Aging and neurodegeneration - Revision history

Andrea at 11:13, 27 December 2022

2022-12-27T11:13:00Z

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	<references />		<references />
	[[Category:Age-related diseases]]		[[Category:Age-related diseases]]
			[[Category:Main list]]

Andrea: category change

2022-12-27T09:35:38Z

category change

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	==References==		==References==
	<references />		<references />
	~~[[Category:Longevity]]~~
	[[Category:Age-related diseases]]		[[Category:Age-related diseases]]

Andrea: category

2022-12-27T09:30:54Z

Andrea: Andrea moved page Aging and Neurodegeneration to Aging and neurodegeneration: Changed title

2022-08-25T17:22:45Z

Andrea moved page Aging and Neurodegeneration to Aging and neurodegeneration: Changed title

← Older revision	Revision as of 17:22, 25 August 2022
(No difference)

Geroscientist: /* Head Trauma */

2022-07-20T05:07:44Z

Head Trauma

Geroscientist: /* How to reduce the risk of exposure to environmental toxins? */

2022-07-20T04:39:19Z

How to reduce the risk of exposure to environmental toxins?

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	Head trauma is a risk factor for a variety of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), FrontoTemporal Dementia (FTD) and chronic traumatic encephalopathy and raises the risk of all-cause dementia by a factor of approximately 1.5.<ref>Li Y, Li Y, Li X, Zhang S, Zhao J, Zhu X, et al. (2017) Head Injury as a Risk Factor for Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of 32 Observational Studies. PLoS ONE 12(1): e0169650. <nowiki>https://doi.org/10.1371/journal.pone.0169650</nowiki></ref> Head trauma has been associated with defects in the blood-brain barrier, neuroinflammation, τ-hyperphosphorylation and TDP-43 aggregation.<ref>Graham NS, Sharp DJ, Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia. ''Journal of Neurology, Neurosurgery & Psychiatry'' 2019;'''90:'''1221-1233.</ref>		Head trauma is a risk factor for a variety of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), FrontoTemporal Dementia (FTD) and chronic traumatic encephalopathy and raises the risk of all-cause dementia by a factor of approximately 1.5.<ref>Li Y, Li Y, Li X, Zhang S, Zhao J, Zhu X, et al. (2017) Head Injury as a Risk Factor for Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of 32 Observational Studies. PLoS ONE 12(1): e0169650. <nowiki>https://doi.org/10.1371/journal.pone.0169650</nowiki></ref> Head trauma has been associated with defects in the blood-brain barrier, neuroinflammation, τ-hyperphosphorylation and TDP-43 aggregation.<ref>Graham NS, Sharp DJ, Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia. ''Journal of Neurology, Neurosurgery & Psychiatry'' 2019;'''90:'''1221-1233.</ref>

	===Social ~~Environmental Factors~~===		===Social environmental factors===
	Social environmental conditions during childhood have been suggested as a risk factor for neurodegenerative diseases. Lower socioeconomic status during early life and childhood trauma appears to be associated with decreased late-life cognitive abilities, but does not directly influence the risk of Alzheimer's disease or the rate of cognitive decline.<ref>Wilson RS, Scherr PA, Hoganson G, Bienias JL, Evans DA, Bennett DA. Early life socioeconomic status and late life risk of Alzheimer's disease. Neuroepidemiology. 2005;25(1):8-14. doi: 10.1159/000085307. </ref>		Social environmental conditions during childhood have been suggested as a risk factor for neurodegenerative diseases. Lower socioeconomic status during early life and childhood trauma appears to be associated with decreased late-life cognitive abilities, but does not directly influence the risk of Alzheimer's disease or the rate of cognitive decline.<ref>Wilson RS, Scherr PA, Hoganson G, Bienias JL, Evans DA, Bennett DA. Early life socioeconomic status and late life risk of Alzheimer's disease. Neuroepidemiology. 2005;25(1):8-14. doi: 10.1159/000085307. </ref>

