Editing Aging brain (section)

==Structural changes==
[[File:Gehirn, medial - Lobi en.svg|thumb|Human brain in the [[sagittal plane]]]]
[[File:Blausen 0896 Ventricles Brain.png|thumb|[[Ventricular system|Ventricles of the brain]]]]

Aging entails many physical, biological, chemical, and psychological changes and the brain is no exception to this phenomenon. These various changes have attempted to be mapped by [[conceptual model]]s like the Scaffolding Theory of Aging and Cognition (STAC) in 2009. The STAC model looks at factors like neural changes to the [[white matter]], [[dopamine]] depletion, shrinkage, and [[Cerebral cortex|cortical]] thinning.<ref>{{Cite journal |last1=Reuter-Lorenz |first1=Patricia A. |last2=Park |first2=Denise C. |date=2014-09-01 |title=How Does it STAC Up? Revisiting the Scaffolding Theory of Aging and Cognition |url=https://doi.org/10.1007/s11065-014-9270-9 |journal=Neuropsychology Review |language=en |volume=24 |issue=3 |pages=355–370 |doi=10.1007/s11065-014-9270-9 |issn=1573-6660 |pmc=4150993 |pmid=25143069}}</ref> [[CT scan]]s have found that the [[Ventricular system|cerebral ventricles]] expand as a function of age. More recent [[MRI]] studies have reported age-related regional decreases in cerebral volume.<ref name="Craic">{{cite book |last1=Craik |first1=F. |last2=Salthouse |first2=T. |year=2000 |title=The Handbook of Aging and Cognition |edition=2nd |location=Mahwah, NJ |publisher=Lawrence Erlbaum |isbn=0-8058-2966-0 |oclc=44957002}}</ref><ref name="Raz 2005">{{cite journal |last=Raz |first=Naftali |year=2005 |title=Regional Brain Changes in Aging Healthy Adults: General Trends, Individual Differences and Modifiers |journal=Cerebral Cortex |volume=15 |issue=11 |pages=1676–1689 |pmid=15703252 |doi=10.1093/cercor/bhi044 |display-authors=etal|doi-access=free|hdl=11858/00-001M-0000-0025-8479-B |hdl-access=free }}</ref> Regional volume reduction is not uniform; some brain regions shrink at a rate of up to 1% per year, whereas others remain relatively stable until the end of the life-span.<ref name="Raz 2006">{{cite journal |last1=Raz |first1=Naftali |last2=Rodrigue |first2=Karen M. |year=2006 |title=Differential aging of the brain: Patterns, cognitive correlates and modifiers |journal=Neuroscience & Biobehavioral Reviews |volume=30 |issue=6 |pages=730–748 |pmid=16919333 |pmc=6601348 |doi=10.1016/j.neubiorev.2006.07.001 |url=http://www.rcgd.isr.umich.edu/life/Readings2007/Raz%20reading.pdf |archiveurl=https://web.archive.org/web/20110723194504/http://www.rcgd.isr.umich.edu/life/Readings2007/Raz%20reading.pdf |archivedate=July 23, 2011 |access-date=January 28, 2010 |url-status=dead }}</ref> The brain is very complex, and is composed of many different areas and types of tissue, or matter. The different functions of different tissues in the brain may be more or less susceptible to age-induced changes.<ref name="Craic"/>  The brain matter can be broadly classified as either grey matter, or white matter. [[Grey matter]] consists of [[cell body|cell bodies]] in the [[Cerebral cortex|cortex]] and [[Basal ganglia|subcortical nuclei]]. [[White matter]] consists of tightly packed [[myelin]]ated [[axon]]s connecting the neurons to each other and with the periphery.<ref name="Craic"/>

