InsulinIGFI Signaling and Lifespan Regulation

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One of the two main classes of the lifespan-extension mutations of C. elegans is related to the insulin/IGF-I signaling. Insulin/IGF-I signaling is mediated by the DAF-2 insulin/IGF-I receptor. The daf-2 mutants that reduce the activity of DAF-2 remain youthful and active much longer than the wild-type animals and live more than twice as long [reviewed in Ref. (9)]. The lifespan-extension phenotype of the daf-2 is suppressed by mutations in daf-16, indicating that daf-16 is negatively regulated by DAF-2 signaling and is the major downstream effector. The daf-16 encodes a FOXO transcription factor (16,17).

Binding of insulin/IGF-I-like ligands to the DAF-2 insulin/IGF-I receptor controls insulin/IGF-I signaling. There are at least 38 genes (ins) encoding insulin/IGF-I-like peptides in C. elegans (49,50). Many of these genes are divergent insulin superfamily members, and as the specific ligand has not yet been identified, these members may be possible to have complex and redundant roles. The daf-28 gene encodes insulin-like peptide. A dominant-negative allele of the daf-28 mutant lives 10% longer than wild-type animals. A phenotype of the daf-28 mutant is rescued by ins-4 or ins-6 transgene, suggesting a redundant nature (51). Some ins genes are expressed in sensory neurons (50,51). Environmental cues such as food, pheromones and temperature may affect insulin/IGF signaling through different expression and the secretion of various INS peptides.

The mutation of age-1, which encodes the PI3 (phosphoinositide-3-OH) kinase catalytic subunit, doubles the lifespan in C. elegans (14,15).

The current model of insulin/IGF-I signaling is as follows (Fig. 4.1). The DAF-2 insulin/IGF-I receptor transduces signals by activating AGE-1. AGE-1 PI3 kinase phosphorylates PIP2 to generate the second messenger PIP3.

Environmental Cues Food

Temperature Pheromone

Sensory Neurons

Environmental Cues Food

Temperature Pheromone

Sensory Neurons

Longevity

Figure 4.1 The signaling pathways regulating lifespan in C. elegans. C. elegans senses environmental cues including food, pheromones, and temperature by sensory organs. The environmental information is transduced into at least four signaling pathways including TGF-y6, cGMP, serotonin, and insulin/IGF-I. The serotonergic signaling affects the TGF-y6 and the insulin/IGF-I signaling. TGF-y6 is secreted by a pair of specific sensory neurons. Insulin/IGF-I ligands appear also to be secreted by sensory neurons and are rendered in neuroendocrine system to bind to the receptor DAF-2. This signal is finally transduced to regulate the activity of the transcription factor DAF-16. TGF-y6, cGMP, and insulin/IGF-I signaling pathways converge in the regulation of the activity of P450 DAF-9 to synthesize lipophilic (steroid?) hormones. Those appear to circulate systemi-cally and activate the nuclear hormone receptor DAF-12. The gonadal tissue and germline cells send the signal that regulates to activate DAF-16 and DAF-12. Various stresses also regulate to activate heat-shock transcription factor HSF-1 as well as DAF-16. These transcription factors in concert regulate the aging rate and lifespan by controlling transcription of the target genes.

Longevity

Figure 4.1 The signaling pathways regulating lifespan in C. elegans. C. elegans senses environmental cues including food, pheromones, and temperature by sensory organs. The environmental information is transduced into at least four signaling pathways including TGF-y6, cGMP, serotonin, and insulin/IGF-I. The serotonergic signaling affects the TGF-y6 and the insulin/IGF-I signaling. TGF-y6 is secreted by a pair of specific sensory neurons. Insulin/IGF-I ligands appear also to be secreted by sensory neurons and are rendered in neuroendocrine system to bind to the receptor DAF-2. This signal is finally transduced to regulate the activity of the transcription factor DAF-16. TGF-y6, cGMP, and insulin/IGF-I signaling pathways converge in the regulation of the activity of P450 DAF-9 to synthesize lipophilic (steroid?) hormones. Those appear to circulate systemi-cally and activate the nuclear hormone receptor DAF-12. The gonadal tissue and germline cells send the signal that regulates to activate DAF-16 and DAF-12. Various stresses also regulate to activate heat-shock transcription factor HSF-1 as well as DAF-16. These transcription factors in concert regulate the aging rate and lifespan by controlling transcription of the target genes.

