CRHA intends to derive effective strategies which prevent, delay or cure aging diseases and improve health, quality of life and socio-economical participation by compressing multi-morbidity thereby contributing to a healthy population. Sub-aims are,
I) acquiring fundamental knowledge on aging (diseases),
II) identifying nutritional-pharmacological-lifestyle interventions promoting healthy aging by targeting the aging process itself,
III) translation to man,
IV) identify determinants of aging for personalized / precision medicine in aging,
V) education and training of scientists and health care professionals in aging research, and
VI) reaching out to society on aging-related topics.
CRHA will capitalize on the unique combination of expertise present in this ACE combined with state-of-the-art tools and technologies to build an interdisciplinary platform for healthy ageing research where various research disciplines such as fundamental biology, population genetics, epidemiology, age-related diseases will synergistically interact with the ultimate aim to provide solutions that promote healthy ageing and vitality. To that end, we will unravel basic biological mechanisms of ageing and age-related diseases in model organisms and human to obtain new leads for interventions.
We will elucidate the genetics of ageing, age-related traits and diseases. Deep molecular phenotyping of human cohorts will provide a detailed molecular landscape of human ageing. Both could lead to biomarker development for personalized medicine. We will be in the unique position to couple research to ageing and age-related diseases in model systems and human to disentangle the molecular mechanisms relevant for human ageing.
In addition, we will analyze how nutrition/lifestyle impinge on ageing and age-related diseases with the aim to develop preventive strategies that promote healthy ageing. CRHA has extensive (inter)national collaborative networks. Key national collaborations represent the LUMC (human ageing), Wageningen university (nutrition and ageing) and UMCG/ERIBA (basic mechanisms of ageing).
In 2018 we have composed a new Zwaartekracht application for the 2019 funding year (Requested budget >19 MEuro): Genomic Research on Aging, Nutrition, and DNA repair (GRAND) project, which involves the majority of the partners within this ACE and in addition partners from LUMC and WUR listed above.
Also the coordinator of this ACE has been invited by Nature Conferences to organize the first Nature Conference on Aging, Health and Rejuvenation, which will be held in Rotterdam in 2019. This honorful invitation is a recognition of the international stature of the research that provides the basis for this ACE.
Members of this ACE contribute to many educational programs at the BSc, MSc level in the Erasmus MC: Bachelor and Master program Medical Curriculum, Bachelor and Master NanoBiology, Bachelor and Master Clinical Technology, Research Master Molecular Medicine, Research Master Infection & immunity, Research Master Neuroscience, NIHES master of Science and Master program COEUR. In addition, ACE members participate in resident education for specialization in Neurology, Pediatrics, Clinical Genetics, OBGYN in the fellow program for subspecialist Reproductive Endocrinology. Some Master programs qualify as TOP-Master, indicating the quality of the education.
Furthermore, ACE members organize and participate in several post-doctoral courses in the form of symposia, courses, hands-on workshops etc., at the local (Erasmus MC), national, and international level. The combined number of PhD Students in all participating groups is 53. The number of international students (MSc or PhD) is 25. We aim to develop a novel educational program (course) at MSc level with topic healthy ageing. Such a course is currently not present in the Erasmus MC. Topics covered in this course will be (amongst others): basic mechanisms of ageing, model systems of ageing, human ageing and disease, diet and lifestyle interventions, genetic epidemiology and complex genetics, etc.
Societal Relevance to Research, Education and Patient Care
Members of our ACE have national and international guidelines, care standards and clinical practice statements, e.g. concerning screening for infertility and cycle disorders. Members also developed guidelines for the interpretation of omics data in clinical practice and into value-based medicine and in collaboration with the VKS (Volwassenen, Kinderen en Stofwisselingsziekten) a national " kenniskaart" and several " zorgpaden". They participate in the committee "Nachtwerk en gezondheidsrisico's" of the Dutch Health Council (Gezondheidsraad).
Several participants have developed specialized courses and curricula in the various BSc and MSc programs and research schools. In addition, we have ample experience in interacting with the general public through public lectures (e.g. Lof der Geneeskunst), science cafés, etc. and contributions to newspapers, magazines, radio and television programs. Our research provides ample opportunities for valorization, e.g. the development of biomarkers for age-related traits, the onset and progression of age-related diseases, chronological and biological age, etc.
