Key Profile Area: Aging-associated Diseases
Prof. Jan H.J. Hoeijmakers
Member of the Global Faculty
Jan Hoeijmakers started the molecular analysis of DNA repair in mammals at the Dept. of Genetics (Erasmus Univ. Rotterdam) in 1981. He cloned the first of many human DNA repair genes, allowing elucidation of the underlying mechanisms and the basis of human repair syndromes, such as the cancer-prone xeroderma pigmentosum disorder and the severe neurodevelopmental conditions Cockayne syndrome and trichothiodystrophy.
His team pioneered DNA repair dynamics in living cells using novel imaging technologies, generated numerous mouse repair mutants, discovered a strong connection between accumulation of DNA damage and accelerated aging and a trade-off between cancer and aging. The mouse mutants appeared superior models for Alzheimer’s disease addressing a tremendous unmet medical need. Accumulation of unrepaired DNA damage causing premature cell death and senescence also triggered an anti-aging ‘survival response’ which enhances maintenance at the expense of growth resembling the longevity response by dietary restriction.
Remarkably, subjecting repair-deficient progeroid mice to actual dietary restriction tripled(!) their lifespan, drastically retarding DNA damage accumulation and accelerated aging most impressively neurodegeneration. These findings open perspectives for preventive interventions for healthy aging, reducing cancer and many aging-related diseases including neurodegeneration, and for therapy of human genome instability syndromes. For his work Jan Hoeijmakers received many prizes and awards.
Five key publications:
Hoeijmakers, J.H.J. Genome maintenance mechanisms for preventing cancer. Nature 411, 366-374 (2001).
de Boer, J., Andressoo, J.O., de Wit, J., Huijmans, J., Beems, R.B., van Steeg, H., Weeda, G., van der Horst, G.T.J., van Leeuwen, W., Themmen, A.P.N., Meradji, M. and Hoeijmakers, J.H.J. Premature aging in mice deficient in DNA repair and transcription. Science (research article), 296, 1276-1279 (2002). (see also Comments in Science, 296, 1250-1251).
Niedernhofer, L.J., Garinis, G.A., Raams, A., Lalai, S.A., Robinson, R.A., Appeldoorn, E., Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., Theil, A., Vermeulen, W., van der Horst, G.T., Meinecke, P., Kleijer, W., Vijg, J., Jaspers, N.G.J., Hoeijmakers, J.H.J. A new progeriod syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature (research article) 444, 1038-1043 (2006). (see also accompanying ‘News and Views’ Nature by Kirkwood).
Marteijn, J.A., Lans, H., Vermeulen, W. and Hoeijmakers J.H.J. Understanding nucleotide excision repair and its roles in cancer and ageing. Nature Rev Mol Cell Biol: 15, 465-481 (2014).
Vermeij W.P., Dollé M.E.T., Reiling E., Jaarsma D., Payan-Gomez C, Bombardieri C.R., Wu H., Roks A.J.M., Botter S.M., van der Eerden B.C., Youssef S.A., Kuiper R.V., Nagarajah B., van Oostrom C.T., Brandt R.M.C., Barnhoorn S., Imholz S., Pennings J.L.A., de Bruin A., Gyenis Á., Pothof J, Vijg J, van Steeg H., and Hoeijmakers J.H.J. Restricted diet delays accelerated aging and genomic stress in DNA repair deficient mice. Nature 537, 427-431 (2016) (see also accompanying Nature ‘News and Views’ of Oshima and Martin).
Contribution to KPA I: Aging-Associated Diseases
Jan Hoeijmakers and his team will contribute to a better understanding of the molecualr basis of skin ageing, which has major clinical consequences and to identify rational-based interventions to prevent or cure aging-related skin disorders. His work has strong connections with other research themes in the CECAD and Max Planck Institute for the Biology of Aging.