Lifespan extension by increased expression of the Drosophila homologue of the IGFBP7 tumour suppressor

Nazif Alic,Linda Partridge,Matthew P Hoddinott,Giovanna Vinti

doi:10.1111/j.1474-9726.2010.00653.x

Nazif Alic, Linda Partridge + Show 2 more

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https://doi.org/10.1111/j.1474-9726.2010.00653.x

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Journal: Aging Cell	Publication Date: Jan 12, 2011
Citations: 124	License type: unspecified-oa

Affiliation: University College London

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.

Highlights

The insulin ⁄ insulin-like growth factor (IGF) signalling (IIS) pathway is an evolutionarily conserved neuroendocrine signalling pathway that controls a variety of processes and traits in animals, including growth and development, energy metabolism, reproduction and stress resistance
We first determined if increasing the amount of Imaginal morphogenesis protein-Late 2 (Imp-L2) can modulate IIS in adult flies at a molecular level
This manipulation resulted in viable flies and an 80% increase in the levels of Imp-L2 mRNA in the adult female (Fig. 1A), as detected by qPCR

Summary

Introduction

The insulin ⁄ insulin-like growth factor (IGF) signalling (IIS) pathway is an evolutionarily conserved neuroendocrine signalling pathway that controls a variety of processes and traits in animals, including growth and development, energy metabolism, reproduction and stress resistance. Genetic manipulations of pathway components that result in dampened IIS extend lifespan in worms, flies and mice, and ameliorate age-dependent functional decline (Tatar et al, 2003; Piper et al, 2008). Central to the pathway are insulin-like ligands, which include insulin, IGF-I and IGF-II in mammals (White, 2006); 38 insulin-like peptides in worms (Pierce et al, 2001) and the seven Drosophila insulin-like peptide (DILPs) in flies (Brogiolo et al, 2001). The ligands mediate cell-to-cell signalling by activating an insulin receptor-like receptor, leading to the activation of PI3-kinase – Akt, TOR and ERK intracellular signalling pathways (Tatar et al, 2003; White, 2006; Piper et al, 2008). Not all manipulations of the pathway result in lifespan extension (Clancy et al, 2001; Tatar et al, 2001; Hwangbo et al, 2004; Selman et al, 2008; Ikeya et al, 2009), suggesting that the pathway needs to be manipulated to a specific level of signal reduction and in specific tissues to achieve enhanced longevity

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