Peroxisomal Dysfunction in Ageing

Peroxisomes are small, single-membrane organelles whose functions connect lipid metabolism, redox control, and intracellular signalling. Their name reflects their close relationship with hydrogen peroxide: several peroxisomal oxidases produce it, while catalase converts it to water and oxygen. Peroxisomes also shorten very-long-chain and branched-chain fatty acids and contribute to the synthesis of plasmalogens, a class of ether phospholipids found in cellular membranes. [1] [2]

Who This Is Useful For

This page is useful for readers exploring organelle quality control, oxidative metabolism, lipid biology, or the relationship between peroxisomes and mitochondria. It also provides context for interpreting studies that describe peroxisomal changes as either causes or consequences of ageing.

What Peroxisomal Dysfunction Means

Peroxisomal dysfunction is not one defect. It can involve reduced organelle biogenesis, inefficient import of enzymes into the peroxisomal matrix, altered membrane transport, impaired metabolic enzyme activity, disturbed redox balance, or inappropriate removal of peroxisomes by selective autophagy, known as pexophagy. [1] [2]

These failures need not move together. A cell can contain many peroxisome-like structures while still importing matrix enzymes poorly, so organelle number alone is not a reliable measure of peroxisomal function. Late-passage human fibroblasts, for example, showed altered peroxisome abundance alongside impaired protein import and greater hydrogen-peroxide accumulation. [3]

Age-Related Evidence

In cultured human fibroblasts approaching replicative senescence, import through the PTS1 pathway became less efficient, with catalase particularly affected. The import receptor PEX5 accumulated on peroxisomal membranes, and cellular hydrogen peroxide increased. Because this is an in-vitro model of replicative ageing, it does not by itself establish the same sequence in intact human tissues. [3]

Organismal studies point in a similar direction but also show biological variation. Proteomic analysis in ageing Caenorhabditis elegans found declining abundance of roughly 30 proteins involved in peroxisomal import and metabolism, including PRX-3 and PRX-5, the worm counterparts of PEX3 and PEX5. [4] In mouse cortex, neuronal PEX5 protein was lower in old than young animals, although age and sex patterns differed between protein and messenger-RNA measurements. [5]

Mechanisms That May Link Peroxisomes to Ageing

Protein Import and the Catalase Problem

Most peroxisomal matrix proteins are synthesized in the cytosol and recognized by import receptors. PEX5 binds proteins carrying a PTS1 targeting signal, docks at the peroxisomal membrane, releases its cargo, and is recycled. Catalase has a relatively weak, non-canonical targeting signal, which may make its import particularly vulnerable when this machinery is impaired. [3]

This creates a potential feedback loop. Oxidative conditions can impair import, while failure to place catalase inside peroxisomes can weaken local hydrogen-peroxide control. Such a loop is supported by fibroblast experiments, but how often it occurs, and whether it initiates decline rather than follows it, is not established across ageing human tissues. [3] [7]

Lipid Metabolism and Membrane Biology

Peroxisomes handle lipid substrates that mitochondria cannot process alone. They shorten very-long-chain fatty acids and participate in branched-chain fatty-acid metabolism, bile-acid synthesis, and the early steps of plasmalogen synthesis. Products can then be transferred to other cellular compartments for further metabolism. [1] [2]

Age-related reductions in peroxisomal metabolic proteins could therefore alter both the accumulation of substrates and the supply of membrane lipids. These mechanisms are biologically plausible, and severe inherited peroxisomal disorders demonstrate their physiological importance, but those disorders are not direct models of the smaller, heterogeneous changes observed during normal ageing. [1] [4] [7]

Pexophagy and Quality Control

Cells balance peroxisome formation with selective removal by pexophagy. This can eliminate damaged or surplus organelles, but either insufficient or excessive turnover could disturb the functional peroxisome pool. [1] [8]

Live imaging in C. elegans found substantial peroxisome turnover at tubular lysosomes during early adulthood. Genetic changes that altered age-dependent peroxisome loss also changed lifespan in this model. The direction was context-dependent, and these experiments do not show that simply raising or lowering pexophagy would have the same effect in mammals. [8]

