Authors: Alic N; Hoddinott MP; Vinti G; Partridge L
Abstract: Mammals possess multiple insulin-like growth factor (IGF) binding proteins (IGFBPs), and related proteins, that modulate the activity of insulin/IGF signalling (IIS), a conserved neuroendocrine signalling pathway that affects animal lifespan. Here, we examine if increased levels of an IGFBP-like protein can extend lifespan, using Drosophila as the model organism. We demonstrate that Imaginal morphogenesis protein-Late 2 (IMP-L2), a secreted protein and the fly homologue of the human IGFBP7 tumour suppressor, is capable of binding at least two of the seven Drosophila insulin-like peptides (DILPs), namely native DILP2 and DILP5 as present in the adult fly. Increased expression of Imp-L2 results in phenotypic changes in the adult consistent with down-regulation of IIS, including accumulation of eIF-4E binding protein mRNA, increase in storage lipids, reduced fecundity and enhanced oxidative stress resistance. Increased Imp-L2 results in up-regulation of dilp2, dilp3 and dilp5 mRNA, revealing a feedback circuit that is mediated via the fly gut and/or fat body. Importantly, over-expression of Imp-L2, ubiquitous or restricted to DILP-producing cells or gut and fat body, extends lifespan. This enhanced longevity can also be observed upon adult-onset induction of Imp-L2, indicating it is not attributable to developmental changes. Our findings point to the possibility that an IGFBP or a related protein, such as IGFBP7, plays a role in mammalian aging.
Keywords: Adipose Tissue/metabolism; Aging/genetics/metabolism; Animals; Down-Regulation; Drosophila/*physiology; Drosophila Proteins/agonists/*genetics/metabolism; Eukaryotic Initiation Factor-4E/genetics/metabolism; Female; Gene Expression/physiology; Inhibitor of Apoptosis Proteins/*agonists/genetics; Insulin/metabolism; Insulin-Like Growth Factor Binding Proteins/*genetics/metabolism; *Longevity/genetics; Male; Oxidative Stress/physiology; Protein Binding/physiology; RNA, Messenger/biosynthesis; Sequence Homology, Amino Acid; Signal Transduction/physiology; Up-Regulation/physiology|
Journal: Aging cell Volume: 10 Issue: 1 Pages: 137-47 Date: Nov. 27, 2010 PMID: 21108726 |
Alic N, Hoddinott MP, Vinti G, Partridge L (2011) Lifespan extension by increased expression of the Drosophila homologue of the IGFBP7 tumour suppressor. Aging cell 10: 137-47.
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