Moreover, our work provides opportunities to develop preventive strategies to promote healthy ageing based on diet, lifestyle, circadian rhythms, etc. and new leads to develop therapeutic interventions against age-related diseases. We are actively pursuing a translation and valorization strategy. Several participants have filed patents or started spin-off companies.
Viability of Research, Education and Patient Care
Our ACE, CRHA, will be a platform for innovative high-level integrated biomedical research on healthy aging with the ambition to solidly anchor aging research in the Erasmus MC scientific domain and reinforce its research to a prominent position in the international arena. Many of the CRHA participants are already part of the absolute top in their respective areas of research.
This is also witnessed by the fact that many former PhD students and postdocs have pursued an international career and obtained leading positions at national and international universities. Several participating departments also installed a talent monitoring program to scout talent and try to keep them within the Erasmus MC. We will combine our complementary scientific resources in such a way that it will build a platform for future research initiatives to accelerate discoveries.
We believe that new discoveries and innovations will be done at the interface of different disciplines, hence the participation of all relevant disciplines in CRHA. A prime example is the translation of anti-aging interventions such as dietary restriction originating from basic research to short-term benefits for patients undergoing surgery or toxic pharmacological therapy.
Key and relevant publications of the last five years
- W.P. Vermeij, M.E.T. Dollé, E. Reiling, D. Jaarsma, C. Payan-Gomez, C.R. Bombardieri, H. Wu, A.J.M. Roks, S.M. Botter, B.C. van der Eerden, S.A. Youssef, R.V. Kuiper, B. Nagarajah, C.T. van Oostrom, R.M.C. Brandt, S. Barnhoorn, S. Imholz, J.L.A. Pennings, A. de Bruin, Á. Gyenis, J. Pothof, J. Vijg, H. van Steeg, and J.H.J. Hoeijmakers. Diet restriction delays accelerated aging and preserves genome function in DNA repair deficient mice. Nature, 2016, accepted
- Peters MJ, …. van Meurs JB, Johnson AD. The transcriptional landscape of age in human peripheral blood, Nature commun 2015 Oct 22;6:857.
- Westra HJ, … van Meurs JB, Franke L.Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013 Oct;45(10):1238-43
- Jongbloed F, de Bruin RW, Klaassen RA, Beekhof P, van Steeg H, Dor FJ, van der Harst E, Dollé ME, IJzermans JN. Short-Term Preoperative Calorie and Protein Restriction Is Feasible in Healthy Kidney Donors and Morbidly Obese Patients Scheduled for Surgery. Nutrients. 2016 May 20;8(5).
- Tresini, M., Warmerdam, D.O., Kolovos, P., Snijder, L., Vrouwe, M.G., Demmers, J.A., van IJcken, W.F., Grosveld, F.G., Medema, R.H., Hoeijmakers, J.H., Mullenders, L.H., Vermeulen, W. and Marteijn, J.A. The core spliceosome as target and effector of non-canonical ATM signaling. Nature, (2015), 523: 53-58.
- Jaarsma D, van der Pluijm I, de Waard MC, Haasdijk ED, Brandt R, Vermeij M, Rijksen Y, Maas A, van Steeg H, Hoeijmakers JH, van der Horst GT. Age-related neuronal degeneration: complementary roles of nucleotide excision repair and transcription-coupled repair in preventing neuropathology. PLoS Genet. 2011 Dec;7(12):e1002405.
- Jonsson T, Stefansson H, Ph D SS, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K.Variant of TREM2 Associated with the Risk of Alzheimer's Disease. N Engl J Med. 2013;368:107-16.
- Stolk …Uitterlinden AG, van Duijn CM, Völzke H, Murray A, Murabito JM, Visser JA, Lunetta KL. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat Genet. 2012 Jan 22;44(3):260-8.
