We study DNA damage and genome stability and its impact on human health using nucleotide excision repair (NER) as paradigm. Patients with NER defects present a perplexing clinical heterogeneity ranging from extreme cancer predisposition to dramatic neurodevelopmental deficits. To elucidate the underlying mechanism we adopted an integral strategy from gene to patient and contributed to resolving the NER reaction in vitro and its dynamic organization in vivo, using molecular genetics, advanced life cell imaging and photobleaching. Mouse NER mutants revealed an unexpected link between DNA damage and (premature) aging, as strong as the DNA damage-cancer connection. We found a striking correlation between type/severity of the repair defect and degree of premature aging, with some mutants dying of aging in 3 weeks! Pathological and functional analysis and expression profiling confirmed that this is bona fide aging. Conditional mutants allowed targeting accelerated aging to specific organs/stages of development e.g. dramatic aging only in brain. Expression profiling revealed that short-lived repair mutants mount a survival response that attempts to extend lifespan by investing in defenses at the expense of growth. The ambitious objective of this multi-disciplinary proposal is to obtain an integral understanding of the biological/medical impact of DNA damage and the important survival response, with emphasis on rational-based prevention and intervention strategies for cancer and other aging-related diseases using the rapidly aging mouse mutants as tools. Triggering the survival response at adulthood is expected to postpone many aging-related diseases including cancer and to strongly improve quality of life at later age. We already identified compounds that influence rapid aging in mice and demonstrated the potency of the survival response to withstand ischemia reperfusion damage. Thus, this proposal addresses the major medical challenges faced by our society.