Products of Transfer RNA Cleavage are Essential for Stress Response Slowing of Aging
Biochemistry is enormously complex. The closer that researchers look, the more that they will find. Details remain incompletely mapped and understood at every level; there are only so many researchers and only so much funding. Much of the ongoing fundamental research into interventions to treat aging remains focused on the ability of mild stress to provoke beneficial changes in cell behavior, such as the way in which calorie restriction or heat produce increased cell maintenance activities. Here, researchers delve into the extremely complex landscape of RNA molecules in the cell to search for specific RNAs that are essential to beneficial stress responses that slow aging.
Transfer RNA (tRNA) halves (tRHs) are generated via the cleavage of tRNAs, but their roles in aging and longevity remain poorly understood. Here, we demonstrate a direct role of tRHs in aging in metazoans. Through a genetic screen using Caenorhabditis elegans, we identify DIS-3/DIS3 as a ribonuclease that catalyzes tRH generation, including 5′-tRH-Gln and 5′-tRH-Asp, from tRNAs. Among them, 5′-tRH-Gln is essential for longevity conferred by various interventions, including dietary restriction.
Generation of 5′-tRH-Gln reduces translation via ribosomal protein binding and upregulates the SKN-1 transcription factor responsible for lifespan extension. We further show that mammalian DIS3 contributes to tRH generation and delays cellular senescence through translation downregulation by another tRH, 5′-tRH-Cys. Overall, our data demonstrate that DIS-3/DIS3 is an evolutionarily conserved tRH-generating ribonuclease that counteracts organismal and cellular aging.