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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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Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model
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Proliferation of hippocampal progenitors relies on p27-dependent regulation of Cdk6 kinase activity
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ANRIL Variants Are Associated with Risk of Neuropsychiatric Conditions
Namvar, A., Kahaei, M. S., Fallah, H., Nicknafs, F., Ghafouri‐Fard, S., & Taheri, M. N. (2019) · Journal of Molecular Neuroscience · doi:10.1007/s12031-019-01447-0 · Cited by 14
Vaishnav, R., Getchell, M. L., Huang, L., Hersh, M. A., Stromberg, A. J., & Getchell, T. V. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21464 · Cited by 14
“Down-regulation of neurogenesis is particularly significant, as the OE and OB are sites of adult neurogenesis, which in the OB is down-regulated with aging and in models of oxidative stress–related neurodegenerative disease (Enwere et al., 2004; Molofsky et al., 2006; Winner et al., 2007).”
BackgroundEditorial: Stem cell exhaustion in aging
Rezazadeh, S., & Ellison, G. M. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1433702 · Cited by 14
Mitochondria in cell senescence: A Friend or Foe?
Chen, Q., Young, L. H., & Barsotti, R. (2023) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2023.02.019 · Cited by 15
Unlocking the role of herbal cosmeceutical in anti-ageing and skin ageing associated diseases
Kumar, P., Verma, A. K., Ashique, S., Bhowmick, M., Mohanto, S., Singh, A., Gupta, M., Gupta, A., & Haider, T. (2024) · Cutaneous and Ocular Toxicology · doi:10.1080/15569527.2024.2380326 · Cited by 15
“Age-related β-cells ability to proliferate and secrete insulin is reduced due to up regulation of P16ink4a/p19ARF expression, declines in bmi-1 and eZH2 levels, and aberrant regulation of platelet-derived growth factor signals [57,58].”
Phage-Based Artificial Niche: The Recent Progress and Future Opportunities in Stem Cell Therapy
Shrestha, K. R., & Yoo, S. Y. (2019) · Stem Cells International · doi:10.1155/2019/4038560 · Cited by 13
Examining how p16INK4a expression levels are linked to handgrip strength in the elderly
Kao, T., Chen, W., Han, D., Huang, Y.-H., Chen, C., & Yang, W. (2016) · Scientific Reports · doi:10.1038/srep31905 · Cited by 13
Infrared Spectroscopy and Imaging in Stem Cells and Aging Research
Aksoy, C., & Severcan, F. (2018) · Methods in molecular biology · doi:10.1007/7651_2018_119 · Cited by 13
Kimata, Y., Leturcq, M., & Aradhya, R. (2020) · FEBS Letters · doi:10.1002/1873-3468.13805 · Cited by 12
Zhang, Y., Shao, C., Li, H., Wu, K., Gong, L., Zheng, Q., Dan, J., Jia, S., Tang, X., Wu, X., et al. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.597566 · Cited by 13
“Compared with wild-type mice, p16-deficient mice have a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors (Molofsky et al., 2006).”
BackgroundPeinado, P. J., & Urbach, A. (2023) · Cells · doi:10.3390/cells12162086 · Cited by 13
Soriano‐Tárraga, C., Jiménez-Conde, J., & Roquer, J. (2019) · Springer eBooks · doi:10.1007/978-3-319-55530-0_123 · Cited by 15
New insights into skin stem cell aging and cancer
Ortells, M. C., & Keyes, W. M. (2014) · Biochemical Society Transactions · doi:10.1042/bst20140045 · Cited by 12
Epigenetic perturbations in aging stem cells
Krauss, S. R., & de Haan, G. (2016) · Mammalian Genome · doi:10.1007/s00335-016-9645-8 · Cited by 14
“Similarly, aging in the nervous system leads to the loss of neuronal stem cells (NSCs) (Molofsky et al. 2006).”
BackgroundAdvances in Cancer Stem Cell Biology
Scatena, R., Giardina, B., & Mordente, A. (2011) · Springer eBooks · doi:10.1007/978-1-4614-0809-3 · Cited by 13
Longevity regulation in flies: A role for p53
Donehower, L. A. (2008) · Aging · doi:10.18632/aging.100010 · Cited by 12
“A number of laboratories have shown that increased activity of tumor suppressors such as p53 and p16 in stem cell compartments can lead to reduced stem cell self renewal, tissue reconstitution function, and early tissue atrophies [10-14].”