Peroxisome-Mitochondria Crosstalk

Peroxisomes and mitochondria share parts of fatty-acid metabolism, redox control, and organelle-division machinery. Experimental disruption of peroxisomal redox balance can alter mitochondrial redox state and morphology, supporting a route by which a local peroxisomal defect can become a broader cellular disturbance. [6] [7]

This relationship is bidirectional rather than a simple upstream-downstream chain. Mitochondrial stress can also change peroxisomal behaviour, and both organelles respond to shared metabolic conditions. Experiments therefore need organelle-specific measurements before assigning the source of a redox or lipid phenotype. [1] [6]

Evidence Quality and Open Questions

Evidence is strongest that peroxisomal composition and function can change with age in cultured cells and several animal tissues. Independent studies have detected impaired import, declining peroxisomal proteins, altered catalase localization, and age-dependent turnover. [3] [4] [5] [8]

Evidence is weaker on causal order in normal human ageing. It remains unclear which peroxisomal changes occur first, whether they are adaptive or damaging in each tissue, and how much they contribute independently of mitochondrial, lysosomal, inflammatory, and metabolic changes. Reviews of the field accordingly treat peroxisomal dysfunction as an emerging contributor rather than a single established cause of ageing. [2] [7] [9]

What This Does Not Mean

• Peroxisomes are not simply smaller mitochondria; they have distinct metabolic reactions and import machinery. [1]
• More peroxisomes do not necessarily mean better function, because defective organelles can accumulate when import or turnover is disturbed. [3]
• Hydrogen peroxide is not exclusively waste; at controlled concentrations it also participates in signalling. [6]
• Associations with age-related diseases do not establish that peroxisomal dysfunction caused those diseases or normal ageing. [7]

Summary

Peroxisomal dysfunction provides a mechanistic link among lipid imbalance, altered redox regulation, organelle quality control, and mitochondrial stress. Age-related changes have been measured in cells, worms, and mouse tissues, with protein import through PEX5 emerging as one recurring vulnerability. The central unresolved question is not whether peroxisomes change with age, but when those changes are causal, compensatory, or secondary in particular human tissues. [2] [3] [4] [5]

References

1. Schrader, M., et al. (2024). "The peroxisome: an update on mysteries 3.0." Histochemistry and Cell Biology. https://pmc.ncbi.nlm.nih.gov/articles/PMC10822820/
2. Titorenko, V. I., and Terlecky, S. R. (2011). "Peroxisome metabolism and cellular aging." Traffic. https://pmc.ncbi.nlm.nih.gov/articles/PMC3077116/
3. Legakis, J. E., et al. (2002). "Peroxisome senescence in human fibroblasts." Molecular Biology of the Cell. https://pubmed.ncbi.nlm.nih.gov/12475949/
4. Narayan, V., et al. (2016). "Deep proteome analysis identifies age-related processes in C. elegans." Cell Systems. https://pmc.ncbi.nlm.nih.gov/articles/PMC5003814/
5. Uzor, N. E., et al. (2020). "Aging lowers PEX5 levels in cortical neurons in male and female mouse brains." Molecular and Cellular Neuroscience. https://pmc.ncbi.nlm.nih.gov/articles/PMC7484460/
6. Pascual-Ahuir, A., et al. (2017). "Pro- and antioxidant functions of the peroxisome-mitochondria connection and its impact on aging and disease." Oxidative Medicine and Cellular Longevity. https://pmc.ncbi.nlm.nih.gov/articles/PMC5546064/
7. Cipolla, C. M., and Lodhi, I. J. (2017). "Peroxisomal dysfunction in age-related diseases." Trends in Endocrinology & Metabolism. https://pubmed.ncbi.nlm.nih.gov/28063767/
8. Dolese, D. A., et al. (2022). "Degradative tubular lysosomes link pexophagy to starvation and early aging in C. elegans." Autophagy. https://pubmed.ncbi.nlm.nih.gov/34689720/
9. Kelly, J. F., and Roth, G. S. (1998). "The role of peroxisomes in aging." Cellular and Molecular Life Sciences. https://pmc.ncbi.nlm.nih.gov/articles/PMC11147293/