Gut-to-brain regulation of aging through neuropeptide F, insulin, and juvenile hormone.

Dietary restriction (DR) slows aging in many animals, while in some cases, the sensory signals from diet alone are sufficient to retard or accelerate lifespan. The digestive tract is a candidate location to sense nutrients, where neuropeptides secreted by enteroendocrine cells (EEC) produce systemic signals in response to food. Here, we measure how neuropeptide F (NPF) is secreted into adult circulation by EEC and find that specific EEC differentially respond to dietary sugar and yeast.

Gut-to-brain regulation of aging through neuropeptide F, insulin and juvenile hormone.

Dietary restriction slows aging in many animals, while in some cases the sensory signals from diet alone are sufficient to retard or accelerate lifespan. The digestive tract is a candidate location to sense nutrients, where neuropeptides secreted by enteroendocrine cells (EEC) produce systemic signals in response to food. Here we measure how neuropeptide F (NPF) is secreted into adult circulation by enteroendocrine cells and find that specific enteroendocrine cells differentially respond to dietary sugar and yeast.

Combinatorial interventions in aging.

Insight on the underlying mechanisms of aging will advance our ability to extend healthspan, treat age-related pathology and improve quality of life. Multiple genetic and pharmacological manipulations extend longevity in different species, yet monotherapy may be relatively inefficient, and we have limited data on the effect of combined interventions. Here we summarize interactions between age-related pathways and discuss strategies to simultaneously retard these in different organisms.

Stalking the link between reproduction and aging: After decades of research, it still remains a mystery whether and how reproduction drives the process of aging: After decades of research, it still remains a mystery whether and how reproduction drives the process of aging.

The hypothesis that aging and number of offspring are linked with each other has attracted much attention and research, but evidence for it remains elusive.

Aging Regulated Through a Stability Model of Insulin/Insulin Growth Factor Receptor Function.

Mutations of the insulin-like receptor in extend lifespan. New research suggests this receptor operates in two modes. The first extends lifespan while slowing reproduction and reducing growth.

Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms.

Mutations of the Drosophila melanogaster insulin/IGF signaling system slow aging, while also affecting growth and reproduction. To understand this pleiotropy, we produced an allelic series of single codon substitutions in the Drosophila insulin receptor, InR. We generated InR substitutions using homologous recombination and related each to emerging models of receptor tyrosine kinase structure and function.

Extracellular matrix induced by steroids and aging through a G-protein-coupled receptor in a model of renal fibrosis.

Aldosterone is produced by the mammalian adrenal cortex to modulate blood pressure and fluid balance; however, excessive, prolonged aldosterone promotes fibrosis and kidney failure. How aldosterone triggers disease may involve actions independent of its canonical mineralocorticoid receptor. Here, we present a model of renal pathology caused by excess extracellular matrix formation, stimulated by exogenous aldosterone and by insect ecdysone.

Regulatory Roles of Insulin-Like Peptide 1 (DILP1) in Metabolism Differ in Pupal and Adult Stages.

The insulin/IGF-signaling pathway is central in control of nutrient-dependent growth during development, and in adult physiology and longevity. Eight insulin-like peptides (DILP1-8) have been identified in , and several of these are known to regulate growth, metabolism, reproduction, stress responses, and lifespan. However, the functional role of DILP1 is far from understood.

The hidden costs of dietary restriction: Implications for its evolutionary and mechanistic origins.

Dietary restriction (DR) extends life span across taxa. Despite considerable research, universal mechanisms of DR have not been identified, limiting its translational potential. Guided by the conviction that DR evolved as an adaptive, pro-longevity physiological response to food scarcity, biomedical science has interpreted DR as an activator of pro-longevity molecular pathways.

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

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, , to evaluate the dynamics of FOXO gene targeting during aging.

Drosophila insulin-like peptide dilp1 increases lifespan and glucagon-like Akh expression epistatic to dilp2.

Insulin/IGF signaling (IIS) regulates essential processes including development, metabolism, and aging. The Drosophila genome encodes eight insulin/IGF-like peptide (dilp) paralogs, including tandem-encoded dilp1 and dilp2. Many reports show that longevity is increased by manipulations that decrease DILP2 levels.

Ecdysone Elicits Chronic Renal Impairment via Mineralocorticoid-Like Pathogenic Activities.

Background/aims: Ecdysteroids are steroidal insect molting hormones that also exist in herbs. Ecdysteroid-containing adaptogens have been popularly used to improve well-being and by bodybuilders for muscle growth. However, the use of ecdysone in mammals is also associated with kidney growth and enlargement, indications of disturbed kidney homeostasis.

Unraveling the Molecular Mechanism of Immunosenescence in .

