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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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Watanabe, K., Ikuno, Y., Kakeya, Y., Kito, H., Matsubara, A., Kaneda, M., Katsuyama, Y., & Naka-Kaneda, H. (2018) · Inflammation and Regeneration · doi:10.1186/s41232-018-0066-9 · Cited by 7
“Dysfunctions of aged tissue stem cells (TSCs) contribute to loss of tissue homeostasis, including reductions in lymphopoiesis and the long-term repopulating abilities of hematopoietic stem/progenitor cells (HSCs) [1, 2], the muscle repair capacity of skeletal muscle satellite cells [3], and the multipotency of mesench…”
Ambrosi, T. H., & Chan, C. K. F. (2021) · Current topics in microbiology and immunology · doi:10.1007/978-3-030-86016-5_1 · Cited by 7
“This includes mutagenesis and epigenetic alterations promoting increased selfrenewal and skewed myeloid lineage output (Rossi et al. 2005; Pang et al. 2011; Beerman and Rossi 2015).”
BackgroundDefining the General Principles of Stem Cell Aging: Lessons from Organismal Models
Koyuncu, S., Irmak, D., Sáez, I., & Vílchez, D. (2015) · Current Stem Cell Reports · doi:10.1007/s40778-015-0017-1 · Cited by 8
Graffmann, N., Brands, J., Görgens, A., Castro, S. V. D. C., Santourlidis, S., Reckert, A., Michele, I., Ritz‐Timme, S., Fischer, J., Adjaye, J., et al. (2015) · Stem Cells and Development · doi:10.1089/scd.2014.0435 · Cited by 6
“This is reflected in (1) a pronounced myeloid skewing of hematopoiesis in elderly mice and (2) a preferential repopulation of the myeloid department after HSC transplantation from old donor mice [4,6–10].”
Older age and capacity of colony forming unit in autologous peripheral derived hematopoietic cells
Bozdağ, S. C., Bay, M., Ayyıldız, E., Topçuoğlu, P., & İlhan, O. (2012) · Transfusion and Apheresis Science · doi:10.1016/j.transci.2012.05.011 · Cited by 7
“While, genes mediating lymphoid specification down regulate with aging, genes mediating myeloid lineage specifying and function upregulate [5].”
BackgroundThe E. Donnall Thomas Lecture: Normal and Neoplastic Stem Cells
Weissman, I. L. (2008) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2008.05.003 · Cited by 7
“First, Sean Morrison and I, and then again recently Derrick Rossi and I, looked at the aging of stem cells, and here is what happens to them [22-24].”
BackgroundSelf-citationA Senescent Cluster in Aged Human Hematopoietic Stem Cell Compartment as Target for Senotherapy
Poisa-Beiro, L., Landry, J. J. M., Yan, B., Kardorff, M., Eckstein, V., Villacorta, L., Krammer, P. H., Zaugg, J. B., Gavin, A., Beneš, V., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26020787 · Cited by 7
Vicenzi, S., Gao, F., Côté, P., Hartman, J. D., Avsharian, L. C., Vora, A. A., Rowe, R. G., Li, H., Skowronska‐Krawczyk, D., & Crews, L. A. (2025) · GeroScience · doi:10.1007/s11357-025-01594-w · Cited by 7
“The aging immune system is typified by increased bone marrow adiposity [1] and a shift towards myeloid cell development [2] at the expense of lymphocyte maturation [3–5].”
Immunotherapies for Aging and Age-Related Diseases: Advances, Pitfalls, and Prospects
Yang, M., Wu, S., Zhang, J., Lu, L., Deng, D., Xia, Q., Lovell, J. F., Shi, X., & Jin, H. (2025) · Research · doi:10.34133/research.0866 · Cited by 7
“In 2005, Rossi et al. [ 36 ] discovered differences in HSCs between young and old mice, with myeloid-biased HSCs (my-HSCs) dominating the HSC pool in old mice and humans, leading to reduction in lymphoid-to-myeloid output weakened lymphocyte production and enhanced myeloid cell production.”
Vukadin, L., Park, B., Mohamed, M., Li, H., Elkholy, A., Torrelli-Diljohn, A., Kim, J., Jeong, K., Murphy, J. M., Harvey, C. A., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.175053 · Cited by 6
“Our study provides a significant guideline for clinical practice for ZTTK syndrome with hematopoietic involvement and suggests the need for monitoring myeloid expansion, including MDS and MPN, in these patients.”
