Association of tsRNAs with aging-regulating pathways. (A) A group of tiRNAs reduce overall translation by displacing eukaryotic initiation factor 4F (eIF4F) complexes from the 5’-cap of mRNAs. In contrast, a specific tRF can increase overall translation rates by enhancing the mRNA translation of ribosomal protein S (RPS) gene. Modulation of protein synthesis by tsRNAs may affect longevity in multiple species, including Caenorhabditis elegans, Drosophila melanogaster, and mouse. (B) tsRNAs may mediate the effects of abnormal tRNA metabolism on aging. Depletion of RNA polymerase III (RNA pol III) may reduce the generation of tRNAs and tsRNAs, possibly contributing to longevity conferred by depletion of RNA pol III in C. elegans and D. melanogaster. Abnormal tRNA processing by the inhibition of HOE-1/ELAC2 causes the accumulation of tsRNAs, likely leading to mitochondrial dysfunction. Mitochondrial impairments enhance or suppress longevity in a context-dependent manner in multiple species, including C. elegans. (C) High-fat diet (HFD) feeding or lipopolysaccharide (LPS) injection alters the composition of sperm tiRNAs and causes metabolic disorders in mice. The tiRNAs in mouse sperm contribute to the inheritance of metabolic diseases to the offspring, and the inherited metabolic diseases may cause premature aging.
