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. 2021 Mar 5;220(5):e202006174. doi: 10.1083/jcb.202006174

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© 2021 Lee et al.

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Figure 5. — zip-10 promotes immune aging by up-regulating ins-7. (A and B) qRT-PCR analysis indicates the effects of daf-16(–) mutation (A; **, P < 0.01, n = 7) and hsf-1 RNAi (B; P = 0.181, n = 3) on the level of zip-10 mRNA in daf-2(–) animals compared with that in WT. ama-1 was used as a normalization control. Error bars represent SEM (two-tailed Student’s t test). (C) Images of ins-7p::gfp transgenic worms in WT (control) and zip-10(ok3462) [zip-10(–)] backgrounds at day 1 or 2 and day 9 of adulthood cultured at 20°C. Scale bar indicates 500 µm (magnification, 50×). (D) Quantification of the data shown in C(n ≥ 3, two-tailed Student’s t test: **, P < 0.01; ***, P < 0.001). (E) zip-10(–) mutations reduced the age-dependent increase in mRNA level of ins-7. ama-1 and pmp-3: normalization controls. Error bars represent SEM (n = 3, two-tailed Student’s t test). (F) The PA14 resistance in day 9 adult worms was increased by zip-10(–). (G) The PA14 resistance in day 9 adult worms was reduced by isy-1(–) mutation. (H) isy-1(–) mutations reduced the enhanced survival of day 9 daf-2(–) animals on PA14. We also measured age-dependent changes in ins-7 mRNA levels in isy-1(–) animals using ins-7p::gfp and qRT-PCR, but the data were inconclusive (Fig. S3, U–X, see Fig. S3 legend for discussion). See Table S4 for additional repeats and statistical analysis for survival data shown in Fig. 5. (I) A schematic model showing the summary of the current study. Age-dependent increases in INS-7 levels activate insulin/IGF-1 signaling in WT, and this in turn down-regulates DAF-16/FOXO and HSF-1, negative regulators of ins-7. In addition, ZIP-10, a positive regulator of INS-7, further increases the level of INS-7 in old WT worms, leading to immune aging. In contrast, hypomorphic mutations in daf-2, which can be further down-regulated (Arantes-Oliveira et al., 2003; Hansen et al., 2005), reduce ins-7 mRNA levels by decreasing the activity of DAF-16/FOXO and HSF-1. Subsequently, decreased INS-7 further down-regulates insulin/IGF-1 signaling through a positive feedback loop in daf-2(–) mutants for delaying immune aging. A.U., arbitrary units.