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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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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
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Aβ1–42 stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor
Sotthibundhu, A., Li, Q.-X., Thangnipon, W., & Coulson, E. J. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.02.004 · Cited by 81
Cigarette Smoke Induces Cellular Senescence via Werner's Syndrome Protein Down-regulation
Nyunoya, T., Monick, M. M., Klingelhutz, A. L., Glaser, H., Cagley, J. R., Brown, C. O., Matsumoto, E., Aykin-Burns, N., Spitz, D. R., Oshima, J., et al. (2009) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200802-320oc · Cited by 79
“Although the causative role of senescence in emphysema pathogenesis is not clear, growing evidence suggests that accumulation of senescent cells may contribute to age-related pathology and tissue dysfunction in bone marrow (46), brain (47), and pancreas (48).”
BackgroundHypothalamic inflammation in metabolic disorders and aging
Bhusal, A., Rahman, M. H., & Suk, K. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04019-x · Cited by 87
Pushkar, Y., Robison, G., Sullivan, B., Fu, S. X., Kohne, M., Jiang, W., Rohr, S. O., Lai, B. C. H., Marcus, M. A., Zakharova, T., et al. (2013) · Aging Cell · doi:10.1111/acel.12112 · Cited by 79
“However, it is well known that adult neurogenesis decreases with age, which is manifested in the decrease in the self-renewal capacity and the number of SVZ progenitors (Maslov et al., 2004; Molofsky et al., 2006).”
BackgroundATR maintains select progenitors during nervous system development
Lee, Y., Shull, E. R. P., Frappart, P., Katyal, S., Enriquez-Rios, V. D., Zhao, J., Russell, H. R., Brown, E. J., & McKinnon, P. J. (2012) · The EMBO Journal · doi:10.1038/emboj.2011.493 · Cited by 78
“The Ink4A/Arf locus can be important for the maintenance of neural stem/progenitor cells and can influence their proliferation (Molofsky et al , 2006).”
Regeneration, Stem Cells, and the Evolution of Tumor SuppressionPreprint
Pearson, B. J., & Alvarado, A. S. (2008) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2008.73.045 · Cited by 79
Pearce, D. J., Anjos‐Afonso, F., Ridler, C. M., Eddaoudi, A., & Bonnet, D. A. (2006) · Stem Cells · doi:10.1634/stemcells.2006-0405 · Cited by 77
Mimeault, M., & Batra, S. K. (2008) · Ageing Research Reviews · doi:10.1016/j.arr.2008.12.001 · Cited by 77
Reece, A. S. (2007) · Immunity & Ageing · doi:10.1186/1742-4933-4-6 · Cited by 81
“Addictive drugs are known to impair cell growth and division [5-7] and therefore might be presumed to impact particularly dividing cells such as stem and progenitor cell pools [8,9].”
BackgroundAblation of the p16INK4a tumour suppressor reverses ageing phenotypes of klotho mice
Sato, S., Kawamata, Y., Takahashi, A., Imai, Y., Hanyu, A., Okuma, A., Takasugi, M., Yamakoshi, K., Sorimachi, H., Kanda, H., et al. (2015) · Nature Communications · doi:10.1038/ncomms8035 · Cited by 77
Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging
Zhu, Y., Demidov, O. N., Goh, A. M., Virshup, D. M., Lane, D. P., & Bulavin, D. V. (2014) · Journal of Clinical Investigation · doi:10.1172/jci73015 · Cited by 73
“A similar effect is achieved through an aging-induced activation of p16Ink4a (1).”
InfluentialBiology of Tendon Stem Cells and Tendon in Aging
Lui, P. P. Y., & Wong, C. M. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2019.01338 · Cited by 77
“…in the expression of p16INK4a with aging was linked to the impairment of the number and/or function of adult stem cells (Janzen et al., 2006; Molofsky et al., 2006; SousaVictor et al., 2014) while abolishing p16INK4a function enhanced the regenerative potential of stem cells (Shibata et…”
BackgroundExpansion of Luminal Progenitor Cells in the Aging Mouse and Human Prostate
Crowell, P. D., Fox, J. J., Hashimoto, T., Diaz, J. A., Navarro, H. I., Henry, G. H., Feldmar, B., Lowe, M. G., Garcia, A. J., Wu, Y. E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.007 · Cited by 78
“, 1975), consistent with a decline in progenitor activity in many of these tissues (Conboy et al., 2003; Molofsky et al., 2006).”
