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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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“Other stem cells have been demonstrated to increase in number but decrease in functional capacity with aging (Rossi et al. 2005), further proving that the cells we found share common features with other adult stem cells, not only skin stem cells.”
BackgroundThe long-lived immune system of centenarians
Plaza‐Florido, A., Carrera‐Bastos, P., Pérez‐Prieto, I., Fiuza‐Luces, C., Radom‐Aizik, S., Cruz, B. D. P., Franceschi, C., López‐Soto, A., López-Otı́n, C., & Lucía, A. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01291-5 · Cited by 13
“For instance, in aged mice, haematopoietic stem cells exhibit clonal skewing towards the myeloid lineage 24,25 .”
Lee, S., Wong, H., Castiglione, M. A., Murphy, M. M., Kaushansky, K., & Zhan, H. (2022) · Stem Cells · doi:10.1093/stmcls/sxac005 · Cited by 12
The eroding chromatin landscape of aging stem cells
Shi, C., Wang, L., & Sen, P. (2020) · Translational Medicine of Aging · doi:10.1016/j.tma.2020.08.002 · Cited by 14
“In fact, heterochronic transplants have shown that old HSCs transplanted to young niches behave like old cells, lending support to the importance of cell-intrinsic detriments [29].”
BackgroundYang, H., Kwon, J. S., Choi, H., Park, S. H., Yang, U. S., Park, H., Ren, L., Chung, K., Kim, Y. U., Park, B., et al. (2011) · PROTEOMICS · doi:10.1002/pmic.201100275 · Cited by 13
“According to increased the rate of ROS production with aging, function of erythrocytes is reduced with reduced replicative capacity and potential of hematopoietic stem cells [10].”
BackgroundAgeing within the hematopoietic stem cell compartment
Pearce, D., & Bonnet, D. A. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.04.005 · Cited by 13
Hüttmann, A., Dührsen, U., Heydarian, K., Klein‐Hitpaß, L., Boes, T., Boyd, A., & Li, C. (2006) · Stem Cells · doi:10.1634/stemcells.2005-0486 · Cited by 13
Forkhead box O proteins: steering the course of stem cell fate
Cheng, M., Nie, Y., Song, M., Chen, F., & Yu, Y. H. (2024) · Cell Regeneration · doi:10.1186/s13619-024-00190-1 · Cited by 13
“As HSCs age, their function decreases (Rossi et al. 2005; Sudo et al. 2000).”
Cui, X., Dong, Y., Zhan, Q., Huang, Y., Zhu, Q., Zhang, Z., Yang, G., Wang, L., Shen, S., Zhao, J., et al. (2024) · Science China Life Sciences · doi:10.1007/s11427-024-2754-9 · Cited by 14
“Of note, aged HSCs already show enhanced expression levels of myeloid-lineage associated genes before LPS stimulation, which is consistent with previous studies (Gekas and Graf, 2013; Pang et al., 2011; Rossi et al., 2005), indicative of transcriptionally priming for differentiation.”
Arber, C., Halter, J. P., Stern, M., Rovó, A., Gratwohl, A. A., & Tichelli, A. (2010) · Bone Marrow Transplantation · doi:10.1038/bmt.2010.193 · Cited by 12
Marrow failure and aging: The role of “Inflammaging”
Zhao, J., Ghimire, A., & Liesveld, J. L. (2021) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2021.101283 · Cited by 12
Stem Cell Aging and Aberrant Differentiation within the Niche
Choi, J., & Artandi, S. E. (2009) · Cell stem cell · doi:10.1016/j.stem.2009.06.006 · Cited by 12
“The altered cell fate of aging HSCs toward the myeloid lineage (Rossi et al., 2005) and the aberrant differentiation of muscle stem cells toward fibrogenic fates (Brack et al., 2007) may also reflect a subtler process by which aging or genotoxic stress influences cell fate in many tissue stem cell…”
BackgroundNew insights into skin stem cell aging and cancer
Ortells, M. C., & Keyes, W. M. (2014) · Biochemical Society Transactions · doi:10.1042/bst20140045 · Cited by 12
An Evolving Model of Hematopoietic Stem Cell Functional Identity
Lensch, M. W. (2012) · Stem Cell Reviews and Reports · doi:10.1007/s12015-012-9347-x · Cited by 15
“negative regulators of HSCs, from the distal to the proximal skeletal spaces within the aged bone marrow [20] point to a combination of cell intrinsic [21] and extrinsic phenomena”
Huang, Y., Li, R., Chen, X., Zhuo, Y., Jin, R., Qian, X. P., Jiang, Y. Q., Zeng, Z. H., Zhang, Y., & Shao, Q. (2011) · International Immunopharmacology · doi:10.1016/j.intimp.2011.03.011 · Cited by 12
Kato, K., Kuwabara, M., & Kashiwakura, I. (2011) · Journal of Radiation Research · doi:10.1269/jrr.10142 · Cited by 14
Epigenetic perturbations in aging stem cells
Krauss, S. R., & de Haan, G. (2016) · Mammalian Genome · doi:10.1007/s00335-016-9645-8 · Cited by 14
“Within the hematopoietic system, stem cells from both old humans and old mice show an increased propensity to differentiate along the myeloid, rather than the lymphoid lineage (Sudo et al. 2000; Rossi et al. 2005; Dykstra et al. 2007; Cho et al. 2008).”
