Proteostasis: Protein Quality Control and Its Role in Ageing
What Is Proteostasis?
Proteostasis (protein homeostasis) refers to the cellular systems that regulate the synthesis, folding, maintenance, and degradation of proteins¹.
Proteins are essential for nearly all biological functions, including enzymatic activity, structural integrity, and intracellular signaling. For cells to function properly, proteins must maintain precise three-dimensional structures.
Proteostasis ensures that misfolded, damaged, or unnecessary proteins are either repaired or removed before they accumulate and disrupt cellular function.
Proteostasis and Cellular Function
Cells are in a constant state of protein turnover.
Proteins are continuously synthesized, folded into functional structures, monitored for damage, and repaired or degraded when necessary.
This dynamic balance is critical because even small disruptions in protein structure can impair function and interfere with cellular processes².
The Core Proteostasis Network
Proteostasis is maintained through an integrated network of systems:
- Molecular Chaperones and Heat Shock Proteins
Molecular chaperones, including heat shock proteins (HSPs), assist in protein folding and refolding of damaged proteins. They act as a primary defense against protein misfolding and aggregation³.
- The Ubiquitin–Proteasome System
Damaged or misfolded proteins are tagged with ubiquitin and degraded by the proteasome. This system provides rapid and selective removal of defective proteins⁴.
- Autophagy and Lysosomal Degradation
Larger protein aggregates and damaged organelles are removed through autophagy. These components are enclosed in vesicles and delivered to lysosomes for breakdown and recycling⁵.
Proteostasis and Ageing
One of the defining features of ageing is a progressive loss of proteostasis.
As these systems decline, misfolded proteins accumulate, protein aggregates form, and cellular function becomes impaired.
This loss of protein quality control is strongly associated with ageing and age-related diseases, particularly neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease⁶.
What Drives the Decline in Proteostasis?
Proteostasis breakdown emerges from multiple interacting processes:
- Reduced chaperone activity: With age, the expression and responsiveness of heat shock proteins decline, reducing the cell’s ability to refold damaged proteins³.
- Impaired proteasome function: Proteasome efficiency decreases over time, slowing the clearance of damaged or misfolded proteins⁴.
- Declining autophagy: Autophagic activity decreases with age, allowing protein aggregates and dysfunctional components to accumulate⁵.
- Increased oxidative stress: Higher levels of reactive oxygen and nitrogen species (RONS) damage proteins directly, increasing the burden on proteostasis systems⁷.
- Chronic inflammation: Inflammaging alters cellular signaling and contributes to protein damage and impaired clearance mechanisms⁸.
Proteostasis in the Ageing Network
Proteostasis is tightly integrated with other longevity pathways.
Mitochondrial dysfunction increases protein damage, NAD⁺ decline reduces repair capacity, sirtuins regulate stress responses, and autophagy determines clearance efficiency.
Disruption in these systems accelerates proteostasis failure.
A Self-Reinforcing Cycle
Proteostasis decline contributes to a feedback loop.
Protein damage increases cellular stress, cellular stress increases oxidative damage, oxidative damage increases protein misfolding, and impaired clearance allows accumulation.
Over time, this leads to progressive loss of cellular function.
Summary - Why Proteostasis Matters for Longevity
Proteostasis is the system responsible for maintaining protein structure, function, and turnover within cells.
It relies on coordinated processes including molecular chaperones, proteasomal degradation, and autophagy.
With age, these systems decline, leading to accumulation of damaged proteins and progressive cellular dysfunction.
As part of the broader ageing network, proteostasis failure contributes to reduced resilience, increased disease risk, and overall biological decline.
Footnotes
1 Proteostasis and protein folding in cellular function https://pubmed.ncbi.nlm.nih.gov/25620043/
2 Protein homeostasis and cellular stress responses https://pubmed.ncbi.nlm.nih.gov/26733247/
3 Heat shock proteins and proteostasis https://pubmed.ncbi.nlm.nih.gov/26874938/
4 The ubiquitin-proteasome system in aging https://pubmed.ncbi.nlm.nih.gov/26450106/
5 Autophagy and protein quality control https://pubmed.ncbi.nlm.nih.gov/29261714/
6 Proteostasis collapse in aging and neurodegeneration https://pubmed.ncbi.nlm.nih.gov/26667669/
7 Oxidative stress and protein damage https://pubmed.ncbi.nlm.nih.gov/29731617/
8 Inflammation and protein homeostasis https://pubmed.ncbi.nlm.nih.gov/29676998/
