Intron retention as a new marker of the pre-disease state and its recovery to the normal state by a traditional Japanese multi-herbal medicine

Intron retention (IR) is an important regulatory mechanism that affects gene expression and protein functions. Using klotho mice as a model, we proposed that retained introns are an excellent marker for the pre-disease state. Surprisingly, among widespread retained introns that accumulated during aging in the liver, a subset was recovered to the normal state by a Japanese traditional herbal medicine. IR-recovered genes fell into two categories: (1) those involved in the spliceosome and (2) those involved in liver-specific metabolism. By integrating data for splicing patterns, transcriptomes, and metabolomes, we hypothesize that this medicine-related IR recovery under the pre-disease state reflects the actual recovery of liver-specific function to the healthy state. Accordingly, the study provides proof-of-concept evidence related to the ancient Chinese statement proposing usefulness of the medicine for treating the pre-disease state. This approach lays out a method for elucidating unknown molecular mechanisms of an herbal medicine with multiple ingredients.