BackgroundAging, Somatic Evolution, and Cancer
Rozhok, A. I., & DeGregori, J. V. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-420190-3.00012-0 · Cited by 6
Liu, L. A., & Rando, T. A. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-378638-8.00006-3 · Cited by 7
Cell competition in hematopoietic cells: Quality control in homeostasis and its role in leukemia
Ramos, C. V., & Martins, V. C. (2021) · Developmental Biology · doi:10.1016/j.ydbio.2021.02.013 · Cited by 7
Hoffman, R. A., Huang, S., Chalasani, G., & Vallejo, A. N. (2021) · Aging and Disease · doi:10.14336/ad.2021.0119 · Cited by 6
“Aging and Disease • Volume 12, Number 5, August 2021 1193 hematopoiesis, including stem cell intrinsic defects and bone marrow niche cell defects [49, 50] and thymic atrophy [51, 52] during aging are likely contributing factors for the failure to populate the immune system depots in aged mice to the same extent as you…”
BackgroundMyeloid Cell Origins, Differentiation, and Clinical Implications
Weiskopf, K., Schnorr, P. J., Pang, W. W., Chao, M. P., Chhabra, A., Seita, J., Feng, M., & Weissman, I. L. (2017) · ASM Press eBooks · doi:10.1128/9781555819194.ch50 · Cited by 6
Self-citationAge-dependent immune responses in COVID-19-mediated liver injury: focus on cytokines
Aghamohamadi, N., Shahba, F., Mehrabadi, A. Z., Khorramdelazad, H., Karimi, M., Falak, R., & Emameh, R. Z. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1139692 · Cited by 7
“This phenomenon is characterized by increased levels of proinflammatory mediators (31, 50, 58).”
BackgroundResultInfluentialDavinelli, S., Vasto, S., Caruso, C., Zella, D., & Scapagnini, G. (2012) · InTech eBooks · doi:10.5772/32944 · Cited by 6
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“2000), and other intrinsic and extrinsic factors that can influence the maintenance of these cells, such as maternal age and use of chemicals (Hardy et al. 2004; Rossi et al. 2005).”
BackgroundProblems in the promised land: Status of adult marrow stem cell biology
Quesenberry, P. J., Dooner, G. J., & Dooner, M. S. (2009) · Experimental Hematology · doi:10.1016/j.exphem.2009.05.003 · Cited by 6
“This lineage-negative population is then labeled with a variety of monoclonal antibodies (with fluorescent tags) recognizing various ‘‘stem’’ cell antigens and the hematopoietic stem cell isolated by FACS [5–25].”
BackgroundMethodAccumulation of prelamin A compromises NF-κB-regulated B-lymphopoiesis in a progeria mouse model
Liu, B., Zhou, S., Liu, X., Zhou, K., Zhang, F., & Zhou, Z. (2013) · Longevity & Healthspan · doi:10.1186/2046-2395-2-1 · Cited by 6
“lymphopoiesis declines significantly with age [12].”
ARAP3 Functions in Hematopoietic Stem Cells
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Young endothelial cells revive aging blood
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Zeng, X., Li, X., Shao, M., Xu, Y., Shan, W., Wei, C., Li, X., Wang, L., Hu, Y., Zhao, Y., et al. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.745786 · Cited by 6
“For instance, microarray analysis of HSC expression profiles revealed that HSC aging was accompanied by downregulation of genes mediating lymphoid specification differentiation and upregulation of genes involved in specifying myeloid fate (Rossi et al., 2005).”
BackgroundRamkumar, C., Gerstein, R. M., & Zhang, H. (2013) · Methods in molecular biology · doi:10.1007/978-1-62703-317-6_2 · Cited by 6
Restoring thymic function: Then and now
El-Kadiry, A. E.-H., & Rafei, M. (2019) · Cytokine · doi:10.1016/j.cyto.2019.05.009 · Cited by 6
Plausible Links Between Metabolic Networks, Stem Cells, and Longevity
Kucia, M., & Ratajczak, M. Z. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-31206-0_15 · Cited by 6
Meglio, F. D., Nurzyńska, D., Castaldo, C., Arcucci, A., Santo, L. S. D., FEO, M. D., Cotrufo, M. F., Montagnani, S., & Giordano-Lanza, G. (2007) · PubMed · doi:10.4081/1152 · Cited by 6
“Lineage negative, c-kit positive or Sca-1 positive cells isolated from murine and dog hearts have been demonstrated to produce cardiomyocytes , smooth muscle and endothelial cells in vitro (Rossi et al. 2005, Linke et al. 2005, Orlic et al. 2001).”
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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