BackgroundNagao, M., Campbell, K., Burns, K. A., Kuan, C.-Y., Trumpp, A., & Nakafuku, M. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200807130 · Cited by 75
“For instance, p16 INK4a and the polycomb group gene product Bmi-1 have been shown to be involved in the maintenance of NSCs in the adult brain ( Bruggeman et al., 2005 ; Molofsky et al., 2005 , 2006 ).”
Neurogenesis in the aged and neurodegenerative brain
Shruster, A., Melamed, E., & Offen, D. (2010) · APOPTOSIS · doi:10.1007/s10495-010-0491-y · Cited by 77
“In the SVZ, findings differ: whereas in mice there was a decrease in proliferation of NPCs with aging [30, 32], in rats there was no change in proliferation of NPCs between the age of 6–21 months [33].”
Hedgehog signaling maintains hair follicle stem cell phenotype in young and aged human skin
Rittié, L., Stoll, S. W., Kang, S., Voorhees, J. J., & Fisher, G. J. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00526.x · Cited by 76
“For instance, the product of the p16INK4a gene is transcriptionally upregulated in forebrain, pancreas, and hematopoietic SCs of older mice (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006), resulting in decline of SC proliferation capacities in these organs.”
BackgroundTherapeutic targeting of replicative immortality
Yaswen, P., MacKenzie, K. L., Keith, W. N., Hentosh, P., Rodier, F., Zhu, J., Firestone, G. L., Matheu, A., Carnero, A., Bilsland, A. E., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.03.007 · Cited by 82
“[148] Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, et al.”
BackgroundAging Neural Progenitor Cells Have Decreased Mitochondrial Content and Lower Oxidative Metabolism
Stoll, E. A., Cheung, W., Mikheev, A. M., Sweet, I. R., Bielas, J. H., Zhang, J., Rostomily, R., & Horner, P. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.252171 · Cited by 75
Xia, M., Zhao, X., Huang, Q., Sun, H., Sun, C., Yuan, J., He, C., Sun, Y., Huang, X., Kong, W., et al. (2017) · FEBS Open Bio · doi:10.1002/2211-5463.12220 · Cited by 75
Cellular senescence: a hitchhiker’s guide
Aravinthan, A. D. (2015) · Human Cell · doi:10.1007/s13577-015-0110-x · Cited by 83
“the regenerative capacity of tissue [168, 169].”
Chapouton, P., Webb, K. J., Stigloher, C., Alunni, A., Adolf, B., Hesl, B., Topp, S., Kremmer, E., & Bally‐Cuif, L. (2011) · The Journal of Comparative Neurology · doi:10.1002/cne.22599 · Cited by 73
“In addition, their expression of cell cycle inhibitors increases with age (Molofsky et al., 2006), and their molecular requirements for self-renewal also change (Molofsky et al., 2005).”
BackgroundReplicative stress, stem cells and aging
Ruzankina, Y., Asare, A., & Brown, E. J. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.03.009 · Cited by 73
“However, in other tissues, stem and progenitor cells were not protected from age-related decline in p16 INK4A knockout mice, indicating that the reduced proliferative potential of some cell types with age does not rely on p16 INK4A (Molofsky et al., 2006) and that other rate-limiting factors may be involved.”
InfluentialMitochondrial fatty acid oxidation drives senescence
Yamauchi, S., Sugiura, Y., Yamaguchi, J., Zhou, X., Takenaka, S., Odawara, T., Fukaya, S., Fujisawa, T., Naguro, I., Uchiyama, Y., et al. (2024) · Science Advances · doi:10.1126/sciadv.ado5887 · Cited by 74
Cdk2: a key regulator of the senescence control function of Myc
Hydbring, P., & Larsson, L. (2010) · Aging · doi:10.18632/aging.100140 · Cited by 71
“This has been confirmed by deletion or overexpression of p16 in hematopoietic stem cells, forebrain neuronal progenitors and pancreatic β-cells [43,46,47,48].”
