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

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.

Activation of OSM-STAT3 Epigenetically Regulates Tumor-Promoting Transcriptional Programs in Cervical Cancer

“…Our results showed that OSM stimulation for 24 h increased both the total STAT3 and phosphorylated STAT3 levels in the cervical cancer cell lines (HeLaS3 and SiHa). In contrast, previous studies reported that short-term exposure to OSM showed a reduction or maintenance pattern of STAT3 through negative feedback mediated by SOCS3 [ 68 , 69 ]. In our case, SD-36, a STAT3-specific degrader, reduces total STAT3 and STAT3 phosphorylation at Ser727.…”

Immunosenescence in Caenorhabditis elegans

“…As many factors that regulate aging and immunity are evolutionarily conserved from C. elegans to mammals, factors and pathways discussed here may also regulate immunosenescence in humans. Consistent with this possibility, p38 MAPK and insulin/IGF-1 signaling contributes to immunosenescence in mammals [5,45]. Thus, further research is required to unravel the molecular mechanism of immunosenescence in humans to improve treatment therapy of age-related pathologies.…”

Characterization of DNA methylation as well as mico-RNA expression and screening of epigenetic markers in adipogenesis

“…The insulin signaling pathway has been widely investigated in fat metabolism [ 26 ]. After insulin binds to the extracellular alpha subunit of the insulin receptor (InsR), it activates tyrosine kinase activity of the intracellular beta subunit, and the beta subunit undergoes autophosphorylation so that the tyrosine of the downstream substrate is phosphorylated and activated [ 27 ]. Insulin promotes the synthesis of fat and glycogen by acting on target tissues and inhibits the decomposition rate of lipids and liver glycogen, strongly promoting the storage of substances in the body.…”