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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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“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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BackgroundSOX2 expression diminishes with ageing in several tissues in mice and humans
Carrasco‐García, E., Moreno‐Cugnon, L., García, I., Borrás, C., Revuelta, M., Izeta, A., López‐Lluch, G., de Pancorbo, M. M., Vergara, I., Viña, J., et al. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2018.03.008 · Cited by 38
Iriyama, S., Yasuda, M., Nishikawa, S., Takai, E., Hosoi, J., & Amano, S. (2020) · Scientific Reports · doi:10.1038/s41598-020-69558-y · Cited by 40
Inhibitors of Glioma Growth that Reveal the Tumour to the Immune System
Nieto‐Sampedro, M., Valle‐Argos, B., Gómez‐Nicola, D., Fernández‐Mayoralas, A., & Nieto‐Díaz, M. (2011) · Clinical Medicine Insights Oncology · doi:10.4137/cmo.s7685 · Cited by 39
Remodeling chromatin for senescence.
Adams, P. D. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00313.x · Cited by 37
Chen, P., Lin, C., Li, N., Wu, Y., Lin, M., Hung, S., & Yen, M. (2015) · Oncotarget · doi:10.18632/oncotarget.6178 · Cited by 37
“Indeed, a few recent reports show that decline in self-renewal pathways may be one of the major mechanisms attributing to MSC senescence [35, 36]; however, the details involved regarding transcriptional silencing of pluripotency genes in senescent MSCs are poorly understood.”
TGFβ Lengthens the G1 Phase of Stem Cells in Aged Mouse Brain
Daynac, M., Pineda, J. R., Chicheportiche, A., Gauthier, L., Morizur, L., Boussin, F. D., & Mouthon, M. (2014) · Stem Cells · doi:10.1002/stem.1815 · Cited by 37
Reproductive Aging Drives Protein Accumulation in the Uterus and Limits Lifespan in C. elegans
Zimmerman, S. M., Hinkson, I. V., Elias, J. E., & Kim, S. K. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005725 · Cited by 35
Lupo, G., Nisi, P. S., Esteve, P., Paul, Y., Novo, C. L., Sidders, B. S., Khan, M. A., Biagioni, S., Liu, H., Bovolenta, P., et al. (2018) · Aging Cell · doi:10.1111/acel.12745 · Cited by 35
“…that affect intracellular molecular pathways, including the altered expression of telomerase and cell cycle regulators, which have been linked to the decline in NSPC proliferation upon aging (Caporaso, Lim, Alvarez-Buylla & Chao, 2003; Molofsky et al., 2006; Nishino, Kim, Chada & Morrison, 2008).”
A role for cellular senescence in birth timing
Cha, J. M., & Aronoff, D. M. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1371888 · Cited by 41
Dong, Q., Gao, H., Shi, Y., Zhang, F., Gu, X., Wu, A., Wang, D., Chen, Y., Bandyopadhyay, A., Yeh, I.-T., et al. (2016) · Aging · doi:10.18632/aging.101082 · Cited by 29
“The upregulation of the Cdkn2a locus in old stromal cells in this study is consistent with increased p16 expression observed in many old mammalian cells including hematopoietic and neural stem cells [52, 53], suggesting a senescence phenotype in old mammary glands [49, 54].”
The remyelination Philosopher's Stone: stem and progenitor cell therapies for multiple sclerosis
Jadasz, J. J., Aigner, L., Rivera, F. J., & Küry, P. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1331-x · Cited by 37
“The neurogenic potential and the replicative function of NSPCs are well established as being diminished with age (Couillard-Despres et al. 2006, 2009; Molofsky et al. 2006).”
BackgroundAbraham, A. B., Bronstein, R. D., Chen, E. I., Koller, A. A., Ronfani, L., Maletić‐Savatić, M., & Tsirka, S. E. (2013) · Proteome Science · doi:10.1186/1477-5956-11-18 · Cited by 36
“A contributor to the decrease in NSC cell numbers in the subventricular zone (SVZ) is the progressive increase in p16 expression [10].”
BackgroundDecottignies, A., & di Fagagna, F. D. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.09.003 · Cited by 37
Cellular senescence and neurodegeneration
Holloway, K., Neherin, K., Dam, K. U., & Zhang, H. (2023) · Human Genetics · doi:10.1007/s00439-023-02565-x · Cited by 40
Gui, H., Li, M., & Tsai, C. (2010) · Developmental Neuroscience · doi:10.1159/000321585 · Cited by 36
The Evolution of Our Understanding on Glioma
Martín-Villalba, A., Okuducu, A. F., & von Deimling, A. (2008) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00136.x · Cited by 37
“Expression of Bmi-1 is highly increased in medulloblastomas (48, 59).”
BackgroundConboy, I. M., Yousef, H., & Conboy, M. J. (2011) · Aging · doi:10.18632/aging.100333 · Cited by 33
“Likewise, genetic inactivation of the cyclindependent kinase (CDK) inhibitor, p16 was shown to rejuvenate responses of tissue dedicated stem cells in blood, brain and pancreas, while the over-expression of p16 caused premature aging of lymphocytes [22-26].”
