Longevity Wiki - User contributions [en-GB]

Aging and neurodegeneration

2021-10-19T09:49:12Z

Habakuk: /* Genetic risk factors */

{{Draft-article }}[[File:Prevalence of neurodegenerative disease in older individuals.jpg|thumb|485x485px|The prevalence of neurodegenerative diseases increases exponentially in older age. a) The prevalence of Alzheimer's disease per 1000 men and women. b) The prevalence of Parkinson's diseases per 100,000 men and women. 2014 US Data.<ref>Mehta, P., Kaye, W., Raymond, J., Wu, R., Larson, T., Punjani, R., Heller, D., Cohen, J., Peters, T., Muravov, O., & Horton, K. (2018). Prevalence of Amyotrophic Lateral Sclerosis - United States, 2014. ''MMWR. Morbidity and mortality weekly report'', ''67''(7), 216–218. <nowiki>https://doi.org/10.15585/mmwr.mm6707a3</nowiki></ref>]]Aging is the major risk factor for most neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease<ref name=":0">Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. ''Nature Reviews Neurology'', ''15''(10), 565-581. https://www.nature.com/articles/s41582-019-0244-7</ref>. The most common types of neurodegenerative diseases primarily occur in older individuals, and the prevalence of these diseases increases exponentially with age.

In elderly populations, neurodegeneration is common, while brains free of disease are rare. As such, neurodegeneration may be considered part of the same continuum as brain aging.<ref name=":0" />

Very few or no effective treatments are available for neurodegenerative conditions. Therefore, targeting the brain process directly to slow the progression of brain aging may offer a new approach to mitigating neurodegenerative disease.

== Aging as a risk factor for neurodegeneration ==
[[File:Aging as a risk factor for Alzheimer's disease.jpg|thumb|421x421px|A comparison of aging versus other risk factors for Alzheimer’s disease. The risk of Alzheimer’s disease increases approximately 100-fold between the ages of 50 and 75. The combined increase in the risk of Alzheimer’s from genetics (ApoE ε4/ε4), sex (female), hypertension, smoking, physical inactivity, and diabetes is approximately 10-fold. Data from the CDC. <ref name=":1">Matt Kaeberlein, PhD, Time for a New Strategy in the War on Alzheimer’s Disease, ''Public Policy & Aging Report'', Volume 29, Issue 4, 2019, Pages 119–122, <nowiki>https://doi.org/10.1093/ppar/prz020</nowiki></ref>]]
There are a number of risk factors for neurodegenerative diseases.

=== Aging ===

Aging is the most significant risk factor for neurodegenerative disease. Over the age of 65, over 10% of individuals have Alzheimer's disease, and the prevalence continues to increase with age. By the age 95, over 50% of individuals 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 combined (genetics, environmental and developmental factors) combined are approximately 10-fold. <ref name=":1" />

=== Genetic risk factors ===
For many of the most prevalent neurodegenerative diseases, there are known genetic risk factors, which explain to varying degrees onset and advance of neurodegenerative diseases. while some neurodegenerative diseases are mediated exclusively by the dysfunction of single genes (such as Huntington's disease), risk factors for other diseases have a more complex relationship with the resulting phenotype.

For Alzheimer's disease and Parkinson's disease, genetic variants with a high penetrance have implicated the production of β-amyloid and α-synuclein in the pathogenesis, respectively. variants with high penetrance lead to familial forms of Alzheimer's disease or Parkinson's disease, which are rare, but have 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 sporadic forms, genome-wide association studies have identified risk-alleles for Alzheimer's disease, such as a mutation in the ''APOE'' gene, and for Parkinson's disease, such as mutations in the ''SNCA'' and ''MAPT'' genes. 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. while the ε2 allele confers a reduced risk for Alzheimer's disease (0.56-fold risk for hetero- and homozygous carriers), compared to the most common ε3 allele, ε4 is 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 ===
For various neurodegenerative diseases, exposition to environmental toxins has been described as a risk factor. Metal toxins like Zinc, Copper and Mercury have been implicated in amyloid-β aggregation and τ-hyperphosphorylation, two of the pathological signs of Alzheimer's disease. Biological toxins, leading to oxidative stress and inflammatory responses, have been suggested to play a role in disease development for Alzheimer's disease<ref>Maryam Vasefi, Ehsan Ghaboolian-Zare, Hamzah Abedelwahab, Anthony Osu, Environmental toxins and Alzheimer's disease progression, Neurochemistry International, Volume 141, 2020, ISSN 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 0891-5849, <nowiki>https://doi.org/10.1016/j.freeradbiomed.2021.07.003</nowiki>.</ref>.

=== 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, frontotemporal dementia 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 and developmental Factors ===
Early development has been implicated as independent risk factors for neurodegenerative diseases. Alzheimer's disease has been associated with lower education levels<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> and lower general cognitive abilities in childhood<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>. Lower socioeconomic status during early life and childhood trauma has been shown to decrease late-life cognitive abilities, but not directly influence the rate of cognitive decline or Alzheimer's disease<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>.

