Combining rapamycin and trametinib seemed to have a cumulative effect in both sexes but mostly in females [1]. These results are probably due to a reduction in both cancer and inflammation.
A winning combo
The idea that combination treatments are the future of life extension is gaining traction. As aging is a complex phenomenon, a single treatment should not be expected to have a profound effect on it. While testing combinations is hard, there have been several successful attempts, and at least for small molecules, it seems like we have a new pair of champions.
A group of researchers, led by the renowned geroscientist Linda Partridge of Max Plank Institute for Biology of Aging in Cologne, started with rapamycin. This well-known compound inhibits the mechanistic target of rapamycin, complex 1 (mTORC1), a protein that serves as a master regulator of nutrient sensing and growth. Generally speaking, rapamycin shifts an organism’s focus from growth to repair.
In their paper, currently published as a pre-print, the researchers reasoned that the mTORC1 pathway is part of a wider nutrient-sensing network, which also includes proteins such as insulin, IGF (insulin-like growth factor) and Ras, a “molecular switch” that lies upstream of mTORC1 and participates in its activation. When one part of the network is inhibited, others might compensate for this by increasing their activity. Hence, inhibiting two or more links in this chain might work better.
“The insulin/IGF/mTORC1/Ras network is characterized by extensive crosstalk between its branches,” the paper explains. “It is therefore possible that simultaneous inhibition of different nodes within the network, by combined drug treatments, could be more effective than suppression of single nodes, by prevention of compensatory responses.”
The drug trametinib is an indirect Ras inhibitor. Trametinib is used in oncology to inhibit cellular growth in cancer cells. Previous research by the same group showed that a combination of rapamycin, trametinib, and lithium produces additive lifespan increases in drosophila flies [2]. However, this approach has not been tested in mammals until now.
Record-breaking increase in lifespan
Mice were fed either rapamycin or trametinib alone, or their combination, starting from the age of 6 months. Both rapamycin and trametinib alone produced sizeable increases in lifespan. However, their combination had a clear cumulative effect, increasing median and maximum lifespan in females by 34.9% and 32.4%, respectively, and in males by 27.4% and 26.1%, respectively.
With rapamycin, the researchers replicated the highest and most effective dose from a previous study (42 mg/kg) [3]. In that study, rapamycin increased median lifespan by 23% in males and 26% in females, which is more than rapamycin alone accomplished in this new study. In most rapamycin studies, males receive slightly smaller longevity bumps. Finally, in these Black 6 mice, males tend to have shorter lifespans.
While these details might complicate analysis, the results still look impressive, especially in females, who were both naturally longer-lived and also enjoyed a bigger increase in lifespan. Importantly, the increase in maximum lifespan was only slightly smaller than in median lifespan, suggesting “true life extension” as opposed to morbidity compression.
Is it just less cancer?
The researchers also collected several health metrics. Overall, the treatment had little effect on them, either positive or negative. In both sexes, the combination treatment led to increased fat content. On the other hand, the treated mice appeared to have higher motivation to move at old age. The treatment slightly attenuated the age-related decline in heart function but did not improve cognitive function. It also reduced inflammation in peripheral tissues and in the brain.
Since lab mice die mostly of cancer, the researchers analyzed tumor burden at various points in time and after the mice had died. Interestingly, only the combination of rapamycin and trametinib significantly affected tumor growth. Rapamycin is used in oncology as an immunosuppressant, although it is also thought to slow tumor growth [4]. If the additional effect of the combination treatment was mostly due to slower cancer development, it raises questions about how effective it can be in humans, who do not have cancer as their main cause of death.
In this study, we establish the FDA-approved drug trametinib, an inhibitor of RAS-Mek-Erk signalling, as a gero-protective drug in mammals. We further show that the combination of trametinib and the mTOR inhibitor rapamycin produces an even greater lifespan extension compared to the single drug treatments in both female and male mice. 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. Several ongoing clinical trials address the potential of mTOR inhibitors as geroprotective drugs in humans. Our study suggests that simultaneous inhibition of the mTOR and Ras-Mek-ERK pathway provides additional benefits that are worth exploring in humans.
Literature
[1] Gkioni, L., Nespital, T., Monzo, C., Bali, J., Nassr, T., Cremer, A. L., … & Partridge, L. (2024). A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone. bioRxiv, 2024-07.
[2] Castillo-Quan, J. I., Tain, L. S., Kinghorn, K. J., Li, L., Grönke, S., Hinze, Y., … & Partridge, L. (2019). A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. Proceedings of the National Academy of Sciences, 116(42), 20817-20819.
[3] Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., … & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging cell, 13(3), 468-477.
[4] Law, B. K. (2005). Rapamycin: an anti-cancer immunosuppressant?. Critical reviews in oncology/hematology, 56(1), 47-60.