===Loss of neural circuits and brain plasticity===
[[Neuroplasticity|Brain plasticity]] refers to the brain's ability to change structure and function.<ref name="Kolb Whishaw 1998">{{cite journal|last1=Kolb|first1=Bryan|title=Brain Plasticity and Behavior|last2=Whishaw|first2=Ian Q.|journal=Annual Review of Psychology|volume=49| issue=1| year=1998| pages=43–64 | doi=10.1146/annurev.psych.49.1.43 |pmid=9496621 |hdl=2027.42/74427|url=https://deepblue.lib.umich.edu/bitstream/2027.42/74427/1/1467-8721.01210.pdf|hdl-access=free}}</ref><ref name="Kolb Gibb 2003">{{cite journal|last1=Kolb| first1=Bryan|last2=Gibb| first2=Robbin|last3=Robinson| first3=Terry E.|title=Brain plasticity and behavior|journal=Current Directions in Psychological Science|volume=12|issue=1|year=2003|pages=1–5|issn=0963-7214|doi=10.1111/1467-8721.01210| hdl=2027.42/74427| s2cid=204347081|url=https://deepblue.lib.umich.edu/bitstream/2027.42/74427/1/1467-8721.01210.pdf|hdl-access=free}}</ref> This ties into the common phrase, "if you don't use it, you lose it," which is another way of saying, if you do not use it, your brain will devote less [[Somatotopic arrangement|somatotopic space]] for it. One proposed mechanism for the observed age-related plasticity deficits in animals is the result of age-induced alterations in [[Calcium metabolism|calcium regulation]].<ref name="Barnes">{{cite journal |last1=Barnes |first1=C. |last2=Burke |first2=S. |year=2006 |title=Neural plasticity in the ageing brain |journal=Nature Reviews Neuroscience |volume=7 |issue=1 |pages=30–40 |doi=10.1038/nrn1809 |pmid=16371948|s2cid=1784238}}</ref>  The changes in the organism's abilities to handle calcium will ultimately influence neuronal firing and the ability to propagate [[action potential]]s, which in turn would affect the ability of the brain to alter its structure or function (i.e. its plastic nature). Due to the complexity of the brain, with all of its structures and functions, it is logical to assume that some areas would be more vulnerable to aging than others. Two circuits worth mentioning here are the [[Hippocampus|hippocampal]] and [[Neocortex|neocortical]] circuits.<ref name="Hof 2004">{{cite journal |vauthors=Hof PR, Morrison JH |title=The aging brain: morphomolecular senescence of cortical circuits |journal=Trends in Neurosciences |volume=27 |issue=10 |pages=607–13 |date=October 2004 |pmid=15374672 |doi=10.1016/j.tins.2004.07.013 |s2cid=31680049}}</ref>  It has been suggested that age-related cognitive decline is due in part not to neuronal death but to [[Synaptic plasticity|synaptic]] alterations. Evidence in support of this idea from animal work has also suggested that this cognitive deficit is due to functional and [[Biochemistry|biochemical]] factors such as changes in [[Enzyme|enzymatic]] activity, chemical messengers, or [[gene expression]] in cortical circuits.<ref name ="Hof 2004"/>

===Thinning of the cortex===
{{Cerebrum labelled map|caption=}}
Advances in MRI technology have provided the ability to see the brain structure in great detail in an easy, non-invasive manner ''[[in vivo]]''. Bartzokis ''et al.'', has noted that there is a decrease in grey matter volume between [[Adult|adulthood]] and [[old age]], whereas white matter volume was found to increase from age 19–40, and decline after this age.<ref name="Sowell 2003">{{cite journal |vauthors=Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW |title=Mapping cortical change across the human life span |journal=Nature Neuroscience |volume=6 |issue=3 |pages=309–15 |date=March 2003 |pmid=12548289 |doi=10.1038/nn1008 |s2cid=23799692}}</ref> Studies using [[Voxel-based morphometry]] have identified areas such as the [[Insular cortex|insula]] and superior [[Parietal lobe|parietal]] gyri as being especially vulnerable to age-related losses in grey matter of older adults.<ref name="Sowell 2003"/> Sowell ''et al.'', reported that the first 6 decades of an individual's life were correlated with the most rapid decreases in grey matter density, and this occurred over [[Dorsal lobe|dorsal]], [[Frontal lobe|frontal]], and [[Parietal lobe|parietal]] lobes on both [[interhemispheric fissure|interhemispheric]] and lateral brain surfaces. It is also worth noting that areas such as the [[cingulate gyrus]], and [[occipital cortex]] surrounding the [[calcarine sulcus]] appear exempt from this decrease in grey matter density over time.<ref name="Sowell 2003"/>  Age effects on grey matter density in the posterior [[Temporal lobe|temporal cortex]] appear more predominantly in the left versus right hemisphere, and were confined to posterior language cortices. Certain language functions such as word retrieval and production were found to be located to more anterior language cortices, and deteriorate as a function of age. Sowell et al., also reported that these anterior language cortices were found to mature and decline earlier than the more posterior language cortices.<ref name="Sowell 2003"/> It has also been found that the width of [[Sulcus (neuroanatomy)|sulcus]] not only increases with age,<ref>{{cite journal |author1=Tao Liu |author2=Wei Wen |author3=Wanlin Zhu |author4=Julian Trollor |author5=Simone Reppermund |author6=John Crawford |author7=Jesse S Jin |author8=Suhuai Luo |author9=Henry Brodaty |author10=Perminder Sachdev |year=2010 |title=The effects of age and sex on cortical sulci in the elderly |journal=[[NeuroImage]] |volume=51 |issue=1 |pmid=20156569 |doi=10.1016/j.neuroimage.2010.02.016 |pages=19–27|s2cid=8158316}}</ref> but also with cognitive decline in the elderly.<ref>{{cite journal |author1=Tao Liu |author2=Wei Wen |author3=Wanlin Zhu |author4=Nicole A Kochan |author5=Julian N Trollor |author6=Simone Reppermund |author7=Jesse S Jin |author8=Suhuai Luo |author9=Henry Brodaty |author10=Perminder S Sachdev |year=2011 |title=The relationship between cortical sulcal variability and cognitive performance in the elderly |journal=NeuroImage |volume=56 |issue=3 |pages=865–873 |pmid=21397704 |doi=10.1016/j.neuroimage.2011.03.015|s2cid=7489380}}</ref>