== Brain aging and functional decline ==
The brain tissue of older adults contains the build-up of protein deposits. These include tau protein and amyloid-β.

== Hallmarks of brain aging ==
[[File:Hallmarks of brain aging.jpg|thumb|552x552px|The nine hallmarks of aging are involved in many neurodegenerative diseases. These include Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), ataxia telangiectasia (AT), Huntington disease (HD), and Parkinson disease (PD).]]
The basic process of neurodegeneration is fundamentally connected to the hallmarks of brain aging.

The nine so-called 'hallmarks of aging' were defined in 2013 and represent the basic biological processes underlying the aging process. These are now widely used in the aging field, and in the context of neurodegenerative diseases.

These are: genomic instability, epigenetic alterations, telomere attrition, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communication. The nine hallmarks of aging have been shown to be linked to brain aging and the main neurodegenerative diseases, as described below.

=== Genomic instability ===
Several types of DNA damage are associated with neurodegeneration. Damage from disruptive molecules known as reactive oxygen species are associated with aging and neurodegenerative disease, and DNA damage leads to genomic instability.

Ongoing damage to the DNA induces a protein called PARP1 to become active, and results in depletion of NAD+. NAD+ is an essential co-factor for sirtuin enzymes that play important roles in health and longevity. DNA damage also causes an increase in cellular senescence and inflammation, which are accelerate brain aging.

=== Telomere attrition ===
Telomeres are the protective 'caps' on the end of chromosomes, composed of protein and DNA. Each time a cell divides, the telomeres generally become shorter. The shortening of telomeres occurs as part of biological aging and causes cellular senescence, and is associated with neurodegeneration and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.

=== Epigenetic alterations ===
Epigenetics describe changes to heritable factors that do not involve changes to the DNA code itself. These include modifications including methylation, by which a methyl group is added to the DNA molecule. Epigenetic changes have been associated with neurodegenerative diseases.

=== Loss of proteostasis ===
Proteostasis refers to the balance of protein production and degradation in cells and tissues. A balance of proteins is crucial for the normal functioning of cells. The misfolding, aggregation or deposition of proteins has been shown to be connected to several neurodegenerative disorders.
=== Mitochondrial dysfunction ===
Neurons are highly metabolically active cells with high energy demands. Mitochondria play a key role in energy production, but become impaired in brain aging and neurodegenerative disease. The production of reactive oxygen species is associated with aging and neurodegenerative diseases. Mitophagy is the process that results in the selective degradation of mitochondria. Growing evidence suggests that defects in mitophagy that occur with aging contribute to the neurodegenerative process. Studies have demonstrated that DNA damage in the cell can contribute to mitochondrial dysfunction. Inducing mitophagy has been suggested as a potential strategy to mitigate brain aging.

=== Cellular senescence ===
Cellular senescence refers to a state of a cell which occurs when dead or dying cells begin releasing inflammatory factors. This can occur as a result of DNA damage to the cell. With age, the number of senescent neurons increases in the brain. Studies in old mice have demonstrated that up to 40% of cortical, hippocampal, and peripheral neurons are senescent. Cellular senescence has been linked with exacerbated age-related brain dysfunction. As such, targeting senescent cells is being considered as a therapeutic strategy for patients with neurodegenerative diseases.

=== Deregulated nutrient sensing and altered metabolism ===
Several nutrient sensing biochemical pathways are linked to aging and longevity. These include insulin-like growth factor 1 (IGF1), mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK) and the sirtuin enzymes. Studies in mice, worm and fly species have demonstrated that modulating these pathways can extend lifespan. Metabolic dysfunction in these pathways is commonly associated with neurological, age-related diseases.

=== Stem cell exhaustion ===
Stem cells are required for the creation of new cells in later life. However, stem cell function declines over an organism's lifespan, due to several other hallmarks including DNA damage, defective proteostasis, and epigenetic deregulation. The loss of stem cells is linked to age-related neurodegeneration.

=== Altered intercellular communication ===

Changes to levels of hormones such as insulin and IGF1 occur with age and are linked with neurodegeneration. In addition, loss of regulation of the immune system with age is implicated in neurodegenerative diseases. For example, inflammation, a protective response to injury, becomes chronically upregulated with age and high levels of inflammation are related to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

== Interconnectedness of the hallmarks ==
The hallmarks of aging are highly interconnected and occur in a complex process that is part of neurodegeneration. For example, the loss of proteostasis is strongly linked to inflammation and senescence. The metabolic dysfunction that occurs with age and is present in neurodegenerative diseases is associated with mitochondrial dysfunction and oxidative stress. The reduction in number of stem cells is linked to almost all the other hallmarks, such as genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence and telomere attrition.
== Aging and Alzheimer's disease ==

