The Hallmark of Ageing 4: Loss of Proteostasis

Written By Leslie Kenny

There’s a certain satisfaction in a well-organised space - everything in its place, neatly arranged, free from clutter. Tidy space, tidy mind, as the saying goes. Surprisingly, your cells work on much the same principle. But rather than managing shelves and drawers, they’re overseeing proteins - the essential molecules that underpin almost every function in your body. From structural support and cellular communication to energy production, tissue repair, and immune defence, proteins must be made, folded, and cleared with regularity and precision. 

However, just like any space left unattended, this internal order doesn’t maintain itself. Over time, the cellular systems responsible for organising, repairing, and clearing proteins can falter. Damaged or misfolded proteins aren’t dealt with as efficiently, and molecular clutter starts to build up. This gradual breakdown in protein quality control is the fourth hallmark of ageing, known as loss of proteostasis [1]. 


What Is Proteostasis?

“Proteostasis” is short for protein homeostasis. This is the body’s way of ensuring proteins are properly made, correctly folded into their functional shapes, and efficiently recycled when damaged or no longer needed .

To unpack the term:

  • Proteins are molecules built from chains of amino acids. They are involved in virtually every cellular process - from carrying oxygen and transmitting signals, to repairing tissue and neutralising threats.

  • Homeostasis means balance. It’s the body’s way of keeping internal systems stable, even as external conditions change.

So, protein homeostasis refers to the ongoing balance of protein creation, folding, maintenance, and disposal [2]. Think of it as your body’s version of sorting laundry: ensuring everything is clean, folded, and returned to the right place. If a protein isn’t folded correctly, it won’t work properly, in fact,  misfolded proteins can become toxic, clumping together and interfering with normal cell activity.


Protein Protection

To maintain proteostasis, your cells are equipped with a quality control network. One important component of this system is a group of molecules known as heat-shock proteins. These act like molecular chaperones, helping misfolded proteins find their correct shape again [3]. If a protein is beyond repair, the cell marks it for removal through a process called ubiquitination - essentially tagging it as waste. This tag sends the protein to the proteasome, the cell’s version of a shredder. Alternatively, larger or bulkier debris that the proteasome can’t handle alone is sent through autophagy, the cell’s overarching recycling system, instead  transporting waste to the lysosome - a larger, sort of cellular digestive chamber [4]. Together, these mechanisms help ensure that only healthy, functional proteins remain in circulation, keeping cells tidy, efficient, and fit for purpose.


What Happens with Age?

As a natural part of ageing, exacerbated by factors such as  long-term stress or inflammation, these protective systems start to weaken. Fewer heat-shock proteins are produced. The proteasome becomes sluggish. Autophagy slows down. As a result, misfolded proteins aren’t as efficiently repaired or cleared away. They begin to accumulate inside cells, forming sticky clumps or aggregates. These can cause inflammation, oxidative stress, and eventually impair the function of entire tissues [5].

This decline in protein management is known as loss of proteostasis, and it's now understood to be a major driver of the ageing process (or Hallmark of Ageing) - disrupting the body at a fundamental level.

The Link to Disease

The brain is particularly vulnerable to disruptions in proteostasis. Brain cells (neurons) don’t divide or regenerate as easily as other cells, so they depend in part on efficient protein quality control systems to stay healthy. When these systems break down, misfolded proteins can start to build up and interfere with neuronal communication [5,6]. Over time, this can contribute to neurodegenerative disease: 

  • In Alzheimer’s disease: misfolded protein structures known as ‘beta-amyloid’ and’tau proteins’ form plaques and tangles that are thought to damage brain tissue and characterise the disease [7].

  • In Parkinson’s disease: a protein called alpha-synuclein clumps into structures known as Lewy bodies, impairing movement and cognitive function [8].

  • In Motor Neurone Disease: aggregates of misfolded proteins can accumulate in nerve cells, disrupting muscle control [9].

Can We Slow or Reverse It?