===Morphology and microstructure===
{{Expand section|date=March 2023}}

Age-related decrease in gray matter volume was the largest contribution to changes in [[brain volume]]. Moreover, neuronal density appears to decrease, white matter microstructure gets altered and energy metabolism in the [[cerebellum]] gets altered.<ref>{{cite journal |last1=Ding |first1=Xiao-Qi |last2=Maudsley |first2=Andrew A. |last3=Sabati |first3=Mohammad |last4=Sheriff |first4=Sulaiman |last5=Schmitz |first5=Birte |last6=Schütze |first6=Martin |last7=Bronzlik |first7=Paul |last8=Kahl |first8=Kai G. |last9=Lanfermann |first9=Heinrich |title=Physiological neuronal decline in healthy aging human brain — An in vivo study with MRI and short echo-time whole-brain 1H MR spectroscopic imaging |journal=NeuroImage |date=15 August 2016 |volume=137 |pages=45–51 |doi=10.1016/j.neuroimage.2016.05.014 |pmid=27164326 |pmc=4914466 |language=en |issn=1053-8119}}</ref> General cortical atrophy occurs in aging and e.g. the [[caudate nucleus]] volume appears to decrease.<ref>{{cite journal |last1=Pini |first1=Lorenzo |last2=Pievani |first2=Michela |last3=Bocchetta |first3=Martina |last4=Altomare |first4=Daniele |last5=Bosco |first5=Paolo |last6=Cavedo |first6=Enrica |last7=Galluzzi |first7=Samantha |last8=Marizzoni |first8=Moira |last9=Frisoni |first9=Giovanni B. |title=Brain atrophy in Alzheimer's Disease and aging |journal=Ageing Research Reviews |date=1 September 2016 |volume=30 |pages=25–48 |doi=10.1016/j.arr.2016.01.002 |pmid=26827786 |s2cid=42793845 |language=en |issn=1568-1637}}</ref>{{explain|date=March 2023}}

===Age-related neuronal morphology===
There is converging evidence from [[Cognitive neuroscience|cognitive neuroscientists]] around the world that age-induced cognitive deficits may not be due to neuronal loss or cell death, but rather may be the result of small region-specific changes to the [[Morphology (biology)|morphology]] of neurons.<ref name="Barnes"/> Studies by Duan et al., have shown that [[dendritic arbor]]s and [[dendritic spine]]s of [[Cerebral cortex|cortical]] [[pyramidal neuron]]s decrease in size and/or number in specific regions and layers of human and [[non-human primate]] cortex as a result of age (Duan ''et al.'', 2003; morph). A 46% decrease in spine number and spine density has been reported in humans older than 50 compared with younger individuals.<ref name="Hof 2004"/> An [[electron microscopy]] study in [[monkey]]s reported a 50% loss in spines on the [[Apical dendrite|apical dendritic]] tufts of [[pyramidal cell]]s in [[prefrontal cortex]] of old animals (27–32 years old) compared with young ones (6–9 years old).<ref name="Hof 2004"/>

====Neurofibrillary tangles====
[[File:TANGLES HIGH.jpg|thumb|[[Tau protein]] disorders cause [[microtubule]] destruction and formation of [[neurofibrillary tangle]]s.]]

