• The combination of Rapamycin and Trametinib extends the lifespan of mice by around 30% and works better than either of the drugs alone.
• The therapy reduces chronic inflammation and delays cancer development
• New mechanisms: The combination influences gene expression differently than the individual drugs, without additional side effects.

The researchers were able to show that Trametinib alone extends the lifespan of mice by 5-10%, while Rapamycin alone increases lifespan by 15-20%. Together, the drugs have a combinatorial effect that extends the life of the mice by around 30%.

The combination therapy also had positive effects on the health of the mice in old age. Less chronic inflammation was observed in the tissue and brain of the treated mice compared to untreated mice, and the onset and development of cancer was delayed.

Rapamycin and Trametinib are drugs used in cancer therapy that act on different points in the Ras/Insulin/TOR network, which plays a central role in ageing. Rapamycin is a potent geroprotector known to prolong the lifespan of animals. Geroprotectors are drugs that slow down the ageing process and extend lifespan. Trametinib acts on the Ras/MEK/ERK signalling pathway. It was not previously known whether Trametinib could extend the lifespan of mice, although previous studies in flies indicated that it might.

Although Rapamycin and Trametinib act on the same network, the combination achieves novel effects that are probably not solely due to an increase in dose. An analysis of gene expression in various tissues shows that the combination of the drugs influences the activity of the genes differently than is achieved by administering the drugs individually. There are specific changes in gene activity that are only caused by the combination of the two drugs.

The researchers plan to determine the optimal dose and route of administration of Trametinib to maximise the health and life-prolonging effects while minimising unwanted side effects. As Trametinib is already approved for human use, it is possible to test it in clinical trials.

“Trametinib, especially in combination with Rapamycin, is a good candidate to be tested in clinical trials as a geroprotector. We hope that our results will be taken up by others and tested in humans. Our focus is on optimising the use of Trametinib in animal models,” explains Sebastian Grönke.

Co-senior author Professor Dame Linda Partridge (UCL Institute of Healthy Ageing and Max Planck Institute for Biology of Ageing) said: “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.”

The research for this study was conducted at the Max Planck Institute for Biology of Ageing with funding from the European Research Council and co-funded by the CECAD Cluster of Excellence for Ageing Research at the University of Cologne.