{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:13:10Z","timestamp":1792624390858,"version":"4.5.0"},"reference-count":58,"publisher":"Society for Neuroscience","issue":"39","license":[{"start":{"date-parts":[[2017,3,28]],"date-time":"2017-03-28T00:00:00Z","timestamp":1490659200000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2016,9,28]]},"abstract":"<jats:p>The impact of aging on CNS white matter (WM) is of general interest because the global effects of aging on myelinated nerve fibers are more complex and profound than those in cortical gray matter. It is important to distinguish between axonal changes created by normal aging and those caused by neurodegenerative diseases, including multiple sclerosis, stroke, glaucoma, Alzheimer's disease, and traumatic brain injury. Using three-dimensional electron microscopy, we show that in mouse optic nerve, which is a pure and fully myelinated WM tract, aging axons are larger, have thicker myelin, and are characterized by longer and thicker mitochondria, which are associated with altered levels of mitochondrial shaping proteins. These structural alterations in aging mitochondria correlate with lower ATP levels and increased generation of nitric oxide, protein nitration, and lipid peroxidation. Moreover, mitochondria\u2013smooth endoplasmic reticulum interactions are compromised due to decreased associations and decreased levels of calnexin and calreticulin, suggesting a disruption in Ca<jats:sup>2+<\/jats:sup>homeostasis and defective unfolded protein responses in aging axons. Despite these age-related modifications, axon function is sustained in aging WM, which suggests that age-dependent changes do not lead to irreversible functional decline under normal conditions, as is observed in neurodegenerative diseases.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Aging is a common risk factor for a number of neurodegenerative diseases, including stroke. Mitochondrial dysfunction and oxidative damage with age are hypothesized to increase risk for stroke. We compared axon\u2013myelin\u2013node\u2013mitochondrion\u2013smooth endoplasmic reticulum (SER) interactions in white matter obtained at 1 and 12 months. We show that aging axons have enlarged volume, thicker myelin, and elongated and thicker mitochondria. Furthermore, there are reduced SER connections to mitochondria that correlate with lower calnexin and calreticulin levels. Despite a prominent decrease in number, elongated aging mitochondria produce excessive stress markers with reduced ATP production. Because axons maintain function under these conditions, our study suggests that it is important to understand the process of normal brain aging to identify neurodegenerative changes.<\/jats:p>","DOI":"10.1523\/jneurosci.1316-16.2016","type":"journal-article","created":{"date-parts":[[2016,9,28]],"date-time":"2016-09-28T16:02:23Z","timestamp":1475078543000},"page":"9990-10001","source":"Crossref","is-referenced-by-count":146,"title":["Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter"],"prefix":"10.1523","volume":"36","author":[{"given":"Katharine E.","family":"Stahon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5759-5496","authenticated-orcid":false,"given":"Chinthasagar","family":"Bastian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelby","family":"Griffith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grahame J.","family":"Kidd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7506-9585","authenticated-orcid":false,"given":"Sylvain","family":"Brunet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1123-3582","authenticated-orcid":false,"given":"Selva","family":"Baltan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2016,9,28]]},"reference":[{"key":"2023041803212006000_36.39.9990.1","doi-asserted-by":"publisher","DOI":"10.1177\/1073858408324788"},{"key":"2023041803212006000_36.39.9990.2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2012.07949.x"},{"key":"2023041803212006000_36.39.9990.3","doi-asserted-by":"crossref","unstructured":"Baltan S (2014) in White matter injury in stroke and CNS disease, Age-dependent mechanisms of white matter injury after stroke, eds Baltan S Carmichael ST Matute C Xi G Zhang JH (Springer, New York), pp 373\u2013403.","DOI":"10.1007\/978-1-4614-9123-1_16"},{"key":"2023041803212006000_36.39.9990.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2015.09.015"},{"key":"2023041803212006000_36.39.9990.5","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5137-07.2008"},{"key":"2023041803212006000_36.39.9990.6","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5956-09.2010"},{"key":"2023041803212006000_36.39.9990.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5379-10.2011"},{"key":"2023041803212006000_36.39.9990.8","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22299"},{"key":"2023041803212006000_36.39.9990.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(02)00385-6"},{"key":"2023041803212006000_36.39.9990.10","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2010.117"},{"key":"2023041803212006000_36.39.9990.11","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00265-3"},{"key":"2023041803212006000_36.39.9990.12","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22379"},{"key":"2023041803212006000_36.39.9990.13","doi-asserted-by":"crossref","unstructured":"Camacho P John L Li Y Paredes RM Roderick HL (2003) in Calreticulin, Calnexin and calreticulin, ER associated modulators of calcium transport in the ER, eds Eggleton P Michalak M (Springer, Boston), pp 126\u2013132.","DOI":"10.1007\/978-1-4419-9258-1_12"},{"key":"2023041803212006000_36.39.9990.14","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-4182(02)80040-0"},{"key":"2023041803212006000_36.39.9990.15","doi-asserted-by":"publisher","DOI":"10.1046\/j.1439-0264.2003.00431.x"},{"key":"2023041803212006000_36.39.9990.16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M503062200"},{"key":"2023041803212006000_36.39.9990.