== New treatments for neurodegenerative diseases ==
Current efforts to develop evidence-based treatments for neurodegenerative diseases are ongoing, but no highly effective treatment approaches have been discovered. Given the complexity of age-related neurodegenerative diseases, the current approach of targeting single pathways may be inadequate. Instead, broader therapeutic approaches that target the brain aging process directly may be considered as a new approach to treating neurodegenerative diseases. Further research into understanding nine hallmarks of aging and targeting these processes may be required to create effective new therapies for neurodegeneration. Some approaches being explored are described below:
==== Supplementing NAD+ ====
NAD+ is an essential molecule involved in energy metabolism in the body. A sufficient supply of NAD+ is necessary for maintenance of mitochondrial health, DNA repair, energy homeostasis and brain health. Levels of NAD+ decline with age in humans, but supplementation can increase levels of NAD+. Supplementation with molecules that turn into NAD+, known as NAD+ precursors, include nicotinimide riboside (NR) and nicotinimide mononucleotide (NMN). These supplements may help to extend healthy lifespan and slow brain aging, thereby delaying or protecting against neurodegeneration. Studies in mice have shown that NR reduces plaque accumulation and improves cognition, as well as including learning and memory. NMN has similarly demonstrated beneficial effects in mice. Clinical trials evaluating the potential benefits of NAD+ in humans are currently underway.

==== Inhibition of cellular senescence ====
Senescence of the astrocytes and microglial cells - cells that support neurons in the brain - accumulate in normal brain aging and patients with Parkinson's disease and Alzheimer's disease. The elimination of these cells may represent a new strategy for extending the healthspan of the brain and treating neurodegenerative diseases. Strategies using have shown beneficial effects in animal models:

* Rapamycin has been shown to delecerate cellular senescence as one of perhaps several neuroprotective effects
* Metformin has been shown to suppress cellular senescence via activation of microRNA-processing proteins that reduce plaque build-up in Alzheimer's disease and Parkinsons's disease.

== Clinical trials targeting age-related mechanisms of neurodegenerative disorders ==
{| class="wikitable"
|+
!Hallmark of aging targeted
!Drug(s)
!Mechanism of action
!Disease
!Actual or Estimated trial completion date
!ClinicalTrials.gov Link
|-
|Altered intercellular communication
|Niacin
|Reducing inflammation
|Parkinson's disease
|April 2020
|https://clinicaltrials.gov/ct2/show/NCT03462680
|-
|Deregulated nutrient sensing
|Resveratrol
|Reducing insulin resistance
|Mild cognitive impairment
|June 2022
|https://clinicaltrials.gov/ct2/show/NCT02502253
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Alzheimer's disease or MCI
|July 2022
|https://clinicaltrials.gov/ct2/show/NCT03061474
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Parkinson's disease
|March 2024
|https://clinicaltrials.gov/ct2/show/NCT03568968
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Alzheimer's disease
|August 2023
|https://clinicaltrials.gov/ct2/show/NCT04063124
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|July 2031
|https://clinicaltrials.gov/ct2/show/NCT04685590
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|June 2023
|https://clinicaltrials.gov/ct2/show/NCT04785300
|-
|Cellular Senescence
|Dasatinib plus Quercetin, Fisetin
|Removing senescent cells
|Skeletal health
|March 2023
|https://clinicaltrials.gov/ct2/show/NCT04313634
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|December 2022
|https://clinicaltrials.gov/ct2/show/NCT04200911
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|August 2024
|https://clinicaltrials.gov/ct2/show/NCT04629495
|}

== References ==
<references />

Aging and neurodegeneration

2021-10-19T09:45:02Z

Habakuk: /* Genetic risk factors */

{{Draft-article }}[[File:Prevalence of neurodegenerative disease in older individuals.jpg|thumb|485x485px|The prevalence of neurodegenerative diseases increases exponentially in older age. a) The prevalence of Alzheimer's disease per 1000 men and women. b) The prevalence of Parkinson's diseases per 100,000 men and women. 2014 US Data.<ref>Mehta, P., Kaye, W., Raymond, J., Wu, R., Larson, T., Punjani, R., Heller, D., Cohen, J., Peters, T., Muravov, O., & Horton, K. (2018). Prevalence of Amyotrophic Lateral Sclerosis - United States, 2014. ''MMWR. Morbidity and mortality weekly report'', ''67''(7), 216–218. <nowiki>https://doi.org/10.15585/mmwr.mm6707a3</nowiki></ref>]]Aging is the major risk factor for most neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease<ref name=":0">Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. ''Nature Reviews Neurology'', ''15''(10), 565-581. https://www.nature.com/articles/s41582-019-0244-7</ref>. The most common types of neurodegenerative diseases primarily occur in older individuals, and the prevalence of these diseases increases exponentially with age.

In elderly populations, neurodegeneration is common, while brains free of disease are rare. As such, neurodegeneration may be considered part of the same continuum as brain aging.<ref name=":0" />

Very few or no effective treatments are available for neurodegenerative conditions. Therefore, targeting the brain process directly to slow the progression of brain aging may offer a new approach to mitigating neurodegenerative disease.