A common feature of the aging process is a decline in immune system performance. Extensive research has sought to elucidate how changes in adaptive immunity contribute to aging and to provide evidence showing that changes in innate immunity have an important role in the overall decline of net immune function. is an emerging model used to address questions related to immunosenescence via research that integrates its capacity for genetic dissection of aging with groundbreaking molecular biology related to innate immunity.

Insulin-Like Peptides DILP2 and DILP5 Differentially Stimulate Cell Signaling and Glycogen Phosphorylase to Regulate Longevity.

Insulin and IGF signaling (IIS) is a complex system that controls diverse processes including growth, development, metabolism, stress responses, and aging. IIS is propagated by eight insulin-like peptides (DILPs), homologs of both mammalian insulin and IGFs, with various spatiotemporal expression patterns and functions. DILPs 1-7 are thought to act through a single insulin/IGF receptor, InR, but it is unclear how the DILPs thereby mediate a range of physiological phenotypes.

Dehydration triggers ecdysone-mediated recognition-protein priming and elevated anti-bacterial immune responses in Drosophila Malpighian tubule renal cells.

Background: Drosophila is a powerful model for the study of factors modulating innate immunity. This study examines the effect of water-loss dehydration on innate immune responsiveness in the Drosophila renal system (Malpighian tubules; MTs), and how this leads to elevated host defense and contributes to immunosenescence.

Results: A short period of desiccation-elevated peptidoglycan recognition protein-LC (PGRP-LC) expression in MTs, increased antimicrobial peptide (AMP) gene induction, and protected animals from bacterial infection.

Drosophila Kruppel homolog 1 represses lipolysis through interaction with dFOXO.

Transcriptional coordination is a vital process contributing to metabolic homeostasis. As one of the key nodes in the metabolic network, the forkhead transcription factor FOXO has been shown to interact with diverse transcription co-factors and integrate signals from multiple pathways to control metabolism, oxidative stress response, and cell cycle. Recently, insulin/FOXO signaling has been implicated in the regulation of insect development via the interaction with insect hormones, such as ecdysone and juvenile hormone.

Total Solid-Phase Synthesis of Biologically Active Drosophila Insulin-Like Peptide 2 (DILP2).

In the fruit fly , there are eight insulin-like peptides (DILPs) with DILPs 1-7 interacting with a sole insulin-like receptor tyrosine kinase (DInR) while DILP8 interacts with a single G protein-coupled receptor (GPCR), Lgr3. Loss-of-function mutation studies show that the neuropeptide DILP2 has a key role in carbohydrate and lipid metabolism as well as longevity and reproduction. A better understanding of the processes whereby DILP2 mediates its specific actions is required.

Reproduction regulates Drosophila nutrient intake through independent effects of egg production and sex peptide: Implications for aging.

The ratio of protein to carbohydrate (P:C) consumed influences reproduction and lifespan, outcomes that are often maximized by different P:C intake. Determine if reproduction in female Drosophila drives elevated P:C intake. Distinguish whether such a preference is driven by egg production or from male-derived sex peptides in seminal fluid.

Mitochondria: Masters of Epigenetics.

Accumulating evidence argues that aging exerts a profound influence on epigenetics, and vice versa. A pair of studies by Merkwirth et al. and Tian et al.

Nutritional Geometric Profiles of Insulin/IGF Expression in Drosophila melanogaster.

Insulin/IGF signaling (IIS) in Drosophila melanogaster is propagated by eight Drosophila insulin-like peptides (dilps) and is regulated by nutrition. To understand how dietary protein and sugar affect dilp expression, we followed the analytical concepts of the Nutritional Geometric Framework, feeding Drosophila adults media comprised of seven protein-to-carbohydrate ratios at four caloric concentrations. Transcript levels of all dilps and three IIS-regulated genes were measured.

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.

Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP.

Mutations of the insulin/IGF signaling (IIS) pathway extend Drosophila lifespan. Based on genetic epistasis analyses, this longevity assurance is attributed to downstream effects of the FOXO transcription factor. However, as reported FOXO accounts for only a portion of the observed longevity benefit, suggesting there are additional outputs of IIS to mediate aging.

Dietary switch reveals fast coordinated gene expression changes in Drosophila melanogaster.

Dietary restriction (DR) reduces age-specific mortality and increases lifespan in many organisms. DR elicits a large number of physiological changes, however many are undoubtedly not related to longevity. Whole-genome gene expression studies have typically revealed hundreds to thousands of differentially expressed genes in response to DR, and a key open question is which subset of genes mediates longevity.

Transcriptional response to dietary restriction in Drosophila melanogaster.

Dietary restriction (DR) extends lifespan in a wide variety of organisms. Although several genes and pathways associated with this longevity response have been identified, the specific mechanism through which DR extends lifespan is not fully understood. We have recently developed a novel methodology to screen for transcriptional changes in response to acutely imposed DR upon adult Drosophila melanogaster and identified groups of genes that switch their transcriptional patterns from a normal diet pattern to a restricted diet pattern, or 'switching genes'.