Cytoprotective gene regulation is essential to lifespan extension by diverse mechanisms.

<p>Twenty-nine gene inactivations required for the appropriate induction of cytoprotective responses following stress (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002792#pgen-1002792-t001" target="_blank">Table 1</a>) were screened for lifespan phenotypes. Each gene inactivation, or an empty-vector RNAi control, was fed to wild-type (N2) animals and each of three long-lived mutants, including the <i>isp-1;ctb-1</i> mitochondrial mutant, <i>daf-2</i> insulin/IGF-1 signaling mutant and <i>eat-2</i> feeding-defective mutant. Lifespan was measured in three replicates comprising an average of 103 worms per condition. Data is presented as mean lifespan (columns 1–4), change mean lifespan in comparison to an empty vector RNAi control (column 5), or as the change in the extension of lifespan induced by each long-lived mutant (columns 6–8; for clarity, only decreases >15% are shown). Only 5 of the 29 gene inactivations result in a 15% or greater reduction in wild-type (N2) lifespan, and most (20 of 29) reduce wild-type lifespan by less than 10% (column 5). Of the 29 genes, 25 demonstrate a significantly greater effect in at least one long-lived mutant background, and 16 gene inactivations abrogate 50% or more of the lifespan extension normally induced by at least one of the tested mutant backgrounds. Because these gene inactivations have small effects on wild-type lifespan but large effects on lifespan extension in long-lived mutant backgrounds, we propose that these gene inactivations are not simply progeric but instead play specific roles in lifespan extension.