Jan H.J. Hoeijmakers

During his PhD (1975-1979) Jan Hoeijmakers characterized the mysterious mitochondrial DNA of trypansomes, which has the remarkable structure of a fishnet. In addition he discovered unexpected DNA rearrangements resolving antigenic variation by which trypanosomes evade immune destruction and cause sleeping sickness (Univ. of Amsterdam, supervisor Piet Borst). In 1981 he started to study DNA repair in mammals at the Erasmus Medical Center Rotterdam and cloned the first human DNA repair gene, followed by ~half of all human genes in nucleotide excision repair (NER) allowing elucidation of the molecular mechanism and discovery of a surprising link with basal transcription. He clarified the basis of rare repair disorders: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. His laboratory generated the largest collection of highly informative mouse NER mutants and disclosed an initially highly controversial, but unequivocal connection between DNA damage and (accelerated) aging, a trade-off between cancer and aging and DNA-damage-induced transcription stress in normal aging, which lowers and skews the transcriptional output of most organs and tissues upon aging, explaining >half of all gene expression changes in aging in organisms ranging from worms to man. Age-related transcription stress is also at the basis of all proteinopathies in neurodegenerative diseases. His team found that calorie restriction (CR) triggers a very potent ‘survival response’, which suppresses growth, but upregulates defense and resilience mechanisms and redesigns metabolism. In repair-deficient mice, CR was found to triple lifespan and enormously delay premature aging, most prominently neurodegeneration by lowering endogenous DNA damage. Reducing nutritional intake also dramatically improved the condition, health, (neuro)function and quality of life of corresponding human syndromes. These findings have wide clinical implications for repair syndromes, dementia’s, treatment by chemo- and radiotherapy and ischemia-reperfusion injury associated with surgery and organ transplantation, which all involve (oxidative) DNA damage induced by the reperfusion causing local aging. In many of these areas clinical trials are ongoing, including the use of nutritional interventions to prevent the long-term accelerated aging associated with chemo- and radiotherapy, which significantly affect quality of life of cancer survivors. Jan Hoeijmakers currently heads research teams in the Erasmus Medical Center (Rotterdam), the Princess Máxima Center for Pediatric Oncology (Utrecht, both the Netherlands), and the CECAD (Cologne, Germany). For his work he received numerous awards and prizes (see below).