The article discusses the proteostasis network and its decline in aging, highlighting its role in maintaining protein homeostasis. The proteostasis network comprises molecular chaperones, proteolytic machineries, and their regulators, which coordinate protein synthesis, folding, conformational maintenance, and degradation. Aging leads to a decline in the network's capacity due to various external and endogenous stresses, resulting in the accumulation of misfolded and aggregated proteins, particularly in postmitotic cell types like neurons. Recent proteome-wide analyses have provided insights into strategies to improve proteostasis, including pharmacological augmentation of the proteostasis network to delay age-related pathologies and extend healthspan. The authors review the organization of the proteostasis network, age-dependent changes in the proteome, and the toxicity of protein aggregates in neurodegenerative diseases. They also discuss mechanisms of aggregate toxicity and means to counteract proteotoxicity, such as chaperone-mediated prevention of amyloid formation and formation of inclusion bodies. The article concludes by exploring adaptations in protein synthesis, degradation, and the chaperone network during aging and the potential for pharmacological interventions to enhance proteostasis and delay degenerative diseases.The article discusses the proteostasis network and its decline in aging, highlighting its role in maintaining protein homeostasis. The proteostasis network comprises molecular chaperones, proteolytic machineries, and their regulators, which coordinate protein synthesis, folding, conformational maintenance, and degradation. Aging leads to a decline in the network's capacity due to various external and endogenous stresses, resulting in the accumulation of misfolded and aggregated proteins, particularly in postmitotic cell types like neurons. Recent proteome-wide analyses have provided insights into strategies to improve proteostasis, including pharmacological augmentation of the proteostasis network to delay age-related pathologies and extend healthspan. The authors review the organization of the proteostasis network, age-dependent changes in the proteome, and the toxicity of protein aggregates in neurodegenerative diseases. They also discuss mechanisms of aggregate toxicity and means to counteract proteotoxicity, such as chaperone-mediated prevention of amyloid formation and formation of inclusion bodies. The article concludes by exploring adaptations in protein synthesis, degradation, and the chaperone network during aging and the potential for pharmacological interventions to enhance proteostasis and delay degenerative diseases.