Rossi DJ, Bryder D, Weissman IL. Hematopoietic stem cell aging: mechanism and consequence

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Experimental Gerontology (Impact Factor: 3.49). 06/2007; 42(5):385-90. DOI: 10.1016/j.exger.2006.11.019
Source: PubMed


Advancing age is frequented by the onset of a variety of hematological conditions characterized by diminished homeostatic control of blood cell production. The fact that upstream hematopoietic stem and progenitor cells are obligate mediators of homeostatic control of all blood lineages, has implicated the involvement of these cells in the pathophysiology of these conditions. Indeed, evidence from our group and others has suggested that two of the most clinically significant age-associated hematological conditions, namely, the diminution of the adaptive immune system and the elevated incidence of myeloproliferative diseases, have their origin in cell autonomous changes in the functional capacity of hematopoietic stem cells.

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    • "With the growing population, aging, extended lifespans, and anti-aging have become popular areas of research in life and social sciences. Studies have shown that tissue-specific stem cells replaces worn out and damaged cells to maintain the internal environment homeostasis of a normal body1,2. It has been proposed that the aging of an organism is actually due to the senescence of these stem cells. "
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    ABSTRACT: Aim: To investigate the effects of ginsenoside Rg1 on the radiation-induced aging of hematopoietic stem/progenitor cells (HSC/HPCs) in mice and the underlying mechanisms. Methods: Male C57BL/6 mice were treated with ginsenoside Rg1 (20 mg·kg−1·d−1, ip) or normal saline (NS) for 7 d, followed by exposure to 6.5 Gy X-ray total body irradiation. A sham-irradiated group was treated with NS but without irradiation. Sca-1+ HSC/HPCs were isolated and purified from their bone marrow using MACS. DNA damage was detected on d 1. The changes of anti-oxidative activities, senescence-related markers senescence-associated β-galactosidase (SA-β-gal) and mixed colony-forming unit (CFU-mix), P16INK4a and P21Cip1/Waf1 expression on d 7, and cell cycle were examined on d 1, d 3, and d 7. Results: The irradiation caused dramatic reduction in the number of Sca-1+ HSC/HPCs on d 1 and the number barely recovered until d 7 compared to the sham-irradiated group. The irradiation significantly decreased SOD activity, increased MDA contents and caused DNA damage in Sca-1+ HSC/HPCs. Moreover, the irradiation significantly increased SA-β-gal staining, reduced CFU-mix forming, increased the expression of P16INK4a and P21Cip1/Waf1 in the core positions of the cellular senescence signaling pathways and caused G1 phase arrest of Sca-1+ HSC/HPCs. Administration of ginsenoside Rg1 caused small, but significant recovery in the number of Sca-1+ HSC/HPCs on d 3 and d 7. Furthermore, ginsenoside Rg1 significantly attenuated all the irradiation-induced changes in Sca-1+ HSC/HPCs, including oxidative stress reaction, DNA damage, senescence-related markers and cellular senescence signaling pathways and cell cycle, etc. Conclusion: Administration of ginsenoside Rg1 enhances the resistance of HSC/HPCs to ionizing radiation-induced senescence in mice by inhibiting the oxidative stress reaction, reducing DNA damage, and regulating the cell cycle.
    Preview · Article · Dec 2013 · Acta Pharmacologica Sinica
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    • "One of the most conspicuous effects is a shift in balance from the lymphoid lineage in young adults to the myeloid lineage in the elderly54, manifested as a reduced number of memory B cells and naïve T cells in the elderly, adversely affecting the immune response. Oxidative stress and reduced telomerase activity are other two factors that affect the functioning of HSCs in the aged population5556. With increasing age there is an accumulation of ROS induced DNA damage, along with a decline in the activity of DNA repair gene expression, resulting in decreased activity of the HSCs. Telomeres are found at the end of eukaryotic chromosomes that prevent chromosomes from fusing with each other. "
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    ABSTRACT: Age associated decline of the immune system continues to be a major health concern. All components of innate and adaptive immunity are adversely affected to lesser or greater extent by ageing resulting in an overall decline of immunocompetence. As a result in the aged population, there is increased susceptibility to infection, poor responses to vaccination, and increased incidence of autoreactivity. There is an increasing focus on the role of T cells during ageing because of their impact on the overall immune responses. A steady decline in the production of fresh naïve T cells, more restricted T cell receptor (TCR) repertoire and weak activation of T cells are some of the effects of ageing. In this review we summarize our present understanding of the effects of ageing on naïve CD4 T cells and potential approaches for therapeutic interventions to restore protective immunity in the aged population.
    Full-text · Article · Nov 2013 · The Indian Journal of Medical Research
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    • "Stem cells maintain tissue homeostasis by replacing damaged or worn-out cells and the deterioration of stem-cell functions, including self-renewal capacity, is one of the key components of organismal ageing (Janzen et al, 2006; Molofsky et al, 2006; Rossi et al, 2007, 2008). Distinct metabolic programmes in stem cells are necessary to protect genomic stability and to generate precursors for macromolecular synthesis to facilitate continued self-renewal. "
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    ABSTRACT: Forkhead Box O (FoxO) transcription factors act in adult stem cells to preserve their regenerative potential. Previously, we reported that FoxO maintains the long-term proliferative capacity of neural stem/progenitor cells (NPCs), and that this occurs, in part, through the maintenance of redox homeostasis. Herein, we demonstrate that among the FoxO3-regulated genes in NPCs are a host of enzymes in central carbon metabolism that act to combat reactive oxygen species (ROS) by directing the flow of glucose and glutamine carbon into defined metabolic pathways. Characterization of the metabolic circuit observed upon loss of FoxO3 revealed a drop in glutaminolysis and filling of the tricarboxylic acid (TCA) cycle. Additionally, we found that glucose uptake, glucose metabolism and oxidative pentose phosphate pathway activity were similarly repressed in the absence of FoxO3. Finally, we demonstrate that impaired glucose and glutamine metabolism compromises the proliferative potential of NPCs and that this is exacerbated following FoxO3 loss. Collectively, our findings show that a FoxO3-dependent metabolic programme supports redox balance and the neurogenic potential of NPCs.
    Full-text · Article · Sep 2013 · The EMBO Journal
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