Recent advances in methotrexate pharmacology and potential therapeutic uses in age-related cardiometabolic and neurodegenerative diseases

Experimental and clinical evidence continues to accumulate, supporting the critical role of dysregulated inflammation, immunity, and redox signaling in the pathophysiology of various age-related cardiometabolic and neurodegenerative diseases. While ongoing research is investigating novel anti-inflammatory and immunomodulatory therapies for such conditions, available antirheumatic drugs may serve a similar purpose. One such drug, methotrexate, has been successfully used at high doses since the 1940s as an anticancer agent and, more recently, at lower doses in patients with autoimmune diseases. Although the effects of methotrexate have traditionally been attributed to its antiproliferative activity via folic acid modulation, additional targets have been identified, including AMP-activated protein kinase, Janus kinase/signal transducer and activator of transcription, high mobility group box 1 protein, the gut microbiota, and additional pharmacological effects of adenosine, a key mediator of methotrexate. The beneficial effects of modulating these targets on downstream inflammatory and immune pathways, cellular senescence, and vascular, metabolic, and brain homeostasis have been increasingly investigated in experimental models. Furthermore, studies conducted over the past 20 years suggest an association between low-dose methotrexate and a decreased risk of certain age-related cardiometabolic and neurodegenerative diseases, particularly in patients with autoimmune conditions. The results of these studies support the potential protective role of methotrexate against age-associated cardiometabolic and neurodegenerative diseases through multiple mechanisms, unlike targeted immunomodulatory and anti-inflammatory drugs, thereby providing a robust framework for investigating its repurposing in future intervention studies. SIGNIFICANCE STATEMENT: New treatments are essential to address the burden of age-related diseases. The important roles of dysregulated inflammation, immunity, and redox signaling in these conditions have spurred research into developing new therapies or repurposing existing drugs to target these dysfunctions. The disease-modifying antirheumatic drug methotrexate has shown potential protective effects against cellular senescence and certain age-related cardiometabolic and neurodegenerative diseases. This knowledge will encourage further research into the repurposing of methotrexate for the treatment of these diseases.