Nicotine Improves Memory Impairment in Aged Rats Through Enhanced Mitochondrial Homeostasis

Aging induces progressive changes that heighten the central nervous system's (CNS) vulnerability to neurological disorders. Emerging evidence suggests that nicotine, an alkaloid primarily derived from plants of the genus Nicotiana, may offer neuroprotective effects against aging. However, its role in maintaining mitochondrial homeostasis during aging remains unexplored. In this study, we demonstrated that nicotine improved recognition memory in aging rats. Additionally, it increased dopamine (DA) levels and upregulated PSD95 and synaptophysin expression in the hippocampus of aged rats. Notably, RNA sequencing (RNA-seq) analysis revealed that nicotine promoted mitochondrial homeostasis in the hippocampus. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that genes enriched in the nicotine-treated group were predominantly associated with axon guidance, cholinergic, GABAergic, and dopaminergic synapses. Similarly, Gene Ontology (GO) enrichment analysis highlighted the involvement of these genes in key biological processes, including learning, memory, and axon guidance. Moreover, nicotine reversed aging-associated gene expression patterns linked to mitochondrial function. Consistently, it upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and Parkin expression both in vivo and in vitro, while also enhancing mitochondrial respiratory capacity in SH-SY5Y cells. Collectively, our findings reveal that nicotine promotes hippocampal PGC-1α expression and mitophagy, thereby preserving mitochondrial homeostasis during aging. This study suggests a potential strategy for mitigating age-related memory decline.