Disruption of tRNA Biogenesis Enhances Proteostatic Resilience and Promotes Longevity

Summary: A recent study published in PLOS Biology investigates the effects of disrupting tRNA biogenesis on health and longevity across multiple species, including worms, flies, and mice. Key findings include:

1. Pol III Activity Reduction: The study demonstrates that a partial reduction in RNA polymerase III (Pol III) activity specifically disrupts tRNA levels, which is conserved across different species.
2. Proteostatic Resilience: This disruption enhances proteostatic resilience by activating the unfolded protein response (UPR), which helps cells manage misfolded proteins.
3. Lifespan Extension: In fruit flies, decreased Pol III transcription initiation at tRNA genes significantly extends lifespan and improves late-life health.
4. Mechanistic Insights: The research indicates that alterations in tRNA metabolism can trigger UPR activation, suggesting a novel role for tRNAs in modulating aging processes.
5. Potential Interventions: These findings highlight the importance of tRNA dynamics in aging and suggest that targeting tRNA biogenesis may offer new strategies for promoting healthy aging.

This study provides valuable insights into the molecular mechanisms underlying aging and opens avenues for future research aimed at enhancing longevity through metabolic interventions.

Abstract: tRNAs are evolutionarily ancient molecular decoders essential for protein translation. In eukaryotes, tRNAs and other short, noncoding RNAs are transcribed by RNA polymerase (Pol) III, an enzyme that promotes ageing in yeast, worms, and flies. Here, we show that a partial reduction in Pol III activity specifically disrupts tRNA levels. This effect is conserved across worms, flies, and mice, where computational models indicate that it impacts mRNA decoding. In all 3 species, reduced Pol III activity increases proteostatic resilience. In worms, it activates the unfolded protein response (UPR) and direct disruption of tRNA metabolism is sufficient to recapitulate this. In flies, decreasing Pol III’s transcriptional initiation on tRNA genes by a loss-of-function in the TFIIIC transcription factor robustly extends lifespan, improves proteostatic resilience and recapitulates the broad-spectrum benefits to late-life health seen following partial Pol III inhibition. We provide evidence that a partial reduction in Pol III activity impacts translation, quantitatively or qualitatively, in both worms and flies, indicating a potential mode of action. Our work demonstrates a conserved and previously unappreciated role of tRNAs in animal ageing.

Reference: Malik, Y., Kulaberoglu, Y., Anver, S., Javidnia, S., Borland, G., Rivera, R., et al. (2024). Disruption of tRNA biogenesis enhances proteostatic resilience, improves later-life health, and promotes longevity. PLOS Biology, 22(10), e3002853. https://doi.org/10.1371/journal.pbio.3002853

Hashtags: #LongevityResearch #tRNA #Proteostasis #Aging #PolIII #HealthyAging #MolecularBiology #CellularMetabolism