Accumulation of “Old Proteins” and the Critical Need for MS‐based Protein Turnover Measurements in Aging and Longevity

Abstract

Aging and age‐related diseases are accompanied by proteome remodeling and progressive declines in cellular machinery required to maintain protein homeostasis (proteostasis), such as autophagy, ubiquitin‐mediated degradation, and protein synthesis. While many studies have focused on capturing changes in proteostasis, the identification of proteins that evade these cellular processes has recently emerged as an approach to studying the aging proteome. With advances in proteomic technology, it is possible to monitor protein half‐lives and protein turnover at the level of individual proteins in vivo. For large‐scale studies, these technologies typically include the use of stable isotope labeling coupled with MS and comprehensive assessment of protein turnover rates. Protein turnover studies have revealed groups of highly relevant long‐lived proteins (LLPs), such as the nuclear pore complexes, extracellular matrix proteins, and protein aggregates. Here, the role of LLPs during aging and age‐related diseases and the methods used to identify and quantify their changes are reviewed. The methods available to conduct studies of protein turnover, used in combination with traditional proteomic methods, will enable the field to perform studies in a systems biology context, as changes in proteostasis may not be revealed in studies that solely measure differential protein abundances.

Interspecies differences in proteome turnover kinetics are correlated with lifespans and energetic demands

“…The distinction between selective and nonselective protein clearance may also provide an explanation for the apparent contradiction in the relationship between turnover rates and longevity that has been observed in different model systems (5). In general, it appears that treatments and genetic modifications that extend the lives of invertebrates such as C. elegans and D. melanogaster model systems result in faster rates of total protein turnover (31,(39)(40)(41).…”

“…A key feature of proteostasis is protein turnover, the process by which cellular proteins are continuously degraded and replaced by newly synthesized proteins (4). Because of its central role in protein quality control, there has been significant interest in understanding the relationship between alterations in protein turnover kinetics and proteostatic disruptions that occur during aging (1,(5)(6)(7).…”

“…In addition to this basal turnover, cells maintain a number of sophisticated pathways for specific detection and selective clearance of proteins that have been damaged through covalent modifications or detrimental conformational alterations (3,24,25). Together, the constitutive and selective clearance of proteins are important for maintaining a healthy proteome within a cell and alterations in protein turnover have been associated with the accumulation of damaged proteins and their pathogenic aggregation during aging and age-associated diseases (5,6,(26)(27)(28).…”

“…For example, the ablation of the insulin-like growth factor 1 receptor daf2 in C. elegans extends lifespan and results in an increase in global protein turnover rates, counteracting the natural decline in turnover that occurs during aging (31,(39)(40)(41). In apparent contrast, a number of studies have shown that protein turnover rates are actually reduced in mammalian model systems whose lifespans have been extended by dietary regiments, therapeutic interventions and genetic modifications (5). For example, mice that have been treated with rapamycin or calorie restriction, both well documented methods of lifespan extension, have reduced protein turnover rates (42)(43)(44)(45).…”

The Emerging Role of Senescence in Ocular Disease

“…An in-depth mass spectroscopic analysis of the published protein composition of soluble factor of senescence [125] and sEV proteomics [148] shows little correlation between both fractions, suggesting that although the downstream signaling is similar, the triggers inducing senescence are diverse. A comprehensive proteomic database of soluble and exosome SASP factors (SASP Atlas), originating from multiple senescence inducers and cell types has appeared recently [149]. The protein cargo of exosomes/EVs released by senescent cells was significantly higher and many protein markers will likely be specific to cell type and originating stimulus when compared to quiescent control cells [149].…”