Ubiquitin ligases join the field of dietary restriction in C.elegans

(DR) has been shown to robustly modulate organismal lifespan in multiple species. The powerful genetic tools in yeast, worms and flies hold great promise in unraveling the secrets of the molecular mechanisms of this process that have been elusive for more than seven decades, since DR was first described to extend lifespan in mice. In a recent study, Carrano and colleagues report the discovery that an E2/E3 ubiquitin ligase set are required for the lifespan extending effects of DR in C.elegans [1]. The authors utilize C. elegans to look at E3 ubiquitin ligases of the conserved HECT (Homologous to E6-AP Carboxyl Terminus) family known to be important in tumorigenesis in mammals [2]. C. elegans contains a single ortholog of the WW class of HECT E3s known as WWP-1. Mutant analysis revealed that the C. elegans gene is required for embryonic development but that weak mutants or naïve adults exposed to wwp-1 dsRNA have wildtype lifespan under normal culture conditions but are sensitive to heat and oxidative stress. Stress response genes are often involved in modulating normal lifespan in a positive manner. Consistent with this notion the authors find that overexpression of wwp-1 leads to a lengthened lifespan in otherwise wildtype animals. As these results implicate WWP-1 as having both a stress resistance and pro-longevity function the authors next test whether the gene contributes to other known longevity pathways. Insulin/IGF signaling, mitochondrial function and nutrients control distinct aspects of C. elegans lifespan. To test whether WWP-1 functions in any of these longe-Commentary vity pathways, the authors examine mutant combinations with essential components of these pathways. They find that a loss of wwp-1 in long lived insulin/IGF and mitochondrial mutants results in a modest shortening of their extended lifespan. However, the lifespan extension in eat-2 mutants, which eat less due to reduced pharyngeal pumping rate and are therefore under DR, is abrogated. They also convincingly show that WWP-1 is involved in DR by using a method that utilizes bacterial dilution to impart lifespan extension. One of the dramatic findings was that the 3 fold extension of lifespan achieved by reducing food concentration in liquid culture is almost entirely suppressed by a loss of wwp-1. These experiments genetically implicate WWP-1 as being a key player in the DR pathways of longevity. WWP-1 is orthologous to mammalian E3 ubiquitin ligases and the authors show biochemically, that WWP-1 also has E3 activity in vitro. Disruption …