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Aging and cancer: The impact of DNA damage

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Inherited defects in nucleotide excision repair (NER) removing helix-distorting DNA lesions are associated with cancer predisposition in xeroderma pigmentosum and neurodevelopmental deficits and segmental progeria in Cockayne syndrome and trichothiodystrophy (TTD). Mutations in single NER genes, such as XPD , are linked with all three disorders. Various single and double NER mouse mutants reveal that the severity of specific repair defects strictly correlates with the acceleration of selective premature aging features, whereas the type of DNA repair defect determines the kind of progeroid symptoms and/or cancer susceptibility. Microarray, functional and physiological studies revealed that persistent DNA damage, like caloric restriction, down-regulates the IGF1 /GH-, lacto- and thyrotropic hormonal axes and upregulates anti-oxidant defenses, favoring maintenance at the expense of growth. This ‘survival response’ links accumulation of DNA damage and IGF1 control of life span. Micro- and mRNA expression profiling of normal, accelerated and delayed aging also revealed a clear parallel with the expression changes triggered by persistent transcription-blocking DNA lesions. These findings strongly support the DNA damage theory of aging. We will present phenotypes of conditional DNA repair models targeting aging to selected organs, parallels with Alzheimer’s disease and the effect of nutritional interventions on the life span of progeroid repair mutants.

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