Alison Miller

University of Kentucky, Lexington, Kentucky, United States

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Publications (3)3.97 Total impact

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    ABSTRACT: There are many definitions of the term “ageing” and perhaps even more theories that seek to explain its causes (Balcombe and Sinclair 2001). From a physiological standpoint, ageing beyond reproductive maturity is often viewed as a progression of multisystem deficits in tissue function. In adult mammals, tissue homeostasis is maintained by stem cell populations that reside in, or migrate between, a variety of adult tissues. These stem cells ensure proper tissue function by generating new cells to replace those lost or damaged over time. Despite the presence of adult stem cells in muscle, nervous, gastrointestinal, hematopoietic, and other tissues, each of these systems exhibit functional decline with age (Edwards et al. 2002, Campisi 2003, Kondo et al. 2003, Penninx et al. 2003, Pinto et al. 2003, Linton and Dorshkind 2004, Balducci and Ershler 2005, Fulle et al. 2005, Kamminga 2005, Bauer et al. 2006, Keller 2006, Theise 2006). It is compelling to consider that functional changes in the stem cell compartment of adult tissues precedes and perhaps contributes to the manifestation of ageing phenotypes. In this chapter we will review literature describing the effects of ageing on the well-characterized stem cells of the hematopoietic system. In this system, ageing is accompanied by immune compromise, anemia, and a dramatic increase in the incidence of malignancy (Edwards et al. 2002, Campisi 2003, Penninx et al. 2003, Pinto et al. 2003, Linton and Dorshkind 2004, Balducci and Ershler 2005). Several studies support the hypothesis that these ageing phenotypes stem from functional changes in hematopoietic stem cells (HSCs).
    Telomeres and Telomerase in Ageing, Disease, and Cancer, 01/2008: pages 111-140; , ISBN: 978-3-540-73708-7
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    ABSTRACT: Aging in a statistical sense is the increasing probability of death with increasing time of an organism’s existence (1, 2). Can we extrapolate this to self-regenerating tissues and most particularly to the stem cells that drive the replenishment of lost and damaged cells throughout life? To be succinct, how close is the linkage between the vitality of the stem cell population and organismal longevity? These questions are currently without clear answers and the nature of the linkage, if any, is likely to be complicated, but is nonetheless conceptually compelling. However, in the most straightforward and blunt analysis, limiting numbers of hematopoietic stem cells, for example, resulting in aplastic anemia is an infrequent cause of death (3). Moreover, the hallmark property that distinguishes stem cells from most other somatic cells, their ability to self-replicate, in theory should provide a life-long supply. It was shown many years ago that hematopoietic stem cells could be transplanted into myeloablated recipients and continue to produce large numbers of differentiated blood cells over a time period that greatly exceeded the lifespan of the donor mouse (4). Serial transplants, in which an original bone marrow graft is passaged through a series of recipients, put even greater demands on stem cell proliferation and differentiation and thus demonstrate the tremendous regenerative potential of these cells. However, the number of transplant iterations that may be carried out is limited using marrow from young mice (5, 6), and further reduced if donors are old (6, 7). In fact it is restricted to less than five, depending on mouse strain, and although it has been argued that the limitation is not so much a result of diminished stem cell potential as in the transplantation procedure itself (8), it is now clear that stem cells’ regenerative properties diminish during the enforced stress of transplantation and during aging (9–15). Thus, there are growing indications that decrements in stem cell numbers and perhaps more importantly, function, play a role in the aging process. For example, it is well known that age-related decline in the immune system is associated with diminished ability to stave off infection and probably accounts for diminished surveillance and killing of malignant cells (16–21). Whether or not the primary lesion for immune decline resides, at least partially, at the stem cell level is without a definitive answer. For example, in the case of the involution of the thymus, more complicated scenarios, including effects on the thymic epithelium, have been invoked (21).
    04/2007: pages 1-19;
  • Alison Miller · Gary Van Zant ·
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    ABSTRACT: Successful bone marrow transplantation involves migration of hematopoietic stem cells through the blood, entering the extravascular hematopoietic cords, lodging in the proper niche, and expanding and differentiating to produce large numbers of mature cells -- all without depletion of the stem cell pool. An additional variable in these processes is the age of both the donor bone marrow and the recipient. Basic stem cell biology and transplant biology aim to uncover the molecular mechanisms controlling these processes. Mouse genetics is a frequently used tool that allows dissection of individual pathways that influence properties of hematopoietic stem cells. Recently, the conception of a niche has been expanded to include evidence for a vascular and an endosteal niche. Additionally, hematopoietic stem cell interactions within the niche have been further defined, documenting the importance of cell cycle, cell adhesion, response to cytokine stimulation and age-dependent functional changes. A new model for hematopoietic stem cell aging was proposed that supports the hypothesis that stem cell aging is at least partially due to an accumulation of DNA damage leading to exhaustion. This review focuses on the last year's progress using mouse genetics as a tool to study intrinsic mechanisms of hematopoietic stem cell biology.
    Current Opinion in Hematology 08/2006; 13(4):209-15. DOI:10.1097/01.moh.0000231416.25956.35 · 3.97 Impact Factor