BackgroundMechanisms underlying the effect of voluntary running on adult hippocampal neurogenesis
Gao, Y., Syed, M., & Zhao, X. (2023) · Hippocampus · doi:10.1002/hipo.23520 · Cited by 37
Lin, J.-P., Brake, A., Donadieu, M., Lee, A., Smith, G., Hu, K., Nair, G., Kawaguchi, R., Sati, P., Geschwind, D. H., et al. (2025) · Science · doi:10.1126/science.adp6325 · Cited by 35
Carrasco‐García, E., Arrizabalaga, O., Serrano, M., Lovell-Badge, R. H., & Matheu, A. (2015) · Aging Cell · doi:10.1111/acel.12343 · Cited by 34
“…specifically Ink4a only show a minimal modification in SVZ proliferation in old mice and without differences in NSC numbers or their self-renewal (Molofsky et al., 2006), the effects of the s-Ink4/Arf/p53 transgenes on NSCs might be explained mainly by the activity of the Arfp53 pathway.”
BackgroundResultInfluentialActivation of neural precursors in the adult neurogenic niches
Vukovic, J., Blackmore, D. G., Jhaveri, D. J., & Bartlett, P. F. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.04.003 · Cited by 37
“…used in the former study (i.e. B6129/F2 strain) impacted on the result, as three other commonly used mouse strains (i.e. BALB/c, CBA and DBA) exhibited 50–75% age-related decreases in total neurosphere numbers (Enwere et al., 2004; Maslov et al., 2004; Molofsky et al., 2006; Walker et al., 2008).”
ResultAt the stem of youth and health
Beltrami, A. P., Cesselli, D., & Beltrami, C. A. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.10.005 · Cited by 36
Premature expression of a muscle fibrosis axis in chronic HIV infection
Kusko, R. L., Banerjee, C., Long, K. K., Darcy, A., Otis, J. S., Sebastiani, P., Melov, S., Tarnopolsky, M. A., Bhasin, S., & Montano, M. A. (2012) · Skeletal Muscle · doi:10.1186/2044-5040-2-10 · Cited by 34
“Expression of both p21/Cip1 and p16INK4a has also been shown to be upregulated in a number of human aging studies in leukocytes, fibroblasts, neural tissue and pancreatic islet cells [18,29-39].”
BackgroundSenotherapy: growing old and staying young?
Schmitt, R. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1972-4 · Cited by 36
“Several studies, in which p16 was deleted in normally aged mice, revealed an improvement of stem cell proliferation in the bone marrow and in the brain, better regeneration of pancreatic islets and better kidney repair after acute injury [6, 24, 27, 40].”
BackgroundTelomere length maintenance in stem cell populations
Allen, N. D., & Baird, D. M. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.02.004 · Cited by 35
“Similar observations were made in neurons from the forebrain, where again p16 levels increased with age, which correlated with a decline in proliferation, this was to some extent ameliorated in p16 -/- mice [7].”
ResultRhee, Y., Kim, T., Jo, A. Y., Chang, M., Park, C., Kim, S.-M., Song, J., Oh, S., Yi, S., Kim, H. H., et al. (2016) · Brain · doi:10.1093/brain/aww203 · Cited by 35
“Specifically, increasing p16 expression in forebrain progenitors decreases neurogenesis during ageing (Molofsky et al., 2006).”
BackgroundPapaconstantinou, J., & Hsieh, C.-C. (2010) · Cell Cycle · doi:10.4161/cc.9.19.13324 · Cited by 34
Adamczak, J. M., Aswendt, M., Kreutzer, C., Rotheneichner, P., Riou, A., Selt, M., Beyrau, A., Uhlenküken, U., Diedenhofen, M., Nelles, M., et al. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.12.015 · Cited by 34
“, 2005) support the hypothesis, that it is the microenvironment of the neurogenic niche that influences the intensity of the response to stroke, rather than cell intrinsic factors (Hamilton et al., 2013; Molofsky et al., 2006; Villeda and Wyss-Coray, 2013).”
Age-dependent decline in neurogenesis of the hippocampus and extracellular nucleotides
Takei, Y. (2019) · Human Cell · doi:10.1007/s13577-019-00241-9 · Cited by 36
How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?
Hinkal, G. W., & Donehower, L. A. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.02.005 · Cited by 33
“…neuronal stem cells, and pancreatic islet cells from p16 INK4a null and p16 INK4a overexpressing mice showed that increased p16 INK4a expression was associated with reduced stem cell proliferation and function during aging (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006).”
Optimal time for passaging neurospheres based on primary neural stem cell cultures
Xiong, F., Gao, H., Yan, Z., Chen, X., Lin, W., Shen, J., Yan, Y., Wang, X., Liu, M., & Gao, Y. (2011) · Cytotechnology · doi:10.1007/s10616-011-9379-0 · Cited by 34
“…Chen W. Lin X. Wang Department of Histology and Embryology, Nantong University, Nantong, China M. Liu (&) Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China e-mail: liumei@ntu.edu.cn 1999; Prestoz et al. 2001; Goldman 2005; Ourednik et al. 2009).”
Control of the Cell Cycle in Adult Neurogenesis and its Relation with Physical Exercise
Vecchioli, S. F., & Tirone, F. (2015) · Brain Plasticity · doi:10.3233/bpl-150013 · Cited by 36
“renewal of SVZ stem cells [58] and the generation of new neurons in old mice (15–19 months; [59]).”
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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