Targeting mitochondrial stress responses: Terbinafine and Miglustat as novel lifespan and healthspan modulators

Mitochondria are key regulators of cellular homeostasis, aging, and age-related diseases. This study investigates the mitochondrial stress response (MSR) and its role in longevity by identifying Terbinafine and Miglustat as novel mitochondrial stress inducers in Caenorhabditis elegans. Using a two-step screening approach, we found that both compounds activate MSR pathways, including the mitochondrial unfolded protein response (UPRmt) via ATFS-1, and modulate mitochondrial function across species, similarly to Doxycycline. To further explore the molecular mechanisms, we performed RNA sequencing (RNA-seq) analysis on C. elegans treated with Terbinafine and Miglustat, as well as controls, to assess transcriptomic changes associated with mitochondrial stress. Gene expression analysis revealed activation of MSR pathways and an interplay between the ATFS-1 and DAF-16 signaling networks. Additionally, validation studies in human HEK293T cells confirmed mitochondrial stress induction and functional modulation, demonstrating the translational potential of these compounds. This dataset provides gene expression profiles of C. elegans under mitochondrial stress conditions, offering insights into the regulatory mechanisms of mitochondrial stress responses and their role in aging. Overall design: Total RNA samples were extracted from C. elegans day 1 adults worms that had been exposed to the compounds-RNAi of interest from the L1 larval stage.