	Lower education levels and lower general cognitive abilities in childhood are associated to a higher risk of developing Alzheimer's disease and to a lower cognitive reserve .<ref>Stern, Yaakov, Cognitive reserve in ageing and Alzheimer's disease, The Lancet Neurology, Volume 11, Issue 11, 1006 - 1012, <nowiki>https://doi.org/10.1016/S1474-4422(12)70191-6</nowiki></ref><ref>Mehta, K.M., Stewart, A.L., Langa, K.M., Yaffe, K., Moody-Ayers, S., Williams, B.A. and Covinsky, K.E. (2009), “Below average” self-assessed school performance and Alzheimer's disease in the Aging, Demographics, and Memory Study. Alzheimer's & Dementia, 5: 380-387. <nowiki>https://doi.org/10.1016/j.jalz.2009.07.039</nowiki></ref> Cognitive reserve (CR) is defined as the resilience that individuals display in terms of ~~behavioural~~ function when there is existing brain damage. Individuals with higher CR will showcase a lesser degree of impairment than individuals with lower CR, when both are subject to the same degree of observable brain damage. In other words, individuals with a higher cognitive reserve are likely to remain functional for longer. Higher levels of education and cognitively complex occupations are associated to a higher CR and seem to be protective against the onset of Alzheimer's disease.<ref>Staff, R., Murray, A., Deary, I., & Whalley, L. (2004). What provides cerebral reserve?. ''Brain'', ''127''(5), 1191-1199. doi: 10.1093/brain/awh144</ref>		Lower education levels and lower general cognitive abilities in childhood are associated to a higher risk of developing Alzheimer's disease and to a lower cognitive reserve .<ref>Stern, Yaakov, Cognitive reserve in ageing and Alzheimer's disease, The Lancet Neurology, Volume 11, Issue 11, 1006 - 1012, <nowiki>https://doi.org/10.1016/S1474-4422(12)70191-6</nowiki></ref><ref>Mehta, K.M., Stewart, A.L., Langa, K.M., Yaffe, K., Moody-Ayers, S., Williams, B.A. and Covinsky, K.E. (2009), “Below average” self-assessed school performance and Alzheimer's disease in the Aging, Demographics, and Memory Study. Alzheimer's & Dementia, 5: 380-387. <nowiki>https://doi.org/10.1016/j.jalz.2009.07.039</nowiki></ref> Cognitive reserve (CR) is defined as the resilience that individuals display in terms of behavioral function when there is existing brain damage. Individuals with higher CR will showcase a lesser degree of impairment than individuals with lower CR, when both are subject to the same degree of observable brain damage. In other words, individuals with a higher cognitive reserve are likely to remain functional for longer. Higher levels of education and cognitively complex occupations are associated to a higher CR and seem to be protective against the onset of Alzheimer's disease.<ref>Staff, R., Murray, A., Deary, I., & Whalley, L. (2004). What provides cerebral reserve?. ''Brain'', ''127''(5), 1191-1199. doi: 10.1093/brain/awh144</ref>

	==Brain aging and functional decline ==		==Brain aging and functional decline ==

Geroscientist: /* Social Environmental Factors */

2022-07-20T04:38:14Z

Social Environmental Factors

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	===Genetic risk factors===		===Genetic risk factors===
	In most common neurodegenerative diseases, there are known genetic risk factors that explain to varying degrees the onset and advance of neurodegeneration. Some neurodegenerative diseases are monogenic, meaning they are ~~mediated exclusively~~ by ~~the dysfunction of~~ a single gene, as is the case of Huntington's disease (which is caused by an abnormal repeat expansion of the Huntingtin ''HTT'' gene). However, most neurodegenerative diseases including Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS) or Parkinson's disease, display a complex genetic relationship and are associated to a plethora of genetic markers, each contributing ~~with~~ a small effect size to the disease phenotype.<ref>Manzoni, C., Lewis, P., & Ferrari, R. (2020). Network Analysis for Complex Neurodegenerative Diseases. ''Current Genetic Medicine Reports'', ''8''(1), 17-25. doi: 10.1007/s40142-020-00181-z</ref>		In most common neurodegenerative diseases, there are known genetic risk factors that explain to varying degrees the onset and advance of neurodegeneration. Some neurodegenerative diseases are monogenic, meaning that they are caused by a single gene, as is the case of Huntington's disease (which is caused by an abnormal repeat expansion of the Huntingtin ''HTT'' gene). However, most neurodegenerative diseases including Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS) or Parkinson's disease, display a complex genetic relationship and are associated with a plethora of genetic markers, each contributing a small effect size to the disease phenotype.<ref>Manzoni, C., Lewis, P., & Ferrari, R. (2020). Network Analysis for Complex Neurodegenerative Diseases. ''Current Genetic Medicine Reports'', ''8''(1), 17-25. doi: 10.1007/s40142-020-00181-z</ref>

