Proteostasis, or protein homeostasis, is a key process for maintaining protein balance in cells by regulating their synthesis, folding, repair, and degradation. The proper quality of proteins ensures the proper functioning of cells and tissues, while disturbances 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 aging process, and to discuss strategies to support this process in order to delay cellular aging.
Proteostasis Mechanisms: Maintaining Protein Quality
Proteostasis relies on three main cellular systems:
- Ubiquitin-proteasome system (UPS): Ubiquitin is a small protein that marks damaged or misfolded proteins, directing them to be degraded in the proteasome. Proteasomes act as “machines” that break down these tagged proteins into shorter peptides. Proteasome activity declines with age, contributing 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, especially in the brain.
- Heat shock proteins (HSP): HSPs, such as HSP70 and HSP90, act as “chaperones,” helping proteins fold correctly and preventing them from aggregating. As we age, HSP expression decreases, making cells more susceptible to protein damage from oxidative and toxic stress.
Proteostasis disorders and cellular aging
Cellular aging is associated with a weakening of proteostasis mechanisms, which leads to:
- Accumulation of damaged proteins: Dysfunction of the UPS and autophagy results in the accumulation of damaged proteins and the formation of toxic aggregates that destabilize cellular functions. 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: Accumulation of damaged proteins causes toxic effects on cells, which leads to activation of cell death pathways such as apoptosis and necroptosis. Proteotoxic stress is a significant factor in accelerating cellular aging and the development of age-related diseases.
- Replicative Aging and SASP: Aging cells secrete pro-inflammatory factors that disrupt proteostasis in neighboring cells, contributing to the development of inflammation at the tissue level and deepening 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 the accumulation of damaged proteins, which contributes to impaired contractile function of the heart and the development of heart failure.
- Liver and kidney diseases: Disturbances of proteostasis in these organs increase the risk of liver cirrhosis and chronic renal failure due to the accumulation of damaged proteins and toxic aggregates.
The impact of lifestyle on proteostasis
- Diet: Consuming a diet rich in antioxidants and polyphenols, calorie restriction, and moderate protein consumption support protein homeostasis.
- Physical activity: Regular physical exercise stimulates autophagy and HSP expression, which supports proteostasis.
- Stress reduction: Practices such as meditation, yoga and mindfulness can affect protein health by reducing oxidative stress and stabilizing proteostasis.
Strategies to Support Proteostasis to Delay Aging
Improvement of proteostasis can be achieved by the following strategies:
- Autophagy induction: Calorie-restricted diets, intermittent fasting, and supplementation with resveratrol, curcumin, and EGCG stimulate autophagy and the removal of damaged proteins.
- Strengthening the UPS system: Supplements like alpha lipoic acid and NRF2 activators support proteasome activity, which helps remove damaged proteins and maintain cell health.
- Induction of heat shock protein (HSP) expression: Techniques such as sauna, heat therapy and supplementation with fisetin, astragalin and sulforaphane support the synthesis of HSPs, 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 aging, and the development of age-related diseases. Strategic interventions such as diet, physical activity, pharmacotherapy, and supplementation can support proteostasis, delaying the aging process and promoting longevity.