The accumulation of senescent cells constitutes a pivotal hallmark of tissue ageing, contributing to disruption of tissue homeostasis and thus, to the development of several aging-related diseases. Despite this, our knowledge about the molecular, spatial and temporal changes that drive aging on a cellular basis remains poorly understood. To elucidate these mechanisms, we employed mass spectrometry-based proteomics to determine changes in the total proteome, the ubiquitin-modified proteome, the phospho-proteome and in protein solubility during replicative senescence in human IMR90 fibroblasts. This accession number contains the data used in the quantification of different ubiquitin linkage using the SureQuant Technique; for the OtUBD pulldown (control and MG132 treated) and solubility datasets.