Prompted by proteostasis being defined as a hallmark of ageing, researchers are exploring meeting the third point of Lopez Otin’s Hallmark criteria - can we enhance proteostasis as a way to delay ageing and prevent disease. Here are some promising developments from the scientific front:

Boosting Heat-Shock Proteins: Heat-shock proteins help cells refold damaged proteins. A drug called arimoclomol, which increases these protective proteins, was tested in patients with Niemann-Pick disease type C - a rare neurodegenerative condition. The treatment appeared to slow disease progression, suggesting that enhancing the body’s own repair systems may hold promise for broader neurodegenerative conditions [10].

Activating Autophagy: A number of interventions are being studied for their ability to delay the loss of proteostasis by activating autophagy - the body’s cellular clean-up and recycling system. Spermidine, found in wheat germ and aged cheese, has been shown to enhance autophagy and improve protein turnover in older adults [11]. Rapamycin, by inhibiting the mTOR pathway, stimulates autophagy and has been linked to reduced protein aggregation in animal models [12]. Caloric restriction and fasting-mimicking diets also promote autophagy and help maintain protein quality control (13).

Chemical Chaperones: Sodium phenylbutyrate, a compound that helps reduce stress in the parts of the cell where proteins are folded, has been studied in combination with another compound known as taurursodiol as a treatment for motor neurone disease. This combination therapy, known as AMX0035, has been shown to slow disease progression and is now approved in several countries [14]. By supporting proper protein folding and reducing cellular stress, AMX0035 may help protect against the accumulation of misfolded proteins - making it a promising example of how targeting protein maintenance systems could help prevent the loss of proteostasis.

Emerging Role of the protein MANF: Recent research from McMaster University has identified a protein called MANF as a promising way of protecting cells from the harmful effects of protein build-up. Using microscopic worms (C. elegans), scientists found that increasing MANF levels helped activate the cell’s natural clean-up systems, especially those involved in breaking down damaged proteins [15]. Since MANF is found in all animals, including humans, it may offer a future therapeutic pathway for preserving proteostasis and slowing age-related decline, particularly in the brain.

These clinical findings suggest that it may indeed be possible to enhance proteostasis as a means of supporting healthy ageing and protecting against age-related diseases. While more research is needed, the results so far are a promising step forward.

What You Can Do: Lifestyle Support for Proteostasis

Outside of ongoing clinical research, thankfully, there are ways to support proteostasis in your day-to-day life. Here are some lifestyle tips to help your natural protein protecting mechanisms and slow this hallmark down:

Intermittent Fasting / Time-Restricted Eating

Fasting activates autophagy, allowing cells to clear out damaged proteins and regenerate more efficiently. Consider eating within a 14:10 or 16:8 window a few days a week.

Heat Exposure (Sauna Use)

Regular sauna sessions trigger the production of heat-shock proteins and may reduce inflammation while boosting protein repair.

Cold Exposure (Cold Showers or Cryotherapy)

Brief cold exposure encourages cellular stress resilience and may support autophagy processes.

Exercise

Movement supports proteasome function and stimulates autophagy, especially in muscle and brain cells. Aim for a mix of cardiovascular, resistance, and mobility training.

Polyphenols & Nutrients

  • Spermidine (wheat germ, aged cheese): Promotes autophagy.

  • Resveratrol (found in red grapes): Activates anti-ageing pathways.

  • Curcumin (from turmeric): Reduces protein damage and inflammation.

Prioritise Quality Sleep

Deep sleep enables the brain’s glymphatic system to clear out waste proteins. It also supports hormonal repair systems that influence overall proteostasis.

Reduce Sugar & Processed Foods

Excess sugar forms sticky molecules called advanced glycation end-products (AGEs) that damage proteins and accelerate ageing. A whole-foods diet rich in antioxidants can help counteract this.


Glossary

  • Proteostasis: The balance of protein production, folding, repair, and recycling in the body.

  • Heat-Shock Proteins: Molecules that help repair or refold damaged proteins.

  • Ubiquitination: A process where damaged proteins are tagged for removal.

