Neuroscience of aging

Neurogenesis occurs very little in adults; it only occurs in the hypothalamus and striatum to a small extent in a process called adult neurogenesis. Environmental enrichment, physical activity and stress (which can stimulate or hinder this process) are key environmental and physiological factors affecting adult neurogenesis.{{Cite journal |last1=Klempin |first1=Friederike |last2=Kempermann |first2=Gerd |date=2007-08-01 |title=Adult hippocampal neurogenesis and aging |url=https://link.springer.com/article/10.1007/s00406-007-0731-5 |journal=European Archives of Psychiatry and Clinical Neuroscience |language=en |volume=257 |issue=5 |pages=271–280 |doi=10.1007/s00406-007-0731-5 |pmid=17401726 |issn=1433-8491|url-access=subscription }} Sensory stimulation, social interactions, and cognitive challenges can describe an enriched environment.{{Cite journal |last1=van Praag |first1=Henriette |last2=Kempermann |first2=Gerd |last3=Gage |first3=Fred H. |date=December 2000 |title=Neural consequences of enviromental enrichment |url=https://www.nature.com/articles/35044558 |journal=Nature Reviews Neuroscience |language=en |volume=1 |issue=3 |pages=191–198 |doi=10.1038/35044558 |pmid=11257907 |issn=1471-0048|url-access=subscription }} Exercising has frequently increased the reproduction of neuronal precursor cells and helped with age-related declines in neurogenesis. The brain volume decreases roughly 5% per decade after forty. It is currently unclear why brain volume decreases with age. However, a few causes may include cell death, decreased cell volume, and changes in synaptic structure. The changes in brain volume are heterogeneous across regions, with the prefrontal cortex receiving the most significant reduction in volume, followed in order by the striatum, the temporal lobe, the cerebellar vermis, the cerebellar hemispheres, and the hippocampus.{{cite journal|last1=Peters|first1=R|title=Ageing and the brain|journal=Postgraduate Medical Journal|date=8 January 2017|volume=82|issue=964|pages=84–88|doi=10.1136/pgmj.2005.036665|pmc=2596698|issn=0032-5473|pmid=16461469}} However, one review found that the amygdala and ventromedial prefrontal cortex remained relatively free of atrophy, consistent with the finding of emotional stability occurring with non-pathological aging.{{cite journal|last1=Mather|first1=Mara|title=The Affective Neuroscience of Aging|journal=Annual Review of Psychology|date=5 October 2015|volume=67|issue=1|pages=213–238|doi=10.1146/annurev-psych-122414-033540|pmc=5780182|pmid=26436717}} Enlargement of the ventricles, sulci and fissures is common in non-pathological aging.{{cite journal|last1=LeMay|first1=Marjorie|title=Radiologic Changes of the Aging Brain and Skull|journal=American Journal of Neuroradiology|date=1984|volume=5|pages=269–275|url=http://www.ajnr.org/content/5/3/269.full.pdf}}

Changes may also be associated with neuroplasticity, synaptic functionality and voltage-gated calcium channels.{{cite journal|last1=Kelly|first1=K. M.|last2=Nadon|first2=N. L.|last3=Morrison|first3=J. H.|last4=Thibault|first4=O.|last5=Barnes|first5=C. A.|last6=Blalock|first6=E. M.|title=The neurobiology of aging|journal=Epilepsy Research|date=1 January 2006|volume=68|issue=Suppl 1 |pages=S5–20|doi=10.1016/j.eplepsyres.2005.07.015|pmid=16386406|s2cid=17123597|issn=0920-1211}} Increased hyperpolarization, possibly due to dysfunctional calcium regulation, decreases neuron firing rate and plasticity. This effect is particularly pronounced in the hippocampus of aged animals and may be an important contributor to age-associated memory deficits. The hyperpolarization of a neuron can be divided into three stages: fast, medium, and slow hyperpolarization. In aged neurons, the medium and slow hyperpolarization phases involve the prolonged opening of calcium-dependent potassium channels. The prolonging of this phase has been hypothesized to result from deregulated calcium and hypoactivity of cholinergic, dopaminergic, serotonergic and glutaminergic pathways.{{cite journal|last1=Kumar|first1=Ashok|last2=Foster|first2=Thomas C.|title=Neurophysiology of Old Neurons and Synapses|journal=Brain Aging: Models, Methods, and Mechanisms|series=Frontiers in Neuroscience|date=1 January 2007|url=https://www.ncbi.nlm.nih.gov/books/NBK3882/|publisher=CRC Press/Taylor & Francis|pmid=21204354|isbn=9780849338182}}