BackgroundTumorigenesis in the Brain: Location, Location, Location
Gilbertson, R. J., & Gutmann, D. H. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0760 · Cited by 71
“The CSC hypothesis is predicated on the idea that not all cancer cells have equal proliferative potential, and that cells with the greatest ability to proliferate and form new tumors have phenotypic and functional properties similar to NSCs.”
BackgroundInfluentialAge-related cognitive decline: Can neural stem cells help us?
Artegiani, B., & Calegari, F. (2012) · Aging · doi:10.18632/aging.100446 · Cited by 70
“In fact, expression of the inhibitors of G1 progression p16 and p19, that were previously linked to cellular senescence [130], were found to increase in the subventricular zone of old animals [131, 132] and deletion of p16 was shown to promote NSC proliferation and neurogenesis in the aged subventricular zone but, app…”
BackgroundIntegrating Physiological Regulation with Stem Cell and Tissue Homeostasis
Nakada, D., Levi, B. P., & Morrison, S. J. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.011 · Cited by 78
Self-citationEffects of dietary restriction on hematopoietic stem-cell aging are genetically regulated
Ertl, R. P., Chen, J., Astle, C. M., Duffy, T. M., & Harrison, D. E. (2007) · Blood · doi:10.1182/blood-2007-01-069807 · Cited by 72
The Role of p16INK4a Pathway in Human Epidermal Stem Cell Self-Renewal, Aging and Cancer
D’Arcangelo, D., Tinaburri, L., & Dellambra, E. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18071591 · Cited by 77
Gopinathan, G., & Khosla, S. (2012) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-4525-4_26 · Cited by 71
DDB1-CUL4 and MLL1 Mediate Oncogene-Induced p16INK4a Activation
Kotake, Y., Zeng, Y., & Xiong, Y. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2739 · Cited by 69
Rescue of key features of the p63‐null epithelial phenotype by inactivation of Ink4a and Arf
Su, X., Cho, M. S., Gi, Y. J., Ayanga, B. A., Sherr, C. J., & Flores, E. R. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.151 · Cited by 71
“…of the Ink4–Arf gene cluster is unknown, although it is now well appreciated that p16Ink4a and p19Arf upregulation can induce age-depen- dent declines in the regenerative potential of various tissues (Janzen et al, 2006; Krishnamurthy et al, 2006; Molofsky et al, 2006; Signer et al, 2008).”
BackgroundThe Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging
Farr, J. N., & Almeida, M. (2018) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3564 · Cited by 70
“Stem cell dysfunction has also been described in the brain,((190,191)) reproductive organs,((192,193)) and muscle.”
BackgroundCRISPR–Cas9 screens reveal regulators of ageing in neural stem cells
Ruetz, T. J., Pogson, A. N., Kashiwagi, C. M., Gagnon, S. D., Morton, B., Sun, E., Na, J., Yeo, R. W., Leeman, D. S., Morgens, D. W., et al. (2024) · Nature · doi:10.1038/s41586-024-07972-2 · Cited by 75
A stress-induced cellular aging model with postnatal neural stem cells
Cm, D., Xl, W., Gm, W., Wj, Z., Zhu, L., Gao, S., Dj, Y., Qin, Y., Qj, L., Yl, C., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.82 · Cited by 73
“The expression of p16 increases in aged mouse and human tissues(34) and the increased expression of p16, p21 and p53 all led to decreased NSC proliferation and neurogenesis.(20) In response to”
BackgroundThe systemic environment: at the interface of aging and adult neurogenesis
Smith, L. K., White, C., & Villeda, S. (2017) · Cell and Tissue Research · doi:10.1007/s00441-017-2715-8 · Cited by 70
“Furthermore, an age-dependent increase in p16, an intrinsic factor commonly associated with senescence, within the progenitor population has also been shown to specifically impair neurogenesis within the SVZ (Molofsky et al. 2006).”
