Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.

Sensory perception modulates lifespan across taxa, presumably due to alterations in physiological homeostasis after central nervous system integration. The coordinating circuitry of this control, however, remains unknown. Here, we used the Drosophila melanogaster gustatory system to dissect one component of sensory regulation of aging. We found that loss of the critical water sensor, pickpocket 28 (ppk28), altered metabolic homeostasis to promote internal lipid and water stores and extended healthy lifespan. Additionally, loss of ppk28 increased neuronal glucagon-like adipokinetic hormone (AKH) signaling, and the AKH receptor was necessary for ppk28 mutant effects. Furthermore, activation of AKH-producing cells alone was sufficient to enhance longevity, suggesting that a perceived lack of water availability triggers a metabolic shift that promotes the production of metabolic water and increases lifespan via AKH signaling. This work provides an example of how discrete gustatory signals recruit nutrient-dependent endocrine systems to coordinate metabolic homeostasis, thereby influencing long-term health and aging.taste | adipokinetic hormone signaling S ensory signaling systems are potent modulators of organismal metabolism and lifespan (1-6) but the mechanisms by which sensory inputs are transduced into relevant physiological outputs remain poorly understood. For even the simplest organisms, an extensive array of sensory stimuli-including chemical, mechanical, thermal, and visual cues-must be properly transduced and integrated to ensure a reliable response to environmental quality. In the nematode Caenorhabditis elegans, sensory neurons alone may accomplish these tasks. They express multiple sensory receptors, which provide simple integrative capabilities to the cell, and they secrete neuropeptides, which can direct cell-nonautonomous responses in peripheral tissues (7). The fruit fly, Drosophila melanogaster, however, is similar to mammals in that sensory neurons are often highly specialized, and elaborate mechanisms of sensory integration and interpretation are performed by specialized processing centers in the central brain (8). Once decoded, sensory signals are presumably relayed to neuroendocrine centers to stimulate appropriate actions in peripheral tissues. Whereas the release of endocrine molecules, including insulinlike peptides, via central nervous system (CNS) control has emerged as a critical regulator of aging across model organisms, the extent to which sensory signals impact such systems, and the underlying neurocircuitry involved, are unknown (9-11).The Drosophila system is a powerful tool for elucidating evolutionarily conserved aspects of neural circuitry that link sensory information to a variety of behavioral and metabolic responses. Although comprised of only ∼100,000 neurons, the fly brain is sufficiently complex to share many aspects of structure and function with humans and mice. This, along with the ability to manipulate neuronal activity in a temporally and spatially controlled manner, ha...

In Caenorhabditis elegans, a subset of gustatory neurons, as well as olfactory neurons, shortens lifespan, whereas a different subset of gustatory neurons lengthens it. Recently, the lifespan-shortening effect of olfactory neurons has been reported to be conserved in Drosophila. Here we show that the Drosophila gustatory system also affects lifespan in a bidirectional manner. We find that taste inputs shorten lifespan through inhibition of the insulin pathway effector dFOXO, whereas other taste inputs lengthen lifespan in parallel to this pathway. We also note that the gustatory influence on lifespan does not necessarily depend on food intake levels. Finally, we identify the nature of some of the taste inputs that could shorten versus lengthen lifespan. Together our data suggest that different gustatory cues can modulate the activities of distinct signaling pathways, including different insulin-like peptides, to promote physiological changes that ultimately affect lifespan.sensory system | insulin signaling | physiology | gustatory receptors | aging A ging is a universal process that causes deterioration in the biological functions of an organism over the progression of its lifetime. This process is affected by genetic and environmental factors, whose interaction could be mediated by the sensory system, which perceives and transmits environmental information to modulate the signaling activities of downstream target tissues. Accordingly, external sensory cues and sensory neuron activities have been shown to alter the lifespan of both Caenorhabditis elegans and Drosophila melanogaster (1-6).In C. elegans, the laser ablation of a specific subset of gustatory or olfactory neurons extends lifespan, whereas ablation of a different subset of gustatory neurons shortens it (1). Interestingly, at least part of this sensory influence on lifespan has also been observed in other animals. In Drosophila, impairment of olfaction through a mutation in Or83b, which encodes a broadly expressed atypical odorant receptor (7), increases lifespan (3). In addition, exposure of dietary-restricted flies to food odors, like live yeast, can partly suppress their long-life phenotype (3). The conservation of the olfactory influence on lifespan is thus consistent with the possibility that gustatory inputs will also bidirectionally alter the lifespan of both C. elegans and D. melanogaster.The effects of sensory neurons on C. elegans lifespan have been shown to be partly mediated by insulin/IGF signaling (1, 2, 8). The insulin/IGF pathway also affects fly lifespan: down-regulation of the activities of the insulin receptor InR and the receptor substrate, CHICO, extends lifespan (9, 10). Moreover, an increase in activity of the downstream transcription factor dFOXO, which is negatively regulated by both InR and CHICO, increases fly lifespan (11,12). Consistent with these observations, mutations in several of the Drosophila insulin-like peptide (dilp) genes (13), which are expressed in the median neurosecretory cells (mNSCs) in the fly brain (14-1...

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