Episodic memory (remembering specific events) declines gradually from middle age, while semantic memory (general knowledge and facts) increases into early old age and then declines thereafter. Older adults can exhibit reduced activity in specific brain regions during cognitive tasks, particularly in medial temporal areas related to memory processing. On the other hand, overrecruitment of other brain areas, mainly in the prefrontal cortex, can be engaged in memory-related tasks.{{Cite journal |last=Grady |first=Cheryl L. |date=2008 |title=Cognitive Neuroscience of Aging |url=https://nyaspubs.onlinelibrary.wiley.com/doi/10.1196/annals.1440.009 |journal=Annals of the New York Academy of Sciences |language=en |volume=1124 |issue=1 |pages=127–144 |doi=10.1196/annals.1440.009 |pmid=18400928 |bibcode=2008NYASA1124..127G |issn=1749-6632|url-access=subscription }} Older adults also tend to engage their prefrontal cortex more often during working memory tasks, possibly to compensate for executive functions. Further impairments of cognitive function associated with aging include decreased processing speed and inability to focus. A model proposed to account for altered activation posits that decreased neural efficiency driven by amyloid plaques and decreased dopamine functionality lead to compensatory activation.{{cite journal|last1=Reuter-Lorenz|first1=Patricia A.|last2=Park|first2=Denise C.|title=Human Neuroscience and the Aging Mind: A New Look at Old Problems|journal=The Journals of Gerontology Series B: Psychological Sciences and Social Sciences|date=8 January 2017|volume=65B|issue=4|pages=405–415|doi=10.1093/geronb/gbq035|pmc=2883872|issn=1079-5014|pmid=20478901}} Decreased processing of negative stimuli, as opposed to positive stimuli, appears in aging and becomes significant enough to detect even with autonomic nervous responses to emotionally charged stimuli.{{cite book|last1=Kaszniak|first1=Alfred W.|last2=Menchola|first2=Marisa|title=Behavioral neuroscience of emotion in aging| series = Current Topics in Behavioral Neurosciences|date=1 January 2012|volume=10|pages=51–66|doi=10.1007/7854_2011_163|pmid=21910076|isbn=978-3-642-23874-1|issn=1866-3370}} Aging is also associated with decreased plantar reflex and Achilles reflex response. Nerve conductance also decreases during normal aging.{{cite journal|last1=Stanton|first1=Biba R.|title=The neurology of old age|journal=Clinical Medicine|date=1 February 2011|volume=11|issue=1|pages=54–56|doi=10.7861/clinmedicine.11-1-54|url=http://www.clinmed.rcpjournal.org/content/11/1/54.full|language=en|issn=1470-2118|pmc=5873804|pmid=21404786}}

DNA damage is a major risk factor in neurodegenerative diseases and in the decline of neuronal function with age.{{cite journal |vauthors=Delint-Ramirez I, Madabhushi R |title=DNA damage and its links to neuronal aging and degeneration |journal=Neuron |volume=113 |issue=1 |pages=7–28 |date=January 2025 |pmid=39788088 |doi=10.1016/j.neuron.2024.12.001 |url=}} Certain genes of the human frontal cortex display reduced transcriptional expression after age 40, especially after age 70.{{cite journal |vauthors=Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA |title=Gene regulation and DNA damage in the ageing human brain |journal=Nature |volume=429 |issue=6994 |pages=883–91 |date=June 2004 |pmid=15190254 |doi=10.1038/nature02661 |bibcode=2004Natur.429..883L |s2cid=1867993 }} In particular, genes with central roles in synaptic plasticity display reduced expression with age. The promoters of genes with reduced expression in the cortex of older individuals have a marked increase in DNA damage, likely oxidative DNA damage.

{{Further|Geriatric neurology}}

Roughly 20% of persons greater than 60 years of age have a neurological disorder, with episodic disorders being the most common, followed by extrapyramidal movement disorders and nerve disorders.{{cite journal|last1=Callixte|first1=Kuate-Tegueu|last2=Clet|first2=Tchaleu Benjamin|last3=Jacques|first3=Doumbe|last4=Faustin|first4=Yepnjio|last5=François|first5=Dartigues Jean|last6=Maturin|first6=Tabue-Teguo|title=The pattern of neurological diseases in elderly people in outpatient consultations in Sub-Saharan Africa|journal=BMC Research Notes|date=17 April 2015|volume=8|page=159|doi=10.1186/s13104-015-1116-x|pmc=4405818|issn=1756-0500|pmid=25880073 |doi-access=free }} Diseases commonly associated with old age include

