The global trend of population aging is becoming increasingly prominent, yet our understanding of the natural aging process across multiple organs remains incomplete. While protein restriction (PR) has been shown to extend lifespan and improve metabolic health in model organisms, the organ-specific molecular effects of PR during aging are not fully elucidated. In this study, we performed large-scale proteomic profiling of 41 tissues and plasma from male mice across the aging trajectory and under PR intervention. PR partially attenuated age-associated alterations in tissue-specific protein expression, epigenomic landscapes, and protein phosphorylation patterns.

To extend our findings to humans, we also analyzed paired plasma samples from 272 individuals aged 26 to 88 years, collected in both 2015 and 2018. In addition to proteomic profiling using TMTpro 16-plex labeling, we integrated questionnaire-based dietary assessments and clinical parameters, including insulin, HbA1c, LDL-C, and blood pressure, resulting in a dataset of 544 human plasma proteome profiles.