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Fig. 6 Healthy metabolic aging in male ZAK?/? mice. (A) Schematic of mouse aging experiment. WT (male, n = 7; female, n = 16) and ZAK?/? (male, n = 7; female, n = 12) mice were maintained on a normal chow diet until 14 to 16 months of age (?old group?). Mice were subjected to ipGTT and euthanized 2 weeks later for collection of tissues. Tissues from 6-month-old WT and ZAK?/? male mice (?young group?) were used for comparison. (B) Blood glucose concentrations of ?old? male (top) and female (bottom) mice from (A) subjected to ipGTT assay. Statistical analysis is based on the AUC for each experimental group. (C to E) Basal glucose levels (C), basal insulin levels (D), and HOMA-IR (E) of fasted ?old? male mice from (A). (F) Images of representative H&E-stained liver section from male mice in (A). Arrows indicate areas of steatosis. (G) Scoring of liver steatosis grade (scale, 0 to 4) of male mice from (A). (H) Images of representative H&E-stained sections of BAT from male mice in (A). Arrows indicate areas of notable lipid droplet condensation and BAT whitening. (I) Whole-mount BAT scans from (fig. S10A) were segmented according to lipid droplets. Individual droplet sizes for all aged WT and ZAK?/? samples were computed and represented in the form of histograms (n = 6). (J) Model of metabolic regulation by the RSR in obesity and aging in male mice. ROS produced as a result of HFHS feeding or during the course of aging impair ribosomal translation and activate the RSR sensor ZAK?. Downstream MAP kinase (p38 and JNK) signaling mediates features of metabolic decline such as glucose intolerance, liver steatosis, and BAT whitening. For (B) to (E), all data are plotted as mean and all error bars represent the SEM. *P ? 0.05; **P ? 0.01 by Welch?s t test in (C) and by Mann-Whitney U test in (B), (D), and (E). All scale bars, 50 ?m.