The novel effects of the cardiovascular drug ranolazine on the alleviation of age-related cognitive decline and the underlying mechanisms.

The cognitive decline associated with ageing is the most critical health issue affecting elderly individuals, and there is still a lack of effective interventions available. This study was designed to identify a drug capable of ameliorating age-related cognitive decline and the underlying mechanisms. Utilizing data mining of multisource databases and drug repositioning approaches based on transcriptome similarity, the cardiovascular drug ranolazine (Ran), was identified as a potential candidate with similar effects to those of resveratrol (RSV). Network pharmacology analysis predicted that Ran's effects on cognitive decline through the PI3K/AKT/mTOR signalling pathway. These predictions were subsequently verified using a combination of molecular, cellular, and tissue experiments, animal models of ageing induced by D-galactose, and omics studies. The results revealed that Ran extended the lifespan of Caenorhabditis elegans (C. elegans), improved the head swinging ability of ageing C. elegans, and alleviated mitochondrial membrane potential (MMP) damage in ageing hippocampal neuronal cells (HT22). In ageing rats, Ran not only enhanced spatial memory, exploratory behaviors and motor ability, but also alleviated mitochondrial structural damage in hippocampus and medial prefrontal cortex (mPFC). Notably, Ran alleviated age-related cognitive decline by regulating mitochondrial autophagy in hippocampus and mPFC through the PI3K/AKT/mTOR signalling pathway, rather than through its conventional mechanism of regulating fatty acid metabolism. In summary, this study reveals Ran's previously unrecognized role in alleviating age-related cognitive decline for the first time. These findings provide new options for the treatment of age-related cognitive decline and broaden the potential clinical applications of Ran.