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Additional file 1: Table S1. The 60 noble herbs used to establish the compound library. Table S2. Diet composition of mouse food. Fig. S1. CISD2 reporter assay for hesperetin and its structural analogs. Fig. S2. Serum biochemical analyses revealed that hesperetin has no detectable in vivo toxicity after 6 months of treatment in the old WT mice. Fig. S3. Complete blood count (CBC) analyses revealed that hesperetin has no detectable toxicity on hematological parameters after 7 months of treatment in the old WT mice. Fig. S4. Compound concentrations of hesperetin, and two of the major conjugated metabolites, namely hesperetin-7-O-beta-d-glucuronide (H7G) and hesperetin-7-O-sulfate (H7S), in the dietary hesperetin-treated mice, as well as their bioactivity to enhance CISD2 expression in the HEK293-CISD2 reporter cells. Fig. S5. Comparison of whole body metabolic rate after hesperetin treatment for 1.5 and 6 months in old WT mice. Fig. S6. No significant difference in the glucose tolerance test (GTT) and insulin tolerance test (ITT) between the Veh-treated and Hes-treated old mice. Fig. S7. Hesperetin shifts the expression patterns of several insulin signaling-related differential expression genes (DEGs) in the aged livers toward the patterns of young mice. Fig. S8. Hesperetin delays skeletal muscle aging in a Cisd2-dependent manner. Fig. S9. Hesperetin delays cardiac aging in a Cisd2-dependent manner. Fig. S10. Subgroups of metabolism-related DEGs in the hearts and skeletal muscles. Fig. S11. Subgroups of proteostasis-related DEGs in the hearts and skeletal muscles. Fig. S12. Hesperetin decreases the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and shifts the expression patterns of several ROS-related DEGs in the aged hearts and skeletal muscles toward the patterns of young mice.