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. 2019 Jul 22;29(14):2322–2338.e7. doi: 10.1016/j.cub.2019.06.031

Figure 5.

Figure 5

Intestinal Knockdown of Lysosomal Genes Abolishes Lifespan Extension and Improved Proteostasis in xbp-1s-Expressing Animals

(A) Lifespan analysis of rab-3p::xbp-1s; rde(n219); nhx-2p::rde-1 animals grown on control (empty vector) or (i) xbp-1, (ii) lmp-1, (iii) vha-18, or (iv) asp-3 RNAi. Graphs were plotted as Kaplan-Meier survival curves, and p values were calculated by Mantel-Cox log-rank test; N = 80–120 animals per lifespan.

(i) rab-3p::xbp-1s; rde(n219); nhx-2p::rde-1, control (black), median lifespan 22 days; rab-3p::xbp-1s; rde(n219); nhx-2p::rde-1, xbp-1 (green), median lifespan 16 days, p < 0.0001.

(ii) rab-3p::xbp-1s; rde(n219); nhx-2p::rde-1, control (black), median lifespan 22 days; rab-3p::xbp-1s; rde(n219); nhx-2p::rde-1, lmp-1 (green), median lifespan 16 days, p < 0.0001.

(iii) rab-3p::xbp-1s; rde(n219); nhx-2p::rde-1, control (black), median lifespan 22 days; rab-3p::xbp-1s; rde(n219); nhx-2p::rde-1, vha-18 (green), median lifespan 16 days, p < 0.0001.

(iv) rab-3p::xbp-1s; rde(n219); nhx-2p::rde-1, control (black), median lifespan 22 days; rab-3p::xbp-1s; rde(n219); nhx-2p::rde-1, asp-3 R (green), median lifespan 18 days, p < 0.0001.

(B) Chemotaxis ability in rde(n219); mex-5p::rde-1 animals expressing Aβ1–42 in neurons in combination with neuronal or intestinal xbp-1s, grown on (i) control (empty vector), (ii) xbp-1, or (iii) lmp-1 RNAi. Graphs represent mean chemotaxis index ± SD. N = 80–130 animals per assay; each assay was independently replicated 3 times. Significance between neuronal Aβ1–42 (B) and xbp-1s-expressing (C and D) strains was assessed by two-way ANOVA with Dunnett’s multiple comparisons test, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗∗p < 0.0001.

(C) Chemotaxis ability in rde(n219); mex-5p::rde-1 animals expressing polyQ40 in neurons in combination with neuronal or intestinal xbp-1s, grown on (i) control (empty vector), (ii) xbp-1, or (iii) lmp-1 RNAi. Graphs represent mean chemotaxis index ± SD. N = 80–130 animals per assay; each assay was independently replicated 3 times. Significance between neuronal polyQ40 (B) and xbp-1s-expressing (C and D) strains was assessed by two-way ANOVA with Dunnett’s multiple comparisons test, ∗p < 0.05, ∗∗∗∗p < 0.0001.

(D) Lifespan analysis of rab-3p::xbp-1s animals grown on control (empty vector) or hlh-30 RNAi. rab-3p::xbp-1s, control (black), median lifespan 25 days; rab-3p::xbp-1s, hlh-30 (green), median lifespan 19 days, p < 0.0001. Graphs were plotted as Kaplan-Meier survival curves, and p values were calculated by Mantel-Cox log-rank test; N = 80–120 animals per lifespan.

(E) (i) Chemotaxis ability in animals expressing Aβ1–42 in neurons in combination with neuronal and intestinal xbp-1s, grown on control (empty vector) or hlh-30 RNAi. Bar graphs represent mean chemotaxis index ± SD. N = 70–130 animals per assay; each assay was independently replicated 3 times. Significance was assessed by two-way ANOVA with Dunnett’s multiple comparisons test.

(ii) Chemotaxis ability in animals expressing polyQ40 in neurons in combination with neuronal and intestinal xbp-1s, grown on control (empty vector) or hlh-30 RNAi. Bar graphs represent mean chemotaxis index ± SD. N = 70–130 animals per assay; each assay was independently replicated 3 times. Significance was assessed by two-way ANOVA with Dunnett’s multiple comparisons test, ∗∗p < 0.01. See also Figures S5 and S6 and Table S1.