Neuroscience of aging

Short description: Field of study

The neuroscience of aging is the study of the changes in the nervous system that occur with aging. Aging is associated with many changes in the central nervous system, such as mild atrophy of the cortex, which is considered non-pathological. Aging is also associated with many neurological and neurodegenerative diseases, such as amyotrophic lateral sclerosis, dementia, mild cognitive impairment, Parkinson's disease, and Creutzfeldt–Jakob disease.[1]

## Contents

* 1 Normal structural and neural changes
* 2 Normal functional changes
* 2.1 DNA damage
* 3 Pathological changes
* 3.1 Chemo brain
* 4 Management
* 5 References

## Normal structural and neural changes

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.[2] Sensory stimulation, social interactions, and cognitive challenges can describe an enriched environment.[3] 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.[4] 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.[5] Enlargement of the ventricles, sulci and fissures is common in non-pathological aging.[6]

Changes may also be associated with neuroplasticity, synaptic functionality and voltage-gated calcium channels.[7] 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.[8]

## Normal functional changes

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.[4] 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.[9] 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.[10] 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.[11] Aging is also associated with decreased plantar reflex and Achilles reflex response. Nerve conductance also decreases during normal aging.[12]

### DNA damage

DNA damage is a major risk factor in neurodegenerative diseases and in the decline of neuronal function with age.[13] Certain genes of the human frontal cortex display reduced transcriptional expression after age 40, especially after age 70.[14] 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.[14]

## Pathological changes

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.[15]  Diseases commonly associated with old age include

* Multiple system atrophy[16]
* Parkinson's disease[17]
* Alzheimer's disease[18]
* Stroke.[19]
* Amyotrophic lateral sclerosis[20]
* Creutzfeldt–Jakob disease[21]
* Frontotemporal Dementia[22]
* Dementia with Lewy bodies[23]
* Corticobasal Degeneration[24]
* 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.[25] Another proposed mechanism for Alzheimer's is related to the accumulation of amyloid beta[26] 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.[27] Similarly, the protein alpha-synuclein is hypothesized to accumulate in Parkinson's and related diseases.[28]

### Chemo brain

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.[29]

## Management

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.[30][31] It also confers protective benefits to age-related neurological disease in the consumption of coffee or caffeine.[32][33][34] Consumption of fruits, fish and vegetables confers protection against dementia, as does a Mediterranean diet.[35] In animal experiments, long-term calorie restriction was found to help reduce oxidative DNA damage.[36] Physical exercise significantly lowers the risk of cognitive decline in old age[37] and is an effective treatment for those with dementia[38][39] and Parkinson's disease.[40][41][42][43]

