Starting from the molecular analysis of DNA repair in mammals in 1981 by cloning many human DNA repair genes, which enabled elucidation of the underlying mechanisms and resolved the basis of rare human repair syndromes, we embarked upon the generation of a large series of mouse repair mutants, which we found to display accelerated but fully bona fideaging. This allowed us to reveal time- and exposure-dependent accumulation of DNA damage as the main cause of systemic aging. Whereas DNA-damage-induced mutagenesis underlies carcinogenesis, accumulated DNA damage in proliferating cells also arrests cell cycle progression inducing senescence. In non-dividing cells accumulation of DNA damage was found to interfere with transcription, to lower and skew the transcriptional output, leading to cellular functional decline and cell death and hence aging of the soma. Intriguingly, we found that aging caused by DNA-damage-induced transcription stress, simultaneously triggered a potent and interesting anti-aging, anti-cancer ‘survival’ response, which prioritizes resilience above growth. Caloric restriction (CR), which delays aging, induces a similar response. Applying calorie restriction to progeroid repair mutant mice and patients strongly delayed accelerated aging and even dramatically improved neurofunction, partially reverting neurodegeneration.
As DNA damage is the main culprit for systemic aging, this implies that most genotoxic (anti-cancer) treatments including chemo- and radiotherapy are predicted to cause features of premature aging, consistent with epidemiological studies. Since ~90% of pediatric patients are cured for a large part by virtue of chemotherapy, and ex-patients have a long life expectancy, the long-term pro-aging side effects, which significantly affect well being and QoL, constitute one of the most pressing problems in (pediatric) oncology. However, as outlined above, nutritional interventions are able to delay aging and can trigger a potent ‘survival response’, which boosts resilience and defence systems. These ingredients form the basis of several new research directions with promising perspectives in oncology, surgery and neurodegeneration, which we currently pursue in the following research lines.
- The project aims to extend our understanding of the mechanism by which CR delays aging and exerts strong benefits in repair-deficient progeroid mice and patients, particularly improving neurofunction. The anti-aging effect of CR is still largely unknown. A very relevant observation we made is that CR reduces genome-wide transcription stress, indicating it lowers levels of DNA lesions. As DNA damage causes systemic aging, this finding reveals how CR delays aging, extends lifespan and even allows improved neurofunction. Particularly, we would like to know how CR reduces DNA damage and to get insight into the mechanism by which neurodegeneration is halted and in part even reverted, which is relevant for ex-(pediatric)cancer patients experiencing features of accelerated aging. These studies also aim to identify the components in food that are responsible for the benefits of CR and to search for effective CR-mimicking agents or treatments.
- The ‘survival’ response triggered by CR and accelerated aging induces potent protection against a wide range of stresses. We have shown that pre-treatment fasting (1-3 days water only) in mice induces an exceptionally strong protection against ischemia reperfusion injury (IRI) that occurs after clamping blood supply to kidney and liver. To see whether and to which extent 2-3 days pre-treatment fasting also reduces IRI and improves recovery associated with (oncological) surgery and organ transplantation in humans we have initiated two randomised controlled clinical trials:
- The FIURTT study, Fasting Intervention for children with Unilateral Renal Tumours to reduce Toxicity, and
- The FAST trial, Fasting before live kidney donation, effect on donor wellbeing and postoperative recovery.
- In addition, we started the KetoHeppy investigation, KETOgenic diet therapy in patients with HEPatocellular adenoma. Next to these clinical studies we are performing in vitrostudies at the level of cultured cells, organoids as well as human and mouse organotypical slices to examine the effect of CR-mimicking conditions on metabolism and stress resistance.
- To investigate whether pre-treatment fasting also induces resistance to the short- and long-term side effects of chemo- and radiotherapy we are examining the response of fasting/CR in healthy and PDX-harbouring mice on different types of anti-cancer treatment. Promising initial results have been obtained. This serves as a steppingstone to clinical trials in pediatric and possibly adult cancer patients. The in vitrosystems may also enable the development of a screening platform for CR mimetics or compounds/treatments which synergize with CR.
- Finally, our progeroid mouse repair mutants appeared superior models for Alzheimer’s disease and other dementias and displayed an extraordinary beneficial response to CR. This was even surpassed by applying CR to the first repair-deficient TTD patient, revealing that the mouse model is highly valid for humans. Moreover, we found that CR also alleviated DNA-damage-driven transcription stress in the brain of the mice, and preliminary findings indicate that CR diminished amyloid-like as well as other pathogenic protein aggregates, which spontaneously develop in our repair mutants. These observations may address a tremendous unmet medical need and provide the basis for research directed at better understanding the molecular mechanisms involved and translation to patients, including (ex-)pediatric patients suffering from cognitive decline.