	For Alzheimer's disease and Parkinson's disease, genetic variants with high penetrance have identified β-amyloid and α-synuclein ~~production in the pathogenesis~~, respectively. Variants with high penetrance often lead to familial forms of the disease, which are ~~characterised~~ for early onset and low prevalence in the population, accounting for less than 1% of cases in Alzheimer's disease. <ref>Raimundo, R., Jesus, R., & Veiga, A. (2021). Familial Alzheimer’s Disease due to Presenilin 1 Mutation at the Age of 33: a Case Report. ''SN Comprehensive Clinical Medicine'', ''3''(10), 2021-2023. doi: 10.1007/s42399-021-00982-5</ref> Familial cases have nonetheless been subject to considerable research interest, hoping to identify common disease mechanisms.<ref>Gan, L., Cookson, M.R., Petrucelli, L. ''et al.'' Converging pathways in neurodegeneration, from genetics to mechanisms. ''Nat Neurosci'' 21, 1300–1309 (2018). <nowiki>https://doi.org/10.1038/s41593-018-0237-7</nowiki></ref>		For Alzheimer's disease and Parkinson's disease, genetic variants with high penetrance have identified β-amyloid and α-synuclein proteins that lead to pathology, respectively. Variants with high penetrance often lead to familial forms of the disease, which are characterized for early onset and low prevalence in the population, accounting for less than 1% of cases in Alzheimer's disease. <ref>Raimundo, R., Jesus, R., & Veiga, A. (2021). Familial Alzheimer’s Disease due to Presenilin 1 Mutation at the Age of 33: a Case Report. ''SN Comprehensive Clinical Medicine'', ''3''(10), 2021-2023. doi: 10.1007/s42399-021-00982-5</ref> Familial cases have nonetheless been subject to considerable research interest, hoping to identify common disease mechanisms.<ref>Gan, L., Cookson, M.R., Petrucelli, L. ''et al.'' Converging pathways in neurodegeneration, from genetics to mechanisms. ''Nat Neurosci'' 21, 1300–1309 (2018). <nowiki>https://doi.org/10.1038/s41593-018-0237-7</nowiki></ref>

	In sporadic forms of the disease (occurring with no ~~discernible~~ pattern), Genome-Wide Association Studies (GWAS) have been able to identify important risk-alleles, such as mutations in the ''APOE'' gene for Alzheimer's disease, or mutations in the ''SNCA'' and ''MAPT'' genes for Parkinson's. Mutations associated with Alzheimer's disease and Parkinson's disease do not seem to overlap to a significant degree.<ref>Moskvina V, Harold D, Russo G, et al. Analysis of Genome-Wide Association Studies of Alzheimer Disease and of Parkinson Disease to Determine If These 2 Diseases Share a Common Genetic Risk. ''JAMA Neurol.'' 2013;70(10):1268–1276. doi:10.1001/jamaneurol.2013.448</ref>		In sporadic forms of the disease (occurring with no apparent pattern), Genome-Wide Association Studies (GWAS) have been able to identify important risk-alleles, such as mutations in the ''APOE'' gene for Alzheimer's disease, or mutations in the ''SNCA'' and ''MAPT'' genes for Parkinson's. Mutations associated with Alzheimer's disease and Parkinson's disease do not seem to overlap to a significant degree.<ref>Moskvina V, Harold D, Russo G, et al. Analysis of Genome-Wide Association Studies of Alzheimer Disease and of Parkinson Disease to Determine If These 2 Diseases Share a Common Genetic Risk. ''JAMA Neurol.'' 2013;70(10):1268–1276. doi:10.1001/jamaneurol.2013.448</ref>

