Low-dose naltrexone extends healthspan and lifespan in C. elegans via SKN-1 activation
Weisha Li,
Rebecca L. McIntyre,
Bauke V. Schomakers,
Rashmi Kamble,
Anne H.G. Luesink,
Michel van Weeghel,
Riekelt H. Houtkooper,
Arwen W. Gao,
Georges E. Janssens
Affiliations
Weisha Li
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Rebecca L. McIntyre
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Bauke V. Schomakers
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Rashmi Kamble
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Anne H.G. Luesink
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Michel van Weeghel
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Riekelt H. Houtkooper
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
Arwen W. Gao
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Corresponding author
Georges E. Janssens
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Corresponding author
Summary: As the global aging population rises, finding effective interventions to improve aging health is crucial. Drug repurposing, utilizing existing drugs for new purposes, presents a promising strategy for rapid implementation. We explored naltrexone from the Library of Integrated Network-based Cellular Signatures (LINCS) based on several selection criteria. Low-dose naltrexone (LDN) has gained attention for treating various diseases, yet its impact on longevity remains underexplored. Our study on C. elegans demonstrated that a low dose, but not high dose, of naltrexone extended the healthspan and lifespan. This effect was mediated through SKN-1 (NRF2 in mammals) signaling, influencing innate immune gene expression and upregulating oxidative stress responses. With LDN’s low side effects profile, our findings underscore its potential as a geroprotector, suggesting further exploration for promoting healthy aging in humans is warranted.
