SAAR‐induced changes in molecular markers of serinogenesis and lipid metabolism are dependent on sex, dietary fat content, and age‐at‐onset. Young (8‐week‐old, circles) and adult (18‐month‐old, triangles) male (blue circles) and female (red circles) C57BL/6J mice were fed CD and SAAR diets with either 10% fat or 60% fat for at least 3 months. Statistical significance of SAAR‐induced changes in hepatic glutathione (a–c), hepatic protein expressions of Nrf2 (d–f), Phgdh (g–i), and Pck2 (j–l), plasma triglycerides (m–o), and perigonadal adipose tissue weights (p–r) were analyzed by 2‐way ANOVA. The interaction of SAAR‐induced changes with dietary fat in young mice and sex in adult mice are indicated by μint. Pairwise comparisons between CD and SAAR are indicated by μ. n = 8/group; PGAT—perigonadal adipose tissue; error bars indicate means and standard error of means. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n.s. = not significant