Phosphoproteome profiling of mouse liver during normal aging.

Background: Aging is a complex biological process accompanied by a time-dependent functional decline that affects most living organisms. Omics studies help to comprehensively understand the mechanism of aging and discover potential intervention methods. Old mice are frequently obese with a fatty liver.

Methods: We applied mass spectrometry-based phosphoproteomics to obtain a global phosphorylation profile of the liver in mice aged 2 or 18 months. MaxQuant was used for quantitative analysis and PCA was used for unsupervised clustering.

Results: Through phosphoproteome analysis, a total of 5,685 phosphosites in 2,335 proteins were filtered for quantitative analysis. PCA analysis of both the phosphoproteome and transcriptome data could distinguish young and old mice. However, from kinase prediction, kinase-substrate interaction analysis, and KEGG functional enrichment analysis done with phosphoproteome data, we observed high phosphorylation of fatty acid biosynthesis, β-oxidation, and potential secretory processes, together with low phosphorylation of the Egfr-Sos1-Araf/Braf-Map2k1-Mapk1 pathway and Ctnnb1 during aging. Proteins with differentially expressed phosphosites seemed more directly related to the aging-associated fatty liver phenotype than the differentially expressed transcripts. The phosphoproteome may reveal distinctive biological functions that are lost in the transcriptome.

Conclusions: In summary, we constructed a phosphorylation-associated network in the mouse liver during normal aging, which may help to discover novel antiaging strategies.