Changes in Hematopoietic Stem Cell Activity with Aging

Hematopoietic stem cells (HSCs) reside it the bone marrow and produce all of the different types of blood and immune cell, via a cascade of various types of progenitor cell. Stem cell behavior changes in a number of ways with aging, most notably in a general reduction of activity that leads to inadequate tissue maintenance, but also in other possibly damaging ways. For example, HSCs tend to bias their production of progenitors more towards myeloid cell types and less towards lympoid cell types, which is thought to contribute to the growing disarray of the immune system. In this open access paper, researchers examine an aspect of this phenomenon.

Age-related phenotypes within the hematopoietic system can be influenced by cell-extrinsic alterations, such as changes in the bone marrow (BM) microenvironment. However, in mice, ample evidence points to intrinsic alterations in the hematopoietic stem cells (HSCs) themselves as the main drivers of hematological aging. These include functional, genetic, and epigenetic modifications. In mice, HSCs increase in frequency that however is paralleled by a decreased proliferative capacity on a per-cell basis. In several reports, aged murine HSCs have been characterized by an increased myeloid-to-lymphoid output, often referred to as a myeloid bias (My-bi), although also their myeloid cell forming ability is decreased on a per cell basis when compared to younger HSCs.

These observations are presumably coupled to an age-related clonal shift within the aged HSC compartment towards increased My-bi HSC frequency at the expense of lymphoid-biased (Ly-bi) HSCs. Regardless, the lineage skewing with murine HSC aging has been linked to an upregulation of myeloid-specific genes and a downregulation of lymphoid-specific genes, although many of previous transcriptome analyses were based on a selection and manual curation of lineage-associated genes. By contrast, recent global transcriptome analysis of single HSCs based on more objectively defined lineage-affiliated transcription programs revealed a molecular and functional platelet bias, rather than a My-bi, in aged murine HSC.

Human HSC and progenitor cell aging has not been characterized as extensively as within the murine system, but several parallels suggest that aging characteristics at least to some degree might be conserved across species. For instance, HSC proliferation and clonal diversity decline between cord blood (CB) and aged bone marrow (BM). In addition, donor age affects outcome of clinical BM transplantations, although this most likely cannot be solely attributed to reduced HSC performance. More direct evaluations of the frequencies and function of aged human hematopoietic stem and progenitor cells (HSPCs) from a limited number of individuals displayed similarities to previous findings in the mouse, including an increased myeloid-to-lymphoid output ratio and decreased reconstitution potential, although this is not undisputed. In the present study we characterize age-related changes of human HPSCs and compare these to similar studies in mice. By separating the myeloid lineage into megakaryocytic/erythroid and granulocyte/macrophage lineage, we could reveal a molecular underpinning of megakaryocytic/erythroid bias in aged HSC of both humans and mice.

Downstream of human HSCs, we observed decreasing levels of common lymphoid progenitors (CLPs), and increasing frequencies of megakaryocyte/erythrocyte progenitors (MEPs) with age, which could be linked to changes in lineage-affiliated gene expression patterns in aged human HSCs. These findings were paralleled in mice. Therefore, our data support the notion that age-related changes also in human hematopoiesis involve the HSC pool, with a prominent skewing towards the megakaryocytic/erythroid lineages, and suggests conserved mechanisms underlying aging of the blood cell system.

Our results support the notion that an increased HSC frequency with age may be a compensatory mechanism to sustain sufficient blood cell replenishment. However, these compensatory mechanisms do not fully maintain optimal functions of HSCs and progenitor cells in elderly humans, as evidenced by the frequency of age-related hematological defects, including anemia and reduced immune responses. A deeper understanding of the events underlying this functional decline may support interventional approaches to prevent or ameliorate the aging hematopoietic phenotype.



ADA is a gene that activates telomerase in leucocyte telomeres. The rs73598374 C allele of this SNP has been shown to be the allele that confers the telomere lengthening better than the other variant. I am homozygous for the C allele, so I am hoping that my immune system will continue functioning better in old age.

Posted by: Biotechy at July 28th, 2017 1:34 PM
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