Key Points:
- When combined, rapamycin and trametinib targeted interconnected pathways linked to aging and extended the average lifespan by 29% and 27% in middle-aged female and male mice, respectively.
- For the first time, researchers also uncovered that trametinib treatment caused an average lifespan extension of 7.2% and 10.2% in female and male mice, respectively.
- Recapitulating findings from previous research, the group found that rapamycin extended the average lifespan by 17.4% and 16.6% in female and male mice, respectively.
Figuring out which molecular pathways scientists should target to promote longevity has gained momentum in the aging research field in the last two to three decades. For example, in 2003, Müller and colleagues from the University of Fribourg in Switzerland showed that inhibiting a protein that regulates cell growth and proliferation (mTOR) significantly extended worm lifespan. Since that seminal study, Miller and colleagues from the Jackson Laboratory in Maine showed that the mTOR-inhibiting drug rapamycin significantly extends mouse lifespan (14% for females and 9% for males). Such preclinical research done in animal models has paved the way for the discovery and development of drugs as well as nutraceuticals that target aging-associated proteins like mTOR in hopes of promoting human longevity.
As the search continues for new or existing compounds that might target mTOR and other interconnected pathways to perhaps promote longevity, Partridge and colleagues from the Max Planck Institute for Biology of Ageing turned their attention to trametinib, a drug used in cancer treatment. This research team examined trametinib because it targets another protein interconnected with mTOR called MEK. Like mTOR, MEK plays key roles in cell growth, proliferation, and survival. Partridge and colleagues hypothesized that targeting mTOR and MEK, with rapamycin and trametinib, respectively, would serve to home in on two proteins in interconnected aging pathways to additively extend mouse lifespan.
As published in Nature Aging, Partridge and colleagues found that, interestingly, combining oral treatments of rapamycin and trametinib did additively extend lifespan by 29% and 27% in female and male mice, respectively. In a first-of-its-kind experiment, the researchers also uncovered that trametinib conferred a 7.2% and 10.2% lifespan extension in female and male mice, respectively. In addition, the Max Planck Institute-based researchers confirmed previous research showing that rapamycin extends average lifespan in mice, 17.4% and 16.6% in male and female mice, respectively, in their experiment. These findings support that trametinib confers pro-longevity benefits and that combining the drug with rapamycin yields additive effects against aging.
“While we do not expect a similar extension to human lifespans as we found in mice, we hope that the drugs we’re investigating could help people to stay healthy and disease-free for longer late in life. Further research in humans in years to come will help us to elucidate how these drugs may be useful to people, and who might be able to benefit,” said Linda Partridge, lead author of the study, in a press release.
Combining Trametinib and Rapamycin Extends Lifespan More than Either Drug On Its Own
Because treating flies with trametinib and rapamycin to target more than one aging pathway protein additively extended lifespan, Partridge and colleagues sought to find whether the combination does so in a mouse model as well. Before combining the treatments, the researchers needed to confirm that trametinib and rapamycin on their own extend mouse lifespan, so they treated six-month-old mice (roughly equivalent to 31-year-old humans) with either trametinib or rapamycin and measured their lifespan.
Along those lines, for the first time, the researchers showed that trametinib treatments conferred an average lifespan extension of 7.2% and 10.2% in female and male mice, respectively. In a similar vein, recapitulating findings from previous research, the Max Planck Institute researchers demonstrated that intermittent rapamycin treatments extended average lifespan by 17.4% and 16.6% in female and male mice, respectively. These findings set the stage to find whether combining trametinib with rapamycin can additively extend mouse lifespan.
To find whether the combination of the two drugs extends lifespan better than either on its own, Partidge and colleagues treated mice with trametinib and rapamycin starting at six months of age. The researchers found a greater lifespan extension when combining the drugs, with average lifespan extensions of 29% and 27% for female and male mice, respectively. These findings support that combining the two drugs, which target aging pathway proteins involved in interconnected pathways, additively extend lifespan.
Because trametinib and rapamycin serve as cancer chemotherapeutics, the researchers sought to determine whether combining the drugs delays tumor growth. Indeed, treating with the two drugs lowered the prevalence of tumors in the liver and spleen, with no significant increase in tumors with age. These results suggest that the combination of trametinib and rapamycin delays tumor growth.
During aging, inflammation takes hold in multiple organs, leading to age-related sterile, low-grade inflammation (a phenomenon called inflammaging). Research suggests that the mTOR aging-associated pathway plays a role in inflammaging. As such, Partridge and colleagues tested levels of proteins in blood plasma associated with inflammation. They found that the combination of the drugs lowered inflammation-associated proteins, suggesting that trametinib with rapamycin reduces inflammaging.
Human Trials Are Necessary To Determine if the Combination of Drugs Confers Pro-Longevity Effects
Partridge and colleagues’ study suggests that targeting more than one protein in aging-associated pathways can serve to amplify pro-longevity effects compared to targeting only one. Accordingly, these researchers are not the first group to try targeting more than one facet of aging-associated pathways. For example, Seragon conducted a study using their multi-pathway-targeting drug SRN-901, which their product Restorin is roughly based on, to extend the average lifespan of middle-aged mice by 34%. Accordingly, as Seragon’s study supports, SRN-901 extended lifespan more than the combination of trametinib and rapamycin.
Interestingly, SRN-901 also targets the mTOR pathway, like the rapamycin that Partidge and colleagues used in their study. As for additional aging-associated mechanisms that SRN-901 targets, it contains senolytic technology, which facilitates the elimination of dysfunctional cells that accumulate with age (known as senescent cells). Furthermore, SRN-901 has technologies that stimulate autophagy—the cell’s internal cleanup mechanism for disposing of and recycling dysfunctional cellular components. As the data suggests, these components in SRN-901, along with others, may work in a way superior to combining trametinib with rapamycin.
As the search continues for optimal combinations of drugs and nutraceuticals that may intervene against aging, Partridge and colleagues have found that trametinib and rapamycin work effectively in mice. Moreover, Seragon may have found an even better pro-longevity mixture of components with SRN-901. Only human trials testing whether these combinations improve things like epigenetic age (which gauges how fast someone is aging based on molecular tags on DNA) will tell whether their effects against aging apply to humans. Results from such trials may come about in the next decade or so, but in the meantime, anyone hedging their bet on the preclinical efficacy of technologies like those contained in SRN-901 can try products like Seragon’s Restorin.
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