In summary, our research aims to elucidate the surprisingly simple, globally-applicable, inexpensive potential of nutritional interventions on (accelerated) aging and on health and to pioneer their application in important areas in medicine, including surgery, organ transplantation, chemo- and radiotherapy and proteinopathies in common forms of dementia.
- 2021: Official recognition of the Erasmus MC clinical expertise center for Rare Genome Instability Disorders, a multi-disciplinary clinic for children with DNA repair syndromes, initiated by Jan Hoeijmakers
- 2020: Ammodo Research Team Award” to ‘Guardians and Caretakers of the Genome’ together with other members of the Erasmus Dept. Mol. Genet.
- 2019: “EMGS Award” of the Environmental Mutagenesis and Genetics Soc. (Washington DC)
- 2018: Knowledge Ambassador of the City of Rotterdam
- 2017: International Olav Thon Foundation personal Award
- 2017: Honorary TEFAF Oncology Chair of the Maastricht Univ. Medical Center
- 2016: NVHG Galjaard Prize of the Netherlands Society of Human Genetics
- 2016: Professor International Faculty, Cologne University (Cologne, Guest Professor)
- 2016: Selected for the Nobel-Forum lecture at the Karolinska Institute
- 2015: ERC PoC grant DEMENTIA European Research Council
- 2014: Consulted by the Nobel Committee for the Nobel Prize in Chemistry for DNA repair (2014-2015)
- 2013: Royal distinction Knight in the Order of the Dutch Lion for important scientific achievements in the area of cancer and aging research (2013).
- 2012: Mendel Medal on the occasion of the 190th anniversary of Mendel’s birth
- 2011: Koningin Wilhelmina Research Prize of the Dutch Cancer Society, for research on DNA damage response in prostate and urinary bladder cancer (2M€) (Leiden, 2011)
- 2011: Academy Professor of the Royal Academy of Sciences of The Netherlands (KNAW), First Academy Professor new style in the broad domain of Beta sciences
- 2011: Cancer Research Prize of the Charles Rudolph Brupbacher Stiftung for research on the role of genome stability in cancer and aging, shared with Bert Vogelstein
- 2008: ERC Advanced Grant DamAge – Multi-disciplinary Sciences European Research Council
- 2008: Seneca Medaille des Industrie-Clubs für Altensforschung Prize, for pioneering research on the molecular basis of aging (First awardee)
- 2001: ‘Josephine Nefkens Prize’ for cancer research
- 2000: Elected member of KNAW (section ‘Medicine’, dept. ‘Physics’)
- 2000: ‘EC-Descartes’ Award for European collaboration on DNA repair
- 2000: ‘Van Gogh’ Prize from the Dutch Science Organization
- 2000: ‘Descartes-Huygens’ Award for French-Dutch scientific collaborations
- 1999: ‘Spinoza’ Prize, most recognized prize of the Dutch Science Organization
- 1995: The very prestigious 'Louis Jeantet' Prize for Medical Research in Europe for the entire work on DNA repair (Geneva, 1995)
- 1995: EMBO
- 1986: 'Snoo van t' Hoogerhuys' Prize (isolation of the first human DNA repair gene)
- 1983: 'Harold Quintus Bosz' Prize (for the discovery of the molecular mechanism of antigenic variation in trypanosomes, PhD thesis)
- Hoeijmakers, J. H. (2001). Genome maintenance mechanisms for preventing cancer. nature, 411(6835), 366.
- De Boer, J., Andressoo, J. O., de Wit, J., Huijmans, J., Beems, R. B., van Steeg, H., ... & Hoeijmakers, J.H. (2002). Premature aging in mice deficient in DNA repair and transcription. Science, 296(5571), 1276-1279.
- Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., ... & Hoeijmakers, J.H. (2006). A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature, 444(7122), 1038.
- Marteijn, J. A., Lans, H., Vermeulen, W., & Hoeijmakers, J. H. (2014). Understanding nucleotide excision repair and its roles in cancer and ageing. Nature reviews Molecular cell biology, 15(7), 465.
- Vermeij, W. P., Dollé, M. T., Reiling, E., Jaarsma, D., Payan-Gomez, C., Bombardieri, C. R., ... & Hoeijmakers, J.H. (2016). Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature, 537(7620), 427.
- Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J.H. (2021). The central role of DNA damage in the ageing process. Nature, 592(7856), 695.