Heat processing of food has been well validated as the trigger to generate heat-processing side product of advanced lipoxidation end products (ALEs), which potentially engenders the threat on systemic health or progression of diseases, especially the accumulated effect after long-term intake. Thus, the study was proposed to evaluate the effect of dietary ALEs on health after long-term ingestion, specifically through simulating the intake of dietary ALE in mice within 9 months to investigate the intervention effect and underlying mechanism. The unexpected observation of renal insufficiency or impairment after long-term intake of dietary ALEs indicated the negative impact on renal health, which has been verified by the pathological analysis. Further studies revealed that a high-ALEs diet disrupted the intestinal barrier, with enhanced impact after disturbing the gut microbiota to potentially lower the abundance of beneficial microbiome through producing nephrotoxic metabolites. Correlation analysis showed that the proliferation of harmful bacteria and the reduction of beneficial bacteria were strongly correlated with intestinal barrier damage and the development of renal insufficiency. Furthermore, the underlying mechanism was unveiled as that ALEs could inhibit AMPK/SIRT1 signaling to fundamentally induce renal inflammation and oxidative stress. Thus, it was revealed that long-term intake of dietary ALE could result in renal impairment, and the results emphasized the control or intervention on dietary ALE to decrease to accumulated impairment on systemic health.