"Genome Instability has been recognized as causal factor of cancer and recently also as a major contributing factor of aging. A number of progeroid (premature aging-like) syndromes are linked to defects in nucleotide excision repair (NER). NER thus provides a highly relevant experimental system to study the role of genome stability in aging. Using the NER system we recently uncovered a novel link between DNA damage accumulation and the regulation of longevity assurance programs. We propose to use the powerful genetic system of C. elegans to identify mechanisms through which the stochastic accumulation of damage impacts aging and genetic pathways of longevity regulation. We will pursue three complementary experimental strategies: (1) genetic identification of novel response pathways to persistent DNA damage, (2) investigation of DNA damage resistance mechanisms that promote longevity, and (3) a targeted candidate approach to uncover the underlying mechanisms that ensure genome integrity in lifespan extension. This proposal aims at the discovery of novel genes functioning in genome stability and longevity regulation that might be instrumental for the development of preventive therapeutic strategies for age-related pathologies as well as for the treatment of rare genetic progeroid disorders."