inhibitor of a protein phosphatase was used to ablate the corpora allata while permitting normal development of adult flies. Corpora allata knockout adults had greatly reduced fecundity, inhibited oogenesis, impaired adult fat body development and extended lifespan. Treating these adults with the juvenile hormone analog methoprene restored all traits toward wildtype. Knockout females remained relatively long-lived even when crossed into a genotype that blocked all egg production. Dietary restriction further extended the lifespan of knockout females. In an analysis of expression profiles of knockout females in fertile and sterile backgrounds, about 100 genes changed in response to loss of juvenile hormone independent of reproductive state. Conclusions: Reduced juvenile hormone alone is sufficient to extend the lifespan of Drosophila melanogaster. Reduced juvenile hormone limits reproduction by inhibiting the production of yolked eggs, and this may arise because juvenile hormone is required for the post-eclosion development of the vitellogenin-producing adult fat body. Our data do not support a mechanism for juvenile hormone control of longevity simply based on reducing the physiological costs of egg production. Nor does the longevity benefit appear to function through mechanisms by which dietary restriction extends longevity. We identify transcripts that change in response to juvenile hormone independent of reproductive state and suggest these represent somatically expressed genes that could modulate how juvenile hormone controls persistence and longevity

Age-Dependent Changes in Transcription Factor FOXO Targeting in Female Drosophila

FOXO transcription factors have long been associated with longevity control and tissue homeostasis. Although the transcriptional regulation of FOXO have been previously characterized (especially in long-lived insulin mutants and under stress conditions), how normal aging impacts the transcriptional activity of FOXO is poorly understood. Here, we conducted a chromatin immunoprecipitation sequencing (ChIP-Seq) analysis in both young (2-week-old) and aged (5-week-old) wild-type female fruit flies, Drosophila melanogaster, to evaluate the dynamics of FOXO gene targeting during aging. Intriguingly, the number of FOXO-bound genes dramatically decreases with age (from 2617 to 224). Consistent to the reduction of FOXO binding activity, many genes targeted by FOXO in young flies are transcriptionally altered with age, either up-regulated (FOXOrepressing genes) or down-regulated (FOXO-activating genes) in adult head tissue. In addition, we show that many FOXO-bound genes in wild-type flies are unique from those in insulin receptor substrate chico mutants. Distinct from chico mutants, FOXO targets specific cellular processes (e.g., actin cytoskeleton) and signaling pathways (e.g., Hippo, MAPK) in young wild-type female flies. FOXO targeting on these pathways decreases with age. Interestingly, FOXO targets in aged flies are enriched in cellular processes like chromatin organization and nucleosome assembly. Furthermore, FOXO binding to core histone genes is well maintained at aged flies. Together, our findings provide new insights into dynamic FOXO targeting under normal aging and highlight the diverse and understudied regulatory mechanisms for FOXO transcriptional activity

Hormonal pleiotropy and the juvenile hormone regulation of Drosophila development and life history

Understandinghowtraits are integrated at the organismal level remains a fundamental problem at the interface of developmental and evolutionary biology. Hormones, regulatory signaling molecules that coordinate multiple developmental and physiological processes, are major determinants underlying phenotypic integration. The probably best example for this is the lipid-like juvenile hormone (JH) in insects. Here we review the manifold effects of JH, the most versatile animal hormone, with an emphasis on the fruit fly Drosophila melanogaster, an organism amenable to both genetics and endocrinology. JH affects a remarkable number of processes and traits in Drosophila development and life history, including metamorphosis, behavior, reproduction, diapause, stress resistance and aging. While many molecular details underlying JH signaling remain unknown, we argue that studying ‘‘hormonal pleiotropy’’ offers intriguing insights into phenotypic integration and the mechanisms underlying life history evolution. In particular, we illustrate the role of JH as a key mediator of life history trade-offs

Juvenile and Steroid Hormones in Drosophila melanogaster Longevity

This chapter reviews hormonal effects on aging in Drosophila melanogaster. The insect juvenile hormone (JH) is a sesquiterpenoid compound produced by the corpora allata (CA), a pair of endocrine glands with nervous connections to the brain. In pre- adult development and metamorphosis, JH functions as a "status quo" hormone, allowing continued growth after ecdysteroid-induced molting. Metamorphosis can only take place when the ecdysteroids act in the absence of JH. During the final larval instar, the JH titer declines because of a cessation of synthesis and increased degradation in the hemolymph and target tissues. Steroid hormones, such as ecdysteroids, are another class of vital hormones in insects. In pre-adult flies, 20E is produced in the larval prothoracic gland, which makes part of the larval ring gland in dipterans. Both JH and 20E play major antagonistic or synergistic roles in regulating Drosophila development. Application of commonly used JH inhibitors, such as precocene or fluvastatin, can reduce or inhibit JH synthesis in the CA and may thus be used to study the effects of JH deficiency on life span

190: In how many patients with Wolff-Parkinson-White syndrome-related adverse presentation isoproterenol infusion was required to reproduce the arrhythmia?

