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bioRxiv · 10.1101/795781

Reduction of insulin/IGF-1 receptor rejuvenates immunity via positive feedback circuit

Lee, Y.·Jeong, D.-E.·Hwang, W.·Ham, S.·Park, H.-E.·Kwon, S.·Jung, Y.·Ashraf, J. M.·Murphy, C.·Lee, S.-J. V.
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Abstract

Immunosenescence is considered an inevitable decline in immune function during aging. Here we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically delays immunosenescence and rejuvenates immunity in C. elegans. We find that p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunosenescence, is dispensable for this rejuvenated immunity. Instead, we demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(-) animals. The upregulation of DAF-16/FOXO and HSF-1 decreases the expression of the zip-10/bZIP transcription factor, which in turn downregulates INS-7, an agonistic insulin-like peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS bypasses immunosenescence and rejuvenates immunity via the upregulation of anti-aging transcription factors that modulate an endocrine insulin-like peptide through a positive feedback mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies for human immune rejuvenation.

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Lee, Y., Jeong, D.-E., Hwang, W., Ham, S., Park, H.-E., Kwon, S., Jung, Y., Ashraf, J. M., Murphy, C., Lee, S.-J. V.. 2019-10-07. Reduction of insulin/IGF-1 receptor rejuvenates immunity via positive feedback circuit. https://doi.org/10.1101/795781

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