  • Proteasome: A cellular complex that breaks down faulty proteins.

  • Autophagy: The process by which cells recycle their internal components.

  • Lysosome: A compartment in the cell filled with enzymes to digest waste.

  • Chaperone-Mediated Autophagy: A selective form of autophagy where specific proteins are delivered directly to the lysosome.

  • MANF (Mesencephalic Astrocyte-Derived Neurotrophic Factor): A naturally occurring protein found in all animals, including humans, that helps protect cells from stress and supports the breakdown of misfolded or damaged proteins.

  • AGEs (Advanced Glycation End-products): Harmful molecules formed when proteins or fats combine with sugar, often linked to ageing and inflammation.

References: 

  1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001

  2. Noormohammadi A, Calculli G, Gutierrez-Garcia R, Khodakarami A, Koyuncu S, Vilchez D. Mechanisms of protein homeostasis (proteostasis) maintain stem cell identity in mammalian pluripotent stem cells. Cell Mol Life Sci. 2018 Jan;75(2):275-290. doi: 10.1007/s00018-017-2602-1

  3. Hu C, Yang J, Qi Z, Wu H, Wang B, Zou F, Mei H, Liu J, Wang W, Liu Q. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm (2020). 2022 Aug 2;3(3):e161. doi: 10.1002/mco2

  4. Li, Y.; Li, S.; Wu, H. Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress. Cells 2022, 11, 851. https://doi.org/10.3390/cells11050851

  5. Ajmal MR. Protein Misfolding and Aggregation in Proteinopathies: Causes, Mechanism and Cellular Response. Diseases. 2023 Feb 9;11(1):30. doi: 10.3390/diseases11010030. PMID: 36810544

  6. Sweeney, P., Park, H., Baumann, M. et al. Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener 6, 6 (2017). https://doi.org/10.1186/s40035-017-0077-5  

  7. Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014 Apr;71(4):505-8. doi: 10.1001/jamaneurol.2013.5847. PMID: 24493463

  8. Meade, R.M., Fairlie, D.P. & Mason, J.M. Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles. Mol Neurodegeneration 14, 29 (2019). https://doi.org/10.1186/s13024-019-0329-1

  9. Cristofani R, Crippa V, Cicardi ME, Tedesco B, Ferrari V, Chierichetti M, Casarotto E, Piccolella M, Messi E, Galbiati M, Rusmini P, Poletti A. A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases. Front Aging Neurosci. 2020 Jul 21;12:191. doi: 10.3389/fnagi.2020.00191

  10. Kirkegaard T, Gray J, Priestman DA, Wallom KL, Atkins J, Olsen OD, Klein A, Drndarski S, Petersen NH, Ingemann L, Smith DA, Morris L, Bornæs C, Jørgensen SH, Williams I, Hinsby A, Arenz C, Begley D, Jäättelä M, Platt FM. Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci Transl Med. 2016 Sep 7;8(355):355ra118. doi: 10.1126/scitranslmed.aad9823

  11.  Bhukel A, Madeo F, Sigrist SJ. Spermidine boosts autophagy to protect from synapse aging. Autophagy. 2017 Feb;13(2):444-445. doi: 10.1080/15548627.2016.1265193

  12. Lin DS, Huang YW, Lee TH, Chang L, Huang ZD, Wu TY, Wang TJ, Ho CS. Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy. Cells. 2023 Mar 24;12(7):993. doi: 10.3390/cells12070993

  13. Chung KW, Chung HY. The Effects of Calorie Restriction on Autophagy: Role on Aging Intervention. Nutrients. 2019 Dec 2;11(12):2923. doi: 10.3390/nu11122923

  14. Sun Y, Li X, Bedlack R. An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis. Expert Rev Neurother. 2023 Jan;23(1):1-7. doi: 10.1080/14737175.2023.2174018

  15. Taylor SKB, Hartman JH, Gupta BP. The neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2024 Oct 22;121(43):e2403906121. doi: 10.1073/pnas.2403906121

Leslie Kenny https://www.oxfordhealthspan.com
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