== Aging as a risk factor for neurodegeneration ==
[[File:Aging as a risk factor for Alzheimer's disease.jpg|thumb|421x421px|A comparison of aging versus other risk factors for Alzheimer’s disease. The risk of Alzheimer’s disease increases approximately 100-fold between the ages of 50 and 75. The combined increase in the risk of Alzheimer’s from genetics (ApoE ε4/ε4), sex (female), hypertension, smoking, physical inactivity, and diabetes is approximately 10-fold. Data from the CDC. <ref name=":1">Matt Kaeberlein, PhD, Time for a New Strategy in the War on Alzheimer’s Disease, ''Public Policy & Aging Report'', Volume 29, Issue 4, 2019, Pages 119–122, <nowiki>https://doi.org/10.1093/ppar/prz020</nowiki></ref>]]
There are a number of risk factors for neurodegenerative diseases.

=== Aging ===

Aging is the most significant risk factor for neurodegenerative disease. Over the age of 65, over 10% of individuals have Alzheimer's disease, and the prevalence continues to increase with age. By the age 95, over 50% of individuals 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 combined (genetics, environmental and developmental factors) combined are approximately 10-fold. <ref name=":1" />

=== Genetic risk factors ===
For many of the most prevalent neurodegenerative diseases, there are known genetic risk factors, which explain to varying degrees onset and advance of neurodegenerative diseases. while some neurodegenerative diseases are mediated exclusively by the dysfunction of single genes (such as Huntington's disease), risk factors for other diseases have a more complex relationship with the resulting phenotype.

For Alzheimer's disease and Parkinson's disease, genetic variants with a high penetrance have implicated the production of β-amyloid and α-synuclein in the pathogenesis, respectively. variants with high penetrance lead to familial forms of Alzheimer's disease or Parkinson's disease, which are rare, but have 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 sporadic forms, genome-wide association studies have identified risk-alleles for Alzheimer's disease, such as a mutation in the ''APOE'' gene, and for Parkinson's disease, such as mutations in the ''SNCA'' and ''MAPT'' genes. 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. while the ε2 allele confers a reduced risk for ad (0.56-fold risk for hetero- and homozygous carriers), compared to the most common ε3 allele, ε4 is 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 ===
For various neurodegenerative diseases, exposition to environmental toxins has been described as a risk factor. Metal toxins like Zinc, Copper and Mercury have been implicated in amyloid-β aggregation and τ-hyperphosphorylation, two of the pathological signs of Alzheimer's disease. Biological toxins, leading to oxidative stress and inflammatory responses, have been suggested to play a role in disease development for Alzheimer's disease<ref>Maryam Vasefi, Ehsan Ghaboolian-Zare, Hamzah Abedelwahab, Anthony Osu, Environmental toxins and Alzheimer's disease progression, Neurochemistry International, Volume 141, 2020, ISSN 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 0891-5849, <nowiki>https://doi.org/10.1016/j.freeradbiomed.2021.07.003</nowiki>.</ref>.

=== 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, frontotemporal dementia 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 and developmental Factors ===
Early development has been implicated as independent risk factors for neurodegenerative diseases. Alzheimer's disease has been associated with lower education levels<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> and lower general cognitive abilities in childhood<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>. Lower socioeconomic status during early life and childhood trauma has been shown to decrease late-life cognitive abilities, but not directly influence the rate of cognitive decline or Alzheimer's disease<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>.

== Brain aging and functional decline ==
The brain tissue of older adults contains the build-up of protein deposits. These include tau protein and amyloid-β.

== Hallmarks of brain aging ==
[[File:Hallmarks of brain aging.jpg|thumb|552x552px|The nine hallmarks of aging are involved in many neurodegenerative diseases. These include Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), ataxia telangiectasia (AT), Huntington disease (HD), and Parkinson disease (PD).]]
The basic process of neurodegeneration is fundamentally connected to the hallmarks of brain aging.

The nine so-called 'hallmarks of aging' were defined in 2013 and represent the basic biological processes underlying the aging process. These are now widely used in the aging field, and in the context of neurodegenerative diseases.

These are: genomic instability, epigenetic alterations, telomere attrition, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communication. The nine hallmarks of aging have been shown to be linked to brain aging and the main neurodegenerative diseases, as described below.

=== Genomic instability ===
Several types of DNA damage are associated with neurodegeneration. Damage from disruptive molecules known as reactive oxygen species are associated with aging and neurodegenerative disease, and DNA damage leads to genomic instability.

Ongoing damage to the DNA induces a protein called PARP1 to become active, and results in depletion of NAD+. NAD+ is an essential co-factor for sirtuin enzymes that play important roles in health and longevity. DNA damage also causes an increase in cellular senescence and inflammation, which are accelerate brain aging.

