The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan

Suppression of the insulin-IGF-mTORC1-Ras network ameliorates aging in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signaling, and trametinib inhibits the Ras-MEK-ERK pathway. In this study, we assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. We show here that trametinib treatment extended lifespan in both sexes and that its combination with rapamycin was additive. Combination treatment reduced liver tumors in both sexes and spleen tumors in male mice, blocked the age-related increase in brain glucose uptake and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. We conclude that trametinib is a geroprotector in mice and that its combination with rapamycin is more effective than either drug alone, making the combination a candidate for repurposing as a gerotherapy in humans. Female and male mice were treated from 6 months of age with (1) rapamycin (biweekly 42mg/kg), (2) trametinib (continuously 1.44mg/kg diet), (3) rapamycin /trametinib (biweekly 42mg/kg/continuously 1.44mg/kg) and (4) control food. At 24 months of age, kidney, muscle and spleen tissues were collected and used for RNA seq analysis to measure the influence of the drug treatments on age-related gene expression.