Available online 10 November 2023

The highly conserved target of rapamycin (TOR) pathway plays an important role in aging across species. Previous studies have established that inhibition of the TOR complex 1 (TORC1) significantly extends lifespan in C. elegans. However, it has not been clear whether TORC1 perturbation affects aging in a spatiotemporal manner. Here we applied the auxin-inducible degradation (AID) tool to knockdown endogenous DAF-15, the C. elegans ortholog of regulatory associated protein of TOR (Raptor), to characterize its roles in aging. Global or tissue-specific inhibition of DAF-15 during development results in various growth defects, whereas neuron-specific knockdown of DAF-15 during adulthood significantly extends lifespan and healthspan. The neuronal DAF-15 deficiency-induced longevity requires the intestinal activities of DAF-16/FOXO and PHA-4/FOXA transcription factors, as well as the AAK-2/AMP-activated protein kinase (AMPK) α catalytic subunit. Transcriptome profiling revealed that the neuronal DAF-15 knockdown promotes expression of genes involved in protection. These findings define the tissue-specific roles of TORC1 in healthy aging and highlight the importance of neuronal modulation of aging.

© 2023 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press.