{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:18:06Z","timestamp":1787163486228,"version":"build-2736575974"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:00:00Z","timestamp":1710892800000},"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. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      As the population over the age of 65 increases, rates of neurodegenerative disorders and dementias will rise \u2013 necessitating further research into the cellular and molecular mechanisms that contribute to brain aging. With the critical importance of astrocytes to neuronal health and functioning, we hypothesized that alterations in astrocyte expression of aging-associated markers p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      (p16) and sirtuin 1 (SIRT1) with age would correlate with increased rates of neurodegeneration, as measured by FluoroJade C (FJC) staining.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To test this hypothesis, 19 rhesus macaques at the Tulane National Primate Research Center were selected based on the following criteria: archival FFPE CNS tissue available to use, no noted neuropathology, and an age range of 5\u201330\u2009years. Tissues were cut at 5\u2009\u03bcm and stained for GFAP, p16, SIRT1, and FJC, followed by whole-slide imaging and HALO\u00ae image analysis for percentage of marker-positive cells and relative intensity of each stain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found the percentage of p16+ cells increases with age in total cells and astrocytes of the frontal (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0021,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0012 respectively) and temporal (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0226,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0203 respectively) lobes, as well as the relative intensity of p16 staining (frontal lobe:\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0060; temporal lobe:\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0269). For SIRT1, we found no correlation with age except for an increase in the relative intensity of SIRT1 in the temporal lobe (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0033). There was an increase in neurodegeneration, as measured by the percentage of FJC+ cells in the frontal lobe with age (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0057), as well as in the relative intensity of FJC staining in the frontal (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0030) and parietal (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0481) lobes. Importantly, increased p16 and SIRT1 expression in astrocytes correlated with increasing neurodegeneration in the frontal lobe (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0009,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0095 respectively).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Together, these data suggest that age-associated alterations in astrocytes contribute to neurodegeneration and provide a target for mechanistic studies in the future.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2024.1368517","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:32:49Z","timestamp":1710894769000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Astrocyte expression of aging-associated markers positively correlates with neurodegeneration in the frontal lobe of the rhesus macaque brain"],"prefix":"10.3389","volume":"16","author":[{"given":"Miranda D.","family":"Horn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia C.","family":"Forest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad A.","family":"Saied","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"MacLean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,3,20]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1161\/01.RES.0000267723.65696.4a","article-title":"Sirt1 regulates aging and resistance to oxidative stress in the heart","volume":"100","author":"Alcendor","year":"2007","journal-title":"Circ. Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1038\/s41467-019-14198-8","article-title":"Identification of region-specific astrocyte subtypes at single cell resolution","volume":"11","author":"Batiuk","year":"2020","journal-title":"Nat. Commun."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"615.3","DOI":"10.1096\/fasebj.25.1_supplement.615.3","article-title":"Human astrocytes exhibit an increased expression of the cellular senescence biomarker p16INK4a in aged human brain and Alzheimer\u2019s disease","volume":"25","author":"Bhat","year":"2011","journal-title":"FASEB J."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"167","DOI":"10.3389\/fncel.2015.00167","article-title":"Differential expression of sirtuins in the aging rat brain","volume":"9","author":"Braidy","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1038\/s41586-018-0543-y","article-title":"Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline","volume":"562","author":"Bussian","year":"2018","journal-title":"Nature"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e45250","DOI":"10.1371\/journal.pone.0045250","article-title":"The neuron-astrocyte-microglia triad in Normal brain ageing and in a model of neuroinflammation in the rat hippocampus","volume":"7","author":"Cerbai","year":"2012","journal-title":"PLoS One"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0304-3940(97)00708-8","article-title":"Glial reaction in the hippocampal formation is highly correlated with aging in human brain","volume":"235","author":"David","year":"1997","journal-title":"Neurosci. Lett."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1177\/0300985815622974","article-title":"Contributions of nonhuman Primates to research on aging","volume":"53","author":"Didier","year":"2016","journal-title":"Vet. Pathol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s12993-016-0111-2","article-title":"Age, environment, object recognition and morphological diversity of GFAP-immunolabeled astrocytes","volume":"12","author":"Diniz","year":"2016","journal-title":"Behav. Brain Funct."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1111\/j.1460-9568.2010.07296.x","article-title":"Environmental impoverishment and aging alter object recognition, spatial learning, and dentate gyrus astrocytes","volume":"32","author":"Diniz","year":"2010","journal-title":"Eur. J. Neurosci."