Jan H.J. Hoeijmakers

Global Faculty University of Cologne, Department of Molecular Genetics at Erasmus University Rotterdam

Prof. Dr. Jan H.J. Hoeijmakers CECAD Cologne
Prof. Dr. Jan H.J. Hoeijmakers

Principal Investigator
Global Faculty University of Cologne
Professor of Molecular Genetics at Erasmus University Rotterdam

Research Areas

1
3

The role of DNA Damage and Nutrition in Aging

Using DNA repair-deficient mouse mutants and human syndromes we discovered that DNA damage-induced transcription stress is a main cause of systemic aging, and that nutritional interventions delay aging and transcription stress and extend healthspan.

Research Focus

Previously, we generated a world-wide unique collection of mouse models with DNA damage repair defects, which proved to be excellent paradigms for very severe human repair disorders. We discovered that these conditions are actually accelerated aging diseases, linking DNA repair not only to cancer but also aging. Our subsequent findings identified DNA damage as main cause of aging and recently also elucidated how: DNA lesions physically block transcription causing genome-wide transcription stress preferentially of long genes, as DNA damage is stochastic. Since gene expression initiates all cellular processes, lowered and particularly dysbalanced transcriptional output with aging affects numerous cellular pathways, explaining multimorbidity and other aging hallmarks as secondary consequences. This includes frailty, neurodegeneration (resembling Alzheimer disease), hepato-, nephro-, and hematological aging, cardiovascular disease, osteoporosis, etc. — addressing a massive unmet medical need and identifying DNA damage as main cause of aging.

Additionally, we discovered that reducing calorie intake triples lifespan and enormously delays accelerated aging in our repair-deficient mice. Translating reduced caloric intake to progeroid DNA repair-deficient children with Cockayne syndrome and trichothiodystrophy, disorders with a life expectancy often limited to childhood and no cure, strongly improved all disease parameters, most impressively neurofunction and significantly extends lifespan. This has led to a complete reversal of nutritional guidelines: counterintuitively these growth-retarded patients should have low instead of high calorie intake and it constitutes the first very effective treatment of any DNA repair disorder. Moreover, we discovered that calorie restriction reduces genome-wide transcription stress by lowering DNA damage, explaining its universal anti-aging, lifespan-extending activity, which has been elusive for almost a century.

By understanding the main cause of aging and the underlying mechanisms of aging-associated diseases we hope to find ways to effectively delay/prevent aging pathologies and promote healthy aging — improving quality of life of a significant fraction of the human population.

Our Goals

The overall goal of the Hoeijmakers lab is to fully understand how accumulating DNA damage contributes to systemic aging and to various age-related processes like stem cell exhaustion, cell death, cellular senescence and functional decline. Detailed gene expression analysis of progeroid DNA repair-deficient mouse mutants revealed close similarity to natural aging but also to a highly conserved anti-aging ‘survival’ response, which resembles the response to calorie restriction. Hence, DNA damage-driven premature aging links with both aging and longevity.

 

Specific questions we would like to explore are:

      • How does aging-related, DNA damage-driven, gene length-dependent transcription stress trigger both pro-aging as well as anti-aging responses?
         
      • What is the contribution of accumulating DNA damage to dementias such as Alzheimer, Parkinson and Huntington disease, which are characterized by aggregation of numerous proteins?
         
      • How does calorie restriction lower genome-wide DNA damage levels, with disproportional benefit for neurodegeneration? Does this treatment also benefit other genome instability disorders such as ataxia telangiectasia and Fanconi anemia?
         
      • What is the role of the IGF1 somatotrophic axis in relation to DNA damage-induced transcription stress and the ‘survival’ response?
         
      • In view of gene length-dependent transcription stress, what is the importance of gene length in aging, development and evolution?
         
      • Can we derive valid biomarkers for aging using transcription stress as read-out?
         

      To obtain answers to the above questions we aim for an integral, multi-omics approach in multiple organs and tissues of normal and accelerated aging models and after interventions influencing aging. This insight is indispensable to design rational-based strategies, which effectively prevent or delay major aging-associated diseases, most notably neurodegeneration, to promote healthy aging.

      Key Publications


      1. Gyenis A, Chang J, Demmers JJPG, Bruens ST, Barnhoorn S, Brandt RMC, Baar MP, Raseta M, Derks KWJ, Hoeijmakers JHJ, Pothof J. Genome-wide RNA polymerase stalling shapes the transcriptome during aging. Nat Genet. 2023 Feb;55(2):268-279. doi: 10.1038/s41588-022-01279-6. Epub 2023 Jan 19.PMID: 36658433 Free PMC article.
      2. Schumacher B, Pothof J, Vijg J, Hoeijmakers JHJ. The central role of DNA damage in the ageing process. Nature. 2021 Apr;592(7856):695-703. doi: 10.1038/s41586-021-03307-7. Epub 2021 Apr 28.PMID: 33911272 Free PMC article. Review
      3. Vermeij WP, Dollé ME, Reiling E, Jaarsma D, Payan-Gomez C, Bombardieri CR, Wu H, Roks AJ, Botter SM, van der Eerden BC, Youssef SA, Kuiper RV, Nagarajah B, van Oostrom CT, Brandt RM, Barnhoorn S, Imholz S, Pennings JL, de Bruin A, Gyenis Á, Pothof J, Vijg J, van Steeg H, Hoeijmakers JH. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature. 2016 Sep 15;537(7620):427-431. doi: 10.1038/nature19329. Epub 2016 Aug 24.PMID: 27556946 Free PMC article
      4. Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR, Appeldoorn E, Odijk H, Oostendorp R, Ahmad A, van Leeuwen W, Theil AF, Vermeulen W, van der Horst GT, Meinecke P, Kleijer WJ, Vijg J, Jaspers NG, Hoeijmakers JH. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature. 2006 Dec 21;444(7122):1038-43. doi: 10.1038/nature05456.PMID: 17183314
      5. de Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB, van Steeg H, Weeda G, van der Horst GT, van Leeuwen W, Themmen AP, Meradji M, Hoeijmakers JH. Premature aging in mice deficient in DNA repair and transcription. Science. 2002 May 17;296(5571):1276-9. doi: 10.1126/science.1070174. Epub 2002 Apr 11.PMID: 11950998
      Prof. Dr. Jan H.J. Hoeijmakers CECAD Cologne
      Prof. Dr. Jan H.J. Hoeijmakers

      Principal Investigator
      Global Faculty University of Cologne
      Professor of Molecular Genetics at Erasmus University Rotterdam

      Research Areas

      1
      3