Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

Abstract

SummaryCombating the social and economic consequences of a growing elderly population will require the identification of interventions that slow the development of age‐related diseases. Preserved cellular homeostasis and delayed aging have been previously linked to reduced cell proliferation and protein synthesis rates. To determine whether changes in these processes may contribute to or predict delayed aging in mammals, we measured cell proliferation rates and the synthesis and replacement rates (RRs) of over a hundred hepatic proteins in vivo in three different mouse models of extended maximum lifespan (maxLS): Snell Dwarf, calorie‐restricted (CR), and rapamycin (Rapa)‐treated mice. Cell proliferation rates were not consistently reduced across the models. In contrast, reduced hepatic protein RRs (longer half‐lives) were observed in all three models compared to controls. Intriguingly, the degree of mean hepatic protein RR reduction was significantly correlated with the degree of maxLS extension across the models and across different Rapa doses. Absolute rates of hepatic protein synthesis were reduced in Snell Dwarf and CR, but not Rapa‐treated mice. Hepatic chaperone levels were unchanged or reduced and glutathione S‐transferase synthesis was preserved or increased in all three models, suggesting a reduced demand for protein renewal, possibly due to reduced levels of unfolded or damaged proteins. These data demonstrate that maxLS extension in mammals is associated with improved hepatic proteome homeostasis, as reflected by a reduced demand for protein renewal, and that reduced hepatic protein RRs hold promise as an early biomarker and potential target for interventions that delay aging in mammals.

Ageing in men with normal spermatogenesis alters spermatogonial dynamics and nuclear morphology in Sertoli cells

“…‘Anti‐ageing’ treatments (e.g. with rapamycin or through calorie restriction) led to a reduced protein synthesis in mice (Karunadharma et al ., ; Thompson et al ., ). Probably, age‐dependent changes in protein turnover are specific for both, proteins and cell type.…”

Mitochondrial‐targeted catalase is good for the old mouse proteome, but not for the young: ‘reverse’ antagonistic pleiotropy?

“…These observations raise the question of whether enhanced protein quality and reduced protein turnover is a common underlying longevity mechanism in these and perhaps other interventions. This has recently been proposed in a study of protein half‐lives across multiple longevity interventions (Thompson et al ., ).…”

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

“…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). Conversely, in mammalian models, life-extending treatments and genetic modifications are associated with slower protein turnover (42)(43)(44)(45).…”

“…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). Similarly, in long-lived Snell dwarf mutant (Pit1 dw ) mice, rates of protein turnover are diminished (45).…”

“…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). Similarly, in long-lived Snell dwarf mutant (Pit1 dw ) mice, rates of protein turnover are diminished (45). Thus, the nature of the relationship between protein turnover and longevity appears complex and remains enigmatic.…”