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Cell intrinsic alterations underlie hematopoietic stem cell aging
Open accessAbstract
Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.
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“The age-related increase in expression of myeloid lineage genes in the studies noted above (11,17) likely resulted from the accumulation of myeloid-biased HSCs, as these analyses were performed on unseparated pools of HSCs.”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [11]
In the citing paper
“This shift has been correlated with increased expression of myeloid lineage genes and downregulation of those specifying a lymphoid lineage fate (11,17).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [11]
In the citing paper
“The causes of this age-related reduction in lymphocyte development are multifactorial and include changes in HSCs and progenitor cells (11,12) as well as the local tissue and systemic environments (13,14).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [11]
In the citing paper
“From an immunologic perspective, the most profound effect of stem cell aging in both mice (11,18) and humans (17) is a decreased capacity to produce lymphocytes and an increase in myeloid potential.”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [11]
In the citing paper
“young bone marrow cells, when transplanted into aged recipients, engraft worse than when transplanted into young recipients.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [12]
In the citing paper
“examination of donor-derived reconstitution from old HSCs was significantly lower compared to the young with a marked myeloid bias lineage output”
From Quiescent Hematopoietic Stem Cells Accumulate DNA Damage during Aging that Is Repaired upon Entry into Cell Cycle (2014) · cites this paper as Rossi et al., 2005
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Young, K., Eudy, E., Bell, R., Loberg, M. A., Stearns, T., Sharma, D., Velten, L., Haas, S., Filippi, M.-D., & Trowbridge, J. J. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.03.017 · Cited by 216
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Self-citationThe multifaceted role of autophagy in cancer and the microenvironment
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Fgd5 identifies hematopoietic stem cells in the murine bone marrow
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“…when CD34 and Flk2 were used to immunophenotypically define HSCs and multipotent progenitors (Osawa et al., 1996; Christensen and Weissman, 2001; Rossi et al., 2005), HSCs (LSKFlk2CD34) were largely positive, whereas the MPP1/ST-HSC (LSKFlk2 CD34+) population expressed lower levels of signal,…”
MethodSelf-citationB cells and aging: molecules and mechanisms
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BackgroundAdult Stem Cels and Their Niches
Ferraro, F., Celso, C. L., & Scadden, D. T. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-7037-4_11 · Cited by 218
Effects of Age and Heart Failure on Human Cardiac Stem Cell Function
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Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age
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Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS
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Immune checkpoint inhibitors and elderly people: A review
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Age-associated changes in immune and inflammatory responses: impact of vitamin E intervention
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“Although the number of HSCs is shown to increase with age [34, 35], aged HSCs are less efficient in developing into lymphoid- and T-lineage cells according to recent studies [35–37].”
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Ma, S., Wang, C., Mao, X., & Hao, Y. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00318 · Cited by 184
“This phenomenon is ascribed to both cell-intrinsic changes and alterations in lymphoid organ microenvironments, which may be interpreted in 3 different ways (19, 20).”
BackgroundUnderstanding intrinsic hematopoietic stem cell aging
Mejía-Ramírez, E., & Florian, M. C. (2019) · Haematologica · doi:10.3324/haematol.2018.211342 · Cited by 206
Hematopoiesis and Cardiovascular Disease
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Nfatc1 orchestrates aging in hair follicle stem cells
Keyes, B. E., Segal, J. P., Heller, E., Lien, W., Chang, C.-Y., Guo, X., Oristian, D., Zheng, D., & Fuchs, E. V. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320301110 · Cited by 185
Warfvinge, R., Geironson, L., Sommarin, M. N. E., Lang, S., Karlsson, C., Roschupkina, T., Stenke, L., Stentoft, J., Olsson-Strömberg, U., Hjorth-Hansen, H., et al. (2017) · Blood · doi:10.1182/blood-2016-07-728873 · Cited by 154
“The HSC population from the nBM control was to a large extent made up by subpopulations expressing primitive or early myeloid molecular, quiescent signatures, likely reflecting the myeloid bias that has been reported in aged HSCs.37,38 However, in the diagnostic BCR-ABLpos LSC population, this heterogeneity was skewed…”
Verovskaya, E. V., Broekhuis, M., Zwart, E., Ritsema, M., van Os, R. P., de Haan, G., & Bystrykh, L. V. (2013) · Blood · doi:10.1182/blood-2013-01-481135 · Cited by 175
Mitochondrial Potentiation Ameliorates Age-Related Heterogeneity in Hematopoietic Stem Cell Function
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“Since it has been shown that myeloid bias and reduced regenerative capacity of old HSCs are maintained upon transplantation into young mice, it has been suggested that functional alteration with age predominantly results from cell-autologous changes (Rossi et al., 2005).”
