The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Open accessAbstract
Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells. It has been proposed that this is at least partially caused by the senescence of progenitors with age; however, it has not yet been tested whether genes associated with senescence functionally contribute to physiological declines in progenitor activity. Here we show that progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb, as well as multipotent progenitor frequency and self-renewal potential, all decline with age in the mouse forebrain. These declines in progenitor frequency and function correlate with increased expression of p16INK4a, which encodes a cyclin-dependent kinase inhibitor linked to senescence. Ageing p16INK4a-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16INK4a deficiency did not detectably affect progenitor function in the dentate gyrus or enteric nervous system, indicating regional differences in the response of neural progenitors to increased p16INK4a expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The NPC defect that we discovered is partly regulated by Cdkn2a, a central component of aging responsible for decreased neurogenesis and differentiation of NPCs (Abdouh et al., 2012; Molofsky et al., 2006).”
From Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model (2022) · cites this paper as Molofsky et al., 2006
Experimental — accuracy not yet measuredIn the citing paper
“Age-dependent reduction in stem cell number or perturbed cell-cycle activity has been reported in skeletal muscle stem cells, neural stem cells and germline stem cells110, 120–122.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [121]
In the citing paper
“other tumor suppressors (e.g., p16Ink4a) which appear to suppress cancer at the cost of tissue resident stem cells and therefore may contribute to decreased regenerative potential during the aging process (Krishnamurthy et al., 2006; Molofsky et al., 2006).”
From FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis (2009) · cites this paper as Molofsky et al., 2006
In the citing paper
“Because several studies have established a role for the polycomb group protein Bmi1 in the regulation of p16Ink4a (26–28), we analyzed the levels of Bmi1.”
From Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice (2009) · cites this paper as [28]
In the citing paper
“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 [25]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Subventricular zone astrocytes are neural stem cells in the adult mammalian brain
Doetsch, F., Caillé, I., Lim, D. A., García-Verdugo, J. M., & Alvarez-Buylla, A. (1999) · Cell · doi:10.1016/s0092-8674(00)80783-7 · Cited by 3,898
Kuhn, H., Dickinson-Anson, H., & Gage, F. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-06-02027.1996 · Cited by 3,139
Functional neurogenesis in the adult hippocampus
van Praag, H., Schinder, A. F., Christie, B. R., Toni, N., Palmer, T. D., & Gage, F. H. (2002) · Nature · doi:10.1038/4151030a · Cited by 2,853
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,379
Rejuvenation of aged progenitor cells by exposure to a young systemic environment
Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005) · Nature · doi:10.1038/nature03260 · Cited by 2,287
BRAFE600-associated senescence-like cell cycle arrest of human naevi
Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., & Peeper, D. S. (2005) · Nature · doi:10.1038/nature03890 · Cited by 2,160
Identification of a Neural Stem Cell in the Adult Mammalian Central Nervous System
Johansson, C. B., Momma, S., Clarke, D. L., Risling, M., Lendahl, U., & Frisén, J. (1999) · Cell · doi:10.1016/s0092-8674(00)80956-3 · Cited by 1,875
Jacobs, J. J. L., Kieboom, K., Marino, S., DePinho, R. A., & van Lohuizen, M. (1999) · Nature · doi:10.1038/16476 · Cited by 1,580
Ink4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486
Self-citationBmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation
Molofsky, A. V., Pardal, R., Iwashita, T., Park, I.-K., Clarke, M. F., & Morrison, S. J. (2003) · Nature · doi:10.1038/nature02060 · Cited by 1,317
Self-citation
Cited by
Sorted by citations
Items 901–970 of 970
The Effect of Electrical Stimulation on Endogenous Neural Stem and Progenitor Cell Behavior
Sefton, E. (2019) · TSpace (University of Toronto)
Derkach, D. (2019) · TSpace (University of Toronto)
Yeast Genetic Modeling of Pbp1/ATXN2-linked Neurodegenerative Diseases
Szafranski, K. M. J. (2016) · TSpace (University of Toronto)
Muscle-secreted G-CSF as a metabolic niche factor ameliorates loss of muscle stem cell in aged micePreprint
Li, H., Chen, Q., Li, C., Zhong, R., Zhao, Y., Zhang, Q., Tong, W., Zhu, D., & Zhang, Y. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/488874
Senotherapeutics: Experimental therapy of cellular senescence
Justice, J. N., Niedernhofer, L. J., & Orr, M. E. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-815962-0.00012-3
TERT-dependent senescence and inflammation in ageing, using zebrafish as a model
Martins, R. R. (2020) · White Rose eTheses Online (University of Leeds, The University of Sheffield, University of York)
The APOE4 Mouse as a Model of Chemotherapy-induced Cognitive Impairments and Senescence
Demby, T. C. (2021) · DigitalGeorgetown (Georgetown University Library)
Role of Lamina-associated polypeptide 2 alpha in striated muscle differentiation and regeneration
Gotić, I. (2009) · University of Vienna · doi:10.25365/thesis.7771
Faculty Opinions recommendation of Fgfs control homeostatic regeneration in adult zebrafish fins.
