Fig. 1. Identification of a natural structure, isofalcarintriol (IFT) as potent suppressor of ATP generation and activator of NRF2.

a Schematic representation of the compound screening procedure, including an initial ATP screening and NRF2 activation assay in cells, followed by lifespan assays in C. elegans, b ATP assay screening revealed 29 small-molecule candidates (5 µg/ ml) that inhibit cellular ATP levels by 5–10% (average plus SD) compared to DMSO solvent control after 15 min of incubation. 10 µM of oligomycin, piceatannol, and Bz-423 were used as positive controls. c Structure of compound AnalytiCon Discovery GmbH #19 isofalcarintriol (1) as provided by AnalytiCon Discovery GmbH after extraction of Daucus carota. d NRF2 luciferase reporter assay with top ATP inhibitors after overnight treatment in transgenic HEK293 cells. 10-gingerol (2), alnusone (3), and isofalcarintriol (1) were identified as potent NRF2 activators. Sulforaphane was used as positive control. e NRF2 activation over solvent control in a HEK293 homozygote NRF2 deletion reporter cell line, including #19 (1). f Lifespan of WT C. elegans (N2) upon treatment with (synthetic) isofalcarintriol (1a) (1 nM). g Lifespan of C. elegans when supplementing isofalcarintriol (1a) to skn-1 (NRF2) deficient nematodes. Cell data include three technical replicates and are represented as the sum of average + SD, or average + SD. C. elegans data include three biologically independent samples and are represented as average. Statistics: log-rank test, one-way ANOVA and Dunnett’s or Bartlett’s posthoc test. p < 0.0001 = ****. Source data are provided as a Source Data file.