},{"key":"ref11","doi-asserted-by":"publisher","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":"ref12","doi-asserted-by":"publisher","first-page":"3251","DOI":"10.1073\/pnas.1815917116","article-title":"Persistent metabolic youth in the aging female brain","volume":"116","author":"Goyal","year":"2019","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.cger.2013.07.002","article-title":"Normal cognitive aging","volume":"29","author":"Harada","year":"2013","journal-title":"Clin. Geriatr. Med."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.tcb.2018.02.001","article-title":"Hallmarks of cellular senescence","volume":"28","author":"Hernandez-Segura","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1038\/s41581-022-00601-z","article-title":"Cellular senescence: the good, the bad and the unknown","volume":"18","author":"Huang","year":"2022","journal-title":"Nat. Rev. Nephrol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1016\/j.neurobiolaging.2008.07.006","article-title":"Age-related changes in glial cells of dopamine midbrain subregions in rhesus monkeys","volume":"31","author":"Kanaan","year":"2010","journal-title":"Neurobiol. Aging"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e48034","DOI":"10.1371\/journal.pone.0048034","article-title":"Long-term culture of astrocytes attenuates the readily releasable Pool of synaptic vesicles","volume":"7","author":"Kawano","year":"2012","journal-title":"PLoS One"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/nn.4043","article-title":"Diversity of astrocyte functions and phenotypes in neural circuits","volume":"18","author":"Khakh","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref19","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":"ref20","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/nrm.2017.68","article-title":"Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases","volume":"18","author":"Kubben","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"24","DOI":"10.5483\/BMBRep.2019.52.1.290","article-title":"Sirtuin signaling in cellular senescence and aging","volume":"52","author":"Lee","year":"2019","journal-title":"BMB Rep."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"8546","DOI":"10.1073\/pnas.1911999117","article-title":"Sex differences in adult lifespan and aging rates of mortality across wild mammals","volume":"117","author":"Lema\u00eetre","year":"2020","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"L\u00f3pez-Ot\u00edn","year":"2013","journal-title":"Cell"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1101\/gad.188326.112","article-title":"Astrocytes and disease: a neurodevelopmental perspective","volume":"26","author":"Molofsky","year":"2012","journal-title":"Genes Dev."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/0197-4580(93)90100-P","article-title":"GFAP mRNA increases with age in rat and human brain","volume":"14","author":"Nichols","year":"1993","journal-title":"Neurobiol. Aging"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1111\/j.1471-4159.2006.04369.x","article-title":"Astrocytes aged in vitro show a decreased neuroprotective capacity","volume":"101","author":"Pertusa","year":"2007","journal-title":"J. Neurochem."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"2515690X20957225","DOI":"10.1177\/2515690X20957225","article-title":"Dysfunction of the microbiota-gut-brain Axis in neurodegenerative disease: the promise of therapeutic modulation with prebiotics, medicinal herbs, probiotics, and synbiotics","volume":"25","author":"Peterson","year":"2020","journal-title":"J. Evid. Based Complement. Altern. Med."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.bbi.2016.01.006","article-title":"Glial cell morphological and density changes through the lifespan of rhesus macaques","volume":"55","author":"Robillard","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.neurobiolaging.2013.07.002","article-title":"Complex and region-specific changes in astroglial markers in the aging brain","volume":"35","author":"Rodr\u00edguez","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref30","first-page":"179","article-title":"Chapter six - sex and gender differences in dementia","volume-title":"International review of neurobiology sex and gender differences in neurological disease","author":"Salwierz","year":"2022"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"111548","DOI":"10.1016\/j.mad.2021.111548","article-title":"Impact of senescent cell subtypes on tissue dysfunction and repair: importance and research questions","volume":"198","author":"Tripathi","year":"2021","journal-title":"Mech. Ageing Dev."},{"key":"ref32","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":"ref33","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1037\/0033-2909.120.2.272","article-title":"An application of prefrontal cortex function theory to cognitive aging","volume":"120","author":"West","year":"1996","journal-title":"Psychol. Bull."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1017\/S1355617700666109","article-title":"In defense of the frontal lobe hypothesis of cognitive aging","volume":"6","author":"West","year":"2000","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"682","DOI":"10.18632\/aging.100599","article-title":"Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner","volume":"5","author":"Whitaker","year":"2013","journal-title":"Aging (Albany NY)"},{"key":"ref36","year":"2022"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1038\/s41556-020-00579-5","article-title":"SIRT1 is downregulated by autophagy in senescence and ageing","volume":"22","author":"Xu","year":"2020","journal-title":"Nat. Cell Biol."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2024.1368517\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:32:53Z","timestamp":1710894773000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2024.1368517\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,20]]},"references-count":37,"alternative-id":["10.3389\/fnagi.2024.1368517"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2024.1368517","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,20]]},"article-number":"1368517"}}