In vivo characterisation of Zoledronate, a drug which delays or reverses tissue ageing.

By 2050, the number of people aged over 65 is projected to double due to increased longevity. However, healthspan (time spent without disease) is not increasing at the same rate, which has a severe impact on healthcare systems and quality of life of older people. New interventions to reduce the period of morbidity in later life are urgently needed. Zoledronate has recently been shown to increase survival in patients affected by osteoporosis. In addition, our lab has previously shown that zoledronate reduces DNA damage and cellular senescence of human mesenchymal stem cells (hMSC) by inhibition of the mevalonate pathway and mTOR signalling, resulting in extended cellular lifespan and preservation of their function in vitro. Here we test the hypothesis that administration of zoledronate extends the lifespan and healthspan of Drosophila. The research presented here firstly confirms that zoledronate inhibits phosphorylation of AKT(S505), supporting the findings that zoledronate inhibits mTOR signalling via the mevalonate pathway. In addition, flies pre-treated with zoledronate showed a significant increase in lifespan compared with controls when they were fed with hydrogen peroxide as a source of oxidative damage. However, this was not the case when the dFOXO94 mutant was used, confirming that zoledronate requires Foxo to mediate its activity similarly to hMSC. Furthermore, Drosophila larvae treated with zoledronate showed reduced levels of genomic mutation following irradiation, showing that zoledronate reduces the incidence of DNA damage. Significant lifespan extension was observed, in both male and female Drosophila fed with Zoledronate. As markers of improved healthspan we have tested the flies’ climbing ability and proliferation of their intestinal progenitor cells. As expected, climbing ability declined with age but a significant increase in the proportion of high climbers was observed in flies treated with zoledronate from 40 days of age. An increase in intestinal stem-cell proliferation compatible with epithelial dysplasia was observed with age and this was significantly decreased in the intestines of 40, 56, and 63 day-old females treated with zoledronate. These results suggest that pharmacological intervention with zoledronate improves survival and healthspan with age.