BackgroundGeroconversion of aged muscle stem cells under regenerative pressure
Sousa-Victor, P., Perdiguero, E., & Muñoz-Cánoves, P. (2014) · Cell Cycle · doi:10.4161/15384101.2014.965072 · Cited by 68
“Furthermore, comparison with a comprehensive list of genes implicated in cellular senescence(57-59) showed specific up-regulation of several genes, including the master regulator of senescence Cdkn2a (p16).(15,17,49,60,61)”
BackgroundCellular senescence in lymphoid organs and immunosenescence
Budamagunta, V., Foster, T. C., & Zhou, D. (2021) · Aging · doi:10.18632/aging.203405 · Cited by 73
Defining the toxicology of aging
Sorrentino, J. A., Sanoff, H. K., & Sharpless, N. E. (2014) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2014.04.004 · Cited by 69
“Murine genetic studies have indicated that expression of p16 INK4a plays a causal role in the age-associated decline of replicative function in several tissues including neural stem cells [35], hematopoietic progenitors [36], lymphocytes [32, 37], muscle stem cells [38] and pancreatic β -cells [39].”
BackgroundSelf-citationMarusyk, A., & DeGregori, J. V. (2007) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2007.09.001 · Cited by 73
“As INK4A gene expression increases in aged tissues, and disruption of INK4A in mice results in some restoration of the regenerative capacity for particular tissues [80–82], inhibition of INK4A may be selected for in aged tissues.”
BackgroundKiss, T., Nyúl-Tóth, Á., DelFavero, J., Balasubramanian, P., Tarantini, S., Faakye, J., Gulej, R., Ahire, C., Ungvari, A., Yabluchanskiy, A., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00521-7 · Cited by 66
“Accordingly, age-related increases in cerebral expression of biomarkers of cellular senescence has been demonstrated both in laboratory mice [22, 39, 40, 43, 44] and humans [37, 45, 46].”
BackgroundMacleod, K. F. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2504 · Cited by 68
“, not only in the haematopoietic system but also in the pancreas and in neural stem cell”
Fgfs control homeostatic regeneration in adult zebrafish fins
Wills, A. A., Kidd, A. R., Lepilina, A., & Poss, K. D. (2008) · Development · doi:10.1242/dev.024588 · Cited by 68
“…facultative regenerative capacity in mammalian organs tends to decrease with age, a phenomenon observed in concert with age-dependent reductions in the frequency of homeostatic structural cell or progenitor cell proliferation (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006).”
From the Rarest to the Most Common: Insights from Progeroid Syndromes into Skin Cancer and Aging
Capell, B. C., Tlougan, B. E., & Orlow, S. J. (2009) · Journal of Investigative Dermatology · doi:10.1038/jid.2009.103 · Cited by 66
“, 2006), leading to impaired regeneration of pancreatic islets, neuronal progenitors, and the hematopoietic system (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006; Nishino et al., 2008).”
BackgroundWnt Signaling and Aging-Related Heart Disorders
Naito, A. T., Shiojima, I., & Komuro, I. (2010) · Circulation Research · doi:10.1161/circresaha.110.223776 · Cited by 64
Epigenetic Basis of Cellular Senescence and Its Implications in Aging
Nacarelli, T., Liu, P., & Zhang, R. (2017) · Genes · doi:10.3390/genes8120343 · Cited by 66
Aging and neurogenesis in the adult forebrain: what we have learned and where we should go from here
Hamilton, L. K., Joppé, S. E., Cochard, L. M., & Fernandes, K. J. L. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12207 · Cited by 74
“…McGinn et al., 2012; Shook et al., 2012), 8/20 made Young adult to Middle-age comparisons (Kippin et al., 2005; Chen et al., 2006; Luo et al., 2006; Molofsky et al., 2006; Tanaka et al., 2007; Medrano et al., 2009; Bouab et al., 2011; Shook et al., 2012), and 3/20 compared © 2013 Federation of…”
BackgroundInfluentialMas‐Bargues, C., Viña‐Almunia, J., Inglés, M., Sanz‐Ros, J., Gambini, J., Ibáñez-Cabellos, J. S., García‐Giménez, J. L., Viña, J., & Borrás, C. (2017) · Redox Biology · doi:10.1016/j.redox.2017.04.002 · Cited by 63
“Self-renewal of stem cells is critical for their persistence through life, however the capacity to maintain this characteristic declines with age [16,17].”
BackgroundKawada, K., Iekumo, T., Saito, R., Kaneko, M., Mimori, S., Nomura, Y., & Okuma, Y. (2014) · Journal of Neuroscience Research · doi:10.1002/jnr.23389 · Cited by 62
“Neurogenesis declines with age (Molofsky et al., 2006; Pekcec et al., 2008; Knoth et al., 2010) and is impaired by various types of stressors, such as stress hormones (Mirescu and Gould, 2006), and inflammation in regions of the brain (Monje et al.”
