Organisms that protect their germ-cell lineages from damage often do so at considerable cost: limited metabolic resources become partitioned away from maintenance of the soma, leaving the ageing somatic tissues to navigate survival amid an environment containing damaged and poorly functioning proteins. Historically, experimental paradigms that limit reproductive investment result in lifespan extension. We proposed that germline-deficient animals might exhibit heightened protection from proteotoxic stressors in somatic tissues. We find that the forced re-investment of resources from the germ line to the soma in Caenorhabditis elegans results in elevated somatic proteasome activity, clearance of damaged proteins and increased longevity. This activity is associated with increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16. Ectopic expression of rpn-6 is sufficient to confer proteotoxic stress resistance and extend lifespan, indicating that rpn-6 is a candidate to correct deficiencies in age-related protein homeostasis disorders.

The extent to which variation in chromatin structure and transcription factor binding may influence gene expression, and thus underlie or contribute to variation in phenotype, is unknown. To address this question, we cataloged both individual-to-individual variation and differences between homologous chromosomes within the same individual (allele-specific variation) in chromatin structure and transcription factor binding in lymphoblastoid cells derived from individuals of geographically diverse ancestry. Ten percent of active chromatin sites were individual-specific; a similar proportion were allele-specific. Both individual-specific and allele-specific sites were commonly transmitted from parent to child, which suggests that they are heritable features of the human genome. Our study shows that heritable chromatin status and transcription factor binding differ as a result of genetic variation and may underlie phenotypic variation in humans.

Dietary Restriction (DR) extends longevity in diverse species suggesting that there is a conserved mechanism for nutrient regulation and prosurvival responses 1 . We have discovered a role for the HECT E3 ubiquitin ligase WWP-1 as a positive regulator of lifespan in C. elegans in response to diet restriction. We find that overexpression of wwp-1 in worms extends lifespan up to 20% under conditions of ad libitum feeding. This extension is dependent upon the FoxA transcription factor pha-4, and independent of the FoxO transcription factor, daf-16. Reduction of wwp-1 completely suppresses the extended longevity of diet-restricted animals. However, loss of wwp-1 does not affect the long lifespan of animals with compromised mitochondrial function or reduced insulin/IGF-1 signaling. Overexpression of a mutant form of WWP-1 lacking catalytic activity suppresses the increased lifespan of diet-restricted animals, indicating that WWP-1 ubiquitin ligase activity is essential for longevity. Additionally, we find that the E2 ubiquitin conjugating enzyme, UBC-18, is essential and specific for DR induced longevity. UBC-18 interacts with WWP-1 and is required for the ubiquitin ligase activity of WWP-1 and the extended longevity of worms overexpressing wwp-1. Taken together, our results indicate that WWP-1 and UBC-18 function to ubiquitinate substrates that regulate DR induced longevity.HECT (homologous to E6AP C-terminus) E3 ligases promote the ubiquitination of proteins that are essential in a variety of cellular events. The mammalian WWP1, WWP2 and Itch family of WW domain HECT ligases (WWP ligases) were initially identified in a search for novel proteins containing WW domains, which are modular protein interaction domains recognizing short proline motifs in their partners 2 . WWP ligases have an N-terminal C2 domain, a phospholipid membrane interaction motif, followed by four WW domains. To identify cellular pathways in which WWP E3 ligases are required, we have taken advantage of C. elegans as a model organism, which contains a single HECT WWP E3 ligase orthologue, wwp-1 (Y65B4BR.4). Disruption of wwp-1 using RNA interference (RNAi) yields a lethal phenotype late in embryogenesis characterized by abnormal embryogenesis despite normal cell proliferation 3 . The wwp-1(ok1102) mutant allele has a partially penetrant embryonic lethal phenotype 4 . Independent of the early developmental function of wwp-1, we found that loss of wwp-1 decreased stress resistance during adulthood ( Supplementary Fig. 1 a-b, e), leading us to investigate a possible role in longevity. Loss of wwp-1 function by RNAi or mutation reduced lifespan at 25°C ( Supplementary Fig. 2 a-b), but not at 20°C ( Supplementary Fig. 3 a-b Supplementary Fig. 4). Overexpressing wwp-1 transgenic lines (GFP∷WWP-1) lived up to 20% longer than controls expressing gfp under the same promoter (Fig. 1a), indicating that wwp-1 is a positive regulator of lifespan.When diet is restricted lifespan is extended in diverse species suggesting that there is a conserved mechani...