Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in Caenorhabditis elegans.

Chaolie Huang,Clemens F Kaminski,Amberley D Stephens,Raimund Jung,Meng Lu,Sara Wagner-Valladolid,Gabriele S Kaminski Schierle,Nicole Schlörit,Tessa Sinnige,Chetan Poudel,Romain F Laine,Claire H Michel,Marie C Lechler,Della C David,Michele Vendruscolo

doi:10.7554/elife.43059

Abstract

Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life.

Highlights

Aging is a gradual decline in physiological functions and organ integrity
To understand whether KIN-19 and RHO-1 have an intrinsic capacity to aggregate similar to diseaseassociated proteins or whether a progressive accumulation of protein damage caused by non-enzymatic posttranslational modifications is required to induce their aggregation, we evaluated the dynamics of protein aggregation in vivo
Widespread protein aggregation in the context of normal aging has been observed in C. elegans [12, 20, 22], Drosophila [21], Saccharomyces cerevisiae [30] and in mammals, notably in neural stem cells [16], heart [15] and skeletal muscles [18], bone marrow and spleen [14]

Summary

Introduction

Aging is a gradual decline in physiological functions and organ integrity. Diminished physical capacity and cognitive functions are already apparent before midlife, in the third decade of life [1]. A better understanding of what drives aging and in particular functional decline holds the promise of identifying targets to maintain quality of life with age. One of the most universal hallmarks of aging is increased protein instability [3, 4]. An efficient protein homeostasis (proteostasis) network prevents the accumulation of protein instability. Overwhelming evidence points to a collapse in the proteostasis network with age and a decline in the ability to cope with protein instability [5]. Still the role of protein instability in aging is unclear [6, 7]

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Conclusion