Research Square · Jun 14, 2023
Low-dose Naltrexone (LDN) extends healthspan and lifespan through activation of the transcription factor SKN-1/NRF2 in C. elegans
By Li W, McIntyre RL, Schomakers BV et al.
Abstract Aging is a topic of urgency and importance, particularly as the world's aging population continues to grow. Numerous studies have been conducted to identify potential interventions that can improve health and promote longevity, however few are close to implementation. One promising approach to accelerate the implementation is drug repurposing, or using existing drugs for new indications. Here, we selected naltrexone by repurposing existing drugs from the Library of Integrated Network-based Cellular Signatures (LINCS) with several selection criteria. In recent decades, there has been increasing attention and use of low-dose naltrexone (LDN) as an adjunct treatment modality for cancers, autoimmune diseases, chronic pain and mental health issues. We found that a low, but not high dose of naltrexone extended both healthspan and lifespan in C. elegans worms. Further analysis revealed that LDN treatment-induced longevity was dependent on SKN-1 (NRF2 in mammals) signaling. Moreover, LDN treatment not only increased the expression of innate immune genes but also activated the oxidative stress response in worms, which could be abolished by inhibition of SKN-1/NRF2. Overall, paired with LDN’s low side effects profile, our study highlights the great potential of LDN to be repurposed as a geroprotector for promoting healthy aging and suggests further research in humans is warranted.