## References

1. ↑ Brown, Rebecca C.; Lockwood, Alan H.; Sonawane, Babasaheb R. (8 January 2017). "Neurodegenerative Diseases: An Overview of Environmental Risk Factors". Environmental Health Perspectives 113 (9): 1250–1256. doi:10.1289/ehp.7567. ISSN 0091-6765. PMID 16140637.
2. ↑ Klempin, Friederike; Kempermann, Gerd (2007-08-01). "Adult hippocampal neurogenesis and aging" (in en). European Archives of Psychiatry and Clinical Neuroscience 257 (5): 271–280. doi:10.1007/s00406-007-0731-5. ISSN 1433-8491. PMID 17401726. https://link.springer.com/article/10.1007/s00406-007-0731-5.
3. ↑ van Praag, Henriette; Kempermann, Gerd; Gage, Fred H. (December 2000). "Neural consequences of environmental enrichment" (in en). Nature Reviews Neuroscience 1 (3): 191–198. doi:10.1038/35044558. ISSN 1471-0048. PMID 11257907. https://www.nature.com/articles/35044558.
4. ↑ 4.0 4.1 Peters, R (8 January 2017). "Ageing and the brain". Postgraduate Medical Journal 82 (964): 84–88. doi:10.1136/pgmj.2005.036665. ISSN 0032-5473. PMID 16461469.
5. ↑ Mather, Mara (5 October 2015). "The Affective Neuroscience of Aging". Annual Review of Psychology 67 (1): 213–238. doi:10.1146/annurev-psych-122414-033540. PMID 26436717.
6. ↑ LeMay, Marjorie (1984). "Radiologic Changes of the Aging Brain and Skull". American Journal of Neuroradiology 5: 269–275. http://www.ajnr.org/content/5/3/269.full.pdf.
7. ↑ Kelly, K. M.; Nadon, N. L.; Morrison, J. H.; Thibault, O.; Barnes, C. A.; Blalock, E. M. (1 January 2006). "The neurobiology of aging". Epilepsy Research 68 (Suppl 1): S5–20. doi:10.1016/j.eplepsyres.2005.07.015. ISSN 0920-1211. PMID 16386406.
8. ↑ Kumar, Ashok; Foster, Thomas C. (1 January 2007). "Neurophysiology of Old Neurons and Synapses". Brain Aging: Models, Methods, and Mechanisms. Frontiers in Neuroscience (CRC Press/Taylor & Francis). ISBN 978-0-8493-3818-2. PMID 21204354. https://www.ncbi.nlm.nih.gov/books/NBK3882/.
9. ↑ Grady, Cheryl L. (2008). "Cognitive Neuroscience of Aging" (in en). Annals of the New York Academy of Sciences 1124 (1): 127–144. doi:10.1196/annals.1440.009. ISSN 1749-6632. PMID 18400928. Bibcode: 2008NYASA1124..127G. https://nyaspubs.onlinelibrary.wiley.com/doi/10.1196/annals.1440.009.
10. ↑ Reuter-Lorenz, Patricia A.; Park, Denise C. (8 January 2017). "Human Neuroscience and the Aging Mind: A New Look at Old Problems". The Journals of Gerontology Series B: Psychological Sciences and Social Sciences 65B (4): 405–415. doi:10.1093/geronb/gbq035. ISSN 1079-5014. PMID 20478901.
11. ↑ Kaszniak, Alfred W.; Menchola, Marisa (1 January 2012). Behavioral neuroscience of emotion in aging. Current Topics in Behavioral Neurosciences. 10. pp. 51–66. doi:10.1007/7854_2011_163. ISBN 978-3-642-23874-1.
12. ↑ Stanton, Biba R. (1 February 2011). "The neurology of old age" (in en). Clinical Medicine 11 (1): 54–56. doi:10.7861/clinmedicine.11-1-54. ISSN 1470-2118. PMID 21404786. PMC 5873804. http://www.clinmed.rcpjournal.org/content/11/1/54.full.
13. ↑ "DNA damage and its links to neuronal aging and degeneration". Neuron 113 (1): 7–28. January 2025. doi:10.1016/j.neuron.2024.12.001. PMID 39788088.
14. ↑ 14.0 14.1 "Gene regulation and DNA damage in the ageing human brain". Nature 429 (6994): 883–91. June 2004. doi:10.1038/nature02661. PMID 15190254. Bibcode: 2004Natur.429..883L.
15. ↑ Callixte, Kuate-Tegueu; Clet, Tchaleu Benjamin; Jacques, Doumbe; Faustin, Yepnjio; François, Dartigues Jean; Maturin, Tabue-Teguo (17 April 2015). "The pattern of neurological diseases in elderly people in outpatient consultations in Sub-Saharan Africa". BMC Research Notes 8. doi:10.1186/s13104-015-1116-x. ISSN 1756-0500. PMID 25880073.
16. ↑ "Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study". Brain 132 (Pt 1): 156–71. 2008. doi:10.1093/brain/awn291. PMID 19029129.
17. ↑ Carroll, William M. (2016). International Neurology. John Wiley & Sons. p. 188. ISBN 978-1-118-77736-7. https://books.google.com/books?id=mRl6DAAAQBAJ&pg=PA188.
18. ↑ Mendez MF (November 2012). "Early-onset Alzheimer's disease: nonamnestic subtypes and type 2 AD". Archives of Medical Research 43 (8): 677–85. doi:10.1016/j.arcmed.2012.11.009. PMID 23178565.
19. ↑ "Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study". Stroke 33 (1): 21–5. January 2002. doi:10.1161/hs0102.101629. PMID 11779883.
20. ↑ Kiernan, MC; Vucic, S; Cheah, BC; Turner, MR; Eisen, A; Hardiman, O; Burrell, JR; Zoing, MC (12 March 2011). "Amyotrophic lateral sclerosis.". Lancet 377 (9769): 942–55. doi:10.1016/s0140-6736(10)61156-7. PMID 21296405. Bibcode: 2011Lanc..377..942K.
21. ↑ Belay, Ermias D.; Schonberger, Lawrence B. (1 December 2002). "Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy". Clinics in Laboratory Medicine 22 (4): 849–862, v-vi. doi:10.1016/s0272-2712(02)00024-0. ISSN 0272-2712. PMID 12489284.
