Insulin/IGF-1 Signaling (IIS) Pathway

The Insulin/IGF-1 Signaling (IIS) pathway is a significant area of study in the field of longevity and aging research. This pathway is known to play a critical role in the regulation of lifespan across various species, including C. elegans, Drosophila melanogaster, and Mus musculus. Understanding the IIS pathway provides insights into the mechanisms of aging and potential interventions for age-related diseases.

Overview

The IIS pathway is primarily involved in the regulation of growth, development, metabolism, and lifespan. It is activated by the binding of insulin and insulin-like growth factors (IGF) to their respective receptors, leading to a cascade of intracellular events. The pathway influences various cellular processes such as glucose metabolism, protein synthesis, and stress resistance.

Key Components

Insulin and IGF-1 Receptors: These receptors are activated upon binding with insulin and IGF-1.
PI3K (Phosphoinositide 3-kinase): PI3K is activated by insulin and IGF-1 receptors, leading to the activation of downstream signaling molecules.
AKT/PKB (Protein Kinase B): AKT is a critical kinase in the pathway, promoting growth and survival signals.
FOXO (Forkhead box O) Transcription Factors: FOXO factors are negatively regulated by the IIS pathway and are crucial in stress resistance and longevity.

Role in Longevity

Several studies have shown that reduced IIS signaling can lead to an extended lifespan in various organisms. This is primarily due to the enhanced stress resistance and altered metabolism resulting from decreased IIS activity.

C. elegans Studies

In Caenorhabditis elegans, mutations in the daf-2 gene, which encodes an insulin/IGF-1 receptor, lead to a significant increase in lifespan. This effect is mediated through the downstream daf-16 gene, a homolog of the FOXO family of transcription factors.

Mammalian Models

In mice, reduced IGF-1 signaling has been associated with extended lifespan and improved healthspan. Similar findings have been observed in other mammalian models, suggesting a conserved mechanism of lifespan regulation through the IIS pathway.

Potential Therapeutic Implications

The manipulation of the IIS pathway offers potential therapeutic avenues for age-related diseases, including diabetes, neurodegenerative diseases, and cancer. Pharmacological agents that can modulate this pathway may have significant implications in promoting healthy aging and longevity.

References

^[1] – Study on lifespan extension in C. elegans via daf-2 mutation.
^[2] – Investigation of IIS pathway in mammalian aging.
^[3] – Analysis of FOXO transcription factors in longevity.

↑ Schwab M et al.: Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol 2003. (PMID 12359865) [PubMed] [DOI] Abstract
P-glycoprotein is an ATP-dependent efflux pump that contributes to the protection of the body from environmental toxins. It transports a huge variety of structurally diverse compounds. P-glycoprotein is involved in limiting absorption of xenobiotics from the gut lumen, in protection of sensitive tissues (brain, fetus, testis), and in biliary and urinary excretion of its substrates. P-glycoprotein can be inhibited or induced by xenobiotics, thereby contributing to variable drug disposition and drug interactions. Recently, several SNPs have been identified in the MDR1 gene, some of which can affect P-glycoprotein expression and function. Potential implications of MDR1 polymorphisms for drug disposition, drug effects, and disease risk are discussed.
↑ Schernthaner JP et al.: Control of seed germination in transgenic plants based on the segregation of a two-component genetic system. Proc Natl Acad Sci U S A 2003. (PMID 12740441) [PubMed] [DOI] [Full text] Abstract
We have developed a repressible seed-lethal (SL) system aimed at reducing the probability of transgene introgression into a population of sexually compatible plants. To evaluate the potential of this method, tobacco plants were transformed with an SL construct comprising gene 1 and gene 2 from Agrobacterium tumefaciens whereby gene 1 was controlled by the seed-specific phaseolin promoter modified to contain a binding site for the Escherichia coli TET repressor (R). The expression of this construct allows normal plant and seed development but inhibits seed germination. Plants containing the SL construct were crossed with plants containing the tet R gene to derive plant lines where the expression of the SL construct is repressed. Plant lines that contained both constructs allowed normal seed formation and germination, whereas seeds in which the SL construct was separated from the R gene through segregation did not germinate. The requirements of such a method to efficiently control the flow of novel traits among sexually compatible plants are discussed.
↑ Ribasés M et al.: Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 2004. (PMID 15115760) [PubMed] [DOI] Abstract
Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (-270C>T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case-control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the 'Factors in Healthy Eating' project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the -270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.

[pmid12359865-1] Schwab M et al.: Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol 2003. (PMID 12359865) [PubMed] [DOI] Abstract
P-glycoprotein is an ATP-dependent efflux pump that contributes to the protection of the body from environmental toxins. It transports a huge variety of structurally diverse compounds. P-glycoprotein is involved in limiting absorption of xenobiotics from the gut lumen, in protection of sensitive tissues (brain, fetus, testis), and in biliary and urinary excretion of its substrates. P-glycoprotein can be inhibited or induced by xenobiotics, thereby contributing to variable drug disposition and drug interactions. Recently, several SNPs have been identified in the MDR1 gene, some of which can affect P-glycoprotein expression and function. Potential implications of MDR1 polymorphisms for drug disposition, drug effects, and disease risk are discussed.

[pmid12740441-2] Schernthaner JP et al.: Control of seed germination in transgenic plants based on the segregation of a two-component genetic system. Proc Natl Acad Sci U S A 2003. (PMID 12740441) [PubMed] [DOI] [Full text] Abstract
We have developed a repressible seed-lethal (SL) system aimed at reducing the probability of transgene introgression into a population of sexually compatible plants. To evaluate the potential of this method, tobacco plants were transformed with an SL construct comprising gene 1 and gene 2 from Agrobacterium tumefaciens whereby gene 1 was controlled by the seed-specific phaseolin promoter modified to contain a binding site for the Escherichia coli TET repressor (R). The expression of this construct allows normal plant and seed development but inhibits seed germination. Plants containing the SL construct were crossed with plants containing the tet R gene to derive plant lines where the expression of the SL construct is repressed. Plant lines that contained both constructs allowed normal seed formation and germination, whereas seeds in which the SL construct was separated from the R gene through segregation did not germinate. The requirements of such a method to efficiently control the flow of novel traits among sexually compatible plants are discussed.

[pmid15115760-3] Ribasés M et al.: Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 2004. (PMID 15115760) [PubMed] [DOI] Abstract
Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (-270C>T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case-control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the 'Factors in Healthy Eating' project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the -270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.

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