=== Telomere attrition ===
Telomeres are the protective 'caps' on the end of chromosomes, composed of protein and DNA. Each time a cell divides, the telomeres generally become shorter. The shortening of telomeres occurs as part of biological aging and causes cellular senescence, and is associated with neurodegeneration and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.

=== Epigenetic alterations ===
Epigenetics describe changes to heritable factors that do not involve changes to the DNA code itself. These include modifications including methylation, by which a methyl group is added to the DNA molecule. Epigenetic changes have been associated with neurodegenerative diseases.

=== Loss of proteostasis ===
Proteostasis refers to the balance of protein production and degradation in cells and tissues. A balance of proteins is crucial for the normal functioning of cells. The misfolding, aggregation or deposition of proteins has been shown to be connected to several neurodegenerative disorders.
=== Mitochondrial dysfunction ===
Neurons are highly metabolically active cells with high energy demands. Mitochondria play a key role in energy production, but become impaired in brain aging and neurodegenerative disease. The production of reactive oxygen species is associated with aging and neurodegenerative diseases. Mitophagy is the process that results in the selective degradation of mitochondria. Growing evidence suggests that defects in mitophagy that occur with aging contribute to the neurodegenerative process. Studies have demonstrated that DNA damage in the cell can contribute to mitochondrial dysfunction. Inducing mitophagy has been suggested as a potential strategy to mitigate brain aging.

=== Cellular senescence ===
Cellular senescence refers to a state of a cell which occurs when dead or dying cells begin releasing inflammatory factors. This can occur as a result of DNA damage to the cell. With age, the number of senescent neurons increases in the brain. Studies in old mice have demonstrated that up to 40% of cortical, hippocampal, and peripheral neurons are senescent. Cellular senescence has been linked with exacerbated age-related brain dysfunction. As such, targeting senescent cells is being considered as a therapeutic strategy for patients with neurodegenerative diseases.

=== Deregulated nutrient sensing and altered metabolism ===
Several nutrient sensing biochemical pathways are linked to aging and longevity. These include insulin-like growth factor 1 (IGF1), mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK) and the sirtuin enzymes. Studies in mice, worm and fly species have demonstrated that modulating these pathways can extend lifespan. Metabolic dysfunction in these pathways is commonly associated with neurological, age-related diseases.

=== Stem cell exhaustion ===
Stem cells are required for the creation of new cells in later life. However, stem cell function declines over an organism's lifespan, due to several other hallmarks including DNA damage, defective proteostasis, and epigenetic deregulation. The loss of stem cells is linked to age-related neurodegeneration.

=== Altered intercellular communication ===

Changes to levels of hormones such as insulin and IGF1 occur with age and are linked with neurodegeneration. In addition, loss of regulation of the immune system with age is implicated in neurodegenerative diseases. For example, inflammation, a protective response to injury, becomes chronically upregulated with age and high levels of inflammation are related to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

== Interconnectedness of the hallmarks ==
The hallmarks of aging are highly interconnected and occur in a complex process that is part of neurodegeneration. For example, the loss of proteostasis is strongly linked to inflammation and senescence. The metabolic dysfunction that occurs with age and is present in neurodegenerative diseases is associated with mitochondrial dysfunction and oxidative stress. The reduction in number of stem cells is linked to almost all the other hallmarks, such as genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence and telomere attrition.
== Aging and Alzheimer's disease ==

== New treatments for neurodegenerative diseases ==
Current efforts to develop evidence-based treatments for neurodegenerative diseases are ongoing, but no highly effective treatment approaches have been discovered. Given the complexity of age-related neurodegenerative diseases, the current approach of targeting single pathways may be inadequate. Instead, broader therapeutic approaches that target the brain aging process directly may be considered as a new approach to treating neurodegenerative diseases. Further research into understanding nine hallmarks of aging and targeting these processes may be required to create effective new therapies for neurodegeneration. Some approaches being explored are described below:
==== Supplementing NAD+ ====
NAD+ is an essential molecule involved in energy metabolism in the body. A sufficient supply of NAD+ is necessary for maintenance of mitochondrial health, DNA repair, energy homeostasis and brain health. Levels of NAD+ decline with age in humans, but supplementation can increase levels of NAD+. Supplementation with molecules that turn into NAD+, known as NAD+ precursors, include nicotinimide riboside (NR) and nicotinimide mononucleotide (NMN). These supplements may help to extend healthy lifespan and slow brain aging, thereby delaying or protecting against neurodegeneration. Studies in mice have shown that NR reduces plaque accumulation and improves cognition, as well as including learning and memory. NMN has similarly demonstrated beneficial effects in mice. Clinical trials evaluating the potential benefits of NAD+ in humans are currently underway.

==== Inhibition of cellular senescence ====
Senescence of the astrocytes and microglial cells - cells that support neurons in the brain - accumulate in normal brain aging and patients with Parkinson's disease and Alzheimer's disease. The elimination of these cells may represent a new strategy for extending the healthspan of the brain and treating neurodegenerative diseases. Strategies using have shown beneficial effects in animal models:

* Rapamycin has been shown to delecerate cellular senescence as one of perhaps several neuroprotective effects
* Metformin has been shown to suppress cellular senescence via activation of microRNA-processing proteins that reduce plaque build-up in Alzheimer's disease and Parkinsons's disease.