Age-related neuropathologies such as [[Alzheimer's disease]], [[Parkinson's disease]], [[diabetes]], [[hypertension]] and [[arteriosclerosis]] make it difficult to distinguish the normal patterns of aging.<ref name="pmid27045845">{{cite journal |vauthors=Habes M, Janowitz D, Erus G, Toledo JB, Resnick SM, Doshi J, Van der Auwera S, Wittfeld K, Hegenscheid K, Hosten N, Biffar R, Homuth G, Völzke H, Grabe HJ, Hoffmann W, Davatzikos C | title=Advanced brain aging: relationship with epidemiologic and genetic risk factors, and overlap with Alzheimer disease atrophy patterns | journal=[[Translational Psychiatry]] | volume=6 | issue=4 | year=2016 | pages=e775 |  doi=10.1038/tp.2016.39 | pmid=27045845 | pmc=4872397}}</ref><ref name="Gabrieli">{{cite journal |last1=Gabrieli |first1=J. |last2=Hedden |first2=T. |year=2004 |title=Insights into the ageing mind: a view from cognitive neuroscience |journal=Nature Reviews Neuroscience |volume=5 |issue=2 |pages=87–96 |doi=10.1038/nrn1323 |pmid=14735112|s2cid=9398942}}</ref> One of the important differences between normal aging and pathological aging is the location of neurofibrillary tangles.  Neurofibrillary tangles are composed of paired helical filaments (PHF).<ref name="Anderton 2002">{{cite journal |author=Anderton BH |title=Ageing of the brain |journal=Mechanisms of Ageing and Development |volume=123 |issue=7 |pages=811–7 |date=April 2002 |pmid=11869738 |doi=10.1016/S0047-6374(01)00426-2 |s2cid=43097130}}</ref> In normal, non-demented aging, the number of tangles in each affected cell body is relatively low<ref name="Anderton 2002"/> and restricted to the [[Anterior olfactory nucleus|olfactory nucleus]], [[parahippocampal gyrus]], [[amygdala]] and [[entorhinal cortex]].<ref name="Davis 1991">{{cite journal |last1=Davis |first1=P. |last2=Morris |first2=J. |year=1991 |title=The distribution of tangles, plaques, and related immunohistochemical markers in healthy aging and Alzheimer's disease |journal=Neurobiology of Aging |volume=12 |issue=4 |pages=295–312 |pmid=1961359|doi=10.1016/0197-4580(91)90006-6 |s2cid=4060446 |display-authors=etal}}</ref>  As the non-demented individual ages, there is a general increase in the density of tangles, but no significant difference in where tangles are found.<ref name="Davis 1991"/>

The other main neurodegenerative contributor commonly found in the brain of patients with [[Alzheimer's disease|AD]] is [[amyloid plaques]].  However, unlike tangles, plaques have not been found to be a consistent feature of normal aging.<ref name="Davis 1991"/>

===Role of oxidative stress===
{{Main|Oxidative stress}}
[[Cognitive impairment]] has been attributed to oxidative stress, [[Inflammation|inflammatory]] reactions and changes in the cerebral microvasculature.<ref name="Whalley 2004">{{cite journal |vauthors=Whalley LJ, Deary IJ, Appleton CL, Starr JM |title=Cognitive reserve and the neurobiology of cognitive aging |journal=Ageing Research Reviews |volume=3 |issue=4 |pages=369–82 |date=November 2004 |pmid=15541707 |doi=10.1016/j.arr.2004.05.001 |s2cid=6629858}}</ref>  The exact impact of each of these mechanisms in affecting cognitive aging is unknown.  Oxidative stress is the most controllable risk factor and is the best understood.  The online Merriam-Webster Medical Dictionary defines oxidative stress as, "physiological stress on the body that is caused by the cumulative damage done by free radicals inadequately neutralized by [[antioxidant]]s and that is held to be associated with aging."<ref>{{cite web|url=http://www.merriam-webster.com/medical/oxidative_stress |title=Oxidative stress |website=Merriam-Webster Medical dictionary |access-date=24 June 2023}}</ref>  Hence oxidative stress is the damage done to the cells by free radicals that have been released from the oxidation process.{{cn|date=November 2024}}

