The role of insulin/IGF-1 signaling in the longevity of model invertebrates, C. elegans and D. melanogaster

Abstract

Insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway regulates aging in many organisms, ranging from simple invertebrates to mammals, including humans. Many seminal discoveries regarding the roles of IIS in aging and longevity have been made by using the roundworm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. In this review, we describe the mechanisms by which various IIS components regulate aging in C. elegans and D. melanogaster. We also cover systemic and tissue-specific effects of the IIS components on the regulation of lifespan. We further discuss IIS-mediated physiological processes other than aging and their effects on human disease models focusing on C. elegans studies. As both C. elegans and D. melanogaster have been essential for key findings regarding the effects of IIS on organismal aging in general, these invertebrate models will continue to serve as workhorses to help our understanding of mammalian aging. [BMB Reports 2016; 49(2): 81-92].

Fig. 1.. Conserved longevity-regulatory components of insulin/IGF-1 signaling pathway in C. elegans and D. melanogaster. Insulin-like peptides (ILPs in Caenorhabditis elegans and DILPs in Drosophila melanogaster) bind to insulin/IGF-1 receptor (DAF-2 in C. elegans and dInR in D. melanogaster) and lead to its phosphorylation. Inhibition of insulin/IGF-1 receptor results in decreased binding to the insulin receptor substrate (IST-1 in C. elegans and CHICO in D. melanogaster), which in turn decreases the activity of phosphoinositide-3 kinase (AGE-1 in C. elegans and PI3K in D. melanogaster) that converts PIP₂ to PIP₃; conversely, the PTEN phosphatase (DAF-18 in C. elegans and dPTEN in D. melanogaster) functions to antagonize the activity of the phosphoinositide-3 kinase by converting PIP₃ to PIP₂. Decreased PIP₃ levels lead to decreased activities of phosphoinositide-dependent kinase 1 (PDK-1 in C. elegans and dPDK1 in D. melanogaster) and the serine/threonine-specific protein kinase B (AKT-1/-2 in C. elegans and dAkt1 in D. melanogaster), and the activation of downstream transcription factor FOXO (DAF-16 in C. elegans and dFOXO in D. melanogaster). Reduced insulin/IGF-1 signaling in C. elegans also increases the activities of heat shock transcription factor-1 (HSF-1) and SKN-1 (NRF2). These transcription factors regulate the expression of target genes, which contribute to longevity.

Fig. 2.. The role of insulin/IGF-1 signaling in C. elegans physiology and age-related disease models. Insulin/IGF-1 signaling (IIS) regulates dauer formation, stress resistance, and the models of age-related diseases in C. elegans. Reduced IIS promotes dauer formation and enhances resistance to various external and internal stresses, and pathogens. Inhibition of IIS also ameliorates defects associated with various human disease models. These protective effects of reduced IIS contribute to organismal longevity.