The proteome is defined as the entire set of proteins expressed in a given cell-type or organism, which can vary with time and physiological status. The integrity of the cellular proteome is supported by quality control networks. The human proteostasis network involves >1000 accessory factors and regulatory components, which govern protein synthesis, folding, and degradation. Otherwise, defective folding could result in increased abundance of toxic protein aggregates, which endanger the integrity of the entire proteome. Molecular chaperones additionally participate in refolding of damaged proteins that accumulate upon proteotoxic stress conditions. In case protein refolding cannot be sufficiently executed, chaperones team up with the ubiquitin/proteasome-system (UPS) or autophagy pathway to trigger degradation of unwanted proteins (Fig. 1). Recent studies in different organisms supported the idea that the activity of the 26S proteasome progressively declines during aging, although molecular aspects of this regulation have not been addressed. The goal of our research is to understand both, spatiotemporal control of protein quality control activity as well as substrate processing. We believe that deciphering the molecular mechanisms underlying the regulation of protein quality control interventions and substrate specificity could be the basis to develop novel therapeutic strategies to treat age-related diseases, including metabolic and neurodegenerative disorders.