BackgroundSmurf2‐mediated ubiquitination and degradation of Id1 regulates p16 expression during senescence
Kong, Y., Cui, H., & Zhang, H. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00746.x · Cited by 62
“Stem cells derived from old mice lacking p16 have enhanced regenerative capacity (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006), whereas the opposite is true in mice with increased p16 expression (Krishnamurthy et al.”
BackgroundFatt, M. P., Tran, L. M., Vetere, G., Storer, M. A., Simonetta, J. V., Miller, F. D., Frankland, P. W., & Kaplan, D. R. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.12.010 · Cited by 58
“Indeed, increased expression of P16, a cell-cycle regulator associated with senescence, causes decreased stem cell-mediated neurogenesis in aging mice (Micheli et al., 2019; Molofsky et al., 2006).”
BackgroundRando, T. A., Brunet, A., & Goodell, M. A. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.06.004 · Cited by 68
“47 It should be noted that different tissues use different mechanisms to maintain or renew their quiescent stem cell populations, and the impact of aging on these processes has not been well studied.”
Rapamycin increases oxidative stress response gene expression in adult stem cells
Kofman, A. E., McGraw, M. R., & Payne, C. J. (2012) · Aging · doi:10.18632/aging.100451 · Cited by 62
“cular zone of lateral ventricles in the aging mouse brain due to genomic instability and upregulated cyclindependent kinase inhibitor 2a (Cdkn2a; p16), which activates DNA-damage response pathways that induce apoptosis or senescence [5, 6].”
BackgroundVeeraraghavalu, K., Choi, S. H., Zhang, X., & Sisodia, S. S. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0527-10.2010 · Cited by 60
“The number of neurospheres obtained was divided by total number of viable cells seeded, and this ratio is represented as the percentage of multipotent neurospheres from each animal, as previously described (Molofsky et al., 2006).”
BackgroundMethodInfluentialCellular senescence: unravelling complexity
Passos, J. F., Simillion, C., Hallinan, J. S., Wipat, A., & von Zglinicki, T. (2009) · AGE · doi:10.1007/s11357-009-9108-1 · Cited by 61
“…et al. 2002), while a p21 knock-out rescued at least some accelerated aging phenotypes in telomerase (mTERC) knock-out mice (Choudhury et al. 2007), and p16 knockout rescued various mice stem cell systems from agerelated decline (Janzen et al. 2006; Krishnamurthy et al. 2006; Molofsky et al. 2006).”
BackgroundHwang, I., Uchida, H., Dai, Z., Li, F., Sanchez, T., Locasale, J. W., Cantley, L. C., Zheng, H., & Paik, J. (2021) · Nature Communications · doi:10.1038/s41467-020-20839-0 · Cited by 61
Cellular Mechanisms of Somatic Stem Cell Aging
Jung, Y., & Brack, A. S. (2014) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-416022-4.00014-7 · Cited by 63
“Expression of p16Ink4a increases with age in neural progenitors (Molofsky et al., 2006).”
BackgroundInfluentialRomán-Trufero, M., Méndez‐Gómez, H. R., Pérez‐Martínez, C., Hijikata, A., Fujimura, Y., Endo, T. A., Koseki, H., Vicario‐Abejón, C., & Vidal, M. (2009) · Stem Cells · doi:10.1002/stem.82 · Cited by 65
“These defects are thought to result from premature senescence induced by the accumulation of products of theInk4alocus, which is normally repressed by Bmi1 [23‐25], that are responsible for decreased neurogenesis during ageing [ 49 ].”
