Ubiquitination is a post-translational modification (PTM) that induces protein degradation or function alteration and plays crucial roles in aging and cancer. Previous ubiquitinomes of aging mainly focused on how does ubiquitination change in drosophila and other lower animals, but how does ubiquitination changes during the aging of higher animals and what causes this changes remain unclear. Here, we profiled a whole-life ubiquitinome data of mouse brain, heart, liver, muscle, and spleen, and an integrative analysis of ubiquitinome data with RNA sequencing data. We found the ubiquitination of protein especially histone 2A (H2A) changes intensely during aging due to the regulated expression of E3 ligases (E3s) and deubiquitylating enzymes (DUBs). We developed two distinct H2A’ E3s/DUBs expression subtypes with different prognosis, DNA damage response (DDR), and tumor microenvironment cell infiltration degrees based on an unsupervised method in pan-cancer. In conclusion, our study provided a temporal resolution ubiquitinome data of mouse aging and revealed the important role of H2A ubiquitination in aging and tumor progression.