== Clinical trials targeting age-related mechanisms of neurodegenerative disorders ==
{| class="wikitable"
|+
!Hallmark of aging targeted
!Drug(s)
!Mechanism of action
!Disease
!Actual or Estimated trial completion date
!ClinicalTrials.gov Link
|-
|Altered intercellular communication
|Niacin
|Reducing inflammation
|Parkinson's disease
|April 2020
|https://clinicaltrials.gov/ct2/show/NCT03462680
|-
|Deregulated nutrient sensing
|Resveratrol
|Reducing insulin resistance
|Mild cognitive impairment
|June 2022
|https://clinicaltrials.gov/ct2/show/NCT02502253
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Alzheimer's disease or MCI
|July 2022
|https://clinicaltrials.gov/ct2/show/NCT03061474
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Parkinson's disease
|March 2024
|https://clinicaltrials.gov/ct2/show/NCT03568968
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Alzheimer's disease
|August 2023
|https://clinicaltrials.gov/ct2/show/NCT04063124
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|July 2031
|https://clinicaltrials.gov/ct2/show/NCT04685590
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|June 2023
|https://clinicaltrials.gov/ct2/show/NCT04785300
|-
|Cellular Senescence
|Dasatinib plus Quercetin, Fisetin
|Removing senescent cells
|Skeletal health
|March 2023
|https://clinicaltrials.gov/ct2/show/NCT04313634
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|December 2022
|https://clinicaltrials.gov/ct2/show/NCT04200911
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|August 2024
|https://clinicaltrials.gov/ct2/show/NCT04629495
|}

== References ==
<references />

Aging and neurodegeneration

2021-10-19T09:39:37Z

Habakuk: /* Aging */

{{Draft-article }}[[File:Prevalence of neurodegenerative disease in older individuals.jpg|thumb|485x485px|The prevalence of neurodegenerative diseases increases exponentially in older age. a) The prevalence of Alzheimer's disease per 1000 men and women. b) The prevalence of Parkinson's diseases per 100,000 men and women. 2014 US Data.<ref>Mehta, P., Kaye, W., Raymond, J., Wu, R., Larson, T., Punjani, R., Heller, D., Cohen, J., Peters, T., Muravov, O., & Horton, K. (2018). Prevalence of Amyotrophic Lateral Sclerosis - United States, 2014. ''MMWR. Morbidity and mortality weekly report'', ''67''(7), 216–218. <nowiki>https://doi.org/10.15585/mmwr.mm6707a3</nowiki></ref>]]Aging is the major risk factor for most neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease<ref name=":0">Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. ''Nature Reviews Neurology'', ''15''(10), 565-581. https://www.nature.com/articles/s41582-019-0244-7</ref>. The most common types of neurodegenerative diseases primarily occur in older individuals, and the prevalence of these diseases increases exponentially with age.

In elderly populations, neurodegeneration is common, while brains free of disease are rare. As such, neurodegeneration may be considered part of the same continuum as brain aging.<ref name=":0" />

Very few or no effective treatments are available for neurodegenerative conditions. Therefore, targeting the brain process directly to slow the progression of brain aging may offer a new approach to mitigating neurodegenerative disease.

== Aging as a risk factor for neurodegeneration ==
[[File:Aging as a risk factor for Alzheimer's disease.jpg|thumb|421x421px|A comparison of aging versus other risk factors for Alzheimer’s disease. The risk of Alzheimer’s disease increases approximately 100-fold between the ages of 50 and 75. The combined increase in the risk of Alzheimer’s from genetics (ApoE ε4/ε4), sex (female), hypertension, smoking, physical inactivity, and diabetes is approximately 10-fold. Data from the CDC. <ref name=":1">Matt Kaeberlein, PhD, Time for a New Strategy in the War on Alzheimer’s Disease, ''Public Policy & Aging Report'', Volume 29, Issue 4, 2019, Pages 119–122, <nowiki>https://doi.org/10.1093/ppar/prz020</nowiki></ref>]]
There are a number of risk factors for neurodegenerative diseases.

=== Aging ===

Aging is the most significant risk factor for neurodegenerative disease. Over the age of 65, over 10% of individuals have Alzheimer's disease, and the prevalence continues to increase with age. By the age 95, over 50% of individuals 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 combined (genetics, environmental and developmental factors) combined are approximately 10-fold. <ref name=":1" />

=== Genetic risk factors ===
For many of the most prevalent neurodegenerative diseases, there are known genetic risk factors, which explain to varying degrees onset and advance of neurodegenerative diseases. while some neurodegenerative diseases are mediated exclusively by the dysfunction of single genes (such as Huntington's disease), risk factors for other diseases have a more complex relationship with the resulting phenotype.