BackgroundRoles of Apoptosis and Cellular Senescence in Cancer and Aging
Cerella, C., Grandjenette, C., Dicato, M. A., & Diederich, M. F. (2016) · Current Drug Targets · doi:10.2174/1389450116666150202155915 · Cited by 64
Carbonneau, C. L., Despars, G., Rojas-Sutterlin, S., Fortin, A., Le, O., Hoang, T., & Beauséjour, C. M. (2012) · Blood · doi:10.1182/blood-2011-06-361626 · Cited by 59
Hu, G., Xia, Y., Zhang, J., Chen, Y., Ji, Y., Niu, X., Zhao, B., Li, Q., Wang, Y., & Deng, Z. (2020) · Advanced Science · doi:10.1002/advs.201903330 · Cited by 60
Regulating the Notch pathway in embryonic, adult and old stem cells
Carlson, M. E., & Conboy, I. M. (2007) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2007.02.004 · Cited by 59
Loss of Slug Compromises DNA Damage Repair and Accelerates Stem Cell Aging in Mammary Epithelium
Gross, K. M., Zhou, W., Breindel, J. L., Ouyang, J., Jin, D. X., Sokol, E. S., Gupta, P. B., Huber, K., Zou, L., & Kuperwasser, C. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.043 · Cited by 58
Stem cells of the adult mammalian brain and their niche
Başak, O., & Taylor, V. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8544-x · Cited by 57
Cellular signaling in normal and cancerous stem cells
Grinstein, E., & Wernet, P. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.06.021 · Cited by 58
Kua, H. Y., Liu, H., Leong, W. F., Li, L., Jia, D., Ma, G., Hu, Y., Wang, X., Chau, J. F. L., Chen, Y., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2528 · Cited by 57
The circulatory systemic environment as a modulator of neurogenesis and brain aging
Villeda, S., & Wyss‐Coray, T. (2012) · Autoimmunity Reviews · doi:10.1016/j.autrev.2012.10.014 · Cited by 57
“Intracellular studies in the aging brain have demonstrated that the decline in SVZ progenitor function and olfactory bulb neurogenesis is partially mediated by an age-dependent increase in expression of p16, a cycline-dependent kinase inhibitor linked to cellular senescence mechanisms [22].”
BackgroundAge-Specific Functional Epigenetic Changes in p21 and p16 in Injury-Activated Satellite Cells
Li, J., Han, S., Cousin, W., & Conboy, I. M. (2014) · Stem Cells · doi:10.1002/stem.1908 · Cited by 56
The zebrafish as a gerontology model in nervous system aging, disease, and repair
houcke, J. V., Groef, L. D., Dekeyster, E., & Moons, L. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.10.004 · Cited by 59
Liver regeneration in aged mice: new insights
Pibiri, M. (2018) · Aging · doi:10.18632/aging.101524 · Cited by 57
“com 1811 AGING functional and regenerative tissue capacity which prevents proliferation of somatic and stem cells in a cell intrinsic-manner [216-222].”
BackgroundInfluentialUsing Mice to Examine p53 Functions in Cancer, Aging, and LongevityPreprint
Donehower, L. A. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001081 · Cited by 59
“Recent studies showing increases of the senescence effector p16INK4A protein levels and activity correlating with reduced function in aged stem and progenitor cells support this idea (Janzen et al. 2006; Krishnamurthy et al. 2006; Molofsky et al. 2006).”
BackgroundRegulation of Senescence in Cancer and Aging
Kong, Y., Cui, H., Ramkumar, C., & Zhang, H. (2011) · Journal of Aging Research · doi:10.4061/2011/963172 · Cited by 61
Kim, S. W., Woo, H.-J., Kim, E. H., Kim, H. S., Suh, H. N., Kim, S.-H., Song, J. J., Wulansari, N., Kang, M., Choi, S., et al. (2021) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2021.102086 · Cited by 56
Walters, B. J., & Zuo, J. (2012) · Hearing Research · doi:10.1016/j.heares.2012.11.009 · Cited by 52
“…postnatal regenerative ability, age-induced senescence is related to the upregulation of yet another CDKN, the tumor supressor p16INK4a (a.k.a. CDKN2a) (Dhawan et al., 2009; Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006; Rodriguez-Menocal et al., 2009; Wang et al., 2012b).”
BackgroundPIM ‐1 modulates cellular senescence and links IL ‐6 signaling to heterochromatin formation
Jin, B., Wang, Y., Wu, C., Liu, K. Y., Chen, H., & Mao, Z. B. (2014) · Aging Cell · doi:10.1111/acel.12249 · Cited by 56
“Also, by depleting renewable stem cell populations, senescence is thought to contribute to tissue aging of many multicellular adult animals (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006).”
