Beyond mitophagy: A new ribosome-based mechanism emerges for urolithin A

As the world ages, healthy aging has become one of the fastest-growing areas in nutrition – and over the past few years, urolithin A (UA) has emerged as one of the category’s standout ingredients.

UA is a natural metabolite produced when gut microbiota transform dietary ellagitannins from foods such as pomegranate and walnuts; not everyone’s microbiome performs this conversion efficiently, and the body’s capacity to generate UA tends to decline with age, which is why direct supplementation with high-purity UA offers a more reliable source.¹

Research on UA has long centred on mitochondrial quality control – from inducing mitophagy, extending lifespan in C. elegans and improving muscle function in animals, to the first human trial confirming its safety and a molecular signature of improved mitochondrial health, to several human trials reporting gains in muscle strength and endurance in middle-aged and older adults.^2-5

But for the mitochondrion – the cell’s “power plant” – to keep running, it must not only clear damaged parts but also continually renew its proteins. If mitophagy is the cell’s way of “subtracting” – clearing away what is damaged – then protein synthesis, with the ribosome at its centre, is its way of “adding”: keeping production, maintenance, and clearance in step with the cell’s ongoing needs.

That prompts a further question in aging research: as we age, what happens to the cell’s ability to make and maintain these proteins? The 2025 expansion of the hallmarks of aging to fourteen places loss of proteostasis, impaired autophagy, and mitochondrial dysfunction side by side, as interconnected mechanisms.⁶

Proteostasis: The renewal process

Proteins do much of the cell’s work, and they also become damaged or lose function; the cell must therefore make new proteins on time, fold them correctly, and deliver them to the right place, while clearing abnormal ones. This dynamic balance of production, maintenance, and clearance is proteostasis – and the protein problem in aging is as much about whether new proteins can be made properly as about whether old ones can be cleared.

The ribosome is the core machine for making new protein. The cell first builds and assembles these machines through ribosome biogenesis – the transcription and processing of ribosomal RNA, and the coordinated assembly of ribosomal proteins with rRNA – then uses them to synthesize nascent protein; the former concerns the formation of the machinery, the latter the act of production.

The quality of that work matters too: a 2022 Nature study in yeast and C. elegans found that aging exacerbates ribosome pausing, accompanied by impaired clearance and increased aggregation of abnormal nascent proteins – suggesting that proteostatic imbalance may begin at the point of synthesis.⁷

Maintaining mitochondria depends on the cell’s protein supply

Most mitochondrial proteins are encoded by nuclear DNA, made on cytosolic ribosomes and then imported into the mitochondrion, with synthesis and import able to couple to one another.⁸ The relationship runs both ways: mitochondrial stress can disrupt the synthesis of the relevant proteins, while the abnormal proteins produced may aggregate and impair respiratory-chain function.^9,10

So beyond watching energy output, one can also track how the proteins that maintain mitochondria are made, imported, and renewed – the ribosome and its proteostasis network may be an important mechanistic layer in mitochondrial decline.

Nor is this confined to a single tissue: aging blunts the ribosome-biogenesis response to exercise in skeletal muscle and slows translation in an organ-specific way, a reminder that measures of biogenesis or expression are not the same as the actual rate of protein synthesis.^11,12

A systematic program on urolithin A

Along this line, Tech-Inno Health has run a systematic program on its urolithin A ingredient, MitoIgnite®, in multiple senescent and stressed cell models, following the full arc from ribosome biogenesis to protein output: transcription and processing of ribosomal-RNA precursors, ribosome assembly, polysome formation, and the synthesis of nascent protein. Aging or stress was first used to depress these processes; MitoIgnite was then tested for whether it could bring them back.

The readouts point the same way. In the models studied, MitoIgnite raised levels of ribosomal-RNA precursors and shifted biogenesis markers, and nascent-protein-synthesis assays showed a previously reduced synthesis signal recovery.

In the most direct readout – HPG labelling of newly made protein – three different insults (oxidative stress, cell-cycle arrest, and glycation-induced aging) cut synthesis to roughly a fifth to a third of control in cardiac, liver, and skeletal-muscle cells, and 5 µM MitoIgnite brought it back two- to three-fold, reaching statistical significance in every model while leaving baseline synthesis in unstressed cells unchanged (Figure 1).

The size of the effect varied by model – as expected across different cell types and stressors – but the pattern held along the chain, from the machinery that makes ribosomes to the proteins they produce. Related patent applications are under way, and the programme is now being extended to the mitochondrion’s own ribosome and the synthesis of mitochondrial-genome-encoded proteins – the upstream question raised above.¹³

Newly synthesized proteins were labelled with HPG (click chemistry; green) with nuclei counterstained (blue) in AC16 cardiomyocytes (A, B), AML12 hepatocytes (C, D), and C2C12 skeletal-muscle cells (E, F) after oxidative stress (H₂O₂), cell-cycle arrest (palbociclib), or glycation-induced aging (D-galactose), with or without 5 µM MitoIgnite® Urolithin A (UA).

Bars show relative fluorescence intensity (fold vs DMSO vehicle; individual replicates, n = 4). Each insult reduced synthesis to roughly 20% to 35% of control; MitoIgnite restored it two- to three-fold, with significance in every model (*p<0.05, ***p<0.001, ****p<0.0001; ns, not significant). UA alone did not alter baseline synthesis (DMSO+UA vs DMSO, ns).

For formulators and brands, this adds a second mechanism, documented in cell models, to MitoIgnite’s established mitophagy story – “subtract and add” – for positioning in healthy aging, muscle and energy, and skin. Tech-Inno Health supports partners with the mechanism data package, specifications and CoA, samples in 99% high-purity, 10% water-dispersible and cosmetic grades, and IP due-diligence materials for the ribosome work. Cell-model findings are a starting point, and the team welcomes joint studies to take them further.

Continuous innovation, spanning 10 areas

Tech-Inno Health is built around continuous innovation, spanning 10 areas – scientific discovery, mechanism research, regulatory analysis, patent strategy, formulation research, supply-chain optimisation, quality control, clinical research, turnkey solutions, and end-to-end service – to take an ingredient from early science through to finished product.

Around UA, it supplies MitoIgnite at 99% high purity, in a 10% water-dispersible grade and in a cosmetic grade, for different dosage forms and products.

To find out more about Tech-Inno Health’s UA ingredient, MitoIgnite, visit here – or contact ty-sales@taiyi-nb.com.

References

1. Singh, A.; et al. Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults. Eur J Clin Nutr. 2022;76(2):297–308.
2. Ryu, D.; et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016;22(8):879–888.
3. Andreux, PA.; et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019;1(6):595–603.
4. Singh, A.;et al. Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Rep Med. 2022;3(5):100633.
5. Liu, S.; et al. Effect of Urolithin A supplementation on muscle endurance and mitochondrial health in older adults: a randomized clinical trial. JAMA Netw Open. 2022;5(1):e2144279.
6. Kroemer, G.; et al. From geroscience to precision geromedicine: understanding and managing aging.Cell. 2025;188(8):2043–2062.
7. Stein, KC.; et al. Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis. Nature. 2022;601(7894):637–642.
8. Williams, CC.; et al. Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling. Science. 2014;346(6210):748–751.
9. Guo, X.; et al. Mitochondrial stress is relayed to the cytosol by an OMA1–DELE1–HRI pathway. Nature. 2020;579(7799):427–432.
10. Wrobel, L.; et al. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature. 2015;524(7566):485–488.
11. Stec, MJ.; et al. The effects of age and resistance loading on skeletal muscle ribosome biogenesis. J Appl Physiol (1985). 2015;119(8):851–857.
12. Gerashchenko, MV.; et al. Translation elongation rate varies among organs and decreases with age. Nucleic Acids Res. 2021;49(2):e9.
13. Tharakan, R.; et al. Ribosome profiling analysis of human skeletal muscle identifies reduced translation of mitochondrial proteins with age. RNA Biol. 2021;18(11):1555–1559.