Loss of proteostasis refers to the progressive decline in protein homeostasis mechanisms that occurs during aging. This hallmark encompasses the failure of protein quality control systems, including protein folding, degradation, and clearance pathways, leading to the accumulation of misfolded and aggregated proteins that contribute to cellular dysfunction and age-related diseases.
¶ Definition and Overview
The proteostasis network maintains protein homeostasis through:
- Protein synthesis: Ribosomal translation and co-translational folding
- Protein folding: Molecular chaperones and folding assistants
- Protein degradation: Ubiquitin-proteasome system and autophagy
- Protein trafficking: Cellular localization and transport
- Quality control: Recognition and elimination of defective proteins
During aging, all components of the proteostasis network become compromised:
- Reduced chaperone function and expression
- Impaired proteasome activity and assembly
- Decreased autophagy efficiency
- Altered protein synthesis fidelity
- Accumulation of protein aggregates
¶ Molecular Chaperones and Protein Folding
- HSP90: Assists folding of signaling proteins and transcription factors
- HSP70: Prevents aggregation and assists refolding of denatured proteins
- HSP60: Mitochondrial chaperonin for protein folding
- Small HSPs: α-crystallin family proteins preventing aggregation
- HSP27: Stress response and cytoskeletal protection
- HSP40 (DNAJ): Co-chaperone regulating HSP70 ATPase activity
- HSP110: Nucleotide exchange factor for HSP70
- Bag proteins: Regulate HSP70 function and client protein fate
- Hop (HSP organizing protein): Links HSP70 and HSP90 systems
- Reduced expression: Declining HSP levels with age
- Impaired induction: Blunted heat shock response
- Modified function: Altered chaperone activity and specificity
- Overwhelmed capacity: Insufficient chaperones for protein load
¶ Components and Function
- 26S proteasome: Large multi-subunit protease complex
- 20S catalytic core: Contains proteolytic active sites
- 19S regulatory particles: Recognize and unfold ubiquitinated substrates
- Ubiquitin: Small protein tag marking proteins for degradation
- E1, E2, E3 enzymes: Ubiquitin activation, conjugation, and ligation
- Ubiquitin conjugation: Target proteins tagged with polyubiquitin chains
- Recognition: 26S proteasome binds polyubiquitin signals
- Unfolding: 19S ATPases unfold target proteins
- Degradation: 20S catalytic core degrades unfolded proteins
- Recycling: Ubiquitin and amino acids released for reuse
- Reduced proteasome activity: Decreased peptidase activities
- Altered composition: Changes in proteasome subunit ratios
- Impaired assembly: Defective proteasome biogenesis
- Substrate accumulation: Build-up of polyubiquitinated proteins
- Oxidative damage: Proteasome modification by reactive oxygen species
¶ Autophagy and Lysosomal Degradation
- Macroautophagy: Bulk degradation via autophagosome formation
- Microautophagy: Direct lysosomal uptake of cytoplasmic material
- Chaperone-mediated autophagy (CMA): Selective protein degradation
- Mitophagy: Specific degradation of damaged mitochondria
- Aggrephagy: Selective clearance of protein aggregates
- Initiation: ULK1 complex activation by nutrient/stress signals
- Nucleation: Beclin-1/VPS34 complex forms isolation membrane
- Elongation: LC3 conjugation and autophagosome expansion
- Fusion: Autophagosome-lysosome fusion forming autolysosome
- Degradation: Lysosomal enzymes break down contents
- Reduced autophagy flux: Decreased overall autophagy activity
- Lysosomal dysfunction: Impaired acidification and enzyme activity
- Defective fusion: Problems with autophagosome-lysosome fusion
- Accumulation of substrates: Build-up of autophagy targets
- Lipofuscin formation: Undegradable age pigment accumulation
¶ Protein Aggregation and Misfolding
- Amyloid-β plaques: Alzheimer's disease pathology
- Tau neurofibrillary tangles: Alzheimer's and other tauopathies
- α-synuclein inclusions: Parkinson's disease and Lewy body diseases
- Huntingtin aggregates: Huntington's disease pathology
- TDP-43 inclusions: ALS and frontotemporal dementia
- Nucleation: Formation of aggregation-prone conformations
- Elongation: Addition of monomers to growing aggregates
- Secondary nucleation: Aggregate-catalyzed formation of new nuclei
- Fragmentation: Breaking of aggregates creating new seeds
- Cross-seeding: One protein type inducing aggregation of another
- Proteotoxic stress: Cellular damage from misfolded proteins
- Organelle dysfunction: Disruption of cellular compartments
- Membrane damage: Pore formation and membrane permeabilization
- Synaptic dysfunction: Impaired neuronal communication
- Cell death: Apoptosis, necrosis, or other death pathways
- Calnexin/calreticulin cycle: Quality control for glycoproteins
- BiP/GRP78: Major ER chaperone and stress sensor
- PDI: Protein disulfide isomerase for proper disulfide bonds
- EDEM: ER degradation-enhancing mannosidase-like proteins
- PERK pathway: Phosphorylation of eIF2α reducing translation
- IRE1 pathway: XBP1 mRNA splicing and JNK activation
- ATF6 pathway: Transcriptional activation of ER stress genes
- Adaptive response: Restoration of ER homeostasis
- Cell death: Apoptosis if stress cannot be resolved
- Chronic UPR activation: Persistent ER stress signaling
- Impaired folding capacity: Reduced chaperone function
- Calcium dysregulation: Altered ER calcium homeostasis
- Lipid metabolism changes: Modified ER membrane composition
- Alzheimer's disease: Amyloid-β and tau protein aggregation
- Parkinson's disease: α-synuclein inclusions and dopamine neuron loss