22. ↑ Snowden, Julie S.; Neary, David; Mann, David M.A. (February 2002). "Frontotemporal dementia". Br J Psychiatry 180 (2): 140–3. doi:10.1192/bjp.180.2.140. PMID 11823324.
23. ↑ Dickson, Dennis; Weller, Roy O. (2011) (in en). Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders (2 ed.). John Wiley & Sons. p. 224. ISBN 978-1-4443-4123-2. https://books.google.com/books?id=4SYIwcoH_yoC&pg=PA224.
24. ↑ "Corticobasal Degeneration Information Page: National Institute of Neurological Disorders and Stroke (NINDS)". http://www.ninds.nih.gov/disorders/corticobasal_degeneration/corticobasal_degeneration.htm.
25. ↑ Goedert, M.; Spillantini, M. G.; Crowther, R. A. (1 July 1991). "Tau proteins and neurofibrillary degeneration". Brain Pathology (Zurich, Switzerland) 1 (4): 279–286. doi:10.1111/j.1750-3639.1991.tb00671.x. ISSN 1015-6305. PMID 1669718.
26. ↑ "Amyloid Deposition as the Central Event in the Aetiology of Alzheimer's Disease". Trends in Pharmacological Sciences 12 (10): 383–88. October 1991. doi:10.1016/0165-6147(91)90609-V. PMID 1763432.
27. ↑ Spires-Jones, Tara L.; Attems, Johannes; Thal, Dietmar Rudolf (2017-04-11). "Interactions of pathological proteins in neurodegenerative diseases" (in en). Acta Neuropathologica 134 (2): 187–205. doi:10.1007/s00401-017-1709-7. ISSN 0001-6322. PMID 28401333.
28. ↑ Galpern, Wendy R.; Lang, Anthony E. (1 March 2006). "Interface between tauopathies and synucleinopathies: a tale of two proteins". Annals of Neurology 59 (3): 449–458. doi:10.1002/ana.20819. ISSN 0364-5134. PMID 16489609.
29. ↑ "Chemo brain: From discerning mechanisms to lifting the brain fog-An aging connection". Cell Cycle 16 (14): 1345–1349. July 2017. doi:10.1080/15384101.2017.1334022. PMID 28657421.
30. ↑ Barranco Quintana, JL; Allam, MF; Del Castillo, AS; Navajas, RF (February 2009). "Parkinson's disease and tea: a quantitative review.". Journal of the American College of Nutrition 28 (1): 1–6. doi:10.1080/07315724.2009.10719754. PMID 19571153.
31. ↑ Jung, Se Young; Chun, Sohyun; Cho, Eun Bin; Han, Kyungdo; Yoo, Juhwan; Yeo, Yohwan; Yoo, Jung Eun; Jeong, Su Min et al. (2023-09-13). "Changes in smoking, alcohol consumption, and the risk of Parkinson's disease" (in English). Frontiers in Aging Neuroscience 15. doi:10.3389/fnagi.2023.1223310. ISSN 1663-4365. PMID 37771519.
32. ↑ "Caffeine intake and dementia: systematic review and meta-analysis". J. Alzheimers Dis. 20 (Suppl 1): S187–204. 2010. doi:10.3233/JAD-2010-091387. PMID 20182026.
33. ↑ "Modulating Alzheimer's disease through caffeine: a putative link to epigenetics". J. Alzheimers Dis. 24 (2): 161–71. 2011. doi:10.3233/JAD-2011-110032. PMID 21427489.
34. ↑ "Caffeine and coffee as therapeutics against Alzheimer's disease". J. Alzheimers Dis. 20 (Suppl 1): S117–26. 2010. doi:10.3233/JAD-2010-091249. PMID 20182037.
35. ↑ Lourida, Ilianna; Soni, Maya; Thompson-Coon, Joanna; Purandare, Nitin; Lang, Iain A.; Ukoumunne, Obioha C.; Llewellyn, David J. (July 2013). "Mediterranean Diet, Cognitive Function, and Dementia". Epidemiology 24 (4): 479–489. doi:10.1097/EDE.0b013e3182944410. PMID 23680940.
36. ↑ Vitantonio, Ana T.; Dimovasili, Christina; Mortazavi, Farzad; Vaughan, Kelli L.; Mattison, Julie A.; Rosene, Douglas L. (2024-09-01). "Long-term calorie restriction reduces oxidative DNA damage to oligodendroglia and promotes homeostatic microglia in the aging monkey brain". Neurobiology of Aging 141: 1–13. doi:10.1016/j.neurobiolaging.2024.05.005. ISSN 0197-4580. PMID 38788462.
37. ↑ Andrade, Chittaranjan; Radhakrishnan, Rajiv (1 January 2009). "The prevention and treatment of cognitive decline and dementia: An overview of recent research on experimental treatments". Indian Journal of Psychiatry 51 (1): 12–25. doi:10.4103/0019-5545.44900. ISSN 0019-5545. PMID 19742190.
38. ↑ "The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review". Int Psychogeriatr 26 (1): 9–18. January 2014. doi:10.1017/S1041610213001385. PMID 23962667.
39. ↑ "Systematic review of the effects of exercise on activities of daily living in people with Alzheimer's disease". Am J Occup Ther 68 (1): 50–56. January 2014. doi:10.5014/ajot.2014.009035. PMID 24367955.
40. ↑ "Interventions that improve body and brain bioenergetics for Parkinson's disease risk reduction and therapy". J Parkinsons Dis 4 (1): 1–13. 2014. doi:10.3233/JPD-130335. PMID 24473219.
41. ↑ "Physical exercise and Parkinson's disease: influence on symptoms, disease course and prevention". Rev Neurosci 24 (2): 139–152. 2013. doi:10.1515/revneuro-2012-0087. PMID 23492553.
42. ↑ "Effects of exercise on mobility in people with Parkinson's disease". Mov. Disord. 28 (11): 1587–1596. September 2013. doi:10.1002/mds.25658. PMID 24132847.
43. ↑ "Physiotherapy versus placebo or no intervention in Parkinson's disease". Cochrane Database Syst Rev 2013 (9). September 2013. doi:10.1002/14651858.CD002817.pub4. PMID 24018704.

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