• Multiple system atrophy{{cite journal |vauthors=Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN |title=Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study |journal=Brain |year=2008 |doi=10.1093/brain/awn291 |volume=132 |pages=156–71 |pmid=19029129 |issue=Pt 1 |pmc=2638696}}
• Parkinson's disease{{cite book|last1=Carroll|first1=William M.|title=International Neurology|date=2016|publisher=John Wiley & Sons|isbn=9781118777367|page=188|url=https://books.google.com/books?id=mRl6DAAAQBAJ&pg=PA188}}
• Alzheimer's disease{{cite journal|author=Mendez MF|title=Early-onset Alzheimer's disease: nonamnestic subtypes and type 2 AD|journal=Archives of Medical Research|date=November 2012|volume=43|issue=8|pages=677–85|pmid=23178565|doi=10.1016/j.arcmed.2012.11.009|pmc=3532551}}
• Stroke.{{cite journal | vauthors = Vermeer SE, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM | title = Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study | journal = Stroke | volume = 33 | issue = 1 | pages = 21–5 | date = January 2002 | pmid = 11779883 | doi = 10.1161/hs0102.101629 | doi-access = free }}
• Amyotrophic lateral sclerosis{{cite journal|last1=Kiernan|first1=MC|last2=Vucic|first2=S|last3=Cheah|first3=BC|last4=Turner|first4=MR|last5=Eisen|first5=A|last6=Hardiman|first6=O|last7=Burrell|first7=JR|last8=Zoing|first8=MC|title=Amyotrophic lateral sclerosis.|journal=Lancet|date=12 March 2011|volume=377|issue=9769|pages=942–55|pmid=21296405|doi=10.1016/s0140-6736(10)61156-7|s2cid=14354178}}
• Creutzfeldt–Jakob disease{{cite journal|last1=Belay|first1=Ermias D.|last2=Schonberger|first2=Lawrence B.|title=Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy|journal=Clinics in Laboratory Medicine|date=1 December 2002|volume=22|issue=4|pages=849–862, v-vi|pmid=12489284|issn=0272-2712|doi=10.1016/s0272-2712(02)00024-0}}
• Frontotemporal Dementia{{cite journal |author1=Snowden, Julie S. |author2=Neary, David |author3=Mann, David M.A. |title=Frontotemporal dementia |journal=Br J Psychiatry |volume=180 |issue= 2|pages=140–3 |date=February 2002 |pmid=11823324 |doi=10.1192/bjp.180.2.140 |doi-access=free }}
• Dementia with Lewy bodies{{cite book|last1=Dickson|first1=Dennis|last2=Weller|first2=Roy O.|title=Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders|date=2011|publisher=John Wiley & Sons|isbn=9781444341232|page=224|edition=2|url=https://books.google.com/books?id=4SYIwcoH_yoC&pg=PA224|language=en}}
• Corticobasal Degeneration{{cite web |url=http://www.ninds.nih.gov/disorders/corticobasal_degeneration/corticobasal_degeneration.htm |title=Corticobasal Degeneration Information Page: National Institute of Neurological Disorders and Stroke (NINDS) |access-date=2009-03-20 |archive-url=https://web.archive.org/web/20090323180443/http://www.ninds.nih.gov/disorders/corticobasal_degeneration/corticobasal_degeneration.htm |archive-date=2009-03-23 |url-status=dead }}
• Transient ischemic attack
• Vascular dementia