Compared to other tissues in the body, the brain is deemed unusually sensitive to oxidative damage.<ref name="Keller 2005">{{cite journal |vauthors=Keller JN, Schmitt FA, Scheff SW |title=Evidence of increased oxidative damage in subjects with mild cognitive impairment |journal=Neurology |volume=64 |issue=7 |pages=1152–6 |date=April 2005 |pmid=15824339 |doi=10.1212/01.WNL.0000156156.13641.BA |s2cid=398262 |url=http://www.chem.uky.edu/research/butterfield/dab_pdfs/Keller%20et%20al%202005%20Neurology%2064%201152-1156.pdf|display-authors=etal}}</ref> Increased oxidative damage has been associated with neurodegenerative diseases, mild [[cognitive impairment]] and individual differences in cognition in healthy elderly people.  In 'normal aging', the brain is undergoing oxidative stress in a multitude of ways.  The main contributors include protein oxidation, [[lipid peroxidation]] and oxidative modifications in [[Nuclear DNA|nuclear]] and [[Mitochondrial DNA|mitochondrial]] DNA.<ref name="Keller 2005"/>  Oxidative stress can damage [[DNA replication]] and inhibit [[DNA repair|repair]] through many complex processes, including [[telomere#Shortening|telomere shortening]] in DNA components.<ref name="Harris 2006">{{cite journal |vauthors=Harris SE, Deary IJ, MacIntyre A |title=The association between telomere length, physical health, cognitive ageing, and mortality in non-demented older people |journal=Neuroscience Letters |volume=406 |issue=3 |pages=260–4 |date=October 2006 |pmid=16919874 |doi=10.1016/j.neulet.2006.07.055|s2cid=24592571 |display-authors=etal}}</ref>  Each time a [[somatic cell]] replicates, the telomeric DNA component shortens.  As telomere length is partly inheritable,<ref name="Harris 2006"/> there are individual differences in the age of onset of cognitive decline.

===DNA damage===
At least 25 studies have demonstrated that [[DNA repair#DNA damage|DNA damage]] accumulates with age in the mammalian brain.  This DNA damage includes the oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG), single- and double-strand breaks, DNA-protein [[cross-link]]s and [[malondialdehyde]] [[adduct]]s (reviewed in Bernstein et al.<ref>Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K. (2008) Cancer and aging as consequences of un-repaired DNA damage. In: ''New Research on DNA Damage'' (Editors: Honoka Kimura And Aoi Suzuki) [[Nova Science Publishers, Inc.]], New York, Chapter 1, pp. 1-47. see pg. 18. {{ISBN|978-1-60456-581-2}}</ref>).  Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human.  Young 4-day-old rats have about 3,000 single-strand breaks and 156 double-strand breaks per neuron, whereas in rats older than 2 years the level of damage increases to about 7,400 single-strand breaks and 600 double-strand breaks per neuron.<ref>{{cite journal |vauthors=Mandavilli BS, Rao KS | year = 1996 | title = Accumulation of DNA damage in aging neurons occurs through a mechanism other than apoptosis | journal = J Neurochem | volume = 67 | issue = 4| pages = 1559–65 | pmid = 8858940 | doi = 10.1046/j.1471-4159.1996.67041559.x | s2cid = 42442582}}</ref>

Lu et al.<ref name="Lu 2004">{{cite journal |vauthors=Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA | year = 2004 | title = Gene regulation and DNA damage in the ageing human brain | journal = Nature | volume = 429 | issue = 6994| pages = 883–891 | doi = 10.1038/nature02661 | pmid = 15190254 | bibcode = 2004Natur.429..883L | s2cid = 1867993}}</ref> studied the [[Transcription (biology)|transcriptional]] profiles of the human [[frontal cortex]] of individuals ranging from 26 to 106 years of age. This led to the identification of a set of genes whose [[Gene expression|expression]] was altered after age 40.  They further found that the [[Promoter (genetics)|promoter]] sequences of these particular genes accumulated oxidative DNA damage, including 8-OHdG, with age (see [[DNA damage theory of aging]]).  They concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a pattern of brain aging that starts early in life.{{cn|date=November 2024}}