BackgroundNeural Stem Cell Plasticity: Advantages in Therapy for the Injured Central Nervous System
Ottoboni, L., Merlini, A., & Martino, G. (2017) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00052 · Cited by 56
“Upon sensing DNA damage, SVZ cells upregulate the inhibitor of cyclin kinase to post-pone cell cycle entry and reduce proliferation of NSCs (Molofsky et al., 2006).”
BackgroundLi, H., Chen, Q., Li, C., Zhong, R., Zhao, Y., Zhang, Q., Tong, W., Zhu, D., & Zhang, Y. (2019) · The EMBO Journal · doi:10.15252/embj.2019102154 · Cited by 54
“…hallmarks in mammalian aging (Rando, 2006), and decline in the number and function of adult stem cells is the major causes that contribute to the failure of regeneration in several adult tissues during aging (Conboy et al , 2003; Nishimura et al , 2005; Rossi et al , 2005; Molofsky et al , 2006).”
DeCarolis, N. A., Kirby, E. D., Wyss‐Coray, T., & Palmer, T. D. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025874 · Cited by 55
Kia, S. K., Kartalaei, P. S., Farahbakhshian, E., Pourfarzad, F., Lindern, M. V., & Verrijzer, C. P. (2009) · Epigenetics & Chromatin · doi:10.1186/1756-8935-2-16 · Cited by 56
Gilley, J. A., Yang, C., & Kernie, S. G. (2009) · Hippocampus · doi:10.1002/hipo.20719 · Cited by 54
“Many studies describe characteristics of ‘‘adult’’ stem cells within the dentate gyrus, however, the age at which ‘‘adult’’ is achieved is variable and has been reported to be anywhere from four to 12 weeks postnatal (Kuhn et al., 1996; Tropepe et al., 1997; Wagner et al., 1999; Lemaire et al., 2000; Bailey et al., 20…”
BackgroundHuang, C. Y., Fu, X., Zhou, D., & Li, J. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1614-1 · Cited by 57
Yang, D., Liu, L., & Zheng, X. (2008) · Ageing Research Reviews · doi:10.1016/j.arr.2008.02.001 · Cited by 55
Mechanisms of enhanced quiescence in neural stem cell aging
Audesse, A. J., & Webb, A. E. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111323 · Cited by 54
“p16/Cdkn2a is detectable in vivo in the mouse SVZ niche between 12–18 months of age (Molofsky et al., 2006).”
BackgroundThe generation of oligodendroglial cells is preserved in the rostral migratory stream during aging
Capilla‐González, V., Cebrián‐Silla, A., Guerrero‐Cazares, H., García‐Verdugo, J. M., & Quiñones‐Hinojosa, A. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00147 · Cited by 53
Relationships between stem cell exhaustion, tumour suppression and ageing
Ruzankina, Y., & Brown, E. J. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6604029 · Cited by 53
“Importantly, age-related attrition was not rescued in all stem and progenitor cell types in which p16INK4A was deleted, indicating that reduced proliferative potential of some cell types with age does not rely on p16INK4A (Molofsky et al, 2006) and that other rate-limiting factors may be involved.”
BackgroundString (Cdc25) regulates stem cell maintenance, proliferation and aging in Drosophila testis
Inaba, M., Yuan, H., & Yamashita, Y. M. (2011) · Development · doi:10.1242/dev.072579 · Cited by 50
“For example, it is known that the Ink4a (Cdkn2a) tumor suppressor, which encodes a cyclin-dependent kinase (cdk) inhibitor, accumulates with age in many tissues and its removal can rescue the age-associated decline in stem cell/progenitor number and function (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky e…”
BackgroundBayoğlu, B., Yüksel, H., Çakmak, H. A., Dırıcan, A., & Cengiz, M. (2016) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2016.02.012 · Cited by 54
Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain
Santoro, A., Spinelli, C. C., Martucciello, S., Nori, S. L., Capunzo, M., Puca, A. A., & Ciaglia, E. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mr0118-003r · Cited by 50
Accelerating neuronal aging in in vitro model brain disorders: a focus on reactive oxygen species
Campos, P. B., Paulsen, B. S., & Rehen, S. K. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00292 · Cited by 55
“The aging process in the brain is usually accompanied by an increase in the expression of p16INK4a and a decrease in levels of FGF-2, VEGF, and IGF-1 (Shetty et al., 2005; Molofsky et al., 2006).”
