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The von Hippel Lindau Tumor Suppressor Limits Longevity

Roman-Ulrich Müller^*, Francesca Fabretti^*, Sibylle Zank^*, Volker Burst^*, Thomas Benzing^*, and Bernhard Schermer^*,

*Department of Medicine and Centre for Molecular Medicine and
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany

Correspondence: Dr. Thomas Benzing, Renal Division, Department of Medicine, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Phone: +49-221-478-4480; Fax: +49-221-478-5959; E-mail: thomas.benzing{at}uk-koeln.de

Received for publication May 11, 2009. Accepted for publication August 5, 2009.

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.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673