The misfolding of proteins is a common component of the proposed pathophysiology of many aging-related diseases. However, there is insufficient evidence to prove this. For example, the tau hypothesis for Alzheimer's proposes that tau protein accumulation results in the breakdown of neuron cytoskeletons, leading to Alzheimer's.{{cite journal|last1=Goedert|first1=M.|last2=Spillantini|first2=M. G.|last3=Crowther|first3=R. A.|title=Tau proteins and neurofibrillary degeneration|journal=Brain Pathology (Zurich, Switzerland)|date=1 July 1991|volume=1|issue=4|pages=279–286|pmid=1669718|issn=1015-6305|doi=10.1111/j.1750-3639.1991.tb00671.x|s2cid=33331924|doi-access=free}} Another proposed mechanism for Alzheimer's is related to the accumulation of amyloid beta{{cite journal | vauthors = Hardy J, Allsop D | title = Amyloid Deposition as the Central Event in the Aetiology of Alzheimer's Disease | journal = Trends in Pharmacological Sciences | volume = 12 | issue = 10 | pages = 383–88 | pmid = 1763432 | doi = 10.1016/0165-6147(91)90609-V | date = October 1991}} in a similar mechanism to the prion propagation of Creutzfeldt-Jakob disease. Until a recent study, tau proteins were believed to be the precedents for Alzheimer's but in a combination of amyloid beta.{{Cite journal |last1=Spires-Jones |first1=Tara L. |last2=Attems |first2=Johannes |last3=Thal |first3=Dietmar Rudolf |date=2017-04-11 |title=Interactions of pathological proteins in neurodegenerative diseases |journal=Acta Neuropathologica |language=en |volume=134 |issue=2 |pages=187–205 |doi=10.1007/s00401-017-1709-7 |issn=0001-6322 |pmc=5508034 |pmid=28401333}} Similarly, the protein alpha-synuclein is hypothesized to accumulate in Parkinson's and related diseases.{{cite journal|last1=Galpern|first1=Wendy R.|last2=Lang|first2=Anthony E.|title=Interface between tauopathies and synucleinopathies: a tale of two proteins|journal=Annals of Neurology|date=1 March 2006|volume=59|issue=3|pages=449–458|doi=10.1002/ana.20819|pmid=16489609|s2cid=19395939|issn=0364-5134}}

Treatments with anticancer chemotherapeutic agents often are toxic to the cells of the brain, leading to memory loss and cognitive dysfunction that can persist long after the period of exposure. This condition, termed chemo brain, appears to be due to DNA damages that cause epigenetic changes in the brain that accelerate the brain aging process.{{cite journal |vauthors=Kovalchuk A, Kolb B |title=Chemo brain: From discerning mechanisms to lifting the brain fog-An aging connection |journal=Cell Cycle |volume=16 |issue=14 |pages=1345–1349 |date=July 2017 |pmid=28657421 |pmc=5539816 |doi=10.1080/15384101.2017.1334022 }}

