Prof. Jan H. Hoeijmakers
Erasmus University, Rotterdam, NL
Genome stability: impact on cancer, aging and longevity
Inherited defects in nucleotide excision repair (NER) removing helix-distorting DNA lesions are associated with a striking clinical heterogeneity: cancer predisposition in xeroderma pigmentosum and neuro-developmental deficits in Cockayne syndrome (CS) and trichothiodystrophy (TTD). Even mutations in single NER genes, such as XPD, are linked with all three disorders. XPDTTD mice mimicking human TTD revealed that TTD and CS are segmental premature aging disorders protected from cancer. In contrast, XPDXP/CS mice are cancer-prone and age prematurely, demonstrating co-occurrence of both phenotypes. Various NER 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 premature aging symptoms and/or cancer susceptibility, strongly supporting the DNA damage theory of aging. Microarray, functional and physiological studies revealed that persistent DNA damage, like caloric restriction, downregulates the IGF1/GH axis and upregulates anti-oxidant defences, favouring maintenance/defence at the expense of growth/development. These data link accumulation of DNA damage and IGF1 control of life span and opens perspectives for promotion of healthy aging.
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