- Durik M, Kavousi M, van der Pluijm I, Isaacs A, Cheng C, Verdonk K, Loot AE, Oeseburg H, Bhaggoe UM, Leijten F, van Veghel R, de Vries R, Rudez G, Brandt R, Ridwan YR, van Deel ED, de Boer M, Tempel D, Fleming I, Mitchell GF, Verwoert GC, Tarasov KV, Uitterlinden AG, Hofman A, Duckers HJ, van Duijn CM, Oostra BA, Witteman JC, Duncker DJ, Danser AH, Hoeijmakers JH, Roks AJ. Nucleotide excision DNA repair is associated with age-related vascular dysfunction. Circulation. 2012 Jul 24;126(4):468-78.
- Day FR, Hinds DA, Tung JY, Stolk L, Styrkarsdottir U, Saxena R, Bjonnes A, Broer L, Dunger DB, Halldorsson BV, Lawlor DA, Laval G, Mathieson I, McCardle WL, Louwers Y, Meun C, Ring S, Scott RA, Sulem P, Uitterlinden AG, Wareham NJ, Thorsteinsdottir U, Welt C, Stefansson K, Laven JS, Ong KK, Perry JR. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun. 2015 Sep 29;6:8464.
- J.A. Marteijn, H. Lans, W. Vermeulen, J.H.J. Hoeijmakers. Understanding Nucleotide Excision Repair and its roles in Cancer and Ageing. Nature Rev. Mol. Cell Biol. 15, 465-481. (2014).
- H. Matsumura, Y. Mohri, N. Thanh Binh, H. Morinaga, M. Fukuda, M. Ito, S. Kurata, J.H.J. Hoeijmakers, and E.K. Nishimura. Hair follicle aging is driven by transepidermal elimination of stem cells via Col17A1 proteolysis. Science Feb 5;351(6273):aad4395. doi: 10.1126/science.aad4395. Epub 2016 Feb 4.
- M.P. Baar, R.M. Brandt, D.A. Putavet, J.D. Klein, K.W. Derks, B.R. Bourgeois, S. Stryeck, Y. Rijksen, H. van Willigenburg, D.A. Feijtel, I. van der Pluijm, J. Essers, W.A. van Cappellen, W.F. van IJcken, A.B. Houtsmuller, J. Pothof, R.W. de Bruin, T. Madl, J.H. Hoeijmakers, J. Campisi, P.L. de Keizer. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 169, 132-147 (2017) e16. doi: 10.1016/j.cell.2017.02.031.
- Ribeiro-Silva C, Aydin OZ, Mesquita-Ribeiro R, Slyskova J, Helfricht A, Marteijn JA, Hoeijmakers JHJ, Lans H, Vermeulen W (2018) DNA damage sensitivity of SWI/SNF-deficient cells depends on TFIIH subunit p62/GTF2H1. Nature Communications in press
PhD theses of the last five years
- Lieneke Uittenboogaard (2012): DNA damage and Aging. The role of transcription-blocking lesions
- Marjolein Peters (2016): Integrating genomic approaches to understand ageing
- Leonie Cornelieke Jacobs (2015): Genetic determinants of skin color, aging, and cancer
- M. Verweij (2011): Genetic and nutritional preconditioning against ischemia-reperfusion injury
- M. Durik (2012). From DNA Damage to Protection
- Van Dycke (2016): Working around the clock. Adverse health effects of circadian rhythm disturbance
- A.F. Theil (2014): Functional Analysis of TTDA: From Human to Mouse: Big impact of a small protein
- Wendy van Dorp (2014): Ovarian function in Childhood Cancer survivors
- L Broer (2013). (Genetic) Epidemiology of Aging.
- C Ibrahim-Verbaas (2014): A Genetic Epidemiological Study of Dementia and Cognitive Function.
- Petra Schwertman (2014) Ubiquitination-In the UV-induced DNA damage response-from proteomics to patient.
- Kasper Derks (2014) The genomic nucleic acids dynamics during the DNA damage response: getting it all in sequence
- Lakshmi Chaintanya (2016) Genetic approaches to appearance and ancestry.
- Karolina Lech (2016) Circadian Forensics: Estimating blood trace deposition time using rhythmic biomarkers.
- Leonie Jacobs (2015) Genetic determinants of skin color, aging, and cancer.
- Mijke Visser (2015) From GWAS to Function. Transcriptional regulation of pigmentation genes in humans.
- Marta Baroncelli (2018) The Extracellular Matrix for Bone Regeneration.