	Polymorphisms in the ''APOE'' gene, a gene which encodes a protein mainly involved in lipid metabolism, is the best-described genetic factor for Alzheimer's disease. ''APOE'' has three major variants, ε2, ε3 and ε4. Whilst the ε2 allele confers a reduced risk for Alzheimer's disease (0.56-fold risk for heterozygous and homozygous carriers) compared to the most common ε3 allele, ε4 has shown to be a major risk factor for Alzheimer's disease (3.63-fold risk for heterozygous carriers and 14.49-fold for homozygous carriers).<ref>Yamazaki, Y., Zhao, N., Caulfield, T.R. ''et al.'' Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. ''Nat Rev Neurol'' 15, 501–518 (2019). <nowiki>https://doi.org/10.1038/s41582-019-0228-7</nowiki></ref>		Polymorphisms in the ''APOE'' gene, a gene which encodes a protein mainly involved in lipid metabolism, is the best-described genetic factor for Alzheimer's disease. ''APOE'' has three major variants, ε2, ε3 and ε4. Whilst the ε2 allele confers a reduced risk for Alzheimer's disease (0.56-fold risk for heterozygous and homozygous carriers) compared to the most common ε3 allele, ε4 has shown to be a major risk factor for Alzheimer's disease (3.63-fold risk for heterozygous carriers and 14.49-fold for homozygous carriers).<ref>Yamazaki, Y., Zhao, N., Caulfield, T.R. ''et al.'' Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. ''Nat Rev Neurol'' 15, 501–518 (2019). <nowiki>https://doi.org/10.1038/s41582-019-0228-7</nowiki></ref>

	===Environmental ~~Toxins~~===		===Environmental toxins===
	Long-term exposure to environmental toxins has been described as a risk factor for various neurodegenerative diseases.<ref name=":2" /> Environmental toxins most commonly refers to metals toxins (such as zinc, copper or mercury) and biotoxins, which are toxic substances of a biological origin (bacteria, plants or fungi).		Long-term exposure to environmental toxins has been described as a risk factor for various neurodegenerative diseases.<ref name=":2" /> Environmental toxins most commonly refers to metals toxins (such as zinc, copper or mercury) and biotoxins, which are toxic substances of a biological origin (bacteria, plants or fungi).

	Environmental toxins have been shown to play a role in inducing oxidative stress and up-regulating pro-inflammatory cytokines, which can result in increased inflammatory responses and neuronal damage.<ref name=":2" /> Some studies have found that metal toxins and biotoxins interact together in a complex manner, and that the nature of this relationship can determine the degree of impairment in neurological function.<ref>Kamel, F., & Hoppin, J. A. (2004). Association of pesticide exposure with neurologic dysfunction and disease. ''Environmental health perspectives'', ''112''(9), 950–958. <nowiki>https://doi.org/10.1289/ehp.7135</nowiki></ref>		Environmental toxins have been shown to play a role in inducing oxidative stress and up-regulating pro-inflammatory cytokines, which can result in increased inflammatory responses and neuronal damage.<ref name=":2" /> Some studies have found that metal toxins and biotoxins interact together in a complex manner, and that the nature of this relationship can determine the degree of impairment in neurological function.<ref>Kamel, F., & Hoppin, J. A. (2004). Association of pesticide exposure with neurologic dysfunction and disease. ''Environmental health perspectives'', ''112''(9), 950–958. <nowiki>https://doi.org/10.1289/ehp.7135</nowiki></ref>