Mason, I. J., & Iyengar, L. (2009) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.1160487.620852
Rizos, H., & Scurr, L. L. (2011) · Springer eBooks · doi:10.1007/978-3-7091-0371-5_11
Charruyer, A., & Ghadially, R. (2015) · Springer eBooks · doi:10.1007/978-3-642-27814-3_19-2
Hematopoietic Stem Cell Aging and Malignant Hemopathies
Goodhardt, M., Garrick, D., Dang, L., Salaroli, A., & Bron, D. (2020) · Springer eBooks · doi:10.1007/978-3-319-57415-8_71
Rizos, H., Haferkamp, S., & Scurr, L. L. (2017) · Springer eBooks · doi:10.1007/978-3-319-41319-8_11
Multi-omic analysis of the aging mouse brain
Kluever, V. (2021) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-9022
Faculty Opinions recommendation of The hallmarks of aging.
Hickson, I. D., & Mankouri, H. W. (2013) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.718061760.793481794
Yang, Y., & Maloney, M. T. (2010) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.5328956.5277054
Age-dependent transcriptional and epigenetic alterations in mouse hepatocytes
Sharma, A. (2021) · DR-NTU (Nanyang Technological University) · doi:10.32657/10356/155390
Activity-Dependent Induction of Younger Molecular, Cellular and Organism PhenotypesPreprint
Lissek, T. (2022) · Preprints.org · doi:10.20944/preprints202204.0055.v1
Study of T Cell Immunosenescence in Various Tissue Compartments
Miron, M., Thome, J. J. C., Gordon, C. L., & Färber, D. L. (2019) · Springer eBooks · doi:10.1007/978-3-319-99375-1_79
Mira, H., Díez del Corral, R., & Morales, A. V. (2020) · Frontiers research topics · doi:10.3389/978-2-88963-988-5
Gold, M. R. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734674689.793558446
Tanaka, S. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.736116697.793562471
Pawelec, G. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734674689.793557283
Ishaq, A., & Saretzki, G. C. (2022) · Recent Progress in Nutrition · doi:10.21926/rpn.2203016
Papaconstantinou, J. (2020) · Journal of Skeletal Muscle · doi:10.14302/issn.2832-4048.jsm-20-3211
Elimination of damaged cells-dependent antiaging strategy
Naik, R. A., Dubey, V., Rajpoot, R., Dash, D., Gupta, N., & Koiri, R. K. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90235-9.00013-6
Jensen, C. E., Deal, A. M., Srikanth, S., Nyrop, K. A., Mitin, N., LeBlanc, M. R., Muss, H. B., Rubinstein, S. M., Tuchman, S. A., & Lichtman, E. I. (2024) · Journal of Geriatric Oncology · doi:10.1016/j.jgo.2024.102174
Nephron Senescence and Mechanisms
Healy, H. G., Kassianos, A. J., Ng, M. S. Y., & O'Sullivan, E. D. (2024) · Springer eBooks · doi:10.1007/978-3-031-68460-9_3
Kempermann, G. (2025) · Oxford University Press eBooks · doi:10.1093/med/9780197519233.003.0009
Roles of endocannabinoid in aging
Marchalant, Y., & Cooper, K. (2025) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-443-13908-6.00016-5
Yu, S., Wang, Y., Tang, B., Liu, X., Song, L., Xu, G., Zhu, H., & Sun, H. (2022) · Figshare · doi:10.6084/m9.figshare.19711411
Yu, S., Wang, Y., Tang, B., Liu, X., Song, L., Xu, G., Zhu, H., & Sun, H. (2022) · Figshare · doi:10.6084/m9.figshare.19711414
Yu, S., Wang, Y., Tang, B., Liu, X., Song, L., Xu, G., Zhu, H., & Sun, H. (2022) · Figshare · doi:10.6084/m9.figshare.19711420
Yu, S., Wang, Y., Tang, B., Liu, X., Song, L., Xu, G., Zhu, H., & Sun, H. (2022) · Figshare · doi:10.6084/m9.figshare.19711408
Yu, S., Wang, Y., Tang, B., Liu, X., Song, L., Xu, G., Zhu, H., & Sun, H. (2022) · Figshare · doi:10.6084/m9.figshare.19711417
Cancer Stem Cells and the Central Nervous System
Korur, S., Lino, M. M., & Merlo, A. U. (2011) · Springer eBooks · doi:10.1007/978-1-4614-0809-3_7
Stephan, P., Plassard, D., Keyes, W. M., & Hérault, Y. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06079-3
“However, under neurogenic stimulation such as physical exercise, p16Ink4a KO mice showed increased NSPC activation in the SGZ, albeit without a correspond - ing rise in mature neurone production due to heightened apoptosis [15, 16].”