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407043101"},{"key":"2023041803212006000_36.39.9990.18","first-page":"96","article-title":"Calcium binding chaperones of the endoplasmic reticulum","volume":"28","author":"Coe","year":"2009","journal-title":"Gen Physiol Biophys"},{"key":"2023041803212006000_36.39.9990.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402765101"},{"key":"2023041803212006000_36.39.9990.20","doi-asserted-by":"publisher","DOI":"10.1016\/0013-4694(79)90101-9"},{"key":"2023041803212006000_36.39.9990.21","doi-asserted-by":"publisher","DOI":"10.1038\/nature07534"},{"key":"2023041803212006000_36.39.9990.22","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006926428699"},{"key":"2023041803212006000_36.39.9990.23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2818.2005.01466.x"},{"key":"2023041803212006000_36.39.9990.24","doi-asserted-by":"publisher","DOI":"10.1136\/jamia.2001.0080001"},{"key":"2023041803212006000_36.39.9990.25","doi-asserted-by":"publisher","DOI":"10.1016\/0165-3806(82)90005-0"},{"key":"2023041803212006000_36.39.9990.26","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(01)00055-7"},{"key":"2023041803212006000_36.39.9990.27","doi-asserted-by":"publisher","DOI":"10.1126\/science.1207385"},{"key":"2023041803212006000_36.39.9990.28","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-007-0296-1"},{"key":"2023041803212006000_36.39.9990.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2009.01.019"},{"key":"2023041803212006000_36.39.9990.30","doi-asserted-by":"publisher","DOI":"10.2174\/1874609811104020110"},{"key":"2023041803212006000_36.39.9990.31","unstructured":"Heflin M Lum H (2008) in Pathobiology of ocular disease, Overview of aging, eds Garner A Klintworth GK (CRC, New York), pp 361\u2013370."},{"key":"2023041803212006000_36.39.9990.32","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20886"},{"key":"2023041803212006000_36.39.9990.33","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1949.sp004310"},{"key":"2023041803212006000_36.39.9990.34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703812200"},{"key":"2023041803212006000_36.39.9990.35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.24.13807"},{"key":"2023041803212006000_36.39.9990.36","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00266-5"},{"key":"2023041803212006000_36.39.9990.37","unstructured":"Kemper TL (1994) in Clinical neurology of aging, Neuroanatomical and neuropathological changes during aging and dementia, eds Albert ML Knoefel JE (Oxford UP, New York), pp 3\u201367."},{"key":"2023041803212006000_36.39.9990.38","doi-asserted-by":"publisher","DOI":"10.1007\/BF02705114"},{"key":"2023041803212006000_36.39.9990.39","doi-asserted-by":"publisher","DOI":"10.1038\/nature02246"},{"key":"2023041803212006000_36.39.9990.40","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2009.00462.x"},{"key":"2023041803212006000_36.39.9990.41","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1055"},{"key":"2023041803212006000_36.39.9990.42","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12498"},{"key":"2023041803212006000_36.39.9990.43","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501599200"},{"key":"2023041803212006000_36.39.9990.44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200677200"},{"key":"2023041803212006000_36.39.9990.45","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-016-1848-6"},{"key":"2023041803212006000_36.39.9990.46","doi-asserted-by":"crossref","unstructured":"Peters A (1999) in Cerebral cortex, Normal aging in the cerebral cortex of primates, eds Peters A Morrison JH (Springer, Boston), pp 49\u201380.","DOI":"10.1007\/978-1-4615-4885-0_3"},{"key":"2023041803212006000_36.39.9990.47","doi-asserted-by":"publisher","DOI":"10.3389\/neuro.05.002.2009"},{"key":"2023041803212006000_36.39.9990.48","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(20000410)419:3<364::AID-CNE8>3.0.CO;2-R"},{"key":"2023041803212006000_36.39.9990.49","unstructured":"Ross MH Pawlina W (2016) in Histology: a text and atlas with correlated cell and molecular biology, Nerve tissue, eds Ross M. H. Pawlina W (Wolters Kluwer Health, Philadelphia), pp 356\u2013403."},{"key":"2023041803212006000_36.39.9990.50","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10162"},{"key":"2023041803212006000_36.39.9990.51","doi-asserted-by":"publisher","DOI":"10.1126\/science.1197598"},{"key":"2023041803212006000_36.39.9990.52","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"2023041803212006000_36.39.9990.53","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(00)01735-7"},{"key":"2023041803212006000_36.39.9990.54","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410300309"},{"key":"2023041803212006000_36.39.9990.55","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00046.2007"},{"key":"2023041803212006000_36.39.9990.56","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2009.89"},{"key":"2023041803212006000_36.39.9990.57","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6186-08.2009"},{"key":"2023041803212006000_36.39.9990.58","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3013"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.1316-16.2016","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T10:43:57Z","timestamp":1681814637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.1316-16.2016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,28]]},"references-count":58,"journal-issue":{"issue":"39","published-online":{"date-parts":[[2016,9,28]]},"published-print":{"date-parts":[[2016,9,28]]}},"alternative-id":["10.1523\/JNEUROSCI.1316-16.2016"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.1316-16.2016","relation":{},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,28]]}}}