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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.
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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]
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Shan, W. (2009) · Frontiers in bioscience · doi:10.2741/3511 · Cited by 26
“Similarly, p16 was found to be upregulated with age in the progenitor cells of the mouse brain (67), bone marrow (68), and pancreas (69), along with age-associated decreases in neurogenesis, hematopoiesis, and pancreatic function, respectively.”
BackgroundSoriano‐Cantón, R., Pérez‐Villalba, A., Morante‐Redolat, J. M., Marqués‐Torrejón, M. Á., Pallàs, M., Pérez‐Sánchez, F., & Fariñas, I. (2015) · Aging Cell · doi:10.1111/acel.12328 · Cited by 26
“Reduced levels of olfactory neurogenesis that are primarily due to decreased numbers of stem-like cells are found in elderly animals (Maslov et al., 2004; Luo et al., 2006; Molofsky et al., 2006; Shook et al., 2012).”
BackgroundInfluentialSharpless, N. E., & Schatten, G. P. (2009) · The Journals of Gerontology Series A · doi:10.1093/gerona/gln070 · Cited by 27
Self-citationPM2.5 Exposure Suppresses Dendritic Maturation in Subgranular Zone in Aged Rats
Cheng, L., Lau, W. K., Fung, T. K. H., Lau, B. W.-M., Chau, B. K. H., Liang, Y., Wang, Z., So, K., Wang, T., Chan, C. C. H., et al. (2017) · Neurotoxicity Research · doi:10.1007/s12640-017-9710-4 · Cited by 26
“…process of aging, significant reduction in cell proliferation in both adult SGZ and SVZ can be observed [reviewed by (Rossi et al. 2008)], which takes part in the decline in both sensory and cognitive functions during normal aging (Drapeau et al. 2003; Kuhn et al. 1996; Molofsky et al. 2006).”
BackgroundDivide or Commit – Revisiting the Role of Cell Cycle Regulators in Adult Hippocampal Neurogenesis
Urbach, A., & Witte, O. W. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00055 · Cited by 26
Cheng, T. (2007) · Gene Therapy · doi:10.1038/sj.gt.3303066 · Cited by 26
Long non-coding RNAs and their involvement in bipolar disorders
Bella, F., & Campo, S. (2021) · Gene · doi:10.1016/j.gene.2021.145803 · Cited by 25
Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging
Akbari, M., Shanley, D. P., Bohr, V. A., & Rasmussen, L. J. (2021) · Cells · doi:10.3390/cells10123544 · Cited by 25
Chen, N., Newcomb, J. D., Garbuzova-Davis, S. N., Sanberg, C. D., Sanberg, P. R., & Willing, A. E. (2010) · PubMed Central · Cited by 25
p16INK4a‐mediated suppression of telomerase in normal and malignant human breast cells
Bazarov, A. V., van Sluis, M., Hines, W. C., Bassett, E., Beliveau, A., Campeau, E., Mukhopadhyay, R., Lee, W. J., Melodyev, S., Zaslavsky, Y., et al. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00599.x · Cited by 25
Drug-induced premature senescence model in human dental follicle stem cells
Zhai, Y., Wei, R., Liu, J., Wang, H., Cai, W., Zhao, M., Hu, Y., Wang, S., Yang, T., Liu, X., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.14085 · Cited by 26
“Studies showed p16INK4A was an increased expression in ageing human and murine organs [57] and an elevated expression of tumor protein P53, p21 and p16INK4A all result in declined proliferative capacity and neurogenesis of neural stem cells (NSCs) [58, 59].”
BackgroundINK4a/ARF Expression Impairs Neurogenesis in the Brain of Irradiated Mice
Lê, O., Palacio, L., Bernier, G., Batinic̈‐Haberle, I., Hickson, G. R. X., & Beausejour, C. M. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.025 · Cited by 26
“example, the ability to form new neurons was shown to decline in the SVZ of aged mice brains, a defect that was partially abrogated in mice deficient in p16INK4a (Molofsky et al., 2006).”
BackgroundChromosomal instability and pro-inflammatory response in aging
Barroso‐Vilares, M., & Logarinho, E. (2019) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.111118 · Cited by 26
The molecular basis of ageing in stem cells
Tam, W. L., Ang, Y.-S., & Lim, B. (2006) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2006.11.020 · Cited by 25
“, 2006)) and neural stem cell function (Molofsky et al., 2006).”
BackgroundCellular senescence and frailty: a comprehensive insight into the causal links
Marcozzi, S., Bigossi, G., Giuliani, M. E., Giacconi, R., Piacenza, F., Cardelli, M., Brunetti, D., Segala, A., Valerio, A., Nisoli, E., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00960-w · Cited by 26
“Aged p16 KO mice display preserved cognitive function and reduced decline in subventricular zone proliferation, olfactory bulb neurogenesis, and self-renewal potential of multipotent progenitors compared to the wild-type [121].”
