Scientists have discovered two major biomarkers of intestinal aging and revealed the patterns of mitochondrial DNA (mtDNA) mutations in the intestine, which holds promise for developing new candidate drugs.

It is believed that the imbalance in intestinal organ homeostasis is closely related to individual aging. However, the biomarkers of intestinal aging and the signaling pathways involved are still unclear. The genetic material DNA in mammalian cells is closely related to both development and aging. There are two organelles with genetic material within the cell: the nucleus and the mitochondria. It is currently believed that mitochondrial dysfunction is an important cause of cellular aging. Studies have shown the accumulation of mtDNA mutations in aged human clinical intestinal samples. However, the precise mechanisms linking mtDNA mutations, mitochondrial dysfunction, and cross-talk with the cell nucleus during aging remain unclear. Similarly, whether and how intestinal aging can be regulated is not well understood.

The research group led by Xing-Guo Liu published a paper in Nature Communications titled "NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations." The study found a specific accumulation of low-frequency point mutations (0.005-0.05) in mtDNA in the intestines of aged animals. Using animal models and organoid technologies, the researchers demonstrated that the accumulation of mtDNA mutations leads to the depletion of the NADH/NAD+ redox state during the process of intestinal aging, which activates the mitochondrial unfolded protein response (UPRmt) dependent on the transcription factor 5 (ATF5), thereby impairing the Wnt/β-catenin signaling and exhausting intestinal stem cells to induce intestinal aging. Furthermore, they developed a strategy to reverse aging by supplementing the NAD+ precursor NMN (nicotinamide mononucleotide).