FOXO/DAF-16 Activation Slows Down Turnover of the Majority of Proteins in C. elegans

Abstract

SummaryMost aging hypotheses assume the accumulation of damage, resulting in gradual physiological decline and, ultimately, death. Avoiding protein damage accumulation by enhanced turnover should slow down the aging process and extend the lifespan. However, lowering translational efficiency extends rather than shortens the lifespan in C. elegans. We studied turnover of individual proteins in the long-lived daf-2 mutant by combining SILeNCe (stable isotope labeling by nitrogen in Caenorhabditis elegans) and mass spectrometry. Intriguingly, the majority of proteins displayed prolonged half-lives in daf-2, whereas others remained unchanged, signifying that longevity is not supported by high protein turnover. This slowdown was most prominent for translation-related and mitochondrial proteins. In contrast, the high turnover of lysosomal hydrolases and very low turnover of cytoskeletal proteins remained largely unchanged. The slowdown of protein dynamics and decreased abundance of the translational machinery may point to the importance of anabolic attenuation in lifespan extension, as suggested by the hyperfunction theory.

Dietary Methionine Restriction Upregulates Endogenous H2S via miR‐328‐3p: A Potential Mechanism to Improve Liver Protein Metabolism Efficiency in a Mouse Model of High‐fat‐diet‐induced Obesity

“…reported that sulfur‐containing amino acid restriction decelerates protein synthesis and efficient protein folding . Lower rates of protein synthesis are associated with an increase in longevity . However, limited information is available regarding the effect of MR on the protein fractional synthesis rate (FSR), fractional protein growth rate (FGR), fractional degradation rate (FDR), and retention efficiency (PRE).…”

Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

“…Protein carbonylation, a standard measure of oxidative protein damage, increases at slower rates in the age-1 mutant (Ishii et al, 2002) and in daf-2 mitochondria (Brys et al, 2007) compared to the wild type control. This decrease in the accrual of oxidative protein modifications in IIS mutants was confirmed in studies using mass spectrometry (Knoefler et al, 2012;Dhondt et al, 2016). This phenotype may be linked to increased antioxidant activity in IIS mutants but, again, a direct causal link to lifespan has not been shown.…”

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

“…examined global protein turnover rates in cultured fibroblasts from eight rodent species with diverse lifespans—including mouse, rat, hamster, guinea pig, beaver, chinchilla, blind mole rate, and naked mole rat—found that global protein turnover rates negatively correlated with the lifespans of the species . However, while slower proteome turnover is unambiguously associated with longer lifespan in mammalian studies conducted thus far, a largely opposite trend has been reported invertebrate models, such as C. elegans , where preservation of faster (youthful) rates of protein turnover appear to be beneficial in old age. The reason for the discrepancy between rodent and invertebrate models remains unclear but we speculate that the primary cellular mechanisms driving aging in C. elegans versus rodents is different.…”

“…Recently, protein turnover has been investigated in a series of different mutants, such as long‐lived or short‐lived strains with the goal to assess interventions in invertebrates to reverse aging phenotypes. For example, in the long‐lived insulin‐like growth factor (IGF‐1) receptor mutant (daf‐2 –/– ), most proteins (≈56%) showed longer half‐lives during development, exhibiting a slowdown in protein turnover, specifically for translation‐related and mitochondrial proteins . The authors concluded that lowering translational efficiency extended rather than shortened the lifespan in C. elegans , and that potentially the reduced insulin/IGF‐1 signaling may result in an energy‐conserving state, which may lead to improved protection of proteins.…”