A -Relative expression of HSF-1 target genes following heat shock (33°C, 30 min) compared to control treated animals (20°C) on day 3 of adulthood. Values plotted are the mean of 4 biological replicates.B -Relative expression of HSF-1 target genes on day 3 of adulthood in wild type animals exposed to control conditions (20°C), 25°C for 1 hour or 28°C for 1 hour. Expression was calculated relative to the HK genes cdc-42, rpb-2 and pmp-3. Values plotted are the mean of 4 biological replicates. C -Representative images and fluorescence quantification of hsp-6p::gfp and hsp-16.2p::mcherry reporters on day 3 of adulthood following treatment with DMSO, antimycin A, rotenone or paraquat. Values plotted are the mean fluorescence of at least 15 worms per treatment group. D & E -Representative images and fluorescence quantification of day 3 adult wild type and (D) clk-1(qm30) or (E) glp-1(e2144ts) worms expressing hsp-16.2p::mcherry following exposure to empty vector (EV) control (L4440) or cox-6c(RNAi). Experiments involving glp-1 and clk-1 mutants were performed at 25°C and 20°C respectively. Values plotted are the mean fluorescence of at least 15 worms per treatment group. F-H -Representative images of (F) daf-16p::daf-16::GFP, (G) hsp-6p::gfp and (H) cyp14Ap::gfp worms following growth on empty vector (EV) control, cox-6c(RNAi) or EV/cox-6c(RNAi) combined with (F), daf-16(RNAi), (G) atfs-1(RNAi) or (H) nhr-45(RNAi). I -Fluorescence quantification of day 3 adult daf-16p::daf-16::GFP, hsp-6p::gfp and cyp14Ap::gfp worms. Values plotted are the mean fluorescence of at least 15 worms per treatment group. All scale bars = 250 µM. Statistical significance was calculated by: (B and C) one-way ANOVA with Tukey postanalysis comparison of groups and (D and E) two-way ANOVA with post analysis pairwise comparison of groups. All error bars represent SEM. * p < 0.05, ** p < 0.01, *** p < 0.001.

The RAS/MAPK pathway is a highly conserved signalling pathway with a well-established role in cancer. Mutations that hyperactivate this pathway are associated with unregulated cell proliferation. Evidence from a range of model organisms also links RAS/MAPK signalling to ageing. Genetic approaches that reduce RAS/MAPK signalling activity extend lifespan and also improve healthspan, delaying the onset and/or progression of age-related functional decline. Given its role in cancer, therapeutic interventions that target and inhibit this pathway's key components are under intense investigation. The consequent availability of small molecule inhibitors raises the possibility of repurposing these compounds to ameliorate the deleterious effects of ageing. Here, we review evidence that RAS/MAPK signalling inhibitors already in clinical use, such as trametinib, acarbose, statins, metformin and dihydromyricetin, lead to lifespan extension and to improved healthspan in a range of model systems. These findings suggest that the repurposing of small molecule inhibitors of RAS/MAPK signalling might offer opportunities to improve health during ageing, and to delay or prevent the development of age-related disease. However, challenges to this approach, including poor tolerance to treatment in older adults or development of drug resistance, first need to be resolved before successful clinical implementation.