BackgroundRunx Family Genes in Tissue Stem Cell Dynamics
Wang, C. Q., Mok, M. M. H., Yokomizo, T., Tergaonkar, V., & Osato, M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-3233-2_9 · Cited by 12
Two faces of RUNX3 in myeloid transformation
Yokomizo‐Nakano, T., & Sashida, G. (2021) · Experimental Hematology · doi:10.1016/j.exphem.2021.02.005 · Cited by 12
Cell-Intrinsic WNT4 Promotes Hematopoietic Stem and Progenitor Cell Self-Renewal
Hétu-Arbour, R., Tlili, M., Ferreira, F. L. B., Abidin, B. M., Kwarteng, E. O., & Heinonen, K. M. (2021) · Stem Cells · doi:10.1002/stem.3385 · Cited by 11
“Aging is associated with the expansion of phenotypic HSCs that are frequently biased toward myeloid differentiation and whose capacity to clonally expand is reduced.(39) To evaluate the impact of Wnt4 in early HSC aging, we analyzed HSCs from 8- to 12-month-old mice.”
BackgroundRegulation of hematopoietic stem cell aging by the small RhoGTPase Cdc42
Geiger, H., & Zheng, Y. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.09.001 · Cited by 14
“The lymphoid defect has been attributed to an impaired ability of aged HSCs to differentiate into the common-lymphoid progenitor cell, the progenitor cells that will give rise to both the T- and the B-cell lineage [1,23,24], while at”
BackgroundReece, A. S. (2008) · BDJ · doi:10.1038/sj.bdj.2008.932 · Cited by 13
“Indeed, the ageing process itself has increasingly been characterised as a stem cell disorder”
BackgroundRestoring resident tissue macrophages to combat aging and cancer
Park, M. D., Yatim, N., Zhang, J., Cho, B. A., Yoo, S., Schaefer, M. M., Chowell, D., Puleston, D. J., & Mérad, M. (2025) · Nature Aging · doi:10.1038/s43587-025-00898-y · Cited by 14
“Aged HSCs also exhibit a marked decrease in lymphopoietic potential 46–48 , and their differentiation is considerably biased toward the myeloid lineage 18,49 (Fig.”
15-PGDH regulates hematopoietic and gastrointestinal fitness during aging
Ho, W. J., Smith, J. N. P., Park, Y.-S., Hadiono, M., Christo, K. F., Jogasuria, A. P., Zhang, Y., Broncano, A. V., Kasturi, L., Dawson, D. M., et al. (2022) · PLoS ONE · doi:10.1371/journal.pone.0268787 · Cited by 9
“output of lymphoid cells, aging is associated with overall functional decline of the adaptive 14 immune system [10] [49] [13].”
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Umbayev, B. A., Saliev, T. M., Safarova, Y., Yermekova, A., Olzhayev, F., Bulanin, D. S., Tsoy, A., & Askarova, S. (2023) · Nutrients · doi:10.3390/nu15234964 · Cited by 15
On correlative and causal links of replicative epimutations
Zhou, W., & Reizel, Y. (2024) · Trends in Genetics · doi:10.1016/j.tig.2024.08.008 · Cited by 13
Xinyi, Y., Vladimirovich, R. I., Beeraka, N. M., Satyavathi, A., Kamble, D., Nikolenko, V. N., Lakshmi, A. N., Basappa, B., Padmanabha Reddy, Y., Fan, R., et al. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-04008-4 · Cited by 11
“Cell cycle regulators [221], upregulated myeloid signatures [221, 255], leukemia-causing genes [35], upregulation of inflammatory signaling through NF-kB, TNF-α [256, 257], and mitigation in the DNA repair pathways [36] are predominantly accompanied by aging.”
BackgroundInfluentialHe, T., Falwell, E., Brocca‐Cofano, E., & Pandrea, I. (2017) · Current Opinion in Virology · doi:10.1016/j.coviro.2017.07.012 · Cited by 12
Scheffold, A., Baig, A. H., Chen, Z., von Löhneysen, S., Becker, F. R., Morita, Y., Avila, A. I., Groth, M., Lechel, A., Schmid, F. T., et al. (2019) · Leukemia · doi:10.1038/s41375-019-0641-3 · Cited by 10
Watt, S. M. (2022) · PubMed · doi:10.12336/biomatertransl.2022.01.005 · Cited by 11
Zhou, Y., Yang, B., Yao, X., & Wang, Y. (2010) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-010-9372-5 · Cited by 11
“The latest studies (Rossi et al. 2005, 2007) found that the internal environment homeostasis of a normal body was maintained and controlled by tissue- Groups G0/G1 stage (”
BackgroundGrenier‐Pleau, I., & Abraham, S. A. (2021) · Experimental Hematology · doi:10.1016/j.exphem.2021.08.004 · Cited by 10
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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