	Chronic exposure to environmental toxins has been directly implicated in amyloid-β aggregation and τ-hyperphosphorylation, two pathological traits that lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of Alzheimer's disease.<ref name=":2">Maryam Vasefi, Ehsan Ghaboolian-Zare, Hamzah Abedelwahab, Anthony Osu, Environmental toxins and Alzheimer's disease progression, Neurochemistry International, Volume 141, 2020, ISSN [tel:0197-0186 0197-0186], <nowiki>https://doi.org/10.1016/j.neuint.2020.104852</nowiki>.</ref><ref>Plamena R. Angelova, Sources and triggers of oxidative damage in neurodegeneration, Free Radical Biology and Medicine, Volume 173, 2021, Pages 52-63, ISSN [tel:0891-5849 0891-5849], <nowiki>https://doi.org/10.1016/j.freeradbiomed.2021.07.003</nowiki>.</ref>. Moreover, fetal and even epigenetic mechanisms (before pregnancy) to ~~due~~ maternal exposure to such toxins has been proposed to be the underlying cause of the phenotypic diversity and likelihood in developing neurodegenerative diseases.<ref>Chin-Chan, M., Navarro-Yepes, J., & Quintanilla-Vega, B. (2015). Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. ''Frontiers In Cellular Neuroscience'', ''9''. doi: 10.3389/fncel.2015.00124</ref>		Chronic exposure to environmental toxins has been directly implicated in amyloid-β aggregation and τ-hyperphosphorylation, two pathological traits that lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of Alzheimer's disease.<ref name=":2">Maryam Vasefi, Ehsan Ghaboolian-Zare, Hamzah Abedelwahab, Anthony Osu, Environmental toxins and Alzheimer's disease progression, Neurochemistry International, Volume 141, 2020, ISSN [tel:0197-0186 0197-0186], <nowiki>https://doi.org/10.1016/j.neuint.2020.104852</nowiki>.</ref><ref>Plamena R. Angelova, Sources and triggers of oxidative damage in neurodegeneration, Free Radical Biology and Medicine, Volume 173, 2021, Pages 52-63, ISSN [tel:0891-5849 0891-5849], <nowiki>https://doi.org/10.1016/j.freeradbiomed.2021.07.003</nowiki>.</ref>. Moreover, fetal and even epigenetic mechanisms (before pregnancy), due to maternal exposure to such toxins has been proposed to be the underlying cause of the phenotypic diversity and likelihood of developing neurodegenerative diseases.<ref>Chin-Chan, M., Navarro-Yepes, J., & Quintanilla-Vega, B. (2015). Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. ''Frontiers In Cellular Neuroscience'', ''9''. doi: 10.3389/fncel.2015.00124</ref>

	=====How to reduce the risk of exposure to environmental toxins?=====		=====How to reduce the risk of exposure to environmental toxins?=====

Geroscientist: /* Inhibition of cellular senescence */

2022-07-20T03:57:28Z

Inhibition of cellular senescence

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	\|Altered intercellular communication		\|Altered intercellular communication
	\|Niacin		\|Niacin
	\|~~Reducing inflammation~~		\|Improving mitochondrial function
	\|Parkinson's disease		\|Parkinson's disease
	\|April 2020		\|April 2020
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	\|Altered intercellular communication		\|Altered intercellular communication
	\|Nicotinamide (vitamin B3)		\|Nicotinamide (vitamin B3)
	\|~~Reducing inflammation, improving~~ mitochondrial function,		\|Improving mitochondrial function
	\|Glaucoma		\|Glaucoma
	\|December 2026		\|December 2026

Geroscientist: /* Aging */

2022-07-20T03:45:16Z

Aging

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	===Aging===		===Aging===

	Aging is the most significant risk factor for several neurodegenerative diseases. Over the age of 65, over 10% of individuals are reported to have Alzheimer's disease, and the prevalence continues to increase with age. By the age of 95, over 50% of individuals are estimated to have Alzheimer's disease in the USA.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181909/ Qiu, C., Kivipelto, M., & von Strauss, E. (2009). Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. ''Dialogues in clinical neuroscience'', ''11''(2), 111.]</ref>		Aging is the most significant risk factor for several neurodegenerative diseases. Over the age of 65, over 10% of individuals are reported to have Alzheimer's disease, and the prevalence continues to increase exponentially with age. By the age of 95, over 50% of individuals are estimated to have Alzheimer's disease in the USA.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181909/ Qiu, C., Kivipelto, M., & von Strauss, E. (2009). Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. ''Dialogues in clinical neuroscience'', ''11''(2), 111.]</ref>

	The increased risk of Alzheimer's disease due to aging is over 100-fold, whereas other major risk factors (genetics, environmental and developmental factors) combined are approximately 10-fold. <ref name=":1" />		The increased risk of Alzheimer's disease due to aging is over 100-fold, whereas other major risk factors (genetics, environmental and developmental factors) combined are approximately 10-fold. <ref name=":1" />

