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Ferrata Storti Foundation
Haematologica 2019 Volume 105(1):22-37
Understanding intrinsic hematopoietic stem cell aging
Eva Mejia-Ramirez1,2 and Maria Carolina Florian1,3
1Center for Regenerative Medicine in Barcelona (CMRB), Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain; 2Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, 28029, Spain and 3Institute of Molecular Medicine and Stem Cell Aging, Ulm University, Ulm, Germany
EM-R and MCF contributed equally to this work.
ABSTRACT
Hematopoietic stem cells (HSC) sustain blood production over the entire life-span of an organism. It is of extreme importance that these cells maintain self-renewal and differentiation potential over time in order to preserve homeostasis of the hematopoietic system. Many of the intrinsic aspects of HSC are affected by the aging process resulting in a deterioration in their potential, independently of their microenvironment. Here we review recent findings characterizing most of the intrinsic aspects of aged HSC, ranging from phenotypic to molec- ular alterations. Historically, DNA damage was thought to be the main cause of HSC aging. However, over recent years, many new findings have defined an increasing number of biological processes that intrinsi- cally change with age in HSC. Epigenetics and chromatin architecture, together with autophagy, proteostasis and metabolic changes, and how they are interconnected, are acquiring growing importance for under- standing the intrinsic aging of stem cells. Given the increase in popula- tions of older subjects worldwide, and considering that aging is the pri- mary risk factor for most diseases, understanding HSC aging becomes particularly relevant also in the context of hematologic disorders, such as myelodysplastic syndromes and acute myeloid leukemia. Research on intrinsic mechanisms responsible for HSC aging is providing, and will continue to provide, new potential molecular targets to possibly amelio- rate or delay aging of the hematopoietic system and consequently improve the outcome of hematologic disorders in the elderly. The niche- dependent contributions to hematopoietic aging are discussed in another review in this same issue of the Journal.
Introduction
Aging is the largest risk factor for many chronic diseases and disabilities. Not sur- prisingly, aging is also the major risk factor for several hematologic syndromes and malignancies, such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).1 Moreover, aging has a negative impact on HSC regenerative capacity, and for this reason, cell-intrinsic mechanisms of aging are important puta- tive targets for therapeutic interventions in order to ameliorate the consequences of aging on HSC and on the hematopoietic system.2 Understanding the mechanisms of HSC aging will provide the scientific community with new tools to improve the regenerative capacity of healthy HSC and thus the function of the hematopoietic system in the elderly.
The elderly population is growing rapidly worldwide. In addition, hematologic disorders and leukemia are exponentially growing with aging, without an equiva- lent acceptable growth in the therapeutic management of these diseases in the eld- erly; this is in sharp contrast to the increase in successful therapies for leukemia in younger patients. So far, with conventional induction therapy, many elderly patients experience a very poor overall survival rate, while requiring substantial social and medical assistance during their few remaining months of life, at a signif- icant cost to the health service.3,4
Correspondence:
MARIA CAROLINA FLORIAN
cflorian@cmrb.eu or carolina.florian@uni-ulm.de
Received: July 14, 2019. Accepted: November 14, 2019. Pre-published: December 5, 2019.
doi:10.3324/haematol.2018.211342
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/1/22
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