Younger for Longer: Insulin Signalling, Immunity and Ageing
Francis R.G. Amrit,
Robin C. May.
Genes, the environment and stochastic factors such as lifestyle are major contributors to the universally shared phenomenon of ageing. It is now clear that these different inputs act through evolutionarily conserved pathways to regulate lifespan in a wide range of animals. Among several such pathways, the IIS [Insulin/IGF (Insulin – like growth factor)- like signalling] pathway, initially identified in the roundworm, Caenorhabditis elegans, is the most significant modulator of ageing. Consisting of a PI 3 kinase-signalling cascade downstream of a transmembrane insulin-like growth factor receptor, this pathway ultimately regulates the activity of a transcription factor with a huge repertoire of transcriptional outputs. The effect of this is that the IIS pathway co-ordinately controls several processes, including immunity and stress resistance, which in tandem seem to regulate longevity. Since both the function and molecular architecture of the IIS pathway is conserved from yeast to mammals, this coordinate regulation appears to be a general feature of the ageing processes in animals. Here we review the evolutionary conservation of the IIS pathway and discuss this in relation to recent findings on the molecular basis of ageing. We also reflect on the impact and significance of the evolutionary diversification of this pathway and propose a model for how such differences could explain both inter and intra-species differences in ageing.
Keywords: Ageing, daf-16, insulin signalling, C. elegans, IIS pathway, Caenorhabditis elegans, Quahog (Mercenaria mercenaria, homeostasis, mutations, Antagonistic Pleiotropy Theory, Free Radical Hypothesis, reactive oxygen species (ROS), Oxidative damage theory, Rate of Living Hypothesis, sod, Hayflick limit, Drosophila mela-nogaster, Hermaphro-ditism, tra-2, swm-1, age-1, pdk-1, akt-1, sgk-1, Sirtuin, (Sir2), Class III histone/protein deacetylases (HDACs), Hst1-4, (Sir2.1), (dSir2), Sirt 1-7, NAD+, nicotinamide (NAM), 1-O-acetyl-ADP-ribose, Drosophila, Target of Rapamycin path-way (TOR), daf-2, bec-1, lgg-1, Salmonella typhimurium, autophagy, Pseudomonas aeruginosa, sek-1 (MAPKK), Daf-c, Daf-d, D. melanogaster, Mus musculus, daf-18, ins-7, transmembrane receptor, phosphatidyli-nositol 3-kinase (PI 3-kinase), the PI 3-kinase Dp110/p60, FOXO family, FOXO1, FOXO3a, FOXO4, FOXO6, apoptosis, Leukaemia-Initiating Cells (LICs), smk-1, Serratia marces-cens, glp-1, Ras/Cyr1/PKA pathway
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