Disruption of tRNA biogenesis enhances proteostatic resilience, improves later-life health, and promotes longevity

• DOI: 10.1371/journal.pbio.3002853
• Publication Date: 2024-10-22T17:37:02Z
• Authors: Yasir Malik; Yavuz Kulaberoglu; Shajahan Anver; Sara Javidnia; Gillian Borland; Rene Rivera; Stephen Cranwell; Danel Medelbekova; Tatiana Svermova; Jackie Thomson; Susan Broughton; Tobias von der Haar; Colin Selman; Jennifer M. A. Tu...; Nazif Alic
• Keywords: RNA polymerase III

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