The abundance change of age-regulated secreted proteins affects lifespan of C. elegans.

Abstract

Proteome integrity is vital for survival and failure to maintain it results in uncontrolled protein abundances, misfolding and aggregation which cause proteotoxicity. In multicellular organisms, proteotoxic stress is communicated among tissues to maintain proteome integrity for organismal stress resistance and survival. However, the nature of these signalling molecules and their regulation in extracellular space is largely unknown. Secreted proteins are induced in response to various stresses and aging, indicating their roles in inter-tissue communication. To study the fates of age-regulated proteins with potential localization to extracellular, we analysed publicly available age-related proteome data of C. elegans. We found that abundance of majority of the proteins with signal peptides (SP) increases with age, which might result in their supersaturation and subsequent aggregation. Intriguingly, these changes are differentially regulated in the lifespan mutants. A subset of these SP proteins is also found in the cargo of extracellular vesicles. Many of these proteins are novel and functionally uncharacterized. Reducing levels of a few extracellular proteins results in increasing lifespan. This suggests that uncontrolled levels of extracellular proteins might disturb proteostasis and limit the lifespan. Overall, our findings suggest that the age-induced secreted proteins might be the potential candidates to be considered as biomarkers or for mitigating age-related pathological conditions.