How does methotrexate work?

Developed over 70 years ago as an anti-folate chemotherapy agent, methotrexate (MTX) is a WHO 'essential medicine' that is now widely employed as a first-line treatment in auto-immune, inflammatory diseases such as rheumatoid arthritis (RA), psoriasis and Crone's disease. When used for these diseases patients typically take a once weekly low-dose of MTX - a therapy which provides effective inflammatory control to tens of millions of people worldwide. While undoubtedly effective, our understanding of the anti-inflammatory mechanism-of-action of low-dose MTX is incomplete. In particular, the long-held dogma that this disease-modifying anti-rheumatic drug (DMARD) acts via the folate pathway does not appear to hold up to scrutiny. Recently, MTX has been identified as an inhibitor of JAK/STAT pathway activity, a suggestion supported by many independent threads of evidence. Intriguingly, the JAK/STAT pathway is central to both the inflammatory and immune systems and is a pathway already targeted by other RA treatments. We suggest that the DMARD activity of MTX is likely to be largely mediated by its inhibition of JAK/STAT pathway signalling while many of its side effects are likely associated with the folate pathway. This insight into the mechanism-of-action of MTX opens the possibility for repurposing this low cost, safe and effective drug for the treatment of other JAK/STAT pathway-associated diseases.

Zoledronate Extends Health Span and Survival via the Mevalonate Pathway in a FOXO-dependent Manner.

Over recent decades, increased longevity has not been paralleled by extended health span, resulting in more years spent with multiple diseases in older age. As such, interventions to improve health span are urgently required. Zoledronate (Zol) is a nitrogen-containing bisphosphonate, which inhibits the farnesyl pyrophosphate synthase enzyme, central to the mevalonate pathway. It is already used clinically to prevent fractures in osteoporotic patients, who have been reported to derive unexpected and unexplained survival benefits. Using Drosophila as a model we determined the effects of Zol on life span, parameters of health span (climbing ability and intestinal dysplasia), and the ability to confer resistance to oxidative stress using a combination of genetically manipulated Drosophila strains and Western blotting. Our study shows that Zol extended life span, improved climbing activity, and reduced intestinal epithelial dysplasia and permeability with age. Mechanistic studies showed that Zol conferred resistance to oxidative stress and reduced accumulation of X-ray-induced DNA damage via inhibition of farnesyl pyrophosphate synthase. Moreover, Zol was associated with inhibition of phosphorylated AKT in the mammalian traget of rapamycin pathway downstream of the mevalonate pathway and required dFOXO for its action, both molecules associated with increased longevity. Taken together, our work indicates that Zol, a drug already widely used to prevent osteoporosis and dosed only once a year, modulates important mechanisms of aging. Its repurposing holds great promise as a treatment to improve health span.