{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:58:39Z","timestamp":1788422319999,"version":"build-2803163510"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T00:00:00Z","timestamp":1633564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Human colonic neuromuscular functions decline among the elderly. The aim was to explore the involvement of senescence. A preliminary PCR study looked for age-dependent differences in expression of <jats:italic>CDKN1A<\/jats:italic> (encoding the senescence-related p21 protein) and <jats:italic>CDKN2A<\/jats:italic> (encoding p16 and p14) in human ascending and descending colon (without mucosa) from 39 (approximately 50: 50 male: female) adult (aged 27\u201360 years) and elderly donors (70\u201389 years). Other genes from different aging pathways (e.g., inflammation, oxidative stress, autophagy) and cell-types (e.g., neurons, neuron axonal transport) were also examined. Unlike <jats:italic>CDKN1A, CDKN2A<\/jats:italic> (using primers for p16 and p14 but not when using p14-specific primers) was upregulated in both regions of colon. Compared with the number of genes appearing to upregulate in association with temporal age, more genes positively associated with increased <jats:italic>CDKN2A<\/jats:italic> expression (respectively, 16 and five of 44 genes studied for ascending and descending colon). Confirmation of increased expression of <jats:italic>CDKN2A<\/jats:italic> was sought by immunostaining for p16 in the myenteric plexus of colon from 52 patients, using a semi-automated software protocol. The results showed increased staining not within the glial cells (S100 stained), but in the cytoplasm of myenteric nerve cell bodies (MAP2 stained, with identified nucleus) of ascending, but not descending colon of the elderly, and not in the cell nucleus of either region or age group (5,710 neurons analyzed: <jats:italic>n<\/jats:italic> = 12\u201314 for each group). It was concluded that increased p16 staining within the cytoplasm of myenteric nerve cell bodies of elderly ascending (but not descending) colon, suggests a region-dependent, post-mitotic cellular senescence-like activity, perhaps involved with aging of enteric neurons within the colon.<\/jats:p>","DOI":"10.3389\/fnins.2021.747067","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T22:46:32Z","timestamp":1633819592000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Expression of p16 Within Myenteric Neurons of the Aged Colon: A Potential Marker of Declining Function"],"prefix":"10.3389","volume":"15","author":[{"given":"Alexandra","family":"Palmer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Epton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellie","family":"Crawley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilisa","family":"Straface","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Gammon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan M.","family":"Edgar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shezan","family":"Elahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Chin-Aleong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne E.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cleo L.","family":"Bishop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles H.","family":"Knowles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth J.","family":"Sanger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1007\/s11060-005-9037-9035","article-title":"Cytoplasmic, but not nuclear, p16 expression may signal poor prognosis in high-grade astrocytomas.","volume":"77","author":"Arifin","year":"2006","journal-title":"J. Neurooncol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fgene.2016.00013","article-title":"Cellular senescence as the causal nexus of aging.","volume":"7","author":"Bhatia-Dey","year":"2016","journal-title":"Front. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/nrc3711","article-title":"Unravelling mechanisms of p53-mediated tumour suppression.","volume":"14","author":"Bieging","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1136\/gutjnl-2018-316279","article-title":"Changes in neuromuscular structure and functions of human colon during ageing are region-dependent.","volume":"68","author":"Broad","year":"2019","journal-title":"Gut"},{"key":"B5","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/978-1-62703-239-1_4","article-title":"Markers of cellular senescence.","volume":"965","author":"Carnero","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1097\/j.pain.0000000000001764","article-title":"Functional and anatomical deficits in visceral nociception with age: mechanism of silent appendicitis in the elderly?","volume":"61","author":"Cibert-Goton","year":"2020","journal-title":"Pain"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.21873\/anticanres.11580","article-title":"Expression of cell cycle-related protein p16, p27 and Ki-67 proliferating marker in laryngeal squamous cell carcinomas and in laryngeal papillomas.","volume":"37","author":"Ciesielska","year":"2017","journal-title":"Anticancer. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2106","DOI":"10.1093\/emboj\/18.8.2106","article-title":"The p16(INK4a) tumour suppressor protein inhibits alphavbeta3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alphavbeta3 to focal contacts.","volume":"18","author":"Fahraeus","year":"1999","journal-title":"EMBO J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"13056","DOI":"10.1021\/acs.jafc.9b05202","article-title":"Metabolic analysis of regionally distinct gut microbial communities using an in vitro platform.","volume":"68","author":"Firrman","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e12746","DOI":"10.1111\/acel.12746","article-title":"the effects of graded caloric restriction: xii. comparison of mouse to human impact on cellular senescence in the colon.","volume":"17","author":"Fontana","year":"2018","journal-title":"Aging Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.tem.2016.09.005","article-title":"Inflammaging and \u2019garb-aging\u2019.","volume":"28","author":"Franceschi","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"B12","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.cell.2019.10.005","article-title":"Cellular senescence: defining a path forward.","volume":"179","author":"Gorgoulis","year":"2019","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/aps.2012.188","article-title":"Autophagy in ageing and ageing-associated diseases.","volume":"34","author":"He","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e13071","DOI":"10.1111\/acel.13071","article-title":"Proteostasis failure and cellular senescence in long-term cultured postmitotic rat neurons.","volume":"19","author":"Ishikawa","year":"2019","journal-title":"Aging Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1111\/j.1474-9726.2012.00870.x","article-title":"Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response.","volume":"11","author":"Jurk","year":"2012","journal-title":"Aging Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"829","DOI":"10.3390\/nu11040829","article-title":"Protein supplements and their relation with nutrition, microbiota composition and health: is more protein always better for sportspeople?","volume":"11","author":"Karlund","year":"2019","journal-title":"Nutrients"},{"key":"B17","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/nature10413","article-title":"Mouse genomic variation and its effect on phenotypes and gene regulation.","volume":"477","author":"Keane","year":"2011","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1172\/JCI22475","article-title":"Ink4a\/Arf expression is a biomarker of aging.","volume":"114","author":"Krishnamurthy","year":"2004","journal-title":"J. Clin. Invest."},{"key":"B19","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1113\/JP271493","article-title":"Neural influences on human intestinal epithelium in vitro.","volume":"594","author":"Krueger","year":"2016","journal-title":"J. Physiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1161\/CIRCRESAHA.111.246116","article-title":"Effects of aging on angiogenesis.","volume":"110","author":"Lahteenvuo","year":"2012","journal-title":"Circ. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3412","DOI":"10.1172\/JCI58200","article-title":"Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury.","volume":"121","author":"Laranjeira","year":"2011","journal-title":"J. Clin. Invest."},{"key":"B22","doi-asserted-by":"publisher","first-page":"757","DOI":"10.2147\/CIA.S158513","article-title":"Oxidative stress, aging, and diseases.","volume":"13","author":"Liguori","year":"2018","journal-title":"Clin. Interv. Aging"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging.","volume":"153","author":"Lopez-Otin","year":"2013","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1111\/j.1365-2672.1992.tb04882.x","article-title":"Comparison of fermentation reactions in different regions of the human colon.","volume":"72","author":"Macfarlane","year":"1992","journal-title":"J. Appl. Bacteriol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3389\/fncel.2019.00010","article-title":"p16Ink4a prevents the activation of aged quiescent dentate gyrus stem cells by physical exercise.","volume":"13","author":"Micheli","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"464","DOI":"10.3389\/fnins.2018.00464","article-title":"An overview of the role of lipofuscin in age-related neurodegeneration.","volume":"12","author":"Moreno-Garc\u00eda","year":"2018","journal-title":"Front. Neurosci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1586\/17474124.2015.1092872","article-title":"Age-associated changes of the intestinal epithelial barrier: local and systemic implications.","volume":"9","author":"Nicoletti","year":"2015","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1002\/ijc.21466","article-title":"Subcellular localization, modification and protein complex formation of the cdk-inhibitor p16 in Rb-functional and Rb-inactivated tumor cells.","volume":"118","author":"Nilsson","year":"2006","journal-title":"Int. J. Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"515","DOI":"10.2165\/00002512-200219070-00005","article-title":"Aging and intestinal motility: a review of factors that affect intestinal motility in the aged.","volume":"19","author":"O\u2019Mahony","year":"2002","journal-title":"Drugs Aging"},{"key":"B30","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s00429-004-0426-x","article-title":"Loss of glia and neurons in the myenteric plexus of the aged Fischer 344 rat.","volume":"209","author":"Phillips","year":"2004","journal-title":"Anat. Embryol. (Berl)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1083\/jcb.150.6.1467","article-title":"A novel function for the tumor suppressor p16(INK4a): induction of anoikis via upregulation of the alpha(5)beta(1) fibronectin receptor.","volume":"150","author":"Plath","year":"2000","journal-title":"J. Cell. Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1152\/ajpgi.1990.258.6.G856","article-title":"Transit of solids through the human colon: regional quantification in the unprepared bowel.","volume":"258","author":"Proano","year":"1990","journal-title":"Am. J. Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"586","DOI":"10.3389\/fimmu.2018.00586","article-title":"Age and age-related diseases: role of inflammation triggers and cytokines.","volume":"9","author":"Rea","year":"2018","journal-title":"Front. Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.imlet.2018.01.009","article-title":"CD45 in human physiology and clinical medicine.","volume":"196","author":"Rheinlander","year":"2018","journal-title":"Immunol. Lett."},{"key":"B35","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1093\/gerona\/glv080","article-title":"Measures of healthspan as indices of aging in mice \u2013 a recommendation.","volume":"71","author":"Richardson","year":"2016","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.mad.2004.09.003","article-title":"Ageing of the enteric nervous system.","volume":"125","author":"Saffrey","year":"2004","journal-title":"Mech. Ageing Dev."},{"key":"B37","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1111\/j.1476-5381.2012.02198.x","article-title":"Translational neuropharmacology: the use of human isolated gastrointestinal tissues.","volume":"168","author":"Sanger","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.tips.2011.03.009","article-title":"The translational value of rodent gastrointestinal functions: a cautionary tale.","volume":"32","author":"Sanger","year":"2011","journal-title":"Trends Pharmacol. Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.tcb.2018.03.003","article-title":"Cellular senescence in postmitotic cells: beyond growth arrest.","volume":"28","author":"Sapieha","year":"2018","journal-title":"Trends Cell. Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e320","DOI":"10.1038\/oncsis.2017.5","article-title":"p16 controls epithelial cell growth and suppresses carcinogenesis through mechanisms that do not require Rb1 function.","volume":"6","author":"Sen","year":"2017","journal-title":"Oncogenesis"},{"key":"B41","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/366704a0","article-title":"A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D\/CDK4.","volume":"366","author":"Serrano","year":"1993","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/nrc1954","article-title":"Divorcing ARF and p53: an unsettled case.","volume":"6","author":"Sherr","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"B43","doi-asserted-by":"publisher","first-page":"4102","DOI":"10.1002\/pmic.200700133","article-title":"Proteomic analysis of p16INK4a-binding proteins.","volume":"7","author":"Souza-Rodrigues","year":"2007","journal-title":"Proteomics"},{"key":"B44","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1128\/MCB.19.3.2109","article-title":"Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts.","volume":"19","author":"Stein","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"B45","first-page":"1845","article-title":"Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma.","volume":"6","author":"Straume","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1007\/s10522-014-9532-9531","article-title":"Are there roles for brain cell senescence in aging and neurodegenerative disorders?","volume":"15","author":"Tan","year":"2014","journal-title":"Biogerontol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.arr.2017.01.001","article-title":"Gut microbiota: a player in aging and a target for anti-aging intervention.","volume":"35","author":"Vaiserman","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"B48","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/nature13193","article-title":"The role of senescent cells in ageing.","volume":"509","author":"van Deursen","year":"2014","journal-title":"Nature"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e89811","DOI":"10.1371\/journal.pone.0089811","article-title":"2, 3, 7, 8-Tetrachlorodibenzo-P-dioxin (TCDD) induces premature senescence in human and rodent neuronal cells via ROS-dependent mechanisms.","volume":"9","author":"Wan","year":"2014","journal-title":"PLoS one"},{"key":"B50","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1136\/gut.26.4.384","article-title":"Mechanical properties of the colon: comparison of the features of the African and European colon in vitro.","volume":"26","author":"Watters","year":"1985","journal-title":"Gut"},{"key":"B51","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1007\/s00418-003-0526-3","article-title":"Myenteric nitrergic neurons along the rat esophagus: evidence for regional and strain differences in age-related changes.","volume":"119","author":"Wu","year":"2003","journal-title":"Histochem. Cell Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/bjc.2012.264","article-title":"Different cellular p16(INK4a) localisation may signal different survival outcomes in head and neck cancer.","volume":"107","author":"Zhao","year":"2012","journal-title":"Br. J. Cancer"},{"key":"B53","doi-asserted-by":"publisher","first-page":"2202","DOI":"10.3748\/wjg.v9.i10.2202","article-title":"Expressing patterns of p16 and CDK4 correlated to prognosis in colorectal carcinoma.","volume":"9","author":"Zhao","year":"2003","journal-title":"Wld. J. Gastroenterol."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.747067\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T22:46:40Z","timestamp":1633819600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.747067\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,7]]},"references-count":53,"alternative-id":["10.3389\/fnins.2021.747067"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2021.747067","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,7]]},"article-number":"747067"}}