Aging as an event of proteostasis collapse

Abstract

Aging cells accumulate damaged and misfolded proteins through a functional decline in their protein homeostasis (proteostasis) machinery, leading to reduced cellular viability and the development of protein misfolding diseases such as Alzheimer's and Huntington's. Metabolic signaling pathways that regulate the aging process, mediated by insulin/IGF-1 signaling, dietary restriction, and reduced mitochondrial function, can modulate the proteostasis machinery in many ways to maintain a youthful proteome for longer and prevent the onset of age-associated diseases. These mechanisms therefore represent potential therapeutic targets in the prevention and treatment of such pathologies.

Figure 1.

Pathways that regulate aging. The insulin-signaling pathway and dietary restriction pathway induce longevity through mechanisms that are at least partially understood. Reduced mitochondrial function also increases lifespan, but the signaling components are not clear.

Figure 2.

The life cycle of a protein. After synthesis, proteins require correct folding and trafficking to the correct cellular location. Components of the cell’s proteostasis machinery mediate these functions, as well as detoxifying damaged and misfolded proteins. Pathways that regulate aging can modulate many aspects of proteostasis, through transcription factors such as DAF-16 and HSF-1, and effector molecules such as the kinase mTOR.

Figure 3.

Detoxification of Aβ aggregates by DAF-16 and HSF-1. The Aβ is produced throughout life by proteolysis of the amyloid precursor protein. In youthful animals, Aβ aggregates are believed to be detoxified by an active aggregation activity, regulated by the transcription factor DAF-16, and a disaggregation/proteolytic degradation pathway downstream of the transcription factor HSF-1.