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Premature ageing following allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 55, pages 1438–1446 (2020)Cite this article

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A Correction to this article was published on 08 April 2020

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Abstract

Survivors of hematopoietic cell transplantation (HCT) have been shown to exhibit both clinical and biological features of accelerated ageing. Most studies used frailty measures, comorbidities for clinical assessment and several biological assessment of premature ageing. However, these tests are less suitable for age determination of individual patients. Recently, DNA methylation has emerged as a novel test to measure cellular age. In the present study, we assessed ageing in a cohort of 26 survivors of allogeneic HCT by frailty tests comprising the handgrip and 6 min walk tests and by biological tests including DNA methylation, telomere length and expression of p16INK4A and serum levels of IL-6. DNA methylation was evaluated both in blood and buccal epithelial cells. Physiological reserve was markedly reduced in transplant survivors, reflected by 6 min walk test. Increased IL-6 serum levels and p16ink4A correlated with accelerated ageing. Overall, the measured age of donor blood cells was significantly higher than these blood cells residing in their respective donors, as reflected by DNA methylation and by buccal epithelium methylation status. These clinical and biological observations suggest that allogeneic HCT is associated with accelerated ageing.

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Fig. 1: Differences between transplanted patients and donors’ ages as predicted by blood methylation status.
Fig. 2: Difference between blood and epithelial cells predicted age and chronological age.
Fig. 3: Assessments of accelerating ages using other methods.

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References

  1. Jastrzębski D, Maksymiak M, Kostorz S, Bezubka B, Osmanska I, Młynczak T, et al. Pulmonary rehabilitation in advanced lung cancer patients during chemotherapy. Adv Exp Med Biol. 2015;861:57–64.

    Article  Google Scholar 

  2. Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT. ESMO Guidelines Working Group. et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23(Suppl 7):vii155–66.

    Article  Google Scholar 

  3. Navari RM. Olanzapine for the prevention and treatment of chronic nausea and chemotherapy-induced nausea and vomiting. Eur J Pharm. 2014;722:180–6.

    Article  CAS  Google Scholar 

  4. Taillibert S, Le Rhun E, Chamberlain MC. Chemotherapy-related neurotoxicity. Curr Neurol Neurosci Rep. 2016;16:81.

    Article  Google Scholar 

  5. Shimoni A, Shem-Tov N, Chetrit A, Volchek Y, Tallis E, Avigdor A, et al. Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced. Leukemia. 2013;27:829–35.

    Article  CAS  Google Scholar 

  6. Goldspink DF. Ageing and activity: their effects on the functional reserve capacities of the heart and vascular smooth and skeletal muscles. Ergonomics. 2005;48:1334–51.

    Article  Google Scholar 

  7. Guell C, Panter J, Griffin S, Ogilvie D. Towards co-designing active ageing strategies: a qualitative study to develop a meaningful physical activity typology for later life. Health Expect. 2018;21:919–26.

    Article  Google Scholar 

  8. Ness KK, Krull KR, Jones KE, Mulrooney DA, Armstrong GT, Green DM, et al. Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime cohort study. J Clin Oncol. 2013;31:4496–503.

    Article  Google Scholar 

  9. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146–56.

    Article  CAS  Google Scholar 

  10. Aunan JR, Watson MM, Hagland HR, Søreide K. Molecular and biological hallmarks of ageing. Br J Surg. 2016;103:e29–46.

    Article  CAS  Google Scholar 

  11. Mariani E, Meneghetti A, Formentini I, Neri S, Cattini L, Ravaglia G, et al. Different rates of telomere shortening and telomerase activity reduction in CD8 T and CD16 NK lymphocytes with ageing. Exp Gerontol. 2003;38:653–9.

    Article  CAS  Google Scholar 

  12. James K, Premchand N, Skibinska A, Skibinski G, Nicol M, Mason JI. IL-6, DHEA and the ageing process. Mech Ageing Dev. 1997;93:15–24.

    Article  CAS  Google Scholar 

  13. Szyper-Kravitz M, Uziel O, Shapiro H, Radnay J, Katz T, Rowe JM, et al. Granulocyte colony-stimulating factor administration upregulates telomerase activity in CD34+ haematopoietic cells and may prevent telomere attrition after chemotherapy. Br J Haematol. 2003;120:329–36.

    Article  CAS  Google Scholar 

  14. Lahav M, Uziel O, Kestenbaum M, Fraser A, Shapiro H, Radnay J, et al. Nonmyeloablative conditioning does not prevent telomere shortening after allogeneic stem cell transplantation. Transplantation. 2005;80:969–76.