BackgroundMethodInfluentialIncreased hematopoietic stem cell mobilization in aged mice
Xing, Z., Ryan, M. A., Daria, D., Nattamai, K., Zant, G. E. V., Wang, L., Zheng, Y., & Geiger, H. (2006) · Blood · doi:10.1182/blood-2005-12-010272 · Cited by 178
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“This was also demonstrated in our in vivo transplantation model which showed that HSPCs from Cd82 / mice had reduced long-term repopulating capacity and showed myeloid-biased differentiation (Figure 4E), a unique characteristics of aging HSCs (Rossi et al., 2005, 2008).”
Human skin stem cells and the ageing process
Zouboulis, C. C., Adjaye, J., Akamatsu, H., Moe-Behrens, G., & Niemann, C. (2008) · Experimental Gerontology · doi:10.1016/j.exger.2008.09.001 · Cited by 176
“To understand the mechanisms underlying hematopoietic ageing, highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice have been compared (Rossi et al., 2005).”
BackgroundHematopoietic Stem Cell Heterogeneity Takes Center Stage
Copley, M. R., Beer, P. A., & Eaves, C. J. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.05.006 · Cited by 181
Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells
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“Historically, aging of HSCs was thought to be solely influenced by stem cell intrinsic mechanisms (Rossi et al , 2005; Florian et al , 2012).”
Age-associated inflammation inhibits epidermal stem cell function
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“As some stem cell compartments undergo dramatic ageassociated changes (including alterations in cell number, decreased regenerative capacity, and fate change), a decline in stem cell function is suggested to contribute to the aging process (Conboy et al. 2003; Rossi et al. 2005; Molofsky et al. 2006).”
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“Purified HSCs from old mice have less ability to reconstitute haematopoiesis [27].”
BackgroundRegulation of Hematopoiesis and Osteogenesis by Blood Vessel–Derived Signals
Ramasamy, S. K., Kusumbe, A. P., Itkin, T., Gur‐Cohen, S., Lapidot, T., & Adams, R. H. (2016) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-111315-124936 · Cited by 176
“In humans, aging is strongly associated with bone loss (Dequeker 1975, Rossi et al. 2005), reduced HSC functionality (Morrison et al. 1996, Rossi et al. 2005), and reduced host immunity (Shaw et al. 2010, Weiskopf et al. 2009).”
BackgroundAging, Clonality, and Rejuvenation of Hematopoietic Stem Cells
Akunuru, S., & Geiger, H. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.06.003 · Cited by 178
“Global Epigenetic Shifts and Changes in Polarity Comparative transcriptional profiles of young and aged HSCs indicate that, in aged HSCs, myeloid differentiation linked genes, such as Runx1, Hoxb6, and Osmr, are upregulated, while lymphopoiesis genes are downregulated [24].”
BackgroundIL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice
Kovtonyuk, L. V., Caiado, F., Garcia-Martin, S., Manz, E.-M., Helbling, P., Takizawa, H., Boettcher, S., Al-Shahrour, F., Nombela-Arrieta, C., Slack, E., et al. (2022) · Blood · doi:10.1182/blood.2021011570 · Cited by 166
The RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cells
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“Interestingly, aging HSCs exhibit a differentiation bias favoring the myeloid lineage with a concomitant decrease in lymphoid lineage potential (Rossi et al., 2005).”
Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases
Bleve, A., Motta, F., Durante, B., Pandolfo, C., Selmi, C., & Sica, A. (2022) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-021-08909-7 · Cited by 185
“HSCs committed to the myeloid lineage outnumber lymphoid cells in both mice [28] and humans [29].”
BackgroundStretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer
Ge, Y., & Fuchs, E. V. (2018) · Nature Reviews Genetics · doi:10.1038/nrg.2018.9 · Cited by 172
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“The accumulation of DNA damage with age has been documented in several adult stem cells, including hematopoietic and epidermal stem cells (Rossi et al., 2005; Sotiropoulou et al., 2010).”
B cell maintenance and function in aging
Kogut, I., Scholz, J. L., Cancro, M. P., & Cambier, J. C. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.004 · Cited by 166
Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion
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“Analogous to transplantation studies comparingmurine HSCs from young and old donors (31, 35, 36), the frequency of donorderived HSCs in recipient BM was not reduced by 5-FU treatment, regardless of G1T28 administration (Fig.”
ResultLuo, H., Mu, W.-C., Karki, R., Chiang, H.-H., Mohrin, M., Shin, J. J., Ohkubo, R., Ito, K., Kanneganti, T.-D., & Chen, D. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.101 · Cited by 161
“However, its expression in HSCs is readily detectable in a number of transcriptional profiling studies (Cabezas-Wallscheid et al., 2014; Månsson et al., 2007; Norddahl et al., 2011; Rossi et al., 2005; Sun et al., 2014).”
Immunosenescence: Aging and Immune System Decline
Goyani, P., Christodoulou, R. C., & Vassiliou, E. K. (2024) · Vaccines · doi:10.3390/vaccines12121314 · Cited by 195
Rejuvenating Strategies for Stem Cell-Based Therapies in Aging
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“HSCs express the GDNF family of ligands (GFLs) receptor RET, and GFL signaling through RET in HSCs promotes survival, expansion and in vivo transplantation efficiency (Fonseca-Pereira et al., 2014).”
InfluentialAging by epigenetics—A consequence of chromatin damage?
Sedivy, J. M., Gowrishankar, B., & Adams, P. D. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2008.02.023 · Cited by 159
“Likewise, it might also be possible to use age-associated epigenetic changes in cardiac or immune cells for risk assessment or early detection of cardiovascular disease or declining immune function [104–106].”
BackgroundAging alters the epigenetic asymmetry of HSC division
Florian, M. C., Klose, M., Saçma, M., Jablanovic, J., Knudson, L. A., Nattamai, K., Marka, G., Vollmer, A., Soller, K., Sakk, V., et al. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2003389 · Cited by 160
Rimmelé, P., Bigarella, C. L., Liang, R. H.-S., Izac, B., Dieguez‐Gonzalez, R., Barbet, G., Donovan, M. J., Brugnara, C., Blander, J. M., Sinclair, D. A., et al. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.04.015 · Cited by 154
“3 j 44–59 j July 8, 2014 j a2014 The Authors prominent modifications of HSC properties with age is their biased differentiation toward myeloid lineage at the expense of their lymphoid potential (Challen et al., 2010; Dykstra et al., 2011; Rossi et al., 2005).”
BackgroundResultInfluentialFunctional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells
García‐Prat, L., Sousa‐Victor, P., & Muñoz‐Cánoves, P. (2013) · The FEBS Journal · doi:10.1111/febs.12221 · Cited by 152
Microenvironmental contributions to hematopoietic stem cell aging
Ho, Y., & Méndez‐Ferrer, S. (2019) · Haematologica · doi:10.3324/haematol.2018.211334 · Cited by 156
Immunosenescence and inflammaging: Mechanisms and role in diseases
Ajoolabady, A., Praticò, D., Tang, D., Zhou, S., Franceschi, C., & Ren, J. T. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102540 · Cited by 172
Radiation‐induced tissue damage and response
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“These radiation-induced changes appear to be remarkably similar to aging with its LT-HSC defects [71], and upregulation of genes specifying the myeloid cells at the expense of those of the lymphoid system [72].”
BackgroundMesenchymal stem cell therapy for heart disease
Gnecchi, M., Danieli, P., & Cervio, E. (2012) · Vascular Pharmacology · doi:10.1016/j.vph.2012.04.002 · Cited by 155
“Other unresolved issues are the ef fi cacy and safety concerns surrounding the changes in gene expression and functional properties of MSC with advancing age and disease [ 131 ] .”