BackgroundAmaral, M. L., Mamde, S., Miller, M., Hou, X., Arzavala, J., Osteen, J. K., Johnson, N. D., Smoot, E. W., Yang, Q., Eisner, E. R., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117073 · Cited by 15
Fine-tuned Rest: Unveiling the Regulatory Landscape of Adult Quiescent Neural Stem Cells
Blasco-Chamarro, L., & Fariñas, I. (2023) · Neuroscience · doi:10.1016/j.neuroscience.2023.07.003 · Cited by 14
“As shown by traditional analyses, the number of proliferative cells decrease with age, suggesting a lower neurogenic rate in the elderly as a consequence of NSC loss (Maslov et al., 2004; Luo et al., 2006; Molofsky et al., 2006; Ahlenius et al., 2009).”
BackgroundConcise Review: The Epigenetic Contribution to Stem Cell Ageing: Can We Rejuvenate Our Older Cells?
Armstrong, L., Al-Aama, J. Y., Stojković, M., & Lako, M. (2014) · Stem Cells · doi:10.1002/stem.1720 · Cited by 11
Dementia and Cancer: A Review of the Literature and Current Practice
Solomons, L. C., Solomons, J., & Gosney, M. (2013) · Aging Health · doi:10.2217/ahe.13.27 · Cited by 11
Ceccarelli, M., D’Andrea, G., Micheli, L., & Tirone, F. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00211 · Cited by 11
Liu, J., Yang, L., Wang, X., Wang, S., Huang, Z., Li, C., Liu, Y., Cheng, Y., Liu, C., & Wang, Z. (2020) · Stem Cell Research & Therapy · doi:10.1186/s13287-020-01923-0 · Cited by 11
“A variety of signaling pathways, such as the MAPK, PI3K, and Notch pathways become de cient or inactive in senescent cells, including senescent adult stem cells, leading to anti-proliferation of the organ’s stem cells, which then prevents their regeneration [34-37].”
BackgroundStrategies for future histocompatible stem cell therapy
Nehlin, J. O., & Barington, T. (2009) · Biogerontology · doi:10.1007/s10522-009-9213-7 · Cited by 11
“…suppressors p16INK4a and p19ARF in young cells, whereas in old stem cells the INK4a/ARF locus and JunB are upregulated (Nishino et al. 2008), confirming earlier observations that an increase of p16INK4a expression decreases forebrain progenitors and neurogenesis during aging (Molofsky et al. 2006).”
BackgroundInfluentialCheng, W., Zhang, R., Yao, C., He, L., Jia, K., Yang, B., Du, P., Zhuang, H., Chen, J., Liu, Z., et al. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5390 · Cited by 11
“Although similar evidence for the role of p16-pRb signaling is lacking, as animal models of enhanced p16-pRb signaling remain unavailable, thew induction of p16 expression is a well-known biomarker of aging (20, 25).”
How Xenohormetic Compounds Confer Health Benefits
Morris, B. J. (2008) · Springer eBooks · doi:10.1007/978-1-4020-6869-0_8 · Cited by 11
“Interestingly, two of those suppressed were in the Ras (cancer) pathway (Fig. 6). Resveratrol also suppressed expression of the senescence marker INK4a (recently renamed CDNK2A) (Stefani et al. 2007), that is directly involved in the ageing process (Janzen et al. 2006; Krishnamurthy et al. 2006; Molofsky et al. 2006 ).”
BackgroundLiu, J., Peng, L., He, L., Yin, T., Du, Y., Yang, M., Wu, P., Li, J., Cao, J., Zhu, H., et al. (2024) · Journal of Molecular Neuroscience · doi:10.1007/s12031-024-02191-w · Cited by 11
“Studies have reported that cellular senescence adversely affects cellular functionality (Childs et al. 2015), and NSC senescence limits their proliferation and inhibits neurogenesis (Molofsky et al. 2006).”
