Drug combinations work to synergistically extend the life- and healthspan in worms.
The most successful drug combination tested almost doubled lifespan, a feat never reported before. Furthermore, more than half of the worms receiving the drug combination were still in optimal health after all control animals had died! Finally, the authors show that these drugs also extend the lifespan of fruit flies and in fact the same combination that almost doubled worm lifespan was also the most successful one at extending the lifespan of fruit flies.
In a new paper published on the preprint server bioRxiv Jan Gruber and colleagues test various combinations of life extending drugs in worms.
Preprint servers allow scientists to publish their article to the wide world for anyone to criticize before submitting it to a classical journal for publication.
Furthermore they allow for rapid dissemination of research results as the publication in a peer-reviewed journal can take months to years between submission and publication.
While around a thousand compounds have been found to extend lifespan in at least one study in a model organism few studies have been conducted using combinations of two or more compounds.
A rare example includes the combination of rapamycin with metformin which was shown to outperform either drug alone in mice.
The authors started by identifying well known mechanisms for lifespan extension based on a literature review. Then they looked for drugs that influence these mechanisms and had previously been found to extend lifespan leading to the selection of 12 compounds for testing in this study.
Next the researchers tested these compounds in roundworms, a common model organism in aging research. When tested in isolation five drugs significantly extended mean and maximal lifespan: Psora-4, rifampicin, rapamycin, metformin, and allantoin.
Next the researchers tested all pairwise combinations of these five compounds. The combination of metformin and rapamycin, both at optimal doses, did not lead to a further increase in lifespan.
However if the combination was tested at suboptimal doses than lifespan was further increased.
Given that the optimal dose of metformin and rapamycin in mice is unknown the beneficial effect of the combination observed in the mice study mentioned before could possibly be the result of suboptimal concentrations of both drugs.
Two combinations, rifampicin + rapamycin and rifampicin + Psora-4 all at optimal concentrations did result in synergistic increases in lifespan.
Next the researchers tested triple combinations of the various compounds. As testing all combinations would be impractical (220 different lifespan tests would be necessary) the researchers decided to first try the combination of the 3 most successful compounds so far (rapamycin + rifampicin + Psora-4).
However this combination resulted in a shorter lifespan than the two successful pairwise combinations. Next, the researchers decided to test the two pairwise combinations from before with allantoin added as the third drug.
They chose this combination because allantoin shares no mechanistic overlap with the other drugs. Both of these triple combinations resulted in a significant extension of mean and maximal lifespan with the most successful one (rapamycin + rifampicin + allantoin) resulting in a doubling of mean lifespan! The authors remark that this is the largest lifespan extension ever observed by a drug intervention initiated in adult worms.
Abbreviations: Rif = rifampicin; Rap = rapamycin, Allan = allantoin. Image credit: Sven Bulterijs Certain interventions that result in lifespan extension reduce fertility but neither of the triple drug combinations reduced total fertility and actually slightly extended the fertile period of life.
Furthermore, both drug combinations extended the period of life spend in good health (= the healthspan).
In fact, more than half of the worms receiving the triple drug combination were still in optimal health after all control animals had died! Old animals on the triple drug combinations were indistinguishable from young control worms when judged by spontaneous movement.
Worms really show a significant decrease in spontaneous movement with age. Finally, the two successful triple drug combinations also significantly increased resistance to oxidative and heat stress.
Total mortality is made up of two distinguishable parts: age-dependent and age-independent mortality. The age-dependent mortality is a measure for the rate of aging.
So the authors tested which mortality rate was reduced by the drug combinations. Interestingly, the rifampicin + Psora-4 + allantoin combination significantly reduced the rate of age-dependent and age-independent mortality showing that this drug slows down aging in addition to making them more robust at young ages.
The evolutionary distance between fruit flies and worms is larger than between fruit flies and humans. Hence the fact that the drug combinations worked in both fruit flies and worms offers hope that their lifespan extending effect may be conserved in humans.
The two drug combinations (Rap + Rif and Rap + Rif + Allan) significantly extended mean and maximum lifespan in fruit flies.
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