Electrophysiological study is the main method for the detection of patients with a Wolff-Parkinson-White syndrome (WPW) at risk of adverse presentation (resuscitated ventricular fibrillation (VF), documented life-threatening arrhythmia): the protocol is debated. The purpose of the study was to look in how many patients with WPW-related adverse presentation, atrial fibrillation (AF) or atrial tachycardia with the shortest RR cycle length (CL) with 1/1 conduction over accessory pathway (AP)<250msec was induced in control state (CS) and when isoproterenol was required.Methods63 patients, mean age 38±18, were referred for WPW-related adverse presentation (VF 6, other 56). EPS included in CS atrial pacing and measurement of the shortest CL with 1/1 conduction over AP and programmed stimulation with 1 and 2 extrastimuli. AP effective refractory period (ERP) was determined. In absence of induction of a tachycardia with a CL <250msec, isoproterenol (0.02 to 1μg. min-1) was infused to increase sinus rate to 130bpm; the protocol was repeated.ResultsMean shortest CL conducted over AP was 223±30msec in CS, 192±25msec after isoproterenol. APERP was 225±29msec in CS, 191±19msec after isoproterenol. Atrioventricular orthodromic tachycardia (AVRT) was induced in 34 patients (54%), antidromic tachycardia (ATD) in 13 (21%), AF in 43 (68%). Criteria for a malignant form (induction of AF or ATD with a shortest CL <250mesc) were noted in 42 patients (67%) in CS and were obtained after isoproterenol in remaining 21 patients (33%). Among these patients, 12 had inducible tachycardia in CS (AVRT (n=6), ATD (n=3), AF (n=3) but the shortest CL was >240msec. A tachycardia was only induced after isoproterenol in 9 patients (14%).ConclusionsInfusion of isoproterenol should be systematic when WPW is evaluated. EPS performed only in CS missed at least 14% of patients at risk of life-threatening arrhythmias who had no inducible supraventricular tachyarrhythmia and 33% of patients with a WPW without the classical criteria for a malignant form. Isoproterenol increased the sensitivity of EPS for the detection of malignant form from 67 to 100%

Comparing thyroid and insect hormone signaling

Transitions between different states of development, physiology, and life history are typically mediated by hormones. In insects, metamorphosis and reproductive maturation are regulated by an interaction between the sesquiterpenoid juvenile hormone (JH) and the steroid 20-hydroxy-ecdysone (20E). In vertebrates and some marine invertebrates, the lipophilic thyroid hormones (THs) affect metamorphosis and other life history transitions. Interestingly, when applied to insects, THs can physiologically mimic many facets of JH action, suggesting that the molecular actions of THs and JH/20E might be similar. Here we discuss functional parallels between TH and JH/20E signaling in insects, with a particular focus on the fruit fly, Drosophila melanogaster, a genetically and physiologically tractable model system. Comparing the effects of THs with the well defined physiological roles of insect hormones such as JH and 20E in Drosophila might provide important insights into hormone function and the evolution of endocrine signaling

Counting calories in Drosophila diet restriction

The extension of life span by diet restriction in Drosophila has been argued to occur without limiting calories. Here we directly measure the calories assimilated by flies when maintained on full- and restricted-diets. We find that caloric intake is reduced on all diets that extend life span. Flies on low-yeast diet are long-lived and consume about half the calories of flies on high-yeast diets, regardless of the energetic content of the diet itself. Since caloric intake correlates with yeast concentration and thus with the intake of every metabolite in this dietary component, it is premature to conclude for Drosophila that calories do not explain extension of life span

Correlation analysis reveals the emergence of coherence in the gene expression dynamics following system perturbation

Time course gene expression experiments are a popular means to infer co-expression. Many methods have been proposed to cluster genes or to build networks based on similarity measures of their expression dynamics. In this paper we apply a correlation based approach to network reconstruction to three datasets of time series gene expression following system perturbation: 1) Conditional, Tamoxifen dependent, activation of the cMyc proto-oncogene in rat fibroblast; 2) Genomic response to nutrition changes in D. melanogaster; 3) Patterns of gene activity as a consequence of ageing occurring over a life-span time series (25y–90y) sampled from T-cells of human donors

Tequila Regulates Insulin-Like Signaling and Extends Life Span in Drosophila melanogaster

The aging process is a universal phenomenon shared by all living organisms. The identification of longevity genes is important in that the study of these genes is likely to yield significant insights into human senescence. In this study, we have identified Tequila as a novel candidate gene involved in the regulation of longevity in Drosophila melanogaster. We have found that a hypomorphic mutation of Tequila (Teq(f01792)), as well as cell-specific downregulation of Tequila in insulin-producing neurons of the fly, significantly extends life span. Tequila deficiency-induced life-span extension is likely to be associated with reduced insulin-like signaling, because Tequila mutant flies display several common phenotypes of insulin dysregulation, including reduced circulating Drosophila insulin-like peptide 2 (Dilp2), reduced Akt phosphorylation, reduced body size, and altered glucose homeostasis. These observations suggest that Tequila may confer life-span extension by acting as a modulator of Drosophila insulin-like signaling