A hallmark of aging is immunosenescence, a decline in immune functions, which appeared to be inevitable in living organisms, including Caenorhabditis elegans. Here, we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically enhances immunocompetence in old age in C. elegans. We demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(−) animals. In contrast, p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunity, is only partially required for this rejuvenated immunity. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of the zip-10/bZIP transcription factor, which in turn down-regulates INS-7, an agonistic insulin-like peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS prevents immune aging via the up-regulation of anti-aging transcription factors that modulate an endocrine insulin-like peptide through a feedforward mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies against immune aging in humans.
Reduced insulin/IGF1 signaling prevents immune aging via ZIP-10/bZIP–mediated feedforward loop
D.-E. Jeong’s present address is Department of Pathology, Stanford University School of Medicine, Stanford, CA.
W. Hwang’s present address is SK Biopharmaceuticals, Gyeonggi-do, Korea.
A preprint of this paper was posted in bioRxiv on January 1, 2020.
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Yujin Lee, Yoonji Jung, Dae-Eun Jeong, Wooseon Hwang, Seokjin Ham, Hae-Eun H. Park, Sujeong Kwon, Jasmine M. Ashraf, Coleen T. Murphy, Seung-Jae V. Lee; Reduced insulin/IGF1 signaling prevents immune aging via ZIP-10/bZIP–mediated feedforward loop. J Cell Biol 3 May 2021; 220 (5): e202006174. doi: https://doi.org/10.1083/jcb.202006174
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