Reduced insulin/IGF1 signaling prevents immune aging via ZIP-10/bZIP-mediated feedforward loop

• Published in: The Journal of cell biology Vol. 220; no. 5; p. 1
• Main Authors: Lee, Yujin, Jung, Yoonji, Jeong, Dae-Eun, Hwang, Wooseon, Ham, Seokjin, Park, Hae-Eun H, Kwon, Sujeong, Ashraf, Jasmine M, Murphy, Coleen T, Lee, Seung-Jae V
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 03.05.2021
• Subjects: Aging; Cell Signaling; Forkhead protein; Gene regulation; Immunity; Immunocompetence; Immunosenescence; Insulin; Insulin-like growth factor I; Kinases; MAP kinase; Peptides; Physiology; Protein kinase; Signaling; Transcription factors
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.202006174

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.