For Alzheimer's disease and Parkinson's disease, genetic variants with a high penetrance have implicated the production of β-amyloid and α-synuclein in the pathogenesis, respectively. variants with high penetrance lead to familial forms of Alzheimer's disease or Parkinson's disease, which are rare, but have 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 sporadic forms, genome-wide association studies have identified risk-alleles for Alzheimer's disease, such as a mutation in the ''APOE'' gene, and for Parkinson's disease, such as mutations in the ''SNCA'' and ''MAPT'' genes. 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. while the ε2 allele confers a reduced risk for ad (0.56-fold risk for hetero- and homozygous carriers), compared to the most common ε3 allele, ε4 is a major risk factor for ad (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 ===
For various neurodegenerative diseases, exposition to environmental toxins has been described as a risk factor. Metal toxins like Zinc, Copper and Mercury have been implicated in amyloid-β aggregation and τ-hyperphosphorylation, two of the pathological signs of Alzheimer's disease. Biological toxins, leading to oxidative stress and inflammatory responses, have been suggested to play a role in disease development for Alzheimer's disease<ref>Maryam Vasefi, Ehsan Ghaboolian-Zare, Hamzah Abedelwahab, Anthony Osu, Environmental toxins and Alzheimer's disease progression, Neurochemistry International, Volume 141, 2020, ISSN 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 0891-5849, <nowiki>https://doi.org/10.1016/j.freeradbiomed.2021.07.003</nowiki>.</ref>.

=== 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, frontotemporal dementia 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 and developmental Factors ===
Early development has been implicated as independent risk factors for neurodegenerative diseases. Alzheimer's disease has been associated with lower education levels<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> and lower general cognitive abilities in childhood<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>. Lower socioeconomic status during early life and childhood trauma has been shown to decrease late-life cognitive abilities, but not directly influence the rate of cognitive decline or Alzheimer's disease<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>.

== Brain aging and functional decline ==
The brain tissue of older adults contains the build-up of protein deposits. These include tau protein and amyloid-β.

== Hallmarks of brain aging ==
[[File:Hallmarks of brain aging.jpg|thumb|552x552px|The nine hallmarks of aging are involved in many neurodegenerative diseases. These include Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), ataxia telangiectasia (AT), Huntington disease (HD), and Parkinson disease (PD).]]
The basic process of neurodegeneration is fundamentally connected to the hallmarks of brain aging.

The nine so-called 'hallmarks of aging' were defined in 2013 and represent the basic biological processes underlying the aging process. These are now widely used in the aging field, and in the context of neurodegenerative diseases.

These are: genomic instability, epigenetic alterations, telomere attrition, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communication. The nine hallmarks of aging have been shown to be linked to brain aging and the main neurodegenerative diseases, as described below.

=== Genomic instability ===
Several types of DNA damage are associated with neurodegeneration. Damage from disruptive molecules known as reactive oxygen species are associated with aging and neurodegenerative disease, and DNA damage leads to genomic instability.

Ongoing damage to the DNA induces a protein called PARP1 to become active, and results in depletion of NAD+. NAD+ is an essential co-factor for sirtuin enzymes that play important roles in health and longevity. DNA damage also causes an increase in cellular senescence and inflammation, which are accelerate brain aging.

=== Telomere attrition ===
Telomeres are the protective 'caps' on the end of chromosomes, composed of protein and DNA. Each time a cell divides, the telomeres generally become shorter. The shortening of telomeres occurs as part of biological aging and causes cellular senescence, and is associated with neurodegeneration and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.

=== Epigenetic alterations ===
Epigenetics describe changes to heritable factors that do not involve changes to the DNA code itself. These include modifications including methylation, by which a methyl group is added to the DNA molecule. Epigenetic changes have been associated with neurodegenerative diseases.

=== Loss of proteostasis ===
Proteostasis refers to the balance of protein production and degradation in cells and tissues. A balance of proteins is crucial for the normal functioning of cells. The misfolding, aggregation or deposition of proteins has been shown to be connected to several neurodegenerative disorders.
=== Mitochondrial dysfunction ===
Neurons are highly metabolically active cells with high energy demands. Mitochondria play a key role in energy production, but become impaired in brain aging and neurodegenerative disease. The production of reactive oxygen species is associated with aging and neurodegenerative diseases. Mitophagy is the process that results in the selective degradation of mitochondria. Growing evidence suggests that defects in mitophagy that occur with aging contribute to the neurodegenerative process. Studies have demonstrated that DNA damage in the cell can contribute to mitochondrial dysfunction. Inducing mitophagy has been suggested as a potential strategy to mitigate brain aging.

=== Cellular senescence ===
Cellular senescence refers to a state of a cell which occurs when dead or dying cells begin releasing inflammatory factors. This can occur as a result of DNA damage to the cell. With age, the number of senescent neurons increases in the brain. Studies in old mice have demonstrated that up to 40% of cortical, hippocampal, and peripheral neurons are senescent. Cellular senescence has been linked with exacerbated age-related brain dysfunction. As such, targeting senescent cells is being considered as a therapeutic strategy for patients with neurodegenerative diseases.