    Article  Google Scholar 

  15. Volm M, Koomägi R, Stammler G, Rittgen W, Zintl F, Sauerbrey A. Prognostic implications of cyclins (D1, E, A), cyclin-dependent kinases (CDK2, CDK4) and tumor-suppressor genes (pRB, p16INK4A) in childhood acute lymphoblastic leukemia. Int J Cancer. 1997;74:508–12.

    Article  CAS  Google Scholar 

  16. Sanoff HK, Deal AM, Krishnamurthy J, Torrice C, Dillon P, Sorrentino J, et al. Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer. Natl Cancer Inst. 2014;106:dju057.

    Article  Google Scholar 

  17. Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 2017;7:165–76.

    Article  CAS  Google Scholar 

  18. Wu X, Pertovaara H, Korkola P, Vornanen M, Eskola H, Kellokumpu-Lehtinen PL. Glucose metabolism correlated with cellular proliferation in diffuse large B-cell lymphoma. Leuk Lymphoma. 2012;53:400–5.

    Article  CAS  Google Scholar 

  19. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:R115.

    Article  Google Scholar 

  20. Eipel M, Mayer F, Arent T, Ferreira MR, Birkhofer C, Gerstenmaier U, et al. Epigenetic age predictions based on buccal swabs are more precise in combination with cell type-specific DNA methylation signatures. Aging. 2016;8:1034–48.

    Article  CAS  Google Scholar 

  21. Weidner CI, Lin Q, Koch CM, Eisele L, Beier F, Ziegler P, et al. Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol. 2014;15:R24.

    Article  Google Scholar 

  22. Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: a review. Eur J Intern Med. 2016;31:3–10.

    Article  Google Scholar 

  23. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111–7.

    Article  Google Scholar 

  24. Rufer N, Brümmendorf TH, Chapuis B, Helg C, Lansdorp PM, Roosnek E. Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation. Blood. 2001;97:575–7.

    Article  CAS  Google Scholar 

  25. Skinner R, von Zglinicki T. Accelerated aging in bone marrow transplant survivors. JAMA Oncol. 2016;2:1267–8.

    PubMed  Google Scholar 

  26. Yao S, Sucheston LE, Smiley SL, Davis W, Conroy JM, Nowak NJ, et al. Common genetic variants are associated with accelerated bone mineral density loss after hematopoietic cell transplantation. PLoS ONE 2011;6:e25940.

    Article  CAS  Google Scholar 

  27. Andriani GA, Almeida VP, Faggioli F, Mauro M, Tsai WL, Santambrogio L, et al. Whole chromosome instability induces senescence and promotes SASP. Sci Rep. 2016;6:35218.

    Article  CAS  Google Scholar 

  28. Jurk D, Wilson C, Passos JF, Oakley F, Correia-Melo C, Greaves L, et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun. 2014;2:4172.

    Article  Google Scholar 

  29. Cupit-Link MC, Kirkland JL, Ness KK, Armstrong GT, Tchkonia T, LeBrasseur NK, et al. Biology of premature ageing in survivors of cancer. ESMO Open. 2017;2:e000250.

    Article  Google Scholar 

  30. Stölzel F, Brosch M, Horvath S, Kramer M, Thiede C, von Bonin M, et al. Dynamics of epigenetic age following hematopoietic stem cell transplantation. Haematologica. 2017;102:e321–3.

    Article  Google Scholar 

  31. Diker-Cohen T, Uziel O, Szyper-Kravitz M, Shapira H, Natur A, Lahav M. The effect of chemotherapy on telomere dynamics: clinical results and possible mechanisms. Leuk Lymphoma. 2013;54:2023–9.

    Article  Google Scholar 

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Authors and Affiliations

  1. The Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel

    Orit Uziel, Meir Lahav, Einat Beery, Uri Rozovski & Pia Raanani

  2. Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Orit Uziel, Meir Lahav, Liat Shargian, Oren Pasvolsky, Uri Rozovski, Pia Raanani & Moshe Yeshurun

  3. Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel

    Meir Lahav, Liat Shargian, Oren Pasvolsky, Uri Rozovski, Pia Raanani & Moshe Yeshurun

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  1. Orit Uziel
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Contributions

OU wrote the paper. ML designed the study and contributed to the paper. LS contributed to patient recruitment and to data analysis. EB performed the laboratory tests. OP contributed to patient recruitment and to data analysis. UR contributed to data analysis. PR contributed to data analysis. MY designed, coordinated the study and contributed to the paper.

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Correspondence to Orit Uziel.

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Uziel, O., Lahav, M., Shargian, L. et al. Premature ageing following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 55, 1438–1446 (2020). https://doi.org/10.1038/s41409-020-0839-z

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