Old Drugs, New Tricks

Breakthrough science in the longevity space doesn't always require the development of new medicines. In fact, there are significant advantages to repurposing medicines already in use, since some of the most expensive aspects of drug development lie in establishing human safety in the trial phase. Drugs already in use have a safety profile and a significant body of existing research to draw upon; further trials need focus mainly upon demonstrating efficacy against the new condition. This not only lowers costs for any sponsoring pharmaceutical company, but should deliver effective treatments to patients on a much shorter timescale.

One recent example is the asthma drug, montelukast, which is attracting interest from neurologists as a potential treatment for age-related cognitive impairment. The research was prompted in part by the observation that when young blood rejuvenated an aged brain it reduced inflammation and sparked neuron creation. This led researchers to consider whether montelukast, by blocking receptors responsible for neural inflammation, could have a similar rejuvenating effect – and it appears it does, at least in rats. Results from an animal model are no guarantee of therapeutic success in people, but the approach shows sufficient promise that human trials in patients with Parkinson's disease are expected to commence shortly. This idea of targeting neural inflammation for age-related cognitive disease gained further support from research published in January 2016.

Another drug repurposed to target Parkinson's and similar conditions is the anti-cancer drug nilotinib. Success with a mouse model two years earlier translated into a small human study that presented results in October 2015. The drug, given at significantly lower doses than for leukemia, the condition for which it already has regulatory approval, appeared to force cell repair mechanisms to clear and prevent further accumulation of toxic intracellular proteins. The lack of a control group and small study size necessarily undercuts the reportedly dramatic effects and it remains too early to determine the efficacy of this treatment. It is, however, a striking example of how quickly approved drugs can make the leap from lab research into human studies.

Another recent discovery relates to bisphosphonates, a class of drug previously in use to treat the bone condition osteoporosis. A previous meta-analysis demonstrated that bisphosphonates could be employed against a disease of aging, increasing 10-year survival in breast cancer by reducing the incidence of bone metastases. The new work goes further, however, finding that the specific bisphosphonate zoledronate is effective against aspects of aging itself, by extending the lifespan of mesenchymal stem cells.

Finally, it had long been lamented by biogerontologists that drug trials were only approved for the treatment of a specific disease, and not against the aging damage underlying many different pathologies. Well, this Rubicon has now been crossed, with FDA approval for the MILES trial examining the effectiveness of the type 2 diabetes drug metformin against the condition "Aging". This follows from the observation that participants in trials assigned metformin seemed less vulnerable to various types of cancer than those assigned to other treatments. The MILES trial may help us more fully understand why, and may even result in the first drug targeted at the only terminal condition none of us can avoid.

References

Marschallinger, J. et al. (2015) Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nat Commun. 2015 Oct 27;6:8466. doi: 10.1038/ncomms9466.

Olmos-Alonso, A., Schetters, S. T. T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., Holscher, C., Perry, V. H. and Gomez-Nicola, D. (2016) Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain Jan 2016, DOI: 10.1093/brain/awv379

Hebron, M. L., Lonskaya, I. and Moussa, C. E.-H. (2013) Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson's disease models. Hum. Mol. Genet. (2013) 22 (16): 3315-3328. doi: 10.1093/hmg/ddt192

Early Breast Cancer Trialists' Collaborative Group (2015) Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. The Lancet doi: 10.1016/S0140-6736(15)60908-4

Misra, J., Mohanty, S. T., Madan, S., Fernandes, J. A., Hal Ebetino, F., Russell, R. G. G. and Bellantuono, I. (2015), Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function. STEM CELLS. doi: 10.1002/stem.2255

Kasznicki, J., Sliwinska, A. and Drzewoski, J. (2014) Metformin in cancer prevention and therapy. Annals of Translational Medicine. doi: 10.3978/j.issn.2305-5839.2014.06.01

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