Derailed protein turnover in the aging mammalian brain

Nalini R. Rao, Arun Upadhyay, Jeffrey N. Savas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum. First, we discovered that the brain proteome uniquely undergoes dynamic turnover fluctuations during aging compared to heart and liver tissue. Second, trends in protein turnover in the brain proteome during aging showed sex-specific differences that were tightly tied to cellular compartments. Next, parallel analyses of the insoluble proteome revealed that several cellular compartments experience hampered turnover, in part due to misfolding. Finally, we found that age-associated fluctuations in proteasome activity were associated with the turnover of core proteolytic subunits, which was recapitulated by pharmacological suppression of proteasome activity. Taken together, our study provides a proteome-wide atlas of protein turnover across the aging continuum and reveals a link between the turnover of individual proteasome subunits and the age-associated decline in proteasome activity.

Original languageEnglish (US)
Pages (from-to)120-139
Number of pages20
JournalMolecular Systems Biology
Issue number2
StatePublished - Feb 2 2024


  • Aging
  • proteasome
  • protein turnover
  • quantitative proteomics
  • stable isotope labeling

ASJC Scopus subject areas

  • Information Systems
  • General Immunology and Microbiology
  • Applied Mathematics
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • Computational Theory and Mathematics


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