The von Hippel Lindau tumor suppressor limits longevity

Abstract

Many genes are responsible for the modulation of lifespan in model organisms. In addition to regulating adaptive biologic responses that control stress signaling and longevity, some of these genes participate in tumor formation. The mechanisms that determine longevity and link regulation of lifespan with tumorigenesis are poorly understood. Here, we show that the tumor suppressor von Hippel-Lindau (VHL), which has widely known roles in renal carcinogenesis and the formation of kidney cysts, controls longevity in Caenorhabditis elegans. Loss of vhl-1 significantly increased lifespan and resulted in accelerated basal signaling of the p38 mitogen-activated protein kinase PMK-3. Furthermore, the VHL-1 effect on the regulation of lifespan was independent of the insulin/IGF-1-like signaling pathway, suggesting a mechanism for stress resistance that controls both lifespan and tumorigenesis. These findings define VHL-1 as a player in longevity signaling and connect aging, regulation of lifespan, and stress responses with formation of renal cell carcinomas.

Figure 1.

Loss of vhl-1 increases longevity. (A) Worms lacking vhl-1 (▲) show an extended lifespan as compared with the wild-type N2 strain (■). (B) RNAi-mediated knockdown of vhl-1 using two different RNAi constructs from either the Ahringer (#1) or the Vidal (#2) library confirms the VHL-1 effect on lifespan observed in vhl-1 knockout worms. (C) Lifespan extension mediated by VHL-1 does not depend on insulin/IRS-1–like signaling. Wild-type N2 (squares) or vhl-1 −/− worms (triangles) were grown on RNAi plates for downregulation of either daf-16/FOXO (blue line), simulating increased insulin signaling, or daf-2/insulin receptor (red line), which reduces insulin signaling.

Figure 2.

Loss of vhl-1 is without effect on nuclear translocation of DAF-16. Activity of DAF-16 is dependent on its subcellular localization, because DAF-16 exerts its effects only in the nucleus. (A through C) In contrast to animals grown on bacteria expressing empty vector (A), knockdown of daf-2 leads to strong nuclear translocation of DAF-16 (B), whereas knockdown of vhl-1 is without effect (C).

Figure 3.

Loss of vhl-1 is associated with enhanced PMK-3/p38 MAPK signaling. Phosphorylation of p38 (A, right) and JNK (B, right) MAPKs was assessed using phosphospecific antibodies on Western blots of whole lysates of control versus both vhl-1–deficient and hif-1;vhl-1 double-knockout worms. Equal total amounts of the two MAPKs independent of their phosphorylation status was determined using p38 (A, left) and JNK (B, left) antibodies on blots with the identical lysates.