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^[1]. Similarly, in fruit flies, reduced IGF signaling is associated with increased lifespan^[2].

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^[3]. 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^[4].

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.

↑ Liu Z & Gilbert W: The yeast KEM1 gene encodes a nuclease specific for G4 tetraplex DNA: implication of in vivo functions for this novel DNA structure. Cell 1994. (PMID 8020096) [PubMed] [DOI] We have previously reported the identification of a G4-DNA-dependent nuclease from S. cerevisiae that recognizes a tetrastranded G4-DNA structure and cuts in a single-stranded region 5' to the G4 structure. We purify this activity to homogeneity and show it to be the product of the S. cerevisiae KEM1 gene, which is also known as SEP1, DST2, XRN1, and RAR5. Since a homozygous deletion of the KEM1 gene blocks meiotic cells at the 4N stage, the finding of these G4-dependent DNA binding and cleavage activities for the KEM1 gene product supports the hypothesis that G4-DNA may play a role in meiosis.
↑ Lohmueller KE et al.: Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003. (PMID 12524541) [PubMed] [DOI] Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common disease, but are plagued by the impression that they are not consistently reproducible. In principle, the inconsistency may be due to false positive studies, false negative studies or true variability in association among different populations. The critical question is whether false positives overwhelmingly explain the inconsistency. We analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations (P < 10(-14)). This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. For 8 of these 11 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. Thus, a sizable fraction (but under half) of reported associations have strong evidence of replication; for these, false negative, underpowered studies probably contribute to inconsistent replication. We conclude that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.
↑ Mortazavi A et al.: Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 2008. (PMID 18516045) [PubMed] [DOI] We have mapped and quantified mouse transcriptomes by deeply sequencing them and recording how frequently each gene is represented in the sequence sample (RNA-Seq). This provides a digital measure of the presence and prevalence of transcripts from known and previously unknown genes. We report reference measurements composed of 41-52 million mapped 25-base-pair reads for poly(A)-selected RNA from adult mouse brain, liver and skeletal muscle tissues. We used RNA standards to quantify transcript prevalence and to test the linear range of transcript detection, which spanned five orders of magnitude. Although >90% of uniquely mapped reads fell within known exons, the remaining data suggest new and revised gene models, including changed or additional promoters, exons and 3' untranscribed regions, as well as new candidate microRNA precursors. RNA splice events, which are not readily measured by standard gene expression microarray or serial analysis of gene expression methods, were detected directly by mapping splice-crossing sequence reads. We observed 1.45 x 10(5) distinct splices, and alternative splices were prominent, with 3,500 different genes expressing one or more alternate internal splices.
↑ Couban S et al.: The case for plerixafor to replace filgrastim as the optimal agent to mobilize peripheral blood donors for allogeneic hematopoietic cell transplantation. Exp Hematol 2019. (PMID 30428338) [PubMed] [DOI] Granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood progenitor cells (G-PBs) from either a related or unrelated donor continue to be the preferred donor source for most allogeneic hematopoietic cell transplantation (HCT). Recently, the American Society for Blood and Marrow Transplantation has recommended marrow instead of G-PBs as an unrelated graft source due to its lower rate of chronic graft-versus-host disease (cGVHD). However, the use of marrow is limited by both clinical considerations (slower rate of engraftment and increased donor morbidity) and logistical considerations (use of operating room resources and increased physician utilization), so this recommendation has not been widely adopted. An optimal donor source would include the rapid engraftment characteristic and the low donor morbidity associated with G-PBs and a rate of cGVHD similar to or lower than that of marrow. Recent data suggest that plerixafor mobilized PBs (P-PBs) have the rapid engraftment characteristics of G-PBs in allogeneic HCT with less cGVHD. The biologic mechanism of the lower rate of cGVHD appears to be through mobilization of regulator natural killer cells and plasmacytoid dendritic cell precursors that are associated with lower acute and chronic GVHD compared with G-PBs and rapid engraftment characterized by rapid myeloid-repopulating capacity. We suggest that, based on the experience of the two Phase II clinical trials and the unique biology of plerixafor-mobilized donor product, it should be evaluated in Phase III trials as an approach to replacing G-CSF mobilization for allogeneic HCT.

