Tryptophan metabolite atlas uncovers organ, age, and sex‐specific variations

Tryptophan (Trp) is the largest and most structurally complex amino acid, yet it is the least abundant in the proteome. Its distinct indole ring and high carbon content allow it to give rise to several biologically active metabolites, including serotonin, kynurenine (Kyn), and indole-3-pyruvate (I3P). Dysregulation of Trp metabolism has been implicated in a range of diseases, from depression to cancer. Investigating Trp and its metabolites in healthy tissues provides insight into how disease-associated disruptions may be targeted selectively while preserving essential physiological functions. Whereas previous studies have typically focused on individual organs or single metabolic branches, our analysis spans 12 peripheral organs, the central nervous system, and serum in male and female (C57BL/6) mice across three life stages: young (3 weeks), adult (54 weeks), and aged (74 weeks). We identified striking tissue-, sex-, and age-specific differences in Trp metabolism, including elevated levels of I3P and Kyn, both linked to tumor growth, in aging males. We also compared Trp metabolite profiles in tissues from mice fed a control defined diet versus a Trp-deficient diet for three weeks. This intervention led to a marked reduction in circulating Trp and its metabolites, with more modest effects observed in the liver and central nervous system. These findings underscore the importance of organ-specific and diet-sensitive analyses of Trp metabolism for understanding its role in both normal physiology and disease. Establishing baseline levels of Trp metabolites across tissues may also provide a foundation for identifying organ-specific metabolic reprogramming in cancer and other illnesses.