Reduction of insulin/IGF-1 receptor rejuvenates immunity via positive feedback circuit
Reduction of insulin/IGF-1 receptor rejuvenates immunity via positive feedback circuit
Summary 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.
Lee Yujin、Jeong Dae-Eun、Hwang Wooseon、Park Hae-Eun H.、Kwon Sujeong、Lee Seung-Jae V.、Jung Yoonji、Ashraf Jasmine M.、Ham Seokjin、Murphy Coleen T.
Department of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Life Sciences, Pohang University of Science and TechnologyDepartment of Life Sciences, Pohang University of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyLewis-Sigler Institute for Integrative Genomics, Princeton UniversityDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyLewis-Sigler Institute for Integrative Genomics, Princeton University
基础医学生物科学研究方法、生物科学研究技术分子生物学
Lee Yujin,Jeong Dae-Eun,Hwang Wooseon,Park Hae-Eun H.,Kwon Sujeong,Lee Seung-Jae V.,Jung Yoonji,Ashraf Jasmine M.,Ham Seokjin,Murphy Coleen T..Reduction of insulin/IGF-1 receptor rejuvenates immunity via positive feedback circuit[EB/OL].(2025-03-28)[2025-05-21].https://www.biorxiv.org/content/10.1101/795781.点此复制
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