Proteostasis and Ageing

What Proteostasis Means

Proteostasis, or protein homeostasis, is the set of processes that controls how proteins are made, folded, trafficked, repaired, and removed. In ageing research, loss of proteostasis is treated as a core hallmark because cells depend on this quality-control network to keep proteins functional and to limit the buildup of damaged or aggregation-prone species. [1] [2] [3] [4]

Main Protein Quality-Control Systems

Proteostasis is maintained by overlapping systems rather than a single pathway. Molecular chaperones help nascent or damaged proteins fold correctly, the ubiquitin-proteasome system degrades many short-lived or misfolded proteins, and lysosomal pathways including autophagy clear larger protein aggregates and damaged cellular material. Reviews of the proteostasis network emphasize that these branches are coordinated and can compensate for one another only up to a point. [3] [4] [5] [9]

Where the Unfolded Protein Response Fits

The unfolded protein response (UPR) is a stress-response system activated when misfolded proteins accumulate inside specific cellular compartments. In the endoplasmic reticulum, the UPR adjusts protein synthesis, chaperone expression, and degradation pathways through sensors including IRE1, PERK, and ATF6. Mitochondria have a related quality-control response, often called the mitochondrial UPR, that links proteotoxic stress to chaperones, proteases, and broader metabolic adaptation. [6] [7] [8]

How Proteostasis Changes with Age

Ageing is associated with reduced capacity to maintain protein quality across the cytosol, endoplasmic reticulum, and mitochondria. Experimental work in model organisms shows that stress responses such as the heat shock response and UPR can become less inducible with age, while broad reviews in mammals describe lower buffering capacity against misfolded proteins, declining chaperone support, and less efficient degradation. These shifts do not occur identically in every tissue, but together they increase the likelihood of protein aggregation and proteotoxic stress. [3] [4] [7] [10]

Why It Matters in Ageing Biology

Proteostasis failure is relevant to ageing because proteins sit upstream of most cellular functions, including metabolism, signaling, secretion, and structural maintenance. Once protein quality control weakens, dysfunction can spread into other hallmark processes such as mitochondrial dysfunction, impaired autophagy, and chronic stress signaling. Researchers therefore treat loss of proteostasis as both a distinct hallmark and an interacting node within the wider network of ageing mechanisms rather than as a standalone explanation for ageing. [1] [2] [4] [9]

Summary

Proteostasis describes the cellular systems that preserve protein quality, and ageing is accompanied by progressive strain on those systems. Chaperones, proteasomal degradation, autophagy, and unfolded protein responses together buffer this strain, but evidence across model organisms and mammalian systems suggests that their collective capacity declines over time. [3] [4] [6] [8]

References

1. Lopez-Otin, C. et al. "The Hallmarks of Aging." Cell (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3836174/
2. Lopez-Otin, C. et al. "Hallmarks of aging: An expanding universe." Cell (2023). https://pmc.ncbi.nlm.nih.gov/articles/PMC10809922/
3. Labbadia, J., & Morimoto, R. I. "The Biology of Proteostasis in Aging and Disease." Annu Rev Biochem (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4539002/
4. Hipp, M. S., Kasturi, P., & Hartl, F. U. "The proteostasis network and its decline in ageing." Nat Rev Mol Cell Biol (2019). https://www.nature.com/articles/s41580-019-0101-y
5. Morimoto, R. I., & Cuervo, A. M. "Proteostasis and the Aging Proteome in Health and Disease." J Gerontol A Biol Sci Med Sci (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4022129/
6. Hetz, C., & Papa, F. R. "The Unfolded Protein Response and Cell Fate Control." Mol Cell (2018). https://pubmed.ncbi.nlm.nih.gov/29107536/
7. Martinez, G., Duran-Aniotz, C., Cabral-Miranda, F., Vivar, J. P., & Hetz, C. "Endoplasmic reticulum proteostasis impairment in aging." Aging Cell (2017). https://pmc.ncbi.nlm.nih.gov/articles/PMC5506418/
8. Jensen, M. B., & Jasper, H. "Mitochondrial proteostasis in the control of aging and longevity." Cell Metab (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4274350/
9. Kaushik, S. et al. "Autophagy and the Hallmarks of Aging." Ageing Res Rev (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8616816/
10. Ben-Zvi, A., Miller, E. A., & Morimoto, R. I. "Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging." Proc Natl Acad Sci U S A (2009). https://pmc.ncbi.nlm.nih.gov/articles/PMC2736453/