Geroscientist: /* Risk factors for neurodegenerative diseases */

2022-07-20T03:31:47Z

Risk factors for neurodegenerative diseases

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	\|https://clinicaltrials.gov/ct2/show/NCT04785300		\|https://clinicaltrials.gov/ct2/show/NCT04785300
	\|-		\|-
	\|~~Cellular Senescence~~		\|Altered intercellular communication
	\|~~Dasatinib plus Quercetin, Fisetin~~		\|Nicotinamide (vitamin B3)
	\|~~Removing senescent cells~~		\|Reducing inflammation, improving mitochondrial function,
	\|~~Skeletal health~~		\|Glaucoma
	\|~~March 2023~~		\|December 2026
	\|https://clinicaltrials.gov/ct2/show/~~NCT04313634~~		\|https://clinicaltrials.gov/ct2/show/NCT05275738
	\|-		\|-
	\|Multiple hallmarks		\|Multiple hallmarks

← Older revision		Revision as of 09:30, 27 December 2022
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	<references />		<references />
	[[Category:Longevity]]		[[Category:Longevity]]
			[[Category:Age-related diseases]]

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	*Avoiding the use of pesticides whenever possible. This includes direct exposure to pesticides as well as the preferential consumption of organic food, given that chemical-synthetic pesticides are banned in organic farming.		*Avoiding the use of pesticides whenever possible. This includes direct exposure to pesticides as well as the preferential consumption of organic food, given that chemical-synthetic pesticides are banned in organic farming.
	* Handling wild mushrooms properly before consumption. The outer peel of mushrooms, ~~specially~~ those grown near industrial areas, has been shown to accumulate high levels of heavy metals.<ref>Spencer, P., & Palmer, V. (2021). Direct and Indirect Neurotoxic Potential of Metal/Metalloids in Plants and Fungi Used for Food, Dietary Supplements, and Herbal Medicine. ''Toxics'', ''9''(3), 57. doi: 10.3390/toxics9030057</ref>		* Handling wild mushrooms properly before consumption. The outer peel of mushrooms, especially those grown near industrial areas, has been shown to accumulate high levels of heavy metals.<ref>Spencer, P., & Palmer, V. (2021). Direct and Indirect Neurotoxic Potential of Metal/Metalloids in Plants and Fungi Used for Food, Dietary Supplements, and Herbal Medicine. ''Toxics'', ''9''(3), 57. doi: 10.3390/toxics9030057</ref>
	*Avoiding products contained in aluminium cans (such as beverages, deodorants and other cosmetic products).		*Avoiding products contained in aluminium cans (such as beverages, deodorants and other cosmetic products).
	*Eating seafood with moderation. Despite the fact that consumption of fish and seafood is associated to a reduced risk of cardiovascular disease, a moderate consumption is advised. High mercury levels are observed amongst high-end fish and seafood consumers and it can be particularly dangerous for pregnant women.<ref>Schaefer, Zoffer, Yrastorza, Pearlman, Bossart, Stoessel, & Reif. (2019). Mercury Exposure, Fish Consumption, and Perceived Risk among Pregnant Women in Coastal Florida. ''International Journal Of Environmental Research And Public Health'', ''16''(24), 4903. doi: 10.3390/ijerph16244903</ref>		*Eating seafood with moderation. Despite the fact that consumption of fish and seafood is associated to a reduced risk of cardiovascular disease, a moderate consumption is advised. High mercury levels are observed amongst high-end fish and seafood consumers and it can be particularly dangerous for pregnant women.<ref>Schaefer, Zoffer, Yrastorza, Pearlman, Bossart, Stoessel, & Reif. (2019). Mercury Exposure, Fish Consumption, and Perceived Risk among Pregnant Women in Coastal Florida. ''International Journal Of Environmental Research And Public Health'', ''16''(24), 4903. doi: 10.3390/ijerph16244903</ref>

