Neuronal Metabolism of Branched-Chain Amino Acids Alleviates Lifespan Reduction Caused by High-Salt Diet in Drosophila.

A high-salt diet (HSD) not only triggers a range of adverse neurological responses but is also significantly associated with reduced lifespan. However, the link between salt-induced neurophysiological changes and lifespan shortening remains unclear. Through RNA-seq analysis of the heads of Drosophila fed a HSD, we found that the branched-chain amino acid (BCAA) metabolic pathway was activated. This study aims to investigate the role and mechanism of BCAAs in HSD-induced lifespan reduction in Drosophila. Our results show that dietary supplementation with BCAAs significantly alleviates the lifespan shortening caused by a HSD, suggesting that BCAA metabolism may contribute to lifespan maintenance under salt stress. Further experiments revealed that ubiquitous knockdown of genes related to BCAA metabolism led to increased salt sensitivity and mortality under high-salt conditions. Notably, neuron-specific disruption of BCAA metabolic genes similarly exacerbated these phenotypes, highlighting a critical role for neuronal BCAA metabolism in the response to salt stress. Interestingly, supplementation with other amino acids-such as phenylalanine, glutamate, aspartate, proline, and tyrosine-also partially rescued the lifespan shortening induced by a HSD. These findings not only underscore the central role of BCAAs in salt-mediated lifespan regulation but also suggest a potential synergistic mechanism involving multiple amino acids, offering new insights into intervention strategies for salt-related health risks.