Considering a combination of robustness of data and size of effect, rapamycin is arguably the best of the small molecules known to slow aging to modestly extend life span in animal models. We could mount a good counterargument for the primacy of the dasatinib and quercetin combination, given its ability to dramatically reverse age-related conditions in animal models, but let us put that discussion to one side for the moment. An interesting and understudied question is the degree to which the known promising approaches to slowing aging combine with one another to produce larger benefits, or can be enhanced by the addition of other molecules. Certainly the work of Brian Kennedy, alongside the few others to test many combinations in vivo, suggests that combining any two promising small molecules is just as likely to produce a mutual sabotage of benefits as it is to produce a synergy of benefits.
This may go some way towards explaining why we see few published examples of successful synergies. Today’s open access paper is a rarity, but an interesting one, as the researchers have found a drug that enhances the effect of rapamycin on life span in mice, producing more than a 30% gain in maximum life span in female mice, a sizable outcome that beats out near all other options other than inhibition of growth hormone signaling. Given a favorable safety profile, this approach will no doubt find its way into the expanding off-label use of rapamcyin for anti-aging purposes, as well as into the small number of clinical trials that are intended to further support this application of rapamycin.
The insulin/IGF/mTORC1/Ras nutrient-sensing network is highly conserved in evolution and is implicated in the aetiology of many age-related diseases. There is therefore growing interest in the possibility of repurposing existing drugs with targets in this signalling network as geroprotectors to improve human health during ageing. One such example is inhibition of mTORC1 by rapamycin (sirolimus). Rapamycin robustly extends lifespan in multiple model organisms, ranging from worms and flies to mice, where rapamycin administration later in life at 600 days of age increases median and maximal lifespan in both sexes.
Reduced signalling through the phosphatidylinositol 3-kinase (PI3K) node of the nutrient-sensing network can extend lifespan in C. elegans and Drosophila, and was for long viewed as the primary route by which the anti-ageing effects of reduced upstream insulin/IGF signalling are mediated. However, Ras signalling plays a role in ageing in yeast, while in Drosophila the Ras-MEK-ERK pathway is as important a mediator as the PI3K pathway of the effects of reduced upstream insulin/Igf signalling on lifespan. Indirect inhibition of Ras in mice is associated with increased lifespan and enhanced motor function in old age. These findings suggest that inhibition of Ras pathway signalling may have an evolutionarily conserved, geroprotective effect.
Trametinib (also known as Mekinist) is a potent and highly specific small molecule inhibitor of MEK, and is an FDA-approved drug for the treatment of specific melanomas. Oral administration of trametinib increases Drosophila lifespan, even when started later in life. However, it is yet to be determined whether the lifespan-extending effects of trametinib are evolutionarily conserved. To examine whether trametinib is geroprotective in mice, we orally dosed female and male mice and assessed their ageing phenotypes.
In the present study, we investigated whether administration of trametinib alone or in combination with rapamycin can extend lifespan and improve health at old age in mice. We orally treated male and female mice with trametinib, or rapamycin, or with both drugs at the same doses as in the single drug treatments. We assessed their survival, fitness, brain metabolism, and organismal health. Single administration of trametinib or rapamycin significantly increased male and female mouse lifespan, while the combined treatment produced an additive further increase in both sexes. Additionally, the double combination of trametinib and rapamycin significantly reduced liver tumours in both sexes and spleen tumours in males at old age, and alleviated the age-related increased glucose uptake in the brain. Combination treatment also caused a marked reduction of age-related inflammation in brain, kidney, spleen, and muscle, accompanied by reduced levels of circulating pro-inflammatory cytokines.
As previously shown, intermittent rapamycin treatment extended lifespan in both sexes with an increase in median and maximum lifespan of 17.4% and 16.5% respectively in females and 16.6% and 18.3% respectively in males. Combined treatment caused a larger increase compared to the single treatment in both sexes, with median and maximum lifespan increased by 34.9% and 32.4%, respectively, in females and by 27.4% and 26.1%, respectively, in males.