Treatment of an age-related neurological disease varies from disease to disease. Modifiable risk factors for dementia include diabetes, hypertension, smoking, hyperhomocysteinemia, hypercholesterolemia, and obesity (which are usually associated with many other risk factors for dementia). Paradoxically, drinking and smoking confer protection against Parkinson's disease.{{cite journal|last1=Barranco Quintana|first1=JL|last2=Allam|first2=MF|last3=Del Castillo|first3=AS|last4=Navajas|first4=RF|title=Parkinson's disease and tea: a quantitative review.|journal=Journal of the American College of Nutrition|date=February 2009|volume=28|issue=1|pages=1–6|pmid=19571153|doi=10.1080/07315724.2009.10719754|s2cid=26605333}}{{Cite journal |last1=Jung |first1=Se Young |last2=Chun |first2=Sohyun |last3=Cho |first3=Eun Bin |last4=Han |first4=Kyungdo |last5=Yoo |first5=Juhwan |last6=Yeo |first6=Yohwan |last7=Yoo |first7=Jung Eun |last8=Jeong |first8=Su Min |last9=Min |first9=Ju-Hong |last10=Shin |first10=Dong Wook |date=2023-09-13 |title=Changes in smoking, alcohol consumption, and the risk of Parkinson's disease |journal=Frontiers in Aging Neuroscience |language=English |volume=15 |doi=10.3389/fnagi.2023.1223310 |doi-access=free |issn=1663-4365 |pmc=10525683 |pmid=37771519}} It also confers protective benefits to age-related neurological disease in the consumption of coffee or caffeine.{{cite journal |vauthors=Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N | title = Caffeine intake and dementia: systematic review and meta-analysis | journal = J. Alzheimers Dis. | volume = 20 | pages = S187–204 | year = 2010 | issue = Suppl 1 | pmid = 20182026 | doi = 10.3233/JAD-2010-091387 | doi-access = free | hdl = 10216/160619 | hdl-access = free }}{{cite journal |vauthors=Marques S, Batalha VL, Lopes LV, Outeiro TF | title = Modulating Alzheimer's disease through caffeine: a putative link to epigenetics | journal = J. Alzheimers Dis. | volume = 24 | issue = 2 | pages = 161–71 | year = 2011 | pmid = 21427489 | doi = 10.3233/JAD-2011-110032 }}{{cite journal |vauthors=Arendash GW, Cao C | title = Caffeine and coffee as therapeutics against Alzheimer's disease | journal = J. Alzheimers Dis. | volume = 20 | pages = S117–26 | year = 2010 | issue = Suppl 1 | pmid = 20182037 | doi = 10.3233/JAD-2010-091249 | doi-access = free }} Consumption of fruits, fish and vegetables confers protection against dementia, as does a Mediterranean diet.{{cite journal|last1=Lourida|first1=Ilianna|last2=Soni|first2=Maya|last3=Thompson-Coon|first3=Joanna|last4=Purandare|first4=Nitin|last5=Lang|first5=Iain A.|last6=Ukoumunne|first6=Obioha C.|last7=Llewellyn|first7=David J.|title=Mediterranean Diet, Cognitive Function, and Dementia|journal=Epidemiology|date=July 2013|volume=24|issue=4|pages=479–489|doi=10.1097/EDE.0b013e3182944410|pmid=23680940|s2cid=19602773|doi-access=free}} In animal experiments, long-term calorie restriction was found to help reduce oxidative DNA damage.{{Cite journal |last1=Vitantonio |first1=Ana T. |last2=Dimovasili |first2=Christina |last3=Mortazavi |first3=Farzad |last4=Vaughan |first4=Kelli L. |last5=Mattison |first5=Julie A. |last6=Rosene |first6=Douglas L. |date=2024-09-01 |title=Long-term calorie restriction reduces oxidative DNA damage to oligodendroglia and promotes homeostatic microglia in the aging monkey brain |url=https://linkinghub.elsevier.com/retrieve/pii/S0197458024000964 |journal=Neurobiology of Aging |volume=141 |pages=1–13 |doi=10.1016/j.neurobiolaging.2024.05.005 |issn=0197-4580 |pmc=11318518 |pmid=38788462|pmc-embargo-date=September 1, 2025 }} Physical exercise significantly lowers the risk of cognitive decline in old age{{cite journal|last1=Andrade|first1=Chittaranjan|last2=Radhakrishnan|first2=Rajiv|title=The prevention and treatment of cognitive decline and dementia: An overview of recent research on experimental treatments|journal=Indian Journal of Psychiatry|date=1 January 2009|volume=51|issue=1|pages=12–25|doi=10.4103/0019-5545.44900|pmc=2738400|issn=0019-5545|pmid=19742190 |doi-access=free }} and is an effective treatment for those with dementia{{cite journal | vauthors = Farina N, Rusted J, Tabet N | title = The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review | journal = Int Psychogeriatr | volume = 26 | issue = 1 | pages = 9–18 | date = January 2014 | pmid = 23962667 | doi = 10.1017/S1041610213001385 | s2cid = 24936334 | doi-access = free }}{{cite journal | vauthors = Rao AK, Chou A, Bursley B, Smulofsky J, Jezequel J | title = Systematic review of the effects of exercise on activities of daily living in people with Alzheimer's disease | journal = Am J Occup Ther | volume = 68 | issue = 1 | pages = 50–56 | date = January 2014 | pmid = 24367955 | doi = 10.5014/ajot.2014.009035| pmc = 5360200 }} and Parkinson's disease.{{cite journal | vauthors = Mattson MP | title = Interventions that improve body and brain bioenergetics for Parkinson's disease risk reduction and therapy | journal = J Parkinsons Dis | volume = 4 | issue = 1 | pages = 1–13 | year = 2014 | pmid = 24473219 | doi = 10.3233/JPD-130335 | doi-access = free }}{{cite journal | vauthors = Grazina R, Massano J | title = Physical exercise and Parkinson's disease: influence on symptoms, disease course and prevention | journal = Rev Neurosci | volume = 24 | issue = 2 | pages = 139–152 | year = 2013 | pmid = 23492553 | doi = 10.1515/revneuro-2012-0087 | s2cid = 33890283 }}{{cite journal | vauthors = van der Kolk NM, King LA | title = Effects of exercise on mobility in people with Parkinson's disease | journal = Mov. Disord. | volume = 28 | issue = 11 | pages = 1587–1596 | date = September 2013 | pmid = 24132847 | doi = 10.1002/mds.25658 | s2cid = 22822120 }}{{cite journal | vauthors = Tomlinson CL, Patel S, Meek C, Herd CP, Clarke CE, Stowe R, Shah L, Sackley CM, Deane KH, Wheatley K, Ives N | title = Physiotherapy versus placebo or no intervention in Parkinson's disease | journal = Cochrane Database Syst Rev | volume = 9 | pages = CD002817 | date = September 2013 | issue = 9 | pmid = 24018704 | doi = 10.1002/14651858.CD002817.pub4 | pmc = 7120224 }}

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Category:Developmental neuroscience

Category:Geriatrics

Category:Gerontology