TY - JOUR
T1 - Reduced insulin/igf1 signaling prevents immune aging via zip-10/bzip–mediated feedforward loop
AU - Lee, Yujin
AU - Jung, Yoonji
AU - Jeong, Dae Eun
AU - Hwang, Wooseon
AU - Ham, Seokjin
AU - Park, Hae Eun H.
AU - Kwon, Sujeong
AU - Ashraf, Jasmine M.
AU - Murphy, Coleen T.
AU - Lee, Seung Jae V.
N1 - Funding Information:
We thank Drs. Dennis H. Kim (Harvard Medical School, Boston, MA), You-Hee Cho (CHA University, Gyeonggi-do, South Korea), Emily Troemel (University of California, San Diego, San Diego, CA), Yun Zhang (Harvard University, Cambridge, MA), Dengke Ma (University of California, San Francisco, San Francisco, CA), and the Caenorhabditis Genetics Center for providing some bacteria and C. elegans strains. We also thank all Lee laboratory members and Dr. Kyuhyung Kim (Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea) for providing dauer pheromone and discussion. This study is supported by the Korean Government (Ministry of Science and Information and Communications Technology) through the National Research Foundation of Korea (grant NRF-2019R1A3B2067745 to S.-J.V. Lee). C.T. Murphy is the Director of the Glenn Center for Aging Research at Princeton University. The authors declare no competing financial interests.
Funding Information:
Genetics Center, which is funded by the National Institutes of Health National Center for Resources (p40 OD010440), or the National Bio-Resource Project, Japan. Strains used in this study are as follows: N2 WT, CF1041 daf-2(e1370) III,CF2553 osm-5(p813) X, CF1903 glp-1(e2141) III, CF2172 isp-1(qm150) IV, IJ173 eat-2(ad1116) II obtained by outcrossing DA1116 four times to Lee-laboratory N2, IJ130 pmk-1(km25) IV obtained by outcrossing KU25 four times to Lee-laboratory N2, IJ1147 daf-2(e1370) III; pmk-1(km25) IV,
Funding Information:
This study is supported by the Korean Government (Ministry of Science and Information and Communications Technology) through the National Research Foundation of Korea (grant NRF-2019R1A3B2067745 to S.-J.V. Lee).
Publisher Copyright:
© 2021 Lee et al.
PY - 2021/5/3
Y1 - 2021/5/3
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.202006174
DO - 10.1083/jcb.202006174
M3 - Article
C2 - 33666644
AN - SCOPUS:85102705308
SN - 0021-9525
VL - 220
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
M1 - e202006174
ER -