	===Head ~~Trauma~~===		===Head trauma===
	Head trauma is a risk factor for a variety of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), FrontoTemporal Dementia (FTD) and chronic traumatic encephalopathy and raises the risk of all-cause dementia by a factor of approximately 1.5.<ref>Li Y, Li Y, Li X, Zhang S, Zhao J, Zhu X, et al. (2017) Head Injury as a Risk Factor for Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of 32 Observational Studies. PLoS ONE 12(1): e0169650. <nowiki>https://doi.org/10.1371/journal.pone.0169650</nowiki></ref> Head trauma has been associated with defects in the blood-brain barrier, neuroinflammation, τ-hyperphosphorylation and TDP-43 aggregation.<ref>Graham NS, Sharp DJ, Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia. ''Journal of Neurology, Neurosurgery & Psychiatry'' 2019;'''90:'''1221-1233.</ref>		Head trauma is a risk factor for a variety of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), FrontoTemporal Dementia (FTD) and chronic traumatic encephalopathy and raises the risk of all-cause dementia by a factor of approximately 1.5.<ref>Li Y, Li Y, Li X, Zhang S, Zhao J, Zhu X, et al. (2017) Head Injury as a Risk Factor for Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of 32 Observational Studies. PLoS ONE 12(1): e0169650. <nowiki>https://doi.org/10.1371/journal.pone.0169650</nowiki></ref> Head trauma has been associated with defects in the blood-brain barrier, neuroinflammation, τ-hyperphosphorylation and TDP-43 aggregation.<ref>Graham NS, Sharp DJ, Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia. ''Journal of Neurology, Neurosurgery & Psychiatry'' 2019;'''90:'''1221-1233.</ref>

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	===The Hallmarks of Brain Aging===		===The Hallmarks of Brain Aging===
	Inspired by the original "[[Hallmarks of Aging]]", researchers have attempted to ~~characterise~~ the aging process more specifically in the nervous tissue. A study in 2018 named the "Hallmarks of Brain Aging" revealed that aging of the brain, at the cellular and molecular levels, resembles to a large degree the hallmarks of aging at the whole organism level.<ref name=":3" /><ref name=":4" />		Inspired by the original "[[Hallmarks of Aging]]", researchers have attempted to characterize the aging process more specifically in the nervous tissue. A study in 2018 named the "Hallmarks of Brain Aging" revealed that aging of the brain, at the cellular and molecular levels, resembles to a large degree the hallmarks of aging at the whole organism level.<ref name=":3" /><ref name=":4" />

	Some reported differences between aging of the brain and other tissues are telomere attrition and cellular senescence.<ref name=":3" /> These hallmarks have not been observed in neurons, and it remains to be established whether they occur in other brain cell types such as glial cells. One hypothesis is that differences might arise from the nature of the brain as a non-proliferative, post-mitotic tissue.		Some reported differences between aging of the brain and other tissues are telomere attrition and cellular senescence.<ref name=":3" /> These hallmarks have not been observed in neurons, and it remains to be established whether they occur in other brain cell types such as glial cells. One hypothesis is that differences might arise from the nature of the brain as a non-proliferative, post-mitotic tissue.
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	''See the full article on [[Mitochondrial Dysfunction\|mitochondrial dysfunction]].''		''See the full article on [[Mitochondrial Dysfunction\|mitochondrial dysfunction]].''

	Neurons are metabolically highly active cells that pose high energy demands. [[Mitochondria]] play a key role in energy production, but become impaired in brain aging and neurodegenerative diseases. The production of reactive oxygen species (ROS) is associated with aging and neurodegeneration.		Neurons are metabolically highly active cells that pose high energy demands. [[Mitochondria]] play a key role in energy production, but become impaired in brain aging and neurodegenerative diseases. The production of reactive oxygen species (ROS) is associated with aging and neurodegeneration, though its role in aging is not clear.

