Insulin/IGF-1 Signaling (IIS) Pathway

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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