Figure 4.

The antidepressant mianserin requires ANK3/unc-44 to protect C. elegans from oxidative stress and to extend lifespan. (a) Mianserin-induced protection from oxidative stress requires ANK3/unc-44, the C. elegans homolog of mammalian ANK3. Wild-type (wt) N2 strain (dotted lines) or ANK3/unc-44 mutants (bold lines), at day 1 adult stage, were treated with water (black) or 50 μM mianserin (red), followed by increasing concentrations of paraquat 5 days later. Survival of animals was determined 24 h after paraquat addition and plotted in (%) (Y axis) as a function of paraquat concentration (mM) (X axis). Parallel wt (N2) control experiments (dotted lines) are shown for each graph. Mianserin failed to increase resistance to oxidative stress in three independent alleles (e362, e1197, e1260) of ANK3/unc-44. All error bars show s.e.m. for 3 to 4 independent experiments. (b) Lifespan curves of wt and unc-44(e362) animals treated water or 50 μM mianserin. Graph shows animals alive (%) (Y axis) as a function of time (days) (X axis). Dotted lines represent wt (N2) animals and bold lines represent unc-44(e362) mutants. Black: solvent control; red: mianserin 50 μM. In wt animals, mianserin increases lifespan by +40%, whereas it does not (−9%) in unc-44(e362) mutant animals. Asterisks indicate P values (**P < 0.01, ***P < 0.001). (c) Graph shows mean increase in lifespan (%) (Y axis) as a function of mianserin concentration (μM) (X axis). Solid red line represents unc-44(e362) animals. Dotted red line represents the parallel control experiment of mianserin-treated wt (N2) animals. Error bars show s.d. for experimental replicates. No lifespan extension is observed in ANK3/unc-44(e362) mutants at any mianserin concentration. (d) ANK3/unc-44 expression with age.