	Mitophagy is the process that results in the selective degradation of [[mitochondria]]. Growing evidence suggests that defects in mitophagy occurring in aging contribute to the neurodegenerative process. Studies have demonstrated that DNA damage in the cell can contribute to [[Mitochondrial Dysfunction\|mitochondrial dysfunction]]. Therefore, inducing mitophagy has been suggested as a potential strategy to mitigate brain aging.		Mitophagy is the process that results in the selective degradation of [[mitochondria]]. Growing evidence suggests that defects in mitophagy occurring in aging contribute to the neurodegenerative process. Studies have demonstrated that DNA damage in the cell can contribute to [[Mitochondrial Dysfunction\|mitochondrial dysfunction]]. Therefore, inducing mitophagy has been suggested as a potential strategy to mitigate brain aging.
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	Healthy, young cells are able to clear damaged DNA and rapidly repair it through several mechanisms. However, analysis of brain tissue from old individuals have revealed both increased amounts of damaged DNA as well as decreased expression of DNA repair proteins, suggesting DNA repair mechanisms become increasingly dysfunctional with age.<ref name=":3" /> Impairment of DNA repair pathways is also sufficient to cause accelerated aging phenotypes, as seen in patients with diseases such as the Werner syndrome.<ref>Scheibye-Knudsen M. Neurodegeneration in accelerated aging. ''Dan Med J.'' 2016;63:1–10.</ref>		Healthy, young cells are able to clear damaged DNA and rapidly repair it through several mechanisms. However, analysis of brain tissue from old individuals have revealed both increased amounts of damaged DNA as well as decreased expression of DNA repair proteins, suggesting DNA repair mechanisms become increasingly dysfunctional with age.<ref name=":3" /> Impairment of DNA repair pathways is also sufficient to cause accelerated aging phenotypes, as seen in patients with diseases such as the Werner syndrome.<ref>Scheibye-Knudsen M. Neurodegeneration in accelerated aging. ''Dan Med J.'' 2016;63:1–10.</ref>

	Several types of DNA damage are associated with neurodegeneration.<ref name=":0" /> Disruptive molecules known as reactive oxygen species (ROS) can induce DNA damage and are associated with aging and neurodegenerative disease. Intracellular accumulation of proteins, nucleic acids, and lipids with signs of oxidative damage are seen in neurons. DNA damage itself can lead to genomic instability and cause an increase in cellular senescence and inflammation, which accelerate brain aging. Additionally, ongoing damage to DNA induces activation of a protein called PARP1 which results in depletion of NAD+, an essential co-factor for sirtuin enzymes with important roles in ~~healtspan~~.		Several types of DNA damage are associated with neurodegeneration.<ref name=":0" /> Disruptive molecules known as reactive oxygen species (ROS) can induce DNA damage and are associated with aging and neurodegenerative disease. Intracellular accumulation of proteins, nucleic acids, and lipids with signs of oxidative damage are seen in neurons. DNA damage itself can lead to genomic instability and cause an increase in cellular senescence and inflammation, which accelerate brain aging. Additionally, ongoing damage to DNA induces activation of a protein called PARP1 which results in depletion of NAD+, an essential co-factor for sirtuin enzymes with important roles in healthspan.

	===3. Telomere Attrition===		===3. Telomere Attrition===
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	Stem cells are required for the creation of new cells in later life. Stem cell function appears to decline over an organism's lifespan and has been linked to several hallmarks such as DNA damage, defective proteostasis and epigenetic deregulation. The loss of stem cells is also associated to age-related neurodegeneration.<ref name=":0" />		Stem cells are required for the creation of new cells in later life. Stem cell function appears to decline over an organism's lifespan and has been linked to several hallmarks such as DNA damage, defective proteostasis and epigenetic deregulation. The loss of stem cells is also associated to age-related neurodegeneration.<ref name=":0" />

	New neurons can be generated from neuronal stem cells during adulthood in a process known as neurogenesis.<ref>Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. ''Neuron.'' 2011;70:687–702.</ref> This process is ~~specially~~ important in the hippocampus and the olfactory bulb for maintaining functional learning and memory processes, and it has been shown to decline durning normal aging.<ref>Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H. When neurogenesis encounters aging and disease. ''Trends Neurosci.'' 2010;33:569–579.</ref>		New neurons can be generated from neuronal stem cells during adulthood in a process known as neurogenesis.<ref>Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. ''Neuron.'' 2011;70:687–702.</ref> This process is especially important in the hippocampus and the olfactory bulb for maintaining functional learning and memory processes, and it has been shown to decline durning normal aging.<ref>Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H. When neurogenesis encounters aging and disease. ''Trends Neurosci.'' 2010;33:569–579.</ref>

	=== 6. Loss of Proteostasis===		=== 6. Loss of Proteostasis===