J Korean Med Assoc.  2014 Apr;57(4):334-340. 10.5124/jkma.2014.57.4.334.

Aging and impaired hematopoiesis

• Shin MG

• KMID: 2064891
• DOI: http://doi.org/10.5124/jkma.2014.57.4.334

Abstract

Aging is an universal phenomenon and irreversible syndrome, and its damage occurs to molecules (DNA, proteins, and lipids), to cells, and to organs. Hematopoietic tissue intrinsically has a very high turnover rate; nonetheless, it is not protected from age-related insults. Aging results in the overproduction of myeloid cells, which leads to a pro-inflammatory environment. The selective expansion of a clonal subtype of intrinsically myeloid-biased hematopoietic stem cells (HSCs) is a central component of hematopoietic aging. In the present study, the stress-response and inflammatory genes were up-regulated with age whereas chromatin remodeling and DNA repair genes were down-regulated. Accumulated DNA damage, loss of DNA repair, and epigenetic deregulation are the main molecular mechanisms underlying age-dependent HSC decline. The most profound effect is seen in the adaptive immune system with a marked decline of lymphoid function in the elderly. Mitochondrial dysfunction and mitochondrial DNA mutation are another important contributor to the aging of HSCs, which have been regarded as a part of the mitochondrial theory of aging. Generation of reactive oxygen species during mitochondrial adenosine triphosphate generation, results in damage to mitochondria and mitochondrial DNA, the latter leading to deleterious mutations that directly caused the functional decline of human. Studies have pointed toward intrinsic deficits in HSC function, and epigenetic deregulation as the important contributing factors behind hematopoietic decline and malignancy during aging. Aging-related changes such as hematopoiesis are reflected by a decline in marrow cellularity, increased risk of anemia, marrow failure syndrome, and myeloproliferative neoplasms as well as a decline of adaptive immunity.

Keyword

Aging; Hematopoiesis; Hematopoietic stem cells

MeSH Terms

Adaptive Immunity
Adenosine Triphosphate
Aged
Aging*
Anemia
Bone Marrow
Chromatin Assembly and Disassembly
DNA Damage
DNA Repair
DNA, Mitochondrial
Epigenomics
Hematopoiesis*
Hematopoietic Stem Cells
Humans
Immune System
Mitochondria
Myeloid Cells
Reactive Oxygen Species
Adenosine Triphosphate
DNA, Mitochondrial
Reactive Oxygen Species

Figure

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  Figure 1 Mechanisms of aging hematopoietic stem cell (HSC) and disease phenotypes. Instability of nuclear and mitochondrial genomes, and their altered transcriptions including epigenetic changes plays an essential role in HSC aging, resulting in the development of aging-related diseases. ROS, reactive oxygen species.

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  Figure 2 Mitochondrial DNA mutation in hematopoietic stem cells mainly caused by reactive oxygen species during mitochondrial adenosine triphosphate generation. Due to the aging of hematopoietic tissue, clonal expansion of mtDNA mutations was frequently occurred in hematopoietic tissues and blood cells. ROS, reactive oxygen species.

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  Figure 3 Clinical consequences of hematopoietic stem cell aging. A schematic draw for how the cellular and molecular changes, accompanying hematopoietic stem cell aging, contribute to clinically significant pathophysiological conditions of the aged hematopoietic system.

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