Proteostasis, or protein homeostasis, is a key process for maintaining protein balance in cells by regulating protein synthesis, folding, repair and degradation. Adequate protein quality ensures proper functioning of cells and tissues, while disorders in proteostasis lead to the accumulation of damaged proteins, proteotoxic stress and the development of age-related diseases such as Alzheimer's and Parkinson's disease. The aim of this article is to present the mechanisms of proteostasis, its impact on the ageing process and to discuss strategies to support this process in order to delay cellular ageing.
Mechanisms of proteostasis: maintaining protein quality
Proteostasis relies on three main cellular systems:
- The ubiquitin-proteasome system (UPS): Ubiquitin is a small protein that marks damaged or misfolded proteins, directing them for degradation in proteasomes. Proteasomes act as ‘machines’ that break down these tagged proteins into shorter peptides. As we age, proteasome activity declines, which contributes to the accumulation of damaged proteins in cells and the development of neurodegenerative diseases such as Parkinson's disease.
- Autophagy: This is the process of removing large protein aggregates and dysfunctional cellular organelles by transporting them to lysosomes, where they are degraded. Autophagy is activated during starvation, oxidative stress and cellular damage. With age, autophagy becomes less effective, leading to the accumulation of toxic protein aggregates in tissues, particularly in the brain.
- Heat shock proteins (HSPs): HSPs, such as HSP70 and HSP90, act as ‘chaperones’, helping proteins to fold properly and preventing their aggregation. As we age, HSP expression decreases, making cells more susceptible to protein damage caused by oxidative and toxic stress.
Proteostasis disorders and cellular ageing
Cellular ageing is associated with impaired proteostasis mechanisms, leading to:
- Accumulation of damaged proteins: Dysfunction of UPS and autophagy results in the accumulation of damaged proteins and the formation of toxic aggregates that destabilise cellular function. Examples include the accumulation of beta-amyloid and hyperphosphorylated tau protein in Alzheimer's disease and the aggregation of alpha-synuclein in Parkinson's disease.
- Proteotoxic stress: the accumulation of damaged proteins causes toxic effects on cells, leading to the activation of cell death pathways such as apoptosis and necroptosis. Proteotoxic stress is an important factor in accelerating cellular ageing and the development of age-related diseases.
- Replicative ageing and SASP: Ageing cells secrete pro-inflammatory factors that disrupt proteostasis in neighbouring cells, contributing to inflammation at the tissue level and exacerbating proteostasis dysfunction.

The role of proteostasis in age-related diseases
Proteostasis disorders are a key factor in the development of neurodegenerative diseases and other age-related conditions:
- Neurodegenerative diseases: In Alzheimer's disease, proteostasis disorders lead to the accumulation of beta-amyloid protein and tau protein, which destroys neurons and leads to dementia. Similarly, in Parkinson's disease, the accumulation of alpha-synuclein in dopaminergic neurons contributes to their degeneration.
- Cardiovascular diseases: Dysfunction of proteostasis in cardiomyocytes leads to accumulation of damaged proteins, which contributes to impaired cardiac contractile function and the development of heart failure.
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Liver and kidney disease: Proteostasis dysfunction in these organs increases the risk of cirrhosis and chronic renal failure due to the accumulation of damaged proteins and toxic aggregates.
Lifestyle effects on proteostasis
- Diet: Eating a diet rich in antioxidants and polyphenols, calorie restriction and moderate protein consumption promote protein homeostasis.
- Physical activity: Regular exercise stimulates autophagy and HSP expression, which supports proteostasis.
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Stress reduction: Practices such as meditation, yoga and mindfulness can influence protein health by reducing oxidative stress and stabilising proteostasis.
Strategies to support proteostasis to delay ageing
Improving proteostasis can be achieved through the following strategies:
- Induction of autophagy: Calorie-restricted diets, intermittent fasting, and supplementation with resveratrol, curcumin and EGCG stimulate autophagy and removal of damaged proteins.
- Strengthening the UPS system: Supplements such as alpha-lipoic acid and NRF2 activators support proteasome activity, which helps to remove damaged proteins and maintain cell health.
- Induction of heat shock protein (HSP) expression: Techniques such as sauntering, heat therapy and supplementation with fisetin, astragalin and sulforaphane promote HSP synthesis, which improves protein stability and reduces the risk of protein aggregation.
In summary, proteostasis is a key component of cellular health and its disruption leads to the accumulation of damaged proteins, accelerated ageing and the development of age-related diseases. Strategic interventions such as diet, physical activity, pharmacotherapy and supplementation can support proteostasis, delaying the ageing process and promoting longevity.
Sources:
- Triglyceride Glucose-Body Mass Index Is a Simple and Clinically Useful Surrogate Marker for Insulin Resistance in Nondiabetic Individuals
- Proteostasis and aging
- Build-UPS and break-downs: metabolism impacts on proteostasis and aging
- The proteostasis network and its decline in ageing