Cancer drug combo extends the lifespan of mice by 30%

The combination of two cancer drugs, rapamycin and trametinib, can extend the lifespan of mice by 30%, according to a study led by researchers at UCL and the Max Planck Institute for Biology of Ageing, Germany.

The combination therapy shows greater effects than the individual drugs and offers not only a longer lifespan, but also health benefits in old age. Published in Nature Aging, the results suggest that the drug combination could be a promising strategy for combating age-related diseases and promoting longevity.

Rapamycin and trametinib are drugs currently used in cancer therapy that act on different points in the body's Ras/Insulin/TOR signalling 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 related Ras/MEK/ERK signalling pathway.

It was not previously known whether trametinib could extend the lifespan of mice, although the same research group has conducted previous studies in flies indicating that it could.

In the latest study, the researchers gave mice either trametinib alone, rapamycin alone, both, or neither, with the drugs delivered in their food from six months of age onwards. The researchers found that trametinib alone extends the lifespan of mice by 5-10%, while rapamycin alone increases lifespan by 15-20%. When used together, the drugs have a synergistic 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 cancerous tumours were delayed.

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."

Professor Dame Linda Partridge, co-lead author, UCL Institute of Healthy Ageing and Max Planck Institute for Biology of Ageing

Although rapamycin and trametinib act on the same network, the combination achieves effects that are probably not solely due to an increase in dose. An analysis of gene expression in various tissues sampled from the mice showed that the combination of the drugs influences the activity of the genes differently than when the drugs are administered individually. There are specific changes in gene activity that are only caused by the combination of the two drugs.

The researchers now 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 (as is rapamycin), it is possible to test it in clinical trials.

Co-lead author Dr. Sebastian Grönke (Max Planck Institute for Biology of Ageing) said: "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."

The study was supported by the Max Planck Society, the European Research Council, the European Union's Horizon 2020 research and innovation programme, and the CECAD Cluster of Excellence for Ageing Research at the University of Cologne.