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Lifespan extension by increased expression of the Drosophila homologue of the IGFBP7 tumour suppressor.
Aging Cell. 2011 Feb; 10(1):137-47
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19 Apr 2012
New Finding
DOI: 10.3410/f.14266987.15779100
In this paper, Alic et al. report that Drosophila lifespan is extended by overexpression of Imaginal morphogenesis protein-Late 2 (IMP-L2), a gene previously found to encode an insulin-binding protein that limits insulin ligand availability and systemically antagonizes insulin signaling. Moreover, the...Continue reading
In this paper, Alic et al. report that Drosophila lifespan is extended by overexpression of Imaginal morphogenesis protein-Late 2 (IMP-L2), a gene previously found to encode an insulin-binding protein that limits insulin ligand availability and systemically antagonizes insulin signaling. Moreover, the authors demonstrate that IMP-L2 and insulin-like peptides (ILPs) are involved in a regulatory feedback circuit.
Alic et al. confirm previous findings showing that IMP-L2 can bind to native ILPs and decrease insulin signaling, and demonstrate - for the first time - that IMP-L2 overexpression can extend lifespan, either when activated ubiquitously or when expressed in ILP-producing neurons, the fat body, or gut. Remarkably, the authors go on to show that IMP-L2 is involved in a regulatory feedback loop: IMP-L2 overactivation causes compensatory upregulation of ILP 2, 3, and 5 transcript levels, whereas a genetic deletion encompassing the ilp 2, 3, and 5 loci causes a decrease in IMP-L2 levels. To my mind, this is a very interesting finding for two reasons. First, the results are reminiscent of observations in germline-ablated flies {1}: such flies live longer, exhibit increased levels of IMP-L2, and exhibit downregulation of peripheral insulin signaling, yet at the same time have increased mRNA levels of ILPs 2, 3, and 5; thus, the longevity of germline-less flies is perhaps a direct consequence of increased IMP-L2 activity. Second, and more importantly, the results by Alic et al. support the notion that increased ILP message is not sufficient to compensate for downregulation of insulin signaling by IMP-L2 and does not shorten lifespan. This implies that important aspects of insulin signaling can be uncoupled from the regulation of lifespan. Since IMP-L2 is particularly strongly expressed in the fat body, gut, and gonads, whereas ILPs 2, 3, and 5 are predominantly expressed in the insulin-producing neurons of the fly brain, it will be very interesting to study in further detail whether and how this endocrine inter-tissue communication modulates lifespan.
NB: I am an author on reference {1}.
FOLLOW-UP COMMENT ADDED
Since this evaluation was published, the evaluating Faculty Member or Associate Member has submitted a follow-up comment.
Alic et al. confirm previous findings showing that IMP-L2 can bind to native ILPs and decrease insulin signaling, and demonstrate - for the first time - that IMP-L2 overexpression can extend lifespan, either when activated ubiquitously or when expressed in ILP-producing neurons, the fat body, or gut. Remarkably, the authors go on to show that IMP-L2 is involved in a regulatory feedback loop: IMP-L2 overactivation causes compensatory upregulation of ILP 2, 3, and 5 transcript levels, whereas a genetic deletion encompassing the ilp 2, 3, and 5 loci causes a decrease in IMP-L2 levels. To my mind, this is a very interesting finding for two reasons. First, the results are reminiscent of observations in germline-ablated flies {1}: such flies live longer, exhibit increased levels of IMP-L2, and exhibit downregulation of peripheral insulin signaling, yet at the same time have increased mRNA levels of ILPs 2, 3, and 5; thus, the longevity of germline-less flies is perhaps a direct consequence of increased IMP-L2 activity. Second, and more importantly, the results by Alic et al. support the notion that increased ILP message is not sufficient to compensate for downregulation of insulin signaling by IMP-L2 and does not shorten lifespan. This implies that important aspects of insulin signaling can be uncoupled from the regulation of lifespan. Since IMP-L2 is particularly strongly expressed in the fat body, gut, and gonads, whereas ILPs 2, 3, and 5 are predominantly expressed in the insulin-producing neurons of the fly brain, it will be very interesting to study in further detail whether and how this endocrine inter-tissue communication modulates lifespan.
NB: I am an author on reference {1}.
FOLLOW-UP COMMENT ADDED
Since this evaluation was published, the evaluating Faculty Member or Associate Member has submitted a follow-up comment.
References
1.
Drosophila germ-line modulation of insulin signaling and lifespan.
Proc Natl Acad Sci USA 2008 Apr 29; 17(105):6368-73
PMID: 18434551
Disclosures
None declared
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Flatt T: F1000Prime Recommendation of [Alic N et al., Aging Cell 2011, 10(1):137-47]. In F1000Prime, 19 Apr 2012; DOI: 10.3410/f.14266987.15779100. F1000Prime.com/14266987#eval15779100
F1000Prime Recommendations, Dissents and Comments for [Alic N et al., Aging Cell 2011, 10(1):137-47]. In F1000Prime, 21 May 2013; F1000Prime.com/14266987
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Comment by:
Thomas Flatt,
University of Lausanne
Evaluator | 19 Apr 2012, 11:21 AM
Evaluator | 19 Apr 2012, 11:21 AM
Note that the lifespan extension by overexpression of IMP-L2 reported by Alic et al. has recently been independently confirmed by Paik et al. (2012; "Misexpression screen delineates novel genes controlling Drosophila lifespan", Mechanisms of Ageing and Development, In Press).
Disclosures:
None
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.
DOI: 10.1111/j.1474-9726.2010.00653.x
PMID: 21108726
