A Melatonin–Catechol Hybrid Molecule Prolongs Lifespan via Regulating ROS and Reprogramming Mitochondrial Metabolism

Modulation of mitochondrial dynamics is a viable strategy for lifespan extension. Reactive oxygen species (ROS) play key roles in aging, acting either as signaling molecules to facilitate longevity-associated processes or as stimulators of oxidative stress, exerting deleterious effects on physiological functions. The hybrid molecule MC1 is designed by integrating melatonin and catechol moieties to reconstruct mitochondrial dynamics and selectively regulate the generation of ROS. MC1 combats cell senescence under oxidative stress and DNA damage, and reprograms the mitochondrial energy metabolism by inhibiting the tricarboxylic acid cycle and glycolysis, while initiating fatty acid oxidation to increase energy production. More importantly, MC1 significantly extends the lifespan of Caenorhabditis elegans, accompanied by an improvement in muscle strength and physiological functions. The lifespan-extending effect of MC1 arises from its intervention in mitochondrial membrane fusion, the electron transport chain, and differential modulation of ROS. Regulating mitochondrial dynamics and ROS production shows great potential for longevity extension.