Mifepristone Triggers Some of the Same Benefits as Rapamycin
Mifepristone is known to slow aging in flies. While mifepristone is not a drug that one should take to slow aging, as it has complex, sizeable effects on hormone levels that would tend to outweigh any benefits obtained, it is interesting to see that it has some of the same effects as rapamycin on life span and aspects of autophagy. Autophagy recycles damaged cell structures, and improved autophagy is a feature of many of the interventions known to slow aging in short-lived laboratory species, such as the flies used in this study. The researchers focused on measuring autophagy targeting mitochondria, known as mitophagy. Given the importance of mitochondrial dysfunction to aging, that is a reasonable choice. Nonetheless, it is hard to imagine much in the way of further research emerging based on the use of mifepristone or other near analog small molecules because of the effects on hormonal metabolism.
The drugs mifepristone and rapamycin were compared for their relative ability to increase the life span of mated female Drosophila melanogaster. Titration of rapamycin indicated an optimal concentration of approximately 50 μM, which increased median life span here by average +81%. Meta-analysis of previous mifepristone titrations indicated an optimal concentration of approximately 466 μM, which increased median life span here by average +114%. Combining mifepristone with various concentrations of rapamycin did not produce further increases in life span, and instead reduced life span relative to either drug alone.
Assay of maximum midgut diameter indicated that rapamycin was equally efficacious as mifepristone in reducing mating-induced midgut hypertrophy. The mito-QC mitophagy reporter is a previously described green fluorescent protein (GFP)-mCherry fusion protein targeted to the outer mitochondrial membrane. Inhibition of GFP fluorescence by the acidic environment of the autophagolysosome yields an increased red/green fluorescence ratio indicative of increased mitophagy. Creation of a multi-copy mito-QC reporter strain facilitated assay in live adult flies, as well as in dissected midgut tissue. Mifepristone was equally efficacious as rapamycin in activating the mito-QC mitophagy reporter in the adult female fat-body and midgut. The data suggest that mifepristone and rapamycin act through a common pathway to increase mated female Drosophila life span, and implicate increased mitophagy and decreased midgut hypertrophy in that pathway.