BackgroundThe ageing B cell population: Composition and function
Ademokun, A., Wu, Y.-C. B., & Dunn‐Walters, D. K. (2009) · Biogerontology · doi:10.1007/s10522-009-9256-9 · Cited by 146
“At the molecular level, gene expression profile of HSCs from aged mice has demonstrated a skewing towards genes that promote myeloid lineage commitment at the expense of lymphoid lineage commitment (Rossi et al. 2005).”
Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors
Henry, C. J., Casás-Selves, M., Kim, J., Zaberezhnyy, V., Aghili, L., Daniel, A. E., Jimenez, L., Azam, T., McNamee, E. N., Clambey, E. T., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83024 · Cited by 148
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“In line with previous findings in the murine system [12, 14, 21, 56] and the results of one previous human study [30], we demonstrate that h-HSC and m-HSC frequencies increases with age (Fig 1B and 1D).”
ResultSelf-citationEndothelial transplantation rejuvenates aged hematopoietic stem cell function
Poulos, M. G., Ramalingam, P., Gutkin, M. C., Llanos, P., Gilleran, K., Rabbany, S. Y., & Butler, J. M. (2017) · Journal of Clinical Investigation · doi:10.1172/jci93940 · Cited by 153
Transcriptional Signatures of Aging
Stegeman, R., & Weake, V. M. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.06.019 · Cited by 146
Repair and regeneration in endodontics
Lin, L. M., & Rosenberg, P. A. (2011) · International Endodontic Journal · doi:10.1111/j.1365-2591.2011.01915.x · Cited by 152
“…factors (e.g. DNA damage and epigenetic dysregulation) of stem cells and diminished extrinsic signals (e.g. growth factors/cytokines and bioactive molecules) within the local and systemic environmental cues (Ho et al. 2005, Rossi et al. 2005, 2007, Carlson & Conboy 2007, Silva & Conboy 2008).”
BackgroundNeutrophils in aging and aging‐related pathologies
Avondt, K. V., Strecker, J., Tulotta, C., Minnerup, J., Schulz, C., & Soehnlein, O. (2022) · Immunological Reviews · doi:10.1111/imr.13153 · Cited by 155
Generation of mTert -GFP mice as a model to identify and study tissue progenitor cells
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Self-citationA comprehensive transcriptome signature of murine hematopoietic stem cell aging
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“Gene expression profiling has revealed that HSC aging is accompanied by the systemic downregulation of genes mediating lymphoid specification and function and upregulation of genes involved in specifying myeloid fate and function.(12,13) A study in 273 older patients with AML demonstrated that leukemic blasts were mor…”
BackgroundT cell ageing: effects of age on development, survival & function.
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“Importantly, transplantation of young and old LT-HSC into young recipients revealed that the diminished capacity to give rise to lymphoid progenitors, and the robust capacity to give rise to early myeloid progenitors were transplantable, cell autonomous properties of hematopoietic stem cell aging (Rossi et al., 2005).”
InfluentialSelf-citationIonizing radiation and aging: rejuvenating an old idea
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“As the hematopoietic system ages, the immune function deteriorates, the lymphoid potential diminishes, and the incidence of myeloid leukemia increases [111].”
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Self-citationRetractedPlasma cells are obligate effectors of enhanced myelopoiesis in aging bone marrow
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BackgroundHaematopoietic stem cells in perisinusoidal niches are protected from ageing
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Airway Epithelial Stem Cells and the Pathophysiology of Chronic Obstructive Pulmonary Disease
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“Cell autonomous changes in hematopoietic stem cells in old mice are likely associated with immune decline and the development of leukemia (28), and non–cell autonomous effects of the aging environment surrounding progenitor cells determines the ability of muscle to repair (29).”
BackgroundTargeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease
Cianflone, E., Torella, M., Biamonte, F., Angelis, A. D., Urbanek, K., Costanzo, F. S., Rota, M., Ellison, G. M., & Torella, D. (2020) · Cells · doi:10.3390/cells9061558 · Cited by 137
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“Notably, the majority of LT-HSCs are relatively quiescent and do not undergo major changes in cell cycle status with age, suggesting that HSC expansion is not caused by substantial changes in HSC cycling (Cheshier et al., 1999; Sudo et al., 2000; Chambers et al., 2007; Rossi et al., 2007b).”
