This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "loss_of_proteostasis#Misfolded-Protein Aggregation"). Conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their disease context, substituting the disease-specific aggregating protein and vulnerable cell type. The module is intentionally kept lean: it captures the conserved proteostasis-network decline and its convergence on protein aggregation and proteotoxicity, but deliberately does NOT embed disease-specific aggregate species, seeding/prion spread models, or contested cell-non-autonomous theories, which belong on the relevant disorder entry. Complements deregulated_nutrient_sensing (mTORC1 suppression of autophagy is one contributor to failing clearance) and cellular_senescence. It is distinct from tsr_o_glycosylation_quality_control: that module recognizes correctly folded TSR domains and stabilizes their secretion, rather than modeling declining clearance capacity and accumulation of misfolded proteins. Key conformance target: "loss_of_proteostasis#Misfolded-Protein Aggregation".
A naked mole-rat (Heterocephalus glaber) comparative negative model is attached under animal_models, and is the hallmark where the comparative evidence is longitudinal rather than only cross-species: the proteostasis measures that decline in aging mice do not change over two decades of naked mole-rat life. It is a species comparison, not a disease model, and conforming disorder entries do NOT inherit those links.
Proteostasis Network Decline
trigger
The proteostasis network - molecular chaperones, the ubiquitin-proteasome system, and the autophagy-lysosome pathway, together with their regulators - normally maintains proteome integrity by coordinating folding, conformational maintenance, and degradation. Chronic external and endogenous stresses that accumulate during aging erode the capacity of this network, the initiating lesion of the hallmark.
Loss of Proteostasis
central effector
As the network's folding and clearance capacity falls below demand, protein homeostasis is lost: the cell can no longer keep its proteome correctly folded and turned over. This age-associated collapse of proteostatic control is the central effector state and is a common feature of aging and age-related disease across tissues.
Downstream
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Misfolded-Protein Aggregation
Misfolded-Protein Aggregation
effector
With folding and degradation failing, non-native proteins misfold and self-associate into aggregates - frequently beta-sheet-rich amyloid fibrils and inclusion bodies. This is the conserved central node that disease-specific aggregating proteins (amyloid-beta, tau, alpha-synuclein, polyglutamine huntingtin, TDP-43) converge upon; conforming disorder nodes substitute their particular aggregate species.
Downstream
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Proteotoxic Cell Dysfunction and Neurodegeneration
Proteotoxic Cell Dysfunction and Neurodegeneration
consequence
Accumulating misfolded and aggregated proteins are proteotoxic, especially to long-lived postmitotic cells such as neurons that cannot dilute the burden by division. The resulting cellular dysfunction and death underlies the age-associated proteinopathies, most prominently the neurodegenerative diseases. The specific clinical phenotype is supplied by the conforming disorder.