Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Dec;70(10-12):1043-1061.
doi: 10.1007/s00011-021-01498-3. Epub 2021 Sep 2.

Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases

Antero Salminen  1 , Kai Kaarniranta  2   3 , Anu Kauppinen  4
Affiliations
Review

Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases

Antero Salminen et al. Inflamm Res. 2021 Dec.

Abstract

Background: The insulin/IGF-1 signaling pathway has a major role in the regulation of longevity both in Caenorhabditis elegans and mammalian species, i.e., reduced activity of this pathway extends lifespan, whereas increased activity accelerates the aging process. The insulin/IGF-1 pathway controls protein and energy metabolism as well as the proliferation and differentiation of insulin/IGF-1-responsive cells. Insulin/IGF-1 signaling also regulates the functions of the innate and adaptive immune systems. The purpose of this review was to elucidate whether insulin/IGF-1 signaling is linked to immunosuppressive STAT3 signaling which is known to promote the aging process.

Methods: Original and review articles encompassing the connections between insulin/IGF-1 and STAT3 signaling were examined from major databases including Pubmed, Scopus, and Google Scholar.

Results: The activation of insulin/IGF-1 receptors stimulates STAT3 signaling through the JAK and AKT-driven signaling pathways. STAT3 signaling is a major activator of immunosuppressive cells which are able to counteract the chronic low-grade inflammation associated with the aging process. However, the activation of STAT3 signaling stimulates a negative feedback response through the induction of SOCS factors which not only inhibit the activity of insulin/IGF-1 receptors but also that of many cytokine receptors. The inhibition of insulin/IGF-1 signaling evokes insulin resistance, a condition known to be increased with aging. STAT3 signaling also triggers the senescence of both non-immune and immune cells, especially through the activation of p53 signaling.

Conclusions: Given that cellular senescence, inflammaging, and counteracting immune suppression increase with aging, this might explain why excessive insulin/IGF-1 signaling promotes the aging process.

Keywords: Ageing; Alzheimer’s; FoxO; Immunosenescence; Tolerance; mTOR.

PubMed Disclaimer

Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Fig. 1
Fig. 1
The insulin/IGF-1 signaling pathway including the most relevant connections involved in the activation of STAT3 signaling. The pathway can be inhibited by SOCS, sKlotho, PTEN, and SHIP2 factors. STAT3 signaling can be activated by different pathways; (i) JAK/STAT3/RACK1, (ii) AKT/STAT3, (iii) AKT/PKM2/STAT3, and (iv) AKT/mTOR/STAT3 signaling. AKT signaling activates mTOR kinase and NF-κB signaling, whereas, AKT inhibits the function of FOXO factors. mTOR kinase and the transcription factors STAT3 and NF-κB are associated with the aging process. Moreover, AKT stimulates glucose uptake by inducing the expression of AS160 protein. AKT protein kinase B, AS160 Akt substrate of 160 kDa, FOXO Forkhead box O, IGF-1R insulin-like growth factor-1 receptor, IKKα/β inhibitor of nuclear factor κB kinase α/β, InsR insulin receptor, IRS insulin receptor substrate, JAK1 Janus kinase 1, mTOR mechanistic target of rapamycin, NF-κB nuclear factor κB, PDK1 3-phosphoinositide-dependent kinase 1, PI3K phosphoinositide 3-kinase, PKM2 pyruvate kinase isoenzyme M2, PTEN phosphatase and tensin homolog, RACK1 receptor for activated C kinase 1, SHIP2 SH2-domain containing phosphatidylinositol-3-4-5-trisphosphate 5-phosphatase 2, sKlotho soluble Klotho, SOCS suppressor of cytokine signaling, STAT3 signal transducer and activator of transcription 3
Fig. 2
Fig. 2
The insulin/IGF-1-induced STAT3 pathway in co-operation with SMAD3 and NF-κB signaling promotes the activation of immunosuppressive cells. These transcription factors induce the expression of several immunosuppressive factors, e.g., immunosuppressive cytokines (IL-10 and TGF-β), enzymes catabolizing amino acids to inhibit cellular proliferation (ARG1 and IDO), reactive oxygen and nitrogen species (ROS, RNS), immune checkpoint proteins (PD-1, PD-L1), and inducible nitric oxide synthase (iNOS). These factors enhance the immunosuppressive phenotype of the immune network including MDSC, Treg, M2/M2c macrophages, NKreg, and DCreg cells. ARG1 arginase 1, DCreg regulatory dendritic cell, IDO indoleamine 2,3-dioxygenase, IL-10 interleukin-10, iNOS inducible nitric oxide synthase, M2/M2c macrophage M2/M2c phenotype, MDSC myeloid-derived suppressor cell, NKreg regulatory natural killer phenotype, PD-1/PD-L1 programmed death-1/programmed death-ligand 1, PRR pattern recognition receptor, ROS reactive oxygen species, RNS reactive nitrogen species, SMAD3 mothers against decapentaplegic homolog 3, TGF-β transforming growth factor-β, TLR toll-like receptor, Treg regulative T cell phenotype; others are as in Fig. 1
Fig. 3
Fig. 3
The activation of STAT3 signaling stimulates a negative feedback response through the induction of SOCS factors which inhibit the activity of both insulin/IGF-1 receptors and many cytokine receptors. Accordingly, cytokine receptors can inhibit the activity of insulin/IGF-1 signaling via the STAT3/SOCS signaling and induce insulin resistance. Arrows show the activating responses and stoppers the inhibition of the activity. AKT protein kinase B, AS160 Akt substrate of 160 kDa, FOXO Forkhead box O, IGF-1R insulin-like growth factor-1 receptor, IKKα/β inhibitor of nuclear factor κB kinase α/β, InsR insulin receptor, IRS insulin receptor substrate, JAK1 Janus kinase 1, mTOR mechanistic target of rapamycin, NF-κB nuclear factor κB, PDK1 3-phosphoinositide-dependent kinase 1, PI3K phosphoinositide 3-kinase, PKM2 pyruvate kinase isoenzyme M2, PTEN phosphatase and tensin homolog, RACK1 receptor for activated C kinase 1, SHIP2 SH2-domain containing phosphatidylinositol-3-4-5-trisphosphate 5-phosphatase 2, sKlotho soluble Klotho, SOCS suppressor of cytokine signaling, STAT3 signal transducer and activator of transcription 3
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Barbieri M, Bonafe M, Franceschi C, Paolisso G. Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab. 2003;285:E1064–E1071. doi: 10.1152/ajpendo.00296.2003. - DOI - PubMed
    1. Bartke A, Sun LY, Longo V. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol Rev. 2013;93:571–598. doi: 10.1152/physrev.00006.2012. - DOI - PMC - PubMed
    1. Smith TJ. Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases? Pharmacol Rev. 2010;62:199–236. doi: 10.1124/pr.109.002469. - DOI - PMC - PubMed
    1. Lin K, Hsin H, Libina N, Kenyon C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet. 2001;28:139–145. doi: 10.1038/88850. - DOI - PubMed
    1. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493:338–345. doi: 10.1038/nature11861. - DOI - PMC - PubMed