Widespread Protein Aggregation as an Inherent Part of Aging in C. elegans

Abstract

Several hundred proteins become insoluble and aggregation-prone as a consequence of aging in Caenorhabditis elegans. The data indicate that these proteins influence disease-related protein aggregation and toxicity.

Abstract

Aberrant protein aggregation is a hallmark of many age-related diseases, yet little is known about whether proteins aggregate with age in a non-disease setting. Using a systematic proteomics approach, we identified several hundred proteins that become more insoluble with age in the multicellular organism Caenorhabditis elegans. These proteins are predicted to be significantly enriched in β-sheets, which promote disease protein aggregation. Strikingly, these insoluble proteins are highly over-represented in aggregates found in human neurodegeneration. We examined several of these proteins in vivo and confirmed their propensity to aggregate with age. Different proteins aggregated in different tissues and cellular compartments. Protein insolubility and aggregation were significantly delayed or even halted by reduced insulin/IGF-1-signaling, which also slows aging. We found a significant overlap between proteins that become insoluble and proteins that influence lifespan and/or polyglutamine-repeat aggregation. Moreover, overexpressing one aggregating protein enhanced polyglutamine-repeat pathology. Together our findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease.

Author Summary

In neurodegenerative diseases, such as Alzheimer's disease and Huntington's disease, specific proteins escape the cell's quality-control system and associate together, forming insoluble aggregates. Until now, little was known about whether proteins aggregate in a non-disease context. In this study, we discovered that the aging process itself, in the absence of disease, leads to the insolubilization and increased aggregation propensity of several hundred proteins in the roundworm Caenorhabditis elegans. These aggregation-prone proteins have distinct structural and functional proprieties. We asked if this inherent age-dependent protein aggregation impacts neurodegenerative diseases. We found that proteins similar to those aggregating in old worms have also been identified as minor components of human disease aggregates. In addition, we showed that higher levels of inherent protein aggregation aggravated toxicity in a C. elegans Huntington's disease model. Inherent protein aggregation is a new biomarker of aging. Understanding how to modulate it will lead to important insights into the mechanisms that underlie aging and protein aggregation diseases.