p38‐mediated innate immune signaling pathway is required for lifespan extension in long‐lived genetic mutants. Innate immune signaling was disrupted by knocking down the expression of sek‐1 using RNAi in a panel of nine long‐lived genetic mutants. Knocking down expression of sek‐1 significantly decreased the lifespan of WT worms (a), ife‐2 mutants (b), clk‐1 mutants (c), sod‐2 mutants (d), eat‐2 mutants (e), osm‐5 mutants (f), nuo‐6 mutants (g), isp‐1 mutants (h), and daf‐2 mutants (i). While wild‐type worms grown at 25°C during development showed decreased lifespan when sek‐1 was disrupted (j), glp‐1 lifespan was not affected by sek‐1 RNAi (k). These results indicate that the p38‐mediated innate immune signaling pathway is required for lifespan extension. Three biological replicates were performed. Statistical significance was assessed using the log‐rank test.