The role of telomere binding molecules for normal and abnormal hematopoiesis
Hosokawa, K., & Arai, F. (2018) · International Journal of Hematology · doi:10.1007/s12185-018-2432-4 · Cited by 13
Yu, S., Wang, Y., Tang, B., Liu, X., Song, L., Xu, G., Zhu, H., & Sun, H. (2022) · World Journal of Surgical Oncology · doi:10.1186/s12957-022-02601-6 · Cited by 10
“While it is known that p16 expression was upregulated along with tissue aging and therefore was considered one of the most robust aging biomarkers characterized to date [27, 28].”
BackgroundImpaired Mitochondria Promote Aging-Associated Sebaceous Gland Dysfunction and Pathology
Ahmed, N. S., Foote, J. B., & Singh, K. K. (2022) · American Journal Of Pathology · doi:10.1016/j.ajpath.2022.07.006 · Cited by 10
Opportunities and Challenges in Stem Cell Aging
Larijani, B. A., Heravani, N. F., Alaei, S., Rezaei–Tavirani, M., Alavi-Moghadam, S., Payab, M., Goodarzi, P., Tayanloo-Beik, A., Aghayan, H. R., & Arjmand, B. (2021) · Advances in experimental medicine and biology · doi:10.1007/5584_2021_624 · Cited by 10
The Dual Role of Senescence in Tumorigenesis
Chuaire, L., Sánchez, M. C., & Ramírez-Clavijo, S. R. (2010) · International Journal of Morphology · doi:10.4067/s0717-95022010000100006 · Cited by 10
“…capacity and to the aging of tissues such as the bone marrow, brain and pancreatic islets (Janzen et al., 2006; Krishnamurty et al., 2006; Molofsky et al., 2006). acetylation (Roninson, 2003). p53 and p21 expression in senescent cells is transitory, for it decreases once cellular…”
BackgroundThe Cancer–Aging Interface and the Significance of Telomere Dynamics in Cancer Therapy
Tallen, G. R. N., Soliman, M. A., & Riabowol, K. T. (2007) · Rejuvenation Research · doi:10.1089/rej.2007.0598 · Cited by 10
Polzer, O., Kinloch, E., & Fitzsimons, C. P. (2025) · Aging Brain · doi:10.1016/j.nbas.2025.100141 · Cited by 10
“However, in general, senescent cells only make up a small proportion of a tissue [3,4,39,62,90].”
InfluentialZhu, Y., Fang, X., Zhang, S., Liao, Y., Lin, H., Chen, P., Yang, M., Huang, J. J., & Wang, X. (2026) · International Journal of Nanomedicine · doi:10.2147/ijn.s589123 · Cited by 14
“97 Research involving aged mice indicates that hematopoietic stem cells (HSCs) exhibit a general reduction in cell cycle activity, resulting in fewer cell divisions compared to their younger counterparts.”
Cell ageing: a flourishing field for neurodegenerative diseases
Brites, D. M. T. O. (2015) · AIMS molecular science · doi:10.3934/molsci.2015.3.225 · Cited by 10
“Interestingly, the increase in p16 expression is associated with a reduced cell progenitor function and neurogenesis, thus contributing to reduced regenerative capacity in mammalian ageing [40].”
BackgroundDisease‐associated polymorphisms in 9p21 are not associated with extreme longevity
Congrains, A., Kamide, K., Hirose, N., Arai, Y., Oguro, R., Nakama, C., Imaizumi, Y., Kawai, T., Kusunoki, H., Yamamoto, H., et al. (2014) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.12346 · Cited by 9
Prindull, G. (2008) · Experimental Hematology · doi:10.1016/j.exphem.2008.07.009 · Cited by 9
Briones, B. A., & Gould, E. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813146-6.00007-2 · Cited by 9
Harn, H.-J., Huang, M.-H., Huang, C.-T., Lin, P., Yen, S.-Y., Chou, Y.-W., Ho, T., Chu, H.-Y., Chiou, T., & Lin, S. (2013) · Cell Transplantation · doi:10.3727/096368912x661436 · Cited by 9
“Numerous studies have suggested that adult stem cell populations decline with age (1,4,8,17,23,27,31).”
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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