- Huntington's disease: Huntingtin protein aggregation
- ALS: TDP-43 and FUS protein inclusions
- Prion diseases: Misfolded prion protein propagation
- Cataracts: Crystallin protein aggregation in lens
- Type 2 diabetes: Islet amyloid polypeptide (IAPP) aggregation
- Atherosclerosis: Modified lipoprotein aggregation
- Cancer: Oncogene and tumor suppressor protein dysregulation
- Sarcopenia: Muscle protein degradation and synthesis imbalance
- Werner syndrome: Defective DNA repair and protein stability
- Progeria: Lamin A protein misfolding and nuclear dysfunction
- Cockayne syndrome: DNA repair defects affecting protein homeostasis
¶ Detection and Measurement
- Thioflavin T/S staining: Detects amyloid-like structures
- Congo red binding: Classical amyloid detection method
- Immunofluorescence: Specific protein aggregate visualization
- Electron microscopy: Ultrastructural analysis of aggregates
- Dynamic light scattering: Measures protein aggregation kinetics
- Proteasome activity assays: Chymotrypsin, trypsin, and caspase-like activities
- Autophagy flux measurements: LC3-II turnover and p62 levels
- Chaperone expression: HSP protein levels and induction capacity
- UPR activation: BiP, CHOP, and XBP1 splicing markers
- Circulating aggregates: Blood-based protein aggregate detection
- CSF biomarkers: Tau, amyloid-β, and other CNS proteins
- Imaging: PET scans for protein aggregates in vivo
- Functional assessments: Cognitive and motor function tests
- Heat shock protein induction: Heat, exercise, and pharmacological activators
- Chemical chaperones: Trehalose, glycerol, and other osmolytes
- Chaperone mimetics: Small molecules with chaperone-like activity
- Exogenous chaperones: Delivery of purified chaperone proteins
- Proteasome activators: PA28, PA200, and small molecule enhancers
- Proteasome assembly: Compounds promoting proteasome biogenesis
- Ubiquitin pathway modulators: E3 ligase and DUB inhibitors
- Exercise: Physical activity enhancing proteasome function
- mTOR inhibitors: Rapamycin and rapalogs
- AMPK activators: Metformin and other metabolic modulators
- Autophagy inducers: Spermidine, trehalose, and lithium
- Lysosomal biogenesis: TFEB and MITF transcription factor activation
- Immunotherapy: Antibodies targeting specific protein aggregates
- Small molecule inhibitors: Compounds preventing aggregation
- Disaggregation agents: HSP70/HSP40 system enhancers
- Proteolytic activation: Enhancing cellular clearance mechanisms
- Protein folding networks: Systems-level approaches to proteostasis
- Stress granule dynamics: RNA-protein condensate regulation
- Ribosome-associated quality control: Co-translational protein quality
- Mitochondrial proteostasis: Organelle-specific protein homeostasis
- Proteostasis regulators: Genome-wide screens for modulators
- Protein engineering: Designing more stable protein variants
- Targeted protein degradation: PROTACs and molecular glues
- Single-cell proteomics: Cellular heterogeneity in protein homeostasis
- Personalized proteostasis profiles: Individual protein homeostasis assessment
- Biomarker-guided therapy: Tailored interventions based on proteostasis status
- Combination therapies: Multi-target approaches for proteostasis enhancement
- Preventive strategies: Early intervention before aggregate formation
¶ Lifestyle and Environmental Factors
- Chronic stress: Prolonged activation of stress response systems
- Poor diet: High-fat, high-sugar diets affecting protein homeostasis
- Sedentary lifestyle: Reduced beneficial stress responses
- Environmental toxins: Heavy metals and chemicals disrupting protein function
- Sleep deprivation: Impaired protein clearance during sleep
- Regular exercise: Heat shock response and autophagy activation
- Caloric restriction: Enhanced proteostasis network function
- Intermittent fasting: Autophagy induction and protein recycling
- Mediterranean diet: Antioxidants and protein-protective compounds
- Stress management: Controlled activation of beneficial stress responses
¶ Measurement in Research and Clinic
- Proteostasis network mapping: Systems biology approaches
- Protein folding reporters: Fluorescent sensors for protein misfolding
- Aggregation kinetics: Real-time monitoring of protein aggregation
- Proteome stability: Global protein stability measurements
- Diagnostic biomarkers: Early detection of proteostasis dysfunction
- Prognostic indicators: Disease progression and severity assessment
- Therapeutic monitoring: Treatment response evaluation
- Risk stratification: Identifying individuals at high risk
¶ Videos and Educational Resources
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López-Otín, C., et al. (2023). "Hallmarks of aging: An expanding universe." Cell, 186(2), 243-278. PubMed
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Klaips, C. L., et al. (2018). "Pathways of cellular proteostasis in aging and disease." Journal of Cell Biology, 217(1), 51-63. PubMed
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Morimoto, R. I. (2008). "Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging." Genes & Development, 22(11), 1427-1438. PubMed
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Kaushik, S., & Cuervo, A. M. (2015). "Proteostasis and aging." Nature Medicine, 21(12), 1406-1415. PubMed
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Hipp, M. S., et al. (2019). "The proteostasis network and its decline in ageing." Nature Reviews Molecular Cell Biology, 20(7), 421-435. PubMed
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Rubinsztein, D. C., et al. (2011). "Autophagy and aging." Cell, 146(5), 682-695. PubMed
Part of the Hallmarks of Aging series