OBJECTIVES: Advanced glycation end products (AGEs) have been implicated as an important mediator of metabolic disorders including obesity, insulin resistance, and coronary artery disease. Glyoxalase 1 (Glo1) is a critical enzyme in the clearance of toxic dicarbonyl such as methylglyoxal, precursors of AGEs. The role of AGE-independent mechanisms that underly Glo1-induced metabolic disorders have yet to be elucidated. METHODS: We performed a longitudinal study of female and male RESULTS: Partial loss of CONCLUSIONS: Our results indicate that Glo1 reduction perturbs metabolic health and metabolic pathways in a sex- and age-dependent manner without significant changes in AGEs across metabolic tissues. Rather, tissue-specific gene expression analysis suggests that key transcription factors such as Hfn4a and Arntl as well as metabolite changes from alternative methylglyoxal detoxification such as pyruvate, likely contribute to metabolic dysregulation in