Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Abstract
Stem-cell ageing is thought to contribute to altered tissue maintenance and repair. Older humans experience increased bone marrow failure and poorer haematologic tolerance of cytotoxic injury. Haematopoietic stem cells (HSCs) in older mice have decreased per-cell repopulating activity, self-renewal and homing abilities, myeloid skewing of differentiation, and increased apoptosis with stress. Here we report that the cyclin-dependent kinase inhibitor p16INK4a, the level of which was previously noted to increase in other cell types with age, accumulates and modulates specific age-associated HSC functions. Notably, in the absence of p16INK4a, HSC repopulating defects and apoptosis were mitigated, improving the stress tolerance of cells and the survival of animals in successive transplants, a stem-cell-autonomous tissue regeneration model. Inhibition of p16INK4a may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue.
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Mice lacking p16INK4a develop more malignancies.
“Old p16INK4a−/− HSCs also exhibit increased cell cycle activity and enhanced engraftment128, although these enhancements come with a price, as p16INK4a−/− animals show an increased incidence of malignancy.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [128]
Old p16INK4a−/− HSCs exhibit increased cell cycle activity and enhanced engraftment.
“Old p16INK4a−/− HSCs also exhibit increased cell cycle activity and enhanced engraftment128, although these enhancements come with a price, as p16INK4a−/− animals show an increased incidence of malignancy.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [128]
Knockout of p16 increases the life-span of HSCs by promoting HSC self-renewal.
“but knockout of p16 increases the life-span of HSCs by promoting HSC self-renewal.16-19”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [19]
ROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.
“ROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.15,19,20,35-38”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [19]
Age-induced expression of p16INK4a in adult stem cells seems to be associated with widespread impairment in tissue regeneration.
“age-induced expression of p16INK4a in adult stem cells seems to be associated with widespread impairment in tissue regeneration 23, 24, 25”
From The common biology of cancer and ageing (2007) · cites this paper as [23]
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- Authors
- Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T.
- Affiliations
- Harvard University (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Scadden, David T.
- ORCID
- Venue
- Nature
- Published
- 2006-09
- Volume
- 443
- Issue
- 7110
- Pages
- 421-426
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2084289371
- Cited by
- 1,106
- References
- 33
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 17 · 2023: 21 · 2022: 48 · 2021: 34 · 2020: 37 · 2019: 44 · 2018: 39 · 2017: 57 · 2016: 57 · 2015: 62 · 2014: 66 · 2013: 70 · 2012: 59
- FWCI
- 63.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- p16INK4a, stem cell aging, hematopoietic stem cells, cyclin-dependent kinase inhibitors, tumour suppressor, stem cell self-renewal, apoptosis, stress tolerance, tissue regeneration, pancreatic islet regeneration, brain regeneration, type 2 diabetes, bone marrow failure
- MeSH terms
- Transcription Factor HES-1, Aging, Animals, Cell Count, Hematopoietic Stem Cells, Bone Marrow Transplantation, Cellular Senescence, Apoptosis, Homeodomain Proteins, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Mice, Basic Helix-Loop-Helix Proteins
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