On the other hand, DAF-18 PTEN dephosphorylates PIP3 and thus antagonizes the action of AGE-1. Thus, the PIP3 level is determined by a balance between generation by AGE-1 PI3 kinase and degradation by DAF-18 PTEN. PIP3 activates PDK-1 (3-phosphoinositide-dependent kinase-1), which in turn phos-phorylates and activates AKT-1 /AKT-2/SGK-1 Ser/Thr kinase. AKT-1 / AKT-2/SGK-1 phosphorylates and inactivates the DAF-16 transcription factor to be sequestered from the nucleus to the cytoplasm. In this state, adults age rapidly. On the contrary, when DAF-2 signaling is reduced, DAF-16 is eventually translocated to the nucleus to promote transcription of target genes. In fact, disrupting AKT-consensus phosphorylation sites in DAF-16 causes nuclear accumulation, although the nuclear accumulation is not sufficient for lifespan extension (52,53).

C. elegans worms grow through four larval stages (L1-L4) before reaching maturity. However, when the food supply is limited and the population density is high at the L1 stage, animals become dauer larvae after the L2 stage. The dauer larva is a developmentally arrested dispersal stage and lives up to several months, greatly exceeding the normal adult lifespan of about 3 weeks under stressful environmental conditions (53). It seems that the dauer stage is nonaging, because the post-dauer life span is not affected by a prolonged dauer stage of up to 2 months (54). The dauer larva is more resistant to a variety of environmental stresses, including hypoxia, heat, desiccation, and oxidative stress and has increased levels of SOD and catalase (21,55). The expression of the MnSOD gene (sod-3) is higher in the dauer larvae than in the adults (23). As dauer larvae live much longer than adults, some genes expressing altered levels in dauer state may be the key to longevity. By using serial analysis of gene expression (SAGE), Jones et al. (56) found that the expression of tts-1 (transcribed telomere-like sequence), a variant histone H1 and a nucleosome assembly protein possibly relating to the structure or stability of chromatin is high in dauer larvae. These results suggest that the chromatin structure may change to be more stable in the dauer state than in the growing state. Holt and Riddle (57) examined gene expression profiles of carbohydrate metabolism in dauer larvae by using SAGE. A high gene expression of pyruvate kinase, alcohol dehydrogenase, a putative cytosolic fumarate reductase, two pyruvate dehydrogenase components, and a succinyl CoA synthetase a subunit implies that anaerobic metabolism is prominent in dauer larvae.

By genetic analysis of mutants displaying "dauer larva formation abnormal," Daf phenotype, a number of genes that regulate dauer formation have been identified (53). These genes have been assembled into four neuroendocrine signaling pathways: TGF-ß/SMAD, cGMP, serotonin (58) and insulin/IGF-I. DAF-7, a TGF-b family member expressed in a pair of sensory neurons, signals through transmembrane receptor kinases DAF-4 and DAF-1. These receptors regulate the activities of DAF-8 and DAF-14, dwarfin/MAD/DPC-4, and DAF-3, SMAD transcription factors. The cGMP pathway is composed of DAF-11, transmembrane guanyl cyclase and DAF-21, HSP90. The mutant adults in the TGF-^ and cGMP pathway do not exhibit a lifespan-extension phenotype. The serotonin pathway affects TGF-^ and insulin/IGF-I signaling. The mutant of the serotonin pathway has a longer reproductive period than wild-type animals (58).

TGF-^, insulin/IGF-I, and cGMP signaling pathways converge on DAF-9, a member of the cytochrome P450 hydroxylase family (59,60) that is implicated in the synthesis of a lipophilic hormone acting upstream of DAF-12, nuclear hormone receptor (61,62). Sterols may be the DAF-9 substrate and DAF-12 ligand because cholesterol deprivation displays daf-9 mutant phenotype. DAF-12 is expressed within almost all cells, whereas DAF-9 is expressed within two sensory neurons, hypodermal cells, and somatic gonadal cells thought to be endocrine tissues.

In these pathways, the mutations in the insulin/IGF-I pathway mainly affect the adult lifespan. The simplest interpretation of these observations is that the dauer larvae have an efficient life-maintenance mechanism for long dauer survival under stressful conditions, and that the insulin/IGF-I pathway is closely related to this mechanism (12,63). Although the mutants in the TGF-B and cGMP pathways do not display a lifespan-extension phenotype, these pathways interact with the insulin/IGF-I pathway at daf-9 position to affect lifespan (Fig 4.1). The daf-9 mutations extend lifespan at a certain temperature (59,60). The daf-9 and daf-12 mutations enhance the lifespan-extension of certain daf-2 mutants (63,64).

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