Fig. 5: Nematodal and mammalian Grainyhead TFs are linked to aging and insulin signaling.

a Activation of the GRHL reporter without (scramble control) or with concomitant knockdown of PIK3C2A by shRNA and indicated treatments (NT = no treatment, DMSO = vehicle control, Papav = papaverine at 10 or 20 µM; n = 6 for all). b Lifespan assay of wild-type (WT) N2 nematodes on post-developmental piki-1 RNAi compared to control vector L4440. Both conditions additionally treated with 10 µM papaverine or DMSO control. c RT-qPCR of grh-1, in WT (N2) vs. a daf-2 or age-1 mutant strain (n = 3 for all). d–f Lifespan assays with a daf-2 (d), age-1 (e), or daf-16 (f) mutant strain on post-developmental grh-1 RNAi compared to control vector L4440. g Spearman’s rho correlation between Grhl1 expression in muscle (Z-score normalized) and mean lifespan of chow and high-fat diet-fed mice from the BXD mouse genetic reference population. h Similar as in (g), depicting the correlation of Grhl1 expression in muscle with area under the curve (AUC) glycemia during oral glucose tolerance test (oGTT). i Pearson’s r correlation coefficients between GRHL1 and genes in GO term ‘Insulin receptor signaling pathway’ (GO: 0008286) in human muscle samples, derived from the GTEx database. Gray bars represent non-significant correlations (P-value > 0.05). j Spearman’s rank rho correlation between GRHL1 expression in human skeletal muscle and age at natural death from the GTEx v8 dataset (n = 621). k Spearman’s rank rho correlation between GRHL1 expression in human skeletal muscle and fasting blood glucose in the entire FUSION cohort (All) or in individuals with impaired glucose tolerance (IGT) or type 2 diabetes (T2D). Color of dots indicates IGT individuals (light blue), T2D individuals (blue), and individuals belonging to neither group (black). Data in bar graphs are mean ± SEM, with sample sizes as stated and individual data points representing biological replicates. P-values were determined with two-tailed unequal variances t-tests of the indicated comparisons of unpaired control vs. treatment groups. P-values of C. elegans lifespan assays were determined by log-rank test. See Supplementary Data 1 for detailed lifespan assay statistics. Source data are provided as a Source data file.