Loss of Protein Homeostasis and Aging

Protecting Our Brain and Body

When everything functions properly in our body, our cells produce, fold, utilize, and eventually remove proteins in a balanced way. However, as we age, this system starts to break down, leading to protein homeostasis (proteostasis) loss. This plays a significant role in the development of neurological diseases such as Alzheimer’s, Parkinson’s, and ALS, as well as in general aging.

When proteins misfold, oxidize, or accumulate, they form toxic aggregates and plaques inside or outside cells. These build-ups impair cellular functions and contribute to aging and disease. Loss of proteostasis is now recognized as a major driver of aging and age-related disorders.

Why Does Protein Balance Break Down?

1. Faulty Protein Production

Every day, our body produces thousands of new proteins. However, over time, cells may produce proteins incorrectly or fail to complete their formation. This can disrupt normal cellular functions and increase disease risk. For example, scientists have found that some genetic mutations (such as those in the RPS23 gene) can increase translation errors and accelerate aging.

2. Weakening of Cellular Repair Mechanisms

Our cells contain chaperone proteins that assist in folding proteins correctly and repairing misfolded ones. However, as we age, these systems become less effective. As a result, damaged proteins cannot be repaired and start accumulating inside cells, leading to toxicity.

3. Breakdown of Protein Clearance Systems

Over time, proteins become damaged and need to be removed from the cell. Two major systems are responsible for this:✔ Proteasome System: Proteasomes act as cellular garbage disposals, breaking down old or damaged proteins for recycling. However, with aging, proteasome activity declines, leading to protein accumulation.✔ Lysosomal Clearance Mechanisms (Autophagy and CMA): Lysosomes digest large protein aggregates and other cellular waste. A key player in this process is LAMP2A, a protein that regulates chaperone-mediated autophagy (CMA). However, as we age, LAMP2A levels decrease, reducing the cell’s ability to clear out damaged proteins. This is strongly linked to Alzheimer’s and other neurodegenerative diseases.

How Can We Maintain Protein Balance?

Scientists are working on various strategies to slow aging and restore protein homeostasis.

1. Enhancing the Cell’s Protein Clearance Capacity

✔ HSP70 Protein: Increasing levels of this protein helps cells remove toxic protein accumulations more efficiently. Studies in mice have shown that boosting HSP70 can protect brain health and delay aging.✔ LAMP2A Gene Therapy: Increasing LAMP2A levels enhances lysosomal function, improving the clearance of misfolded proteins and potentially extending lifespan.

2. Improving Protein Production and Quality

✔ Drugs that promote correct protein translation are being explored. For example, 4-phenylbutyrate, a chemical chaperone, has been shown to reduce brain stress and improve cognitive function in aging mice.✔ Activating stress response mechanisms: Certain drugs can enhance the integrated stress response (ISR), which helps the body manage protein misfolding and oxidative stress. One such drug, Guanabenz, is used in ALS treatment and may help regulate proteostasis.

3. Lifestyle and Dietary Interventions

✔ Antioxidants and a Healthy Diet: Consuming foods rich in natural antioxidants (such as fruits, vegetables, and healthy fats) can support proteostasis and reduce oxidative stress.✔ Fasting and Caloric Restriction: Research suggests that intermittent fasting can stimulate autophagy, the process by which cells remove damaged proteins, and potentially slow aging.✔ Regular Exercise: Exercise activates cellular clearance mechanisms, improving proteasome and autophagy function, which helps maintain protein balance.

Future Treatments for Restoring Protein Homeostasis

Scientists are making significant progress in developing treatments to restore protein balance and slow aging. Promising approaches include LAMP2A gene therapy, HSP70 boosters, proteasome activators, and stress response regulators.

New drugs targeting neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and ALS are in development. For example, Guanabenz, a drug used for ALS, helps regulate protein production and may slow disease progression.

In the future, gene therapies and pharmaceuticals that enhance cellular cleanup processes could significantly slow aging and prevent age-related diseases.

Conclusion

Protein homeostasis is essential for keeping our brain and body healthy. Although this system weakens with age, adopting the right lifestyle, maintaining a balanced diet, and leveraging scientific advancements can slow aging and protect brain health.

With future treatments, we may enhance our cells’ ability to produce, repair, and clear proteins more effectively, leading to healthier aging and greater resistance to diseases like Alzheimer’s and Parkinson’s.şayabiliriz hem de Alzheimer ve Parkinson gibi hastalıklara karşı daha dirençli olabiliriz.