Cudejko, C. (2010) · theses.fr (ABES) · doi:10.70675/3be56540zf3b1z4ee1z99ffz2dbbe7a0dc17
Roles of the multifunctional protein E4F1 in cellular senescence
Maciejewska, Z. (2010) · theses.fr (ABES) · doi:10.70675/21f99f8bze775z413fza364z48dd293ca460
Hematopoietic stem cell senescence and opportunities for intervention
Barve, A., Dabas, P., Cain, T. L., & McKinney‐Freeman, S. (2026) · Experimental Hematology · doi:10.1016/j.exphem.2026.105425 · Cited by 1
p16INK4a, régulation du cycle cellulaire et microARN
Chien, W. W. (2009) · theses.fr (ABES) · doi:10.70675/dbb5386dzc679z454fzad91z9d53a61231ff
Ferdousi, L. V. (2014) · theses.fr (ABES) · doi:10.70675/9d73199ez7949z4602zadcfz6763e4bdd1b0
Lemey, C. (2017) · theses.fr (ABES) · doi:10.70675/14dca0fcze537z4da0z9184z9b59c260ea88
Teissier, T. (2019) · theses.fr (ABES) · doi:10.70675/f49bc069z5ee6z4c49zb46fz0a1413dbba95
Generation of antisense RNAs at convergent gene loci in cells undergoing senescence
Deb, M. K. (2016) · theses.fr (ABES) · doi:10.70675/739ebf07zf620z4e1fzb0d4z02066589491f
Natural variations in yeast aging reveal genetic and environmental factors
Barré, B. P. (2018) · theses.fr (ABES) · doi:10.70675/ea0d9b85zd8b9z4fedzae80z738885fb5ca4
Suppressing p16INK4a promotes lung regeneration through a fibroblast lipogenic switch
Zysman, M. (2019) · theses.fr (ABES) · doi:10.70675/c507eaa0z188ez4332z952az2c54118917d6
Dissecting the non-cell autonomous impact of cellular senescence on cellular reprogramming
von Joest, M. (2019) · theses.fr (ABES) · doi:10.70675/01382339z05d9z4aacz911dz62afcc7c9191
Chataigner, M. (2021) · theses.fr (ABES) · doi:10.70675/a4317690zc4c8z4ba6za738zd457c6bb9b74
Mechanisms of spontaneous loss of heterozygosity in adult stem cells
Al-Zoubi, L. (2020) · theses.fr (ABES) · doi:10.70675/c5a4265cz7577z45eeza66bz4aaa728ab681
Drosophila intestinal stem cell response to DNA damage and replication stress
Boumard, B. (2021) · theses.fr (ABES) · doi:10.70675/848566f0z81b5z4b78z9817z58941b02acd2
Somatic Stem Cells: Control of Quiescence Versus Activation in Aging and Cancer
Yi, D., & Kahn, M. (2026) · Cancers · doi:10.3390/cancers18162542
“During our lifetime, SSCs are required for both repair after injury and homeostatic regeneration; however, SSC functionality declines with aging [5–7].”
Sewell, P. E. (2026) · Aging · doi:10.18632/aging.206416
“In preclinical models, BMI-1 overexpression preserves stem-cell self-renewal and reduces p16INK4a accumulation, with reported lifespan effects in mice [50 – 53].”
Chromatin signaling in aging and cellular senescence
Gagné, L. M., Couteau, F., & Mallette, F. A. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-19001-8.00018-0
Choi, Y.-B., Kim, D.-H., & Kim, D. (2026) · Stem Cell Research · doi:10.1016/j.scr.2026.104117
The role of telomerase in brain during ageing and under dietary restriction
Czapiewski, R. (2013)
Liu, K.-W. (2011) · D-Scholarship@Pitt (University of Pittsburgh)
Novel Regulation of the Cell Cycle During Cell Fate Decisions in the Central Nervous System
Lubanska, D. (2013) · Scholarship at UWindsor (University of Windsor)
Functional Analysis of ACD Mutations in Dyskeratosis Congenita.
Koçak, H. (2014) · Deep Blue (University of Michigan)
Yamashita, Y. M. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-227-8_13
“age, contributing to a decline in stem cell function [6–8].”
Background
Metadata
- Authors
- Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N. E., & Morrison, S. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Morrison, Sean J.
- ORCID
- Venue
- Nature
- Published
- 2006-09
- Volume
- 443
- Issue
- 7110
- Pages
- 448-452
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2586960
- OpenAlex
- W2065564965
- Cited by
- 972
- References
- 30
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 18 · 2023: 23 · 2022: 43 · 2021: 37 · 2020: 39 · 2019: 47 · 2018: 47 · 2017: 55 · 2016: 41 · 2015: 48 · 2014: 53 · 2013: 60 · 2012: 54
- FWCI
- 23.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Ellison Medical Foundation
- Sidney Kimmel Foundation for Cancer Research
- Sidney Kimmel Foundation
- National Institutes of Health
- National Institute on Aging (R01AG024945)
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- p16INK4a, cellular senescence, aging, neurogenesis, subventricular zone, olfactory bulb, multipotent progenitors, stem cell self-renewal, tumour suppressor, cyclin-dependent kinase inhibitors, type 2 diabetes, pancreatic islet regeneration
- MeSH terms
- Aging, Animals, Neurons, Olfactory Bulb, Regeneration, Stem Cells, Prosencephalon, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
