TY - JOUR T1 - Reduction of insulin/IGF-1 receptor rejuvenates immunity via positive feedback circuit JF - bioRxiv DO - 10.1101/795781 SP - 795781 AU - Yujin Lee AU - Dae-Eun Jeong AU - Wooseon Hwang AU - Seokjin Ham AU - Hae-Eun H. Park AU - Sujeong Kwon AU - Yoonji Jung AU - Jasmine M. Ashraf AU - Coleen T. Murphy AU - Seung-Jae V. Lee Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/10/07/795781.abstract N2 - 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. ER -