Combining two FDA-approved drugs, trametinib and rapamycin, was found to extend lifespan, improving the effects of either drug alone, prolonging the life of female mice by 35% and male mice by 27%. However, while the combination improved several aspects of health, it also led to some side effects such as fatty liver disease and testicular degeneration.
People are living longer now than they ever have thanks to advances in modern medicine. Around the World, scientists are working to find ways to alleviate the suffering that is caused by diseases that were once unknown in the past that came with living longer and modern lifestyle choices. In their attempts to maximize human life expectancy without suffering, compounds have been discovered that can prolong both life and healthspan, at least in animals, so far that is…
In their endeavors in the quest to maximize lifespan, scientists are testing whether or not combining known life-extending compounds could work synergistically to provide extra benefits. To this effect, recently German scientists investigated whether combining two geroprotecting compounds targeting complementary cellular pathways could bring them closer to discovering the coveted “Fountain of Youth”.
Lifespan extending combination
For this study, the researcher began by administering trametinib, rapamycin, or a combination of the two FDA-approved drugs to 6-month-old mice, which is around the equivalent of a 30-year-old human. 1.44 mg/kg of trametinib was given to the animals every day, and 42 mg/kg of rapamycin was fed to the mice on alternate weeks.
According to the scientists, trametinib on its own led to a median lifespan increase of 7.2% for female mice and a 10.2% increase for males. There was a 15.8% increase in maximum lifespan for female mice while there was no effect on maximum lifespan for the males.
Rapamycin on its own led to a median lifespan increase of 17.4% for the female mice and 16.6% for the males, as well as extending the maximum lifespan by 16.5% for the female mice and 18.3% for the male mice.
However, the best results were seen in the combination, increasing the median lifespan of the female mice by 34.9% and 27.4% in the male mice. The potent combination also increased the maximum lifespan in the female mice by 32.4% and 26.1% in the male mice. These results suggest that combining trametinib with rapamycin provided additive life-prolonging effects in both male and female mice.
Side effects and healthspan
Along with measuring lifespan, the researchers also measured the health of the animals to determine if their healthspan would respond to the drugs. The scientists reported that there were very few effects that were not sex-specific, which included but were not limited to: reduced body weight, reduced liver tumors, reduced spleen pathology, reduced kidney inflammation, and the prevention of increased brain glucose uptake.
In addition, there were also some effects that were significant for one sex but only trended towards significant in the other.
“The combination treatment attenuated the decline in heart function with age, delayed tumour growth and overall tumour load, and reduced brain and peripheral inflammation, suggesting improved health at old age,” wrote the authors.
In addition to extending lifespan, the findings suggest that the drug combination also helped to improve the healthspan of the animals. But this was not without some adverse side effects such as a decrease in the anti-inflammatory molecule IL-10, and the occurrence of testicular degeneration and fatty liver disease, which warrants further investigation for other possible triggered adverse health effects.
Maximizing lifespan with synergy
Both drugs used in this study, trametinib and rapamycin, are FDA-approved, the former is specifically used for BRAF-mutant melanoma while the latter is usually used after an organ transplant to prevent rejection by the immune system. That being said, scientists are learning that certain drugs can target multiple ailments, delay aging, and extend both life and healthspan, at least in animals.
This is not the only combination to work synergistically, other combinations have also extended lifespan in animal studies, like the FDA-approved diabetes medications metformin and acarbose.
“The combination of rapamycin with metformin increased mouse lifespan by 26% and 23% in females and males, respectively, while coadministration of rapamycin and acarbose led to a 28% and 34% increase in median lifespan in females and males, respectively,” wrote the authors.
The scientists are interested in investigating this combination of drugs which have been the focus of many anti-aging studies. The authors note that they would like to combine more than two drugs to investigate the cocktail’s possible synergistic effects of targeting different cellular pathways to alleviate disease and delay aging.
But before this can happen, they must conduct further investigation of the trametinib and rapamycin senolytic combination with the metformin and acarbose combination to see if it could interact to produce negative side effects.
Eventually, if all goes to plan, studies in humans will be carried out to investigate the full potential of the synergy these drug combinations can provide in the quest for the “Fountain of Youth.” But don’t hold your breath, animal studies don’t always translate well to humans, and when they do, it takes decades of research and regulatory “red tape” before they make it to market.
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References/Sources/Materials provided by:
https://www.biorxiv.org/content/10.1101/2024.07.25.605097v1.full
