Insulin/IGF-1 Signaling (IIS) Pathway: Difference between revisions

Latest revision as of 23:40, 15 January 2024

The Insulin/IGF-1 Signaling (IIS) pathway is a significant biochemical pathway that has been extensively studied in the context of aging and longevity. This pathway, conserved across various species, plays a critical role in regulating lifespan, stress resistance, and metabolism.

Overview

The IIS pathway is primarily known for its function in glucose metabolism, growth, and development. It is activated by the binding of insulin and insulin-like growth factors (IGF) to their respective receptors, triggering a cascade of intracellular signaling events. This pathway's significance in longevity research was first highlighted in Caenorhabditis elegans and subsequently in other model organisms, including Drosophila melanogaster (fruit flies) and mice.

Mechanism

The pathway involves several key components:

Insulin and IGF-1 Receptors: These receptors, upon activation by insulin or IGF-1, initiate the signaling cascade.
PI3K-Akt Pathway: Activation of PI3K (phosphoinositide 3-kinase) leads to the activation of Akt, a critical kinase in this pathway.
FOXO Transcription Factors: Akt negatively regulates FOXO transcription factors, which are involved in stress resistance and longevity.
mTOR Complex: The mTOR (mechanistic target of rapamycin) complex, another downstream target, is involved in cell growth and autophagy, processes crucial for aging.

Role in Longevity

Research in model organisms has shown that reducing IIS pathway activity can lead to increased lifespan and enhanced resistance to various stresses. In C. elegans, mutations that reduce the function of the daf-2 gene, which encodes an insulin/IGF-1 receptor, result in a significantly extended lifespan. Similarly, in fruit flies, reduced IGF signaling is associated with increased lifespan.

Human Relevance

The implications of the IIS pathway in human aging are an area of active research. Variations in genes related to this pathway, such as the FOXO3 gene, have been associated with longevity in human populations. However, the exact mechanisms and potential for therapeutic intervention in humans remain to be fully elucidated.

Research and Therapeutic Potentials

There is ongoing research into pharmacological agents that can modulate the IIS pathway to potentially extend healthy lifespan. Drugs like metformin and rapamycin, which indirectly influence this pathway, are of particular interest in longevity research.

Conclusion

The Insulin/IGF-1 Signaling pathway is a cornerstone in the study of the molecular biology of aging. Its conservation across species and clear influence on lifespan and healthspan make it a critical target for aging research. Future studies and clinical trials are expected to further clarify its role in human aging and potential for therapeutic interventions.

References

↑ van Heemst D: Insulin, IGF-1 and longevity. Aging Dis 2010. (PMID 22396862) [PubMed] [Full text] It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. Likewise, substantial increases in lifespan are associated with mutations that reduce insulin/IGF-1 signaling in the fruit fly Drosophila melanogaster. In invertebrates, multiple insulin-like ligands exist that bind to a common single insulin/IGF-1 like receptor. In contrast, in mammals, different receptors exist that bind insulin, IGF-1 and IGF-2 with different affinities. In several mouse models, mutations that are associated with decreased GH/IGF-1 signaling or decreased insulin signaling have been associated with enhanced lifespan. However, the increased complexity of the mammalian insulin/IGF-1 system has made it difficult to separate the roles of insulin, GH and IGF-1 in mammalian longevity. Likewise, the relevance of reduced insulin and IGF-1 signaling in human longevity remains controversial. However, studies on the genetic and metabolic characteristics that are associated with healthy longevity and old age survival suggest that the conserved ancient IIS pathway may also play a role in human longevity.

