We found that the signaling of intracellular amino acids can be sensed by their cognate tRNA synthetases and transmitted via lysine aminoacylation. This provided us opportunities to address questions such as why a given amino acid regulates specific cell signaling pathways and why certain amino acids deregulation is found in different diseases. For example, tyrosyl-tRNA synthetase (YARS) and phenoalanyl-tRNA synthetase (FARS) catalyzed aromatic amino acids modifications in proteins in insulin signaling pathway blunt insulin signaling, induce insulin resistance and type 2 diabetes. Inhibiting aromatic amino acids modifications rejuvenated insulin signals in cultured cells and reversed type 2 diabetes in mice; glutamyl-tRNA synthetase (EARS)-promoted glutamylation in Methyl-CpG binding protein 2 (MeCP2) inactivates MeCP2 and resulted in the expression of a set a genes that are typically altered in Rett syndrome and autism. The levels of glutamate, EARS and glutamylation were positively correlated to the onset of autism in children. These results showed the importance of deregulated amino acids signals in the onset of human diseases and provide novel opportunities for the treatment of these diseases.