Lifespan Extension by Increased Expression of the Drosophila Homologue of the IGFBP7 Tumour Suppressor

Aging Cell. 2011 Feb;10(1):137-47. doi: 10.1111/j.1474-9726.2010.00653.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Aging / genetics
  • Aging / metabolism
  • Animals
  • Down-Regulation
  • Drosophila / physiology*
  • Drosophila Proteins / agonists
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Eukaryotic Initiation Factor-4E / genetics
  • Eukaryotic Initiation Factor-4E / metabolism
  • Female
  • Gene Expression / physiology
  • Inhibitor of Apoptosis Proteins / agonists*
  • Inhibitor of Apoptosis Proteins / genetics
  • Insulin / metabolism
  • Insulin-Like Growth Factor Binding Proteins / genetics*
  • Insulin-Like Growth Factor Binding Proteins / metabolism
  • Longevity* / genetics
  • Male
  • Oxidative Stress / physiology
  • Protein Binding / physiology
  • RNA, Messenger / biosynthesis
  • Sequence Homology, Amino Acid
  • Signal Transduction / physiology
  • Up-Regulation / physiology

Substances

  • DIAP2 protein, Drosophila
  • Drosophila Proteins
  • Eukaryotic Initiation Factor-4E
  • Inhibitor of Apoptosis Proteins
  • Insulin
  • Insulin-Like Growth Factor Binding Proteins
  • RNA, Messenger