tRNA-derived Small Non-Coding RNAs: Roles in Brain Aging and Neurodegenerative Disorders

Transfer RNA-derived small RNAs (tsRNAs) are an emerging class of regulatory non-coding RNAs produced through precise cleavage of mature or precursor tRNAs (pre-tRNAs). Once considered degradation byproducts, tsRNAs are now recognized as key modulators of gene expression, epigenetic regulation, and cellular stress responses. In recent years, growing evidence has implicated tsRNAs in the aging process of the brain and in the pathogenesis of age-related neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic lateral sclerosis (ALS). These small RNAs are involved in modulating synaptic function, neuronal survival, and neuroinflammation, and their expression profiles are dynamically altered in response to aging and disease-associated stressors. This review summarizes the biogenesis, classification, molecular and cellular mechanisms of tsRNAs, with a particular emphasis on their subcellular locations and associated biological functions. We further explore their roles in brain aging and age-related neurodegenerative diseases, emerging potential of tsRNAs as biomarkers and therapeutic targets for age-related neurological disorders, while highlighting current challenges and future directions in this rapidly advancing field.