[pmid22396862-1] van Heemst D: Insulin, IGF-1 and longevity. Aging Dis 2010. (PMID 22396862) [PubMed] [Full text] It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. Likewise, substantial increases in lifespan are associated with mutations that reduce insulin/IGF-1 signaling in the fruit fly Drosophila melanogaster. In invertebrates, multiple insulin-like ligands exist that bind to a common single insulin/IGF-1 like receptor. In contrast, in mammals, different receptors exist that bind insulin, IGF-1 and IGF-2 with different affinities. In several mouse models, mutations that are associated with decreased GH/IGF-1 signaling or decreased insulin signaling have been associated with enhanced lifespan. However, the increased complexity of the mammalian insulin/IGF-1 system has made it difficult to separate the roles of insulin, GH and IGF-1 in mammalian longevity. Likewise, the relevance of reduced insulin and IGF-1 signaling in human longevity remains controversial. However, studies on the genetic and metabolic characteristics that are associated with healthy longevity and old age survival suggest that the conserved ancient IIS pathway may also play a role in human longevity.

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-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.
+The '''Insulin/IGF-1 Signaling (IIS) pathway''' is a significant biochemical pathway that has been extensively studied in the context of aging and longevity. This pathway, conserved across various species, plays a critical role in regulating lifespan, stress resistance, and metabolism.
-==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.
+== Overview ==
-==Key Components==
+The IIS pathway is primarily known for its function in glucose metabolism, growth, and development. It is activated by the binding of insulin and insulin-like growth factors (IGF) to their respective receptors, triggering a cascade of intracellular signaling events. This pathway's significance in longevity research was first highlighted in ''Caenorhabditis elegans'' and subsequently in other model organisms, including ''Drosophila melanogaster'' (fruit flies) and mice.
-*'''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.
+== Mechanism ==
-*'''AKT/PKB (Protein Kinase B)''': AKT is a critical kinase in the pathway, promoting growth and survival signals.
+The pathway involves several key components:
-*'''FOXO (Forkhead box O) Transcription Factors''': FOXO factors are negatively regulated by the IIS pathway and are crucial in stress resistance and longevity.
+* '''Insulin and IGF-1 Receptors:''' These receptors, upon activation by insulin or IGF-1, initiate the signaling cascade.
-==Role in Longevity==
+* '''PI3K-Akt Pathway:''' Activation of PI3K (phosphoinositide 3-kinase) leads to the activation of Akt, a critical kinase in this pathway.
-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.
+* '''FOXO Transcription Factors:''' Akt negatively regulates FOXO transcription factors, which are involved in stress resistance and longevity.
-===''C. elegans'' Studies===
+* '''mTOR Complex:''' The mTOR (mechanistic target of rapamycin) complex, another downstream target, is involved in cell growth and autophagy, processes crucial for aging.
-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===
+== Role in Longevity ==
-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.
+Research in model organisms has shown that reducing IIS pathway activity can lead to increased lifespan and enhanced resistance to various stresses. In ''C. elegans'', mutations that reduce the function of the daf-2 gene, which encodes an insulin/IGF-1 receptor, result in a significantly extended lifespan. Similarly, in fruit flies, reduced IGF signaling is associated with increased lifespan.
-==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.
+== Human Relevance ==
-==References==
+The implications of the IIS pathway in human aging are an area of active research. Variations in genes related to this pathway, such as the FOXO3 gene, have been associated with longevity in human populations. However, the exact mechanisms and potential for therapeutic intervention in humans remain to be fully elucidated.
+== Research and Therapeutic Potentials ==
+There is ongoing research into pharmacological agents that can modulate the IIS pathway to potentially extend healthy lifespan. Drugs like metformin and rapamycin, which indirectly influence this pathway, are of particular interest in longevity research.
+== Conclusion ==
+The Insulin/IGF-1 Signaling pathway is a cornerstone in the study of the molecular biology of aging. Its conservation across species and clear influence on lifespan and healthspan make it a critical target for aging research. Future studies and clinical trials are expected to further clarify its role in human aging and potential for therapeutic interventions.
+== Further Reading ==
+* {{pmid text|22396862}}
+== References ==
+<references />
+[[Category:Pathways]]