Derailed protein turnover in the aging mammalian brain.

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. Synopsis: Continuous pulse-step metabolic labeling with quantitative proteomics in mice reveals sex-specific differences in protein turnover linked to subcellular compartments. Age-related changes in protein turnover result in part from altered proteasome activity and subunit turnover. Brain protein turnover trends during aging display sex-specific differences tied to subcellular compartments. Misfolded proteins contribute to differential turnover trends in the brain. Reduced proteasome activity is associated with slowed turnover of proteasome subunits during aging. Continuous pulse-step metabolic labeling with quantitative proteomics in mice reveals sex-specific differences in protein turnover linked to subcellular compartments. Age-related changes in protein turnover result in part from altered proteasome activity and subunit turnover. [ABSTRACT FROM AUTHOR]