Nicotine rebalances NAD⁺ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity.

Abstract

Imbalances in NAD⁺ homeostasis have been linked to aging and various diseases. Nicotine, a metabolite of the NAD⁺ metabolic pathway, has been found to possess anti-inflammatory and neuroprotective properties, yet the underlying molecular mechanisms remained unknown. Here we find that, independent of nicotinic acetylcholine receptors, low-dose nicotine can restore the age-related decline of NAMPT activity through SIRT1 binding and subsequent deacetylation of NAMPT, thus increasing NAD⁺ synthesis. ¹⁸F-FDG PET imaging revealed that nicotine is also capable of efficiently inhibiting glucose hypermetabolism in aging male mice. Additionally, nicotine ameliorated cellular energy metabolism disorders and deferred age-related deterioration and cognitive decline by stimulating neurogenesis, inhibiting neuroinflammation, and protecting organs from oxidative stress and telomere shortening. Collectively, these findings provide evidence for a mechanism by which low-dose nicotine can activate NAD⁺ salvage pathways and improve age-related symptoms.