Jan Hoeijmakers

Jan HoeijmakersJan Hoeijmakers did his PhD (University of Amsterdam) on the fishnet-like kinetoplast DNA of trypanosomes, which cause sleeping sickness. In ‘spare’ time he discovered unexpected DNA rearrangements underlying antigenic variation by which this parasite evades immune destruction. Subsequently he started the molecular biology of DNA repair in mammals at the Dept. of Molecular Genetics (Erasmus University Rotterdam). He cloned the first human DNA repair gene, Ercc1, followed by many more allowing elucidation of the reaction mechanism of nucleotide excision repair, and discovery of a surprising link with basal transcription.

This clarified the basis of enigmatic human repair disorders, e.g. Cockayne syndrome and trichothiodystrophy and identified a new class of ‘basal transcription disorders’. His team generated the largest series of mouse repair mutants, which enabled detailed insight into the etiology of human repair diseases and disclosed an initially highly controversial connection between DNA damage and accelerated but bona fide aging and a trade-off between cancer and aging. This enabled getting grip on aging in mice by modulating DNA repair and surprisingly by nutritional interventions.

Acceleration of specific aging features was found to strictly correlate with the severity of defects in specific repair pathways. The spectrum of accelerated aging symptoms (which organs age fast) is determined by the type of repair defect (which pathway is affected). Conditional repair mice allow targeting accelerated aging to any organ, tissue or stage of development. Importantly, these mutants appeared a superior model for Alzheimer’s disease addressing a tremendous unmet medical need. Rapid accumulation of unrepaired DNA damage causing premature cell death and senescence also triggered an anti-aging ‘survival response’ which suppresses growth and enhances maintenance resembling the longevity response by dietary restriction (DR).

Remarkably, subjecting the progeroid mice to actual DR tripled(!) their lifespan i.e. the largest increase recorded in mammals, drastically retarding all aspects of accelerated aging most impressively neurodegeneration. These findings strengthen the link between DNA damage and aging, provide insight into the molecular mechanism underlying DR, establish the mutants as powerful model for identifying interventions to promote healthy aging, and suggest a counterintuitive DR-like therapy for human genome instability syndromes and for delaying neurodegeneration.

Email: j.hoeijmakers@erasmusmc.nl
Phone: +31 10 7043199