Loss of Proteostasis

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title: Loss of Proteostasis slug: loss-of-proteostasis category: hallmarks summary: Decline in the cell's ability to fold, refold, and degrade proteins, leading to accumulation of misfolded and aggregated species. lastUpdated: 2026-05-17 tags: [chaperones, ubiquitin proteasome, autophagy, aggregation] references:

• "Hipp, M. S., Kasturi, P. & Hartl, F. U. The proteostasis network and its decline in ageing. Nat. Rev. Mol. Cell Biol. 20, 421–435 (2019)."

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What it is

Proteostasis is the set of processes — chaperone-assisted folding, ubiquitin–proteasome degradation, and autophagy — that maintain the proteome in a functional, soluble state. With age, each component falters, and misfolded proteins accumulate as oligomers and aggregates.

Why it matters in aging

Proteostasis collapse underlies most major neurodegenerative diseases: β-amyloid and tau (Alzheimer’s), α-synuclein (Parkinson’s), TDP-43 (ALS/FTD), huntingtin (Huntington’s). It also drives age-related cataracts, cardiac amyloidosis, and sarcopenia.

Mechanisms

• Heat-shock response — chaperone induction blunts with age.
• Ubiquitin–proteasome system — proteasome activity declines.
• Autophagy — macroautophagy and chaperone-mediated autophagy both decline; see Disabled macroautophagy.
• Aggregation — misfolded species template further misfolding (prion-like propagation in several diseases).

What’s being studied

Caloric restriction and rapamycin (via mTOR inhibition) up-regulate autophagy. Small molecules that boost chaperone activity (e.g. arimoclomol) are in clinical trials for specific proteinopathies. The general principle: keep degradation pathways flowing.

Related entries

See also: Disabled macroautophagy, Deregulated nutrient-sensing, Rapamycin.