BackgroundIn vivo modulation of HMGA2 expression
Ashar, H. R., Chouinard, R. A., Dokur, M., & Chada, K. K. (2010) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2009.11.013 · Cited by 53
“Most notably, selfrenewal capacity declines with age: fetal and young adult stem cells have more self-renewal potential than old adult stem cells [26,27,29].”
BackgroundMicroRNAs as Regulators of Neural Stem Cell-Related Pathways in Glioblastoma Multiforme
González‐Gómez, P., Sánchez, P., & Mira, H. (2011) · Molecular Neurobiology · doi:10.1007/s12035-011-8196-y · Cited by 52
“Interestingly, p16 is also linked to senescence, and deletion of p16 can partially oppose the age-related decline in the number and self-renewal potential of neural progenitors [31].”
BackgroundIncreased Arf/p53 activity in stem cells, aging and cancer
Carrasco‐García, E., Moreno, M., Moreno‐Cugnon, L., & Matheu, A. (2017) · Aging Cell · doi:10.1111/acel.12574 · Cited by 52
“Thus, the effects of a transgenic allele with constitutive and systemic overexpression of p16 are minimal in the pancreatic islets and in the brain (Krishnamurthy et al., 2006; Molofsky et al., 2006), while a luciferase knockin mouse model (p16), which faithfully reports the expression of p16, revealed an exponential”
BackgroundInfluentialNeural Stem Cell Regulation by Adhesion Molecules Within the Subependymal Niche
Morante‐Redolat, J. M., & Porlan, E. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00102 · Cited by 50
“Failure to restrict mitotic activation of NSC leads to premature depletion of the niche (Doetsch et al., 2002; Molofsky et al., 2003, 2005, 2006; Kippin et al., 2005; Marques-Torrejon et al., 2013; Porlan et al., 2013), and in the aged brain, NSC quiescence increases in what has been interpreted as…”
BackgroundAgeing stem and progenitor cells: implications for rejuvenation of the central nervous system
van Wijngaarden, P., & Franklin, R. J. M. (2013) · Development · doi:10.1242/dev.092262 · Cited by 53
“They receive functional afferent connections, spike in response to excitatory inputs and release glutamate onto their post-synaptic neurons (Song et al., 2002; Mongiat et al., 2009; Schmidt-Hieber et al., 2004; Faulkner et al., 2008; Toni et al., 2008).”
BackgroundMoyse, E., Segura, S., Liard, O., Mahaut, S., & Mechawar, N. (2008) · Current Stem Cell Research & Therapy · doi:10.2174/157488808785740334 · Cited by 53
“Agerelated decreases in neural stem cell proliferation have been correlated with increased expression of the CDK-inhibitor p16INK4a [36].”
BackgroundStem Cells Use Distinct Self-renewal Programs at Different AgesPreprint
Levi, B. P., & Morrison, S. J. (2008) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2008.73.049 · Cited by 54
“Deletion of Bmi-1, Hmga2, or p16Ink4a leads to self-renewal phenotypes in multipotent stem cells without affecting the proliferation of many restricted progenitors (Molofsky et al. 2003, 2006; Nishino et al. 2008).”
BackgroundInfluentialSelf-citationDiversity of Neural Precursors in the Adult Mammalian BrainPreprint
Bonaguidi, M. A., Stadel, R. P., Berg, D. A., Sun, J., Ming, G., & Song, H. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018838 · Cited by 51
Bast, L., Calzolari, F., Strasser, M. K., Hasenauer, J., Theis, F. J., Ninkovic, J., & Marr, C. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.088 · Cited by 50
“, 2006) and overall new OB neuron production (Bouab et al., 2011; Molofsky et al., 2006), thus providing a relevant system.”
BackgroundNalapareddy, K., Jiang, H., Gutierrez, L. M. G., & Rudolph, K. L. (2008) · Experimental Gerontology · doi:10.1016/j.exger.2008.09.002 · Cited by 50
“There is evidence that up-regulation of p16 can limit the regenerative capacity of stem cells in aging mice (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006).”
BackgroundThe senescence-associated secretory phenotype: Fueling a wound that never heals
Pulido, T., Velarde, M. C., & Alimirah, F. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111561 · Cited by 54
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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