BackgroundRole of low-dose radiation in senescence and aging: A beneficial perspective
Xu, J., Liu, D., Zhao, D., Jiang, X. M., Meng, X., Jiang, L., Meina, Y., Zhang, L., & Jiang, H. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120644 · Cited by 30
Cheng, X., Guo, S., Liu, Y., Chu, H., Hakimi, P., Berger, N. A., Hanson, R. W., & Kao, H. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.487595 · Cited by 24
Zhang, Y., Hyle, J. W., Wright, S., Shao, Y., Zhao, X., Zhang, H., & Li, C. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1909720116 · Cited by 24
Wang, Y., Xu, Q., Sack, L. M., Kang, C., & Elledge, S. J. (2016) · Genes & Development · doi:10.1101/gad.271445.115 · Cited by 24
“reliable marker for cellular senescence and aging in vivo [59, 60], thus it is imperative to understand how p16 is regulated.”
BackgroundLi, M., Guo, H., Carey, M., & Huang, C. (2024) · Nature Aging · doi:10.1038/s43587-023-00549-0 · Cited by 29
Telomere, DNA damage, and oxidative stress in stem cell aging
Zhang, J., & Ju, Z. (2010) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.20190 · Cited by 25
Liao, J., Suen, H. C., Luk, A. C. S., Yang, L., Lee, A. W.-T., Qi, H., & Lee, T. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009369 · Cited by 28
“It has been suggested that PcG-mediated H3K27me3 alteration drives many agerelated changes and is often dysregulated in human malignancies (Greer et al. 2010; Jones and Rando 2011; Molofsky et al. 2006).”
BackgroundSun, R., Feng, J., & Wang, J. (2023) · Aging and Disease · doi:10.14336/ad.2023.0621 · Cited by 28
“With increasing age, neural stem cells (NSCs) show limited neurogenic capacity, which causes a 2-fold decrease in the number and proliferation of NSCs. Aging is also associated with increased β -galactosidase expression in NSCs [37].”
BackgroundWnt signaling and senescence: A tug of war in early neoplasia?
Adams, P. D., & Enders, G. H. (2008) · Cancer Biology & Therapy · doi:10.4161/cbt.7.11.6943 · Cited by 23
Regulation of asymmetric stem cell division: spindle orientation and the centrosome
Yukiko, M. Y. (2009) · Frontiers in bioscience · doi:10.2741/3430 · Cited by 24
Wang, X., Dong, C., Sun, L., Zhu, L., Sun, C., Ma, R., Ning, K., Lu, B., Zhang, J., & Xu, J. (2016) · Scientific Reports · doi:10.1038/srep37443 · Cited by 23
Neural stem cell heterogeneity in the mammalian forebrain
Adams, K. V., & Morshead, C. M. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.06.005 · Cited by 26
“Support for increased senescence with aging is the observation of increased gene expression of senescence regulators, particularly p16INKA4a in vivo (Molofsky et al., 2006; Nityanandam et al., 2012), and in vitro experiments using conditioned media from old and young SE culture, which reveal that…”
The molecular signature of in vitro senescence in human mesenchymal stem cells
Noh, H. B., Ahn, H.-J., Lee, W., Kwack, K., & Kwon, Y. D. (2010) · Genes & Genomics · doi:10.1007/s13258-010-0868-x · Cited by 23
“involve with age-dependent malfunction in the stem/progenitor cells of mouse brain, bone marrow and pancrease (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006 ).”
BackgroundThe Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging
Romero-García, N., Huete-Acevedo, J., Mas‐Bargues, C., Sanz‐Ros, J., Dromant, M., & Borrás, C. (2023) · Biomolecules · doi:10.3390/biom13010165 · Cited by 25
The impact of age on oncogenic potential: tumor-initiating cells and the brain microenvironment
Stoll, E. A., Horner, P. J., & Rostomily, R. (2013) · Aging Cell · doi:10.1111/acel.12104 · Cited by 23
“, 2004), suggesting that the cellular deficit is due to decreased number of stem-like cells (Molofsky et al., 2006; Ahlenius et al., 2009).”
BackgroundMaintenance of Genomic Stability in Mouse Embryonic Stem Cells: Relevance in Aging and Disease
Giachino, C., Orlando, L., & Turinetto, V. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14022617 · Cited by 23
“Neural stem cells in the subventricular zone of the mammalian brain diminish in number and function with age [27,81].”
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
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