TOR (target of rapamycin) is an evolutionarily conserved nutrient sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast and mice support the notion that the TOR signaling network plays a pivotal role in modulating aging. TOR is emerging as the most robust mediator of the protective effects of various forms of dietary restriction (DR), which has been shown to extend lifespan and slow the onset of certain age-related diseases across species. Here we discuss how modulating the TOR signaling network slows aging by affecting a number of downstream processes including mRNA translation, autophagy, endoplasmic reticulum (ER) stress signaling, stress responses and metabolism. Identifying the mechanisms by which the TOR signaling network works as a pacemaker of aging is a major challenge in the field and may help identify potential drug targets for age–related diseases thereby facilitating healthful lifespan extension in humans.
For more than 100 years, the fruit fly
Drosophila melanogaster
has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula
Drosophilae
, that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type–related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the
Drosophila
community and serves as a reference to study genetic perturbations and disease models at single-cell resolution.
The Drosophila PDGF/VEGF receptor (PVR) has known functions in the guidance of cell migration. We now demonstrate that during embryonic hematopoiesis, PVR has a role in the control of antiapoptotic cell survival. In Pvr mutants, a large fraction of the embryonic hemocyte population undergoes apoptosis, and the remaining blood cells cannibalistically phagocytose their dying peers. Consequently, total hemocyte numbers drop dramatically during embryogenesis, and large aggregates of engorged macrophages carrying multiple apoptotic corpses form. Hemocyte-specific expression of the pan-caspase inhibitor p35 in Pvr mutants eliminates hemocyte aggregates and restores blood cell counts and morphology. Additional rescue experiments suggest involvement of the Ras pathway in PVR-mediated blood cell survival. In cell culture, we demonstrate that PVR directly controls survival of a hemocyte cell line. This function of PVR shows striking conservation with mammalian hematopoiesis and establishes Drosophila as a model to study hematopoietic cell survival in development and disease.
Insulin is a major regulator of metabolism in metazoans, including the fruit fly Drosophila melanogaster. Genome-wide association studies (GWAS) suggest a genetic basis for reductions of both insulin sensitivity and insulin secretion, phenotypes commonly observed in humans with type 2 diabetes mellitus (T2DM). To identify molecular functions of genes linked to T2DM risk, we developed a genetic tool to measure insulin-like peptide 2 (Ilp2) levels in Drosophila, a model organism with superb experimental genetics. Our system permitted sensitive quantification of circulating Ilp2, including measures of Ilp2 dynamics during fasting and re-feeding, and demonstration of adaptive Ilp2 secretion in response to insulin receptor haploinsufficiency. Tissue specific dissection of this reduced insulin signaling phenotype revealed a critical role for insulin signaling in specific peripheral tissues. Knockdown of the Drosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophila mechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics.
SUMMARY
Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila orthologue of Neuromedin U receptors (NMUR), in insulin-producing cells phenocopied limostatin deficiency, and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β-cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output.
The TOR (target of rapamycin) signal transduction network monitors intra-and extracellular conditions that favor cell growth. Research during the last decade has revealed a modular structure of the TOR signaling network. Each signaling module senses a particular set of signals from the cellular milieu and exerts regulatory control towards TOR activity. The TOR pathway responds to growth factor signals, nutrient availability, and cellular stresses like hypoxia and energy stress. The signaling modules and their molecular components constituting the TOR network are remarkably conserved in both sequence and function across species. In yeast, roundworms, flies, and mice, the TOR pathway has been shown to regulate lifespan. Correspondingly, genetic, dietary or pharmacological manipulation of individual signaling modules as well as TOR activity itself extends lifespan in these model organisms. We discuss the potential impact of manipulating TOR activity for human health and lifespan.
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