Nicotine Reprograms Aging‐Related Metabolism and Protects Against Motor Decline in Mice

Abstract The effects of nicotine on aging‐related motor and cognitive decline remain controversial due to limited empirical evidence. Here, mice are permitted to orally consume nicotine over a 22‐month period and observed attenuated motor decline without pathological alterations in major metabolism‐related peripheral organs or immune system dysfunction. Multi‐organ metabolomic profiling and network analysis of aged mice (24 months old) identified nicotine‐responsive pathways related to glycolipid metabolism and energy homeostasis. Dynamic gut microbiota profiling via series expression miner‐based longitudinal analysis reveals that nicotine consumption preserved microbiota composition and altered microbial‐derived metabolites associated with the sphingolipid pathway, known to regulate age‐related muscle dysfunction and sarcopenia. Assays in aged mice and C2C12 cells confirmed that nicotine regulates sphingolipid turnover, particularly via sphingomyelin synthases and neutral sphingomyelinases, to enhance nicotinamide adenine dinucleotide availability and energy metabolism. These metabolic adaptations correlated with reduced ceramide accumulation and improved motor function. Behavior‐Metabolome Age (BMAge) score confirmed a biologically younger phenotype in the nicotine‐treated mice. Together, these findings suggest that life‐long oral nicotine consumption reprograms aging‐associated metabolism through regulation of systemic sphingolipid homeostasis, conferring resilience against age‐related motor decline.