The etiology of the age-associated pathophysiological changes of the hematopoietic system including the onset of anemia, diminished immune competence, and myelogenous disease development suggests profound losses of homeostatic control. Because homeostatic control is mediated by the activity of stem and progenitor cells, we propose that the homeostatic imbalances associated with the aged hematopoietic system result from alterations in the prevalence and/or functional capacity of hematopoietic stem and progenitor cells. The mechanisms driving loss of homeostatic control are poorly understood. The accumulation of somatic damage to cellular macromolecules is considered to be a major cause of cellular attrition and aging. In particular, the accumulation of DMA damage has been implicated as a central mechanism contributing to age-associated decline. In such a model of aging, DMA damage accrues in cells as they age and when accumulated damage becomes sufficiently disruptive can drive cells to 1) malignant transformation 2) cellular senescence, 3) programmed cell death, or 4) dysfunction. When this aging paradigm is considered within the context of stem cell biology, malignant transformation of stem cells would be predicted to result in increased cancer stem cell development, while stem cell senescence, cell death, and dysfunction would be predicted to lead to the diminished functional stem cell reserves. If stem cell depletion surpasses levels of stem cell self-renewal, then homeostatic failure - the physiological hallmark of aging - ensues. The objective of our research is to functionally characterize hematopoietic stem and progenitor cell aging to determine the extent to which dysfunction of these cells contributes to ageassociated pathophysiological decline, and to uncover the extent to which this dysfunction is driven by accumulated DMA damage.
| Gutierrez-Martinez, Paula; Hogdal, Leah; Nagai, Manavi et al. (2018) Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nat Cell Biol 20:413-421 |
| Beerman, Isabel; Rossi, Derrick J (2015) Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease. Cell Stem Cell 16:613-25 |
| Riddell, Jonah; Gazit, Roi; Garrison, Brian S et al. (2014) Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 157:549-64 |
| Beerman, Isabel; Seita, Jun; Inlay, Matthew A et al. (2014) Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15:37-50 |
| Beerman, Isabel; Rossi, Derrick J (2014) Epigenetic regulation of hematopoietic stem cell aging. Exp Cell Res 329:192-9 |
| Stewart, Morag H; Gutierrez-Martinez, Paula; Beerman, Isabel et al. (2014) Growth hormone receptor signaling is dispensable for HSC function and aging. Blood 124:3076-80 |
| Mandal, Pankaj K; Blanpain, Cédric; Rossi, Derrick J (2011) DNA damage response in adult stem cells: pathways and consequences. Nat Rev Mol Cell Biol 12:198-202 |
| Beerman, Isabel; Maloney, William J; Weissmann, Irving L et al. (2010) Stem cells and the aging hematopoietic system. Curr Opin Immunol 22:500-6 |
| Ji, Hong; Ehrlich, Lauren I R; Seita, Jun et al. (2010) Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467:338-42 |
| Warren, Luigi A; Rossi, Derrick J (2009) Stem cells and aging in the hematopoietic system. Mech Ageing Dev 130:46-53 |
