Lifespan extension by increased expression of the Drosophila homologue of the IGFBP7 tumour suppressor.
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.
Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
Nazif
N
Alic
Matthew P
MP
Hoddinott
Giovanna
G
Vinti
Linda
L
Partridge
D000273:Adipose Tissue / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D051034:Inhibitor of Apoptosis Proteins / Q000819:agonists* / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
C111892:DIAP2 protein, Drosophila; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; D051034:Inhibitor of Apoptosis Proteins; D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger