Digging Deeper into Ribosomal Dysfunction in Aging

A ribosome performs the translation portion of the process of gene expression, assembling protein molecules from amino acid building blocks according to the blueprint provided by messenger RNA molecules. The more efficiently a ribosome operates, the better a cell functions. Like all cellular components, the ribosome is negatively impacted by age, leading to a greater rate of errors in protein manufacture. The causes of this decline are not well understood, at least when it comes to drawing a clear line of causation back to the root causes of aging. It is perhaps noteworthy that long-lived naked mole rats have evolved unusually efficient ribosomes - perhaps an indication of their importance.

When folded correctly, proteins carry out their functions and remain soluble in the environment of the cell. Misfolded proteins, by contrast, cannot function properly and tend to stick to each other and other proteins, clogging up cellular processes and generating toxic aggregates. Protein aggregation has been specifically implicated in a wide variety of aging-linked diseases, including Alzheimer's, Parkinson's, frontotemporal dementia, Huntington's disease, and ALS (amyotrophic lateral sclerosis).

To guard against the continual production of misfolded proteins, cells have dedicated "quality control" machinery for fixing or degrading misfolded proteins. Previous research has shown that shortcomings in these processes can lead to aggregation. This research is the first to show the folding defect during ageing starts early in the journey of a protein, when it is made by the ribosome. Because ribosomes are constantly producing large amounts of proteins, these defects cause a subsequent snowball of disfunction.

To start, the researchers used a technique called ribosome profiling, which allowed them to see exactly how ribosomes are moving on the messenger RNA during the act of translation. Amassing data from all the genes translated in young and aged Caenorhabditis elegans roundworms and yeast, the researchers noticed that in older cells ribosomes periodically moved more slowly and were more likely to stall and bump into each other. As one might expect, the researchers saw that decreases in proper ribosome performance aligned with increases in the aging-dependent aggregation of misfolded proteins. One important insight was that the increase in stalling and misfolding overwhelmed the cell's cleaning-up-and-clearing-out quality control failsafes.

In follow-up experiments in worms, the researchers found that even if the overall fraction of newly made proteins with altered translation during aging is low (~10%), this small effect can still be enough to overwhelm the quality control system and trigger significant aggregation that can disrupt many different cellular components or processes. "Every cell normally makes millions of these newly translated proteins. So very slight changes in the efficiency of folding with age will escalate in a vicious cycle where defects in translation lead to an overload of the system, which in turn leads to increased protein aggregates with age that are themselves also toxic."

Link: https://news.stanford.edu/2022/01/19/role-ribosomes-age-related-diseases/


Are any of the new startups working on repair of ribosome function?

Posted by: Morpheus at January 26th, 2022 7:35 AM

wonder if cell reprogramming rejuvenates ribosome

Posted by: ras at January 26th, 2022 8:14 AM

@ras: I wouldn't be surprised to find that to be the case. Ribosomal dysfunction with age has the look of being downstream of protein expression changes, similarly to mitophagy dysfunction.

Posted by: Reason at January 26th, 2022 9:35 AM

@ras Seems like something in embryogenesis certainly resets this perfectly, even when mum & dad are older, right?

Has anyone looked into ribosome resilience in longer lived species?

Posted by: Matt at January 26th, 2022 4:53 PM
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