[pmid8020096-1] Liu Z & Gilbert W: The yeast KEM1 gene encodes a nuclease specific for G4 tetraplex DNA: implication of in vivo functions for this novel DNA structure. Cell 1994. (PMID 8020096) [PubMed] [DOI] We have previously reported the identification of a G4-DNA-dependent nuclease from S. cerevisiae that recognizes a tetrastranded G4-DNA structure and cuts in a single-stranded region 5' to the G4 structure. We purify this activity to homogeneity and show it to be the product of the S. cerevisiae KEM1 gene, which is also known as SEP1, DST2, XRN1, and RAR5. Since a homozygous deletion of the KEM1 gene blocks meiotic cells at the 4N stage, the finding of these G4-dependent DNA binding and cleavage activities for the KEM1 gene product supports the hypothesis that G4-DNA may play a role in meiosis.

[pmid12524541-2] Lohmueller KE et al.: Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003. (PMID 12524541) [PubMed] [DOI] Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common disease, but are plagued by the impression that they are not consistently reproducible. In principle, the inconsistency may be due to false positive studies, false negative studies or true variability in association among different populations. The critical question is whether false positives overwhelmingly explain the inconsistency. We analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations (P < 10(-14)). This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. For 8 of these 11 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. Thus, a sizable fraction (but under half) of reported associations have strong evidence of replication; for these, false negative, underpowered studies probably contribute to inconsistent replication. We conclude that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.

[pmid18516045-3] Mortazavi A et al.: Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 2008. (PMID 18516045) [PubMed] [DOI] We have mapped and quantified mouse transcriptomes by deeply sequencing them and recording how frequently each gene is represented in the sequence sample (RNA-Seq). This provides a digital measure of the presence and prevalence of transcripts from known and previously unknown genes. We report reference measurements composed of 41-52 million mapped 25-base-pair reads for poly(A)-selected RNA from adult mouse brain, liver and skeletal muscle tissues. We used RNA standards to quantify transcript prevalence and to test the linear range of transcript detection, which spanned five orders of magnitude. Although >90% of uniquely mapped reads fell within known exons, the remaining data suggest new and revised gene models, including changed or additional promoters, exons and 3' untranscribed regions, as well as new candidate microRNA precursors. RNA splice events, which are not readily measured by standard gene expression microarray or serial analysis of gene expression methods, were detected directly by mapping splice-crossing sequence reads. We observed 1.45 x 10(5) distinct splices, and alternative splices were prominent, with 3,500 different genes expressing one or more alternate internal splices.

[pmid30428338-4] Couban S et al.: The case for plerixafor to replace filgrastim as the optimal agent to mobilize peripheral blood donors for allogeneic hematopoietic cell transplantation. Exp Hematol 2019. (PMID 30428338) [PubMed] [DOI] Granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood progenitor cells (G-PBs) from either a related or unrelated donor continue to be the preferred donor source for most allogeneic hematopoietic cell transplantation (HCT). Recently, the American Society for Blood and Marrow Transplantation has recommended marrow instead of G-PBs as an unrelated graft source due to its lower rate of chronic graft-versus-host disease (cGVHD). However, the use of marrow is limited by both clinical considerations (slower rate of engraftment and increased donor morbidity) and logistical considerations (use of operating room resources and increased physician utilization), so this recommendation has not been widely adopted. An optimal donor source would include the rapid engraftment characteristic and the low donor morbidity associated with G-PBs and a rate of cGVHD similar to or lower than that of marrow. Recent data suggest that plerixafor mobilized PBs (P-PBs) have the rapid engraftment characteristics of G-PBs in allogeneic HCT with less cGVHD. The biologic mechanism of the lower rate of cGVHD appears to be through mobilization of regulator natural killer cells and plasmacytoid dendritic cell precursors that are associated with lower acute and chronic GVHD compared with G-PBs and rapid engraftment characterized by rapid myeloid-repopulating capacity. We suggest that, based on the experience of the two Phase II clinical trials and the unique biology of plerixafor-mobilized donor product, it should be evaluated in Phase III trials as an approach to replacing G-CSF mobilization for allogeneic HCT.

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