BackgroundMethodInfluentialThe microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications
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Effects of Aging on the Common Lymphoid Progenitor to Pro-B Cell Transition
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“intrinsic defects in early B-lymphoid progenitors exists is consistent with data demonstrating that hemopoietic stem cells from old mice do not efficiently repopulate lymphoid cells in young recipients (25) and down-regulate genes necessary for lymphoid specification (26).”
BackgroundResultStem cells and aging in the hematopoietic system
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“which have looked at reconstituting activity on a per-HSC basis have measured a decline in potential with age (Morrison et al., 1996; Rossi et al., 2005; Sudo et al., 2000).”
InfluentialSelf-citationHematopoietic stem cell exhaustion impacted by p18INK4C and p21Cip1/Waf1 in opposite manners
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“Both aged mice (Rossi et al., 2005) and human (Pang et al.”
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BackgroundInfluentialSelf-citationImmunology of the ageing kidney
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Origins of aberrant DNA methylation in acute myeloid leukemia
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BackgroundInfluentialNiche recycling through division-independent egress of hematopoietic stem cells
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“For example, the number of HSCs expands dramatically with age, with 5–10 fold increases in HSC numbers in 24-mo-old animals vs. 12-wk-old animals ( Harrison et al., 1989 ; Morrison et al., 1996 ; de Haan and Van Zant, 1999 ; Sudo et al., 2000 ; Rossi et al., 2005 ).”
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“Together with an overall decline in multilineage HSC contribution of aged mice, these results strongly propose a model in which aging associates with reduced/compromised HSC differentiation, which in combination with the well-established expansion of HSCs with age (Morrison et al., 1996; Rossi et al., 2005; Sudo et al…”
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Mechanisms and rejuvenation strategies for aged hematopoietic stem cells
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BackgroundBone Marrow Fat and Hematopoiesis
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The Satb1 Protein Directs Hematopoietic Stem Cell Differentiation toward Lymphoid Lineages
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“The downregulation of genes mediating lymphoid specification and function is likely a major cause (Rossi et al., 2005).”
InfluentialAge-associated alterations in immune function and inflammation
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Regulation of cell differentiation by the DNA damage response
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“It has been idely demonstrated that the function of HSC significantly declines ith age (Pang et al., 2011; Rossi et al., 2005).”
BackgroundÁlvarez, S., Díaz, M., Flach, J., Rodríguez‐Acebes, S., Lopez-Contreras, A. J., Martínez, D., Cañamero, M., Fernández-Capetillo, Ó., Isern, J., Passegue, E. A., et al. (2015) · Nature Communications · doi:10.1038/ncomms9548 · Cited by 115
“With age, HSCs lose reconstitution potential for causes that have been debated 44–48 (reviewed in references 49–50).”
Metadata
- Authors
- Rossi, D. J., Bryder, D., Zahn, J. M., Ahlenius, H., Sonu, R., Wagers, A. J., & Weissman, I. L.
- Affiliations
- Joslin Diabetes Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-06-20
- Volume
- 102
- Issue
- 26
- Pages
- 9194-9199
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1153718
- OpenAlex
- W2131263031
- Cited by
- 1,152
- References
- 47
- Citations by year
- 2026: 44 · 2025: 56 · 2024: 49 · 2023: 55 · 2022: 56 · 2021: 80 · 2020: 57 · 2019: 71 · 2018: 57 · 2017: 59 · 2016: 67 · 2015: 54 · 2014: 56 · 2013: 63 · 2012: 55
- FWCI
- 24.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Institutes of Health
- Medical Research Council
- National Cancer Institute (R01CA086065)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- hematopoietic stem cell aging, long-term hematopoietic stem cells, stem cell self-renewal, leukemic transformation, age-related immune decline, gene expression profiling
- MeSH terms
- Animals, Cell Separation, Cell Transformation, Neoplastic, Flow Cytometry, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Leukemia, Mice, Inbred C57BL, Software, Stem Cells, Down-Regulation, Up-Regulation, Genome, Cellular Senescence, Cell Transplantation, Cell Lineage, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Mice
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