=== Deregulated nutrient sensing and altered metabolism ===
Several nutrient sensing biochemical pathways are linked to aging and longevity. These include insulin-like growth factor 1 (IGF1), mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK) and the sirtuin enzymes. Studies in mice, worm and fly species have demonstrated that modulating these pathways can extend lifespan. Metabolic dysfunction in these pathways is commonly associated with neurological, age-related diseases.

=== Stem cell exhaustion ===
Stem cells are required for the creation of new cells in later life. However, stem cell function declines over an organism's lifespan, due to several other hallmarks including DNA damage, defective proteostasis, and epigenetic deregulation. The loss of stem cells is linked to age-related neurodegeneration.

=== Altered intercellular communication ===

Changes to levels of hormones such as insulin and IGF1 occur with age and are linked with neurodegeneration. In addition, loss of regulation of the immune system with age is implicated in neurodegenerative diseases. For example, inflammation, a protective response to injury, becomes chronically upregulated with age and high levels of inflammation are related to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

== Interconnectedness of the hallmarks ==
The hallmarks of aging are highly interconnected and occur in a complex process that is part of neurodegeneration. For example, the loss of proteostasis is strongly linked to inflammation and senescence. The metabolic dysfunction that occurs with age and is present in neurodegenerative diseases is associated with mitochondrial dysfunction and oxidative stress. The reduction in number of stem cells is linked to almost all the other hallmarks, such as genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence and telomere attrition.
== Aging and Alzheimer's disease ==

== New treatments for neurodegenerative diseases ==
Current efforts to develop evidence-based treatments for neurodegenerative diseases are ongoing, but no highly effective treatment approaches have been discovered. Given the complexity of age-related neurodegenerative diseases, the current approach of targeting single pathways may be inadequate. Instead, broader therapeutic approaches that target the brain aging process directly may be considered as a new approach to treating neurodegenerative diseases. Further research into understanding nine hallmarks of aging and targeting these processes may be required to create effective new therapies for neurodegeneration. Some approaches being explored are described below:
==== Supplementing NAD+ ====
NAD+ is an essential molecule involved in energy metabolism in the body. A sufficient supply of NAD+ is necessary for maintenance of mitochondrial health, DNA repair, energy homeostasis and brain health. Levels of NAD+ decline with age in humans, but supplementation can increase levels of NAD+. Supplementation with molecules that turn into NAD+, known as NAD+ precursors, include nicotinimide riboside (NR) and nicotinimide mononucleotide (NMN). These supplements may help to extend healthy lifespan and slow brain aging, thereby delaying or protecting against neurodegeneration. Studies in mice have shown that NR reduces plaque accumulation and improves cognition, as well as including learning and memory. NMN has similarly demonstrated beneficial effects in mice. Clinical trials evaluating the potential benefits of NAD+ in humans are currently underway.

==== Inhibition of cellular senescence ====
Senescence of the astrocytes and microglial cells - cells that support neurons in the brain - accumulate in normal brain aging and patients with Parkinson's disease and Alzheimer's disease. The elimination of these cells may represent a new strategy for extending the healthspan of the brain and treating neurodegenerative diseases. Strategies using have shown beneficial effects in animal models:

* Rapamycin has been shown to delecerate cellular senescence as one of perhaps several neuroprotective effects
* Metformin has been shown to suppress cellular senescence via activation of microRNA-processing proteins that reduce plaque build-up in Alzheimer's disease and Parkinsons's disease.

== Clinical trials targeting age-related mechanisms of neurodegenerative disorders ==
{| class="wikitable"
|+
!Hallmark of aging targeted
!Drug(s)
!Mechanism of action
!Disease
!Actual or Estimated trial completion date
!ClinicalTrials.gov Link
|-
|Altered intercellular communication
|Niacin
|Reducing inflammation
|Parkinson's disease
|April 2020
|https://clinicaltrials.gov/ct2/show/NCT03462680
|-
|Deregulated nutrient sensing
|Resveratrol
|Reducing insulin resistance
|Mild cognitive impairment
|June 2022
|https://clinicaltrials.gov/ct2/show/NCT02502253
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Alzheimer's disease or MCI
|July 2022
|https://clinicaltrials.gov/ct2/show/NCT03061474
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Parkinson's disease
|March 2024
|https://clinicaltrials.gov/ct2/show/NCT03568968
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Alzheimer's disease
|August 2023
|https://clinicaltrials.gov/ct2/show/NCT04063124
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|July 2031
|https://clinicaltrials.gov/ct2/show/NCT04685590
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|June 2023
|https://clinicaltrials.gov/ct2/show/NCT04785300
|-
|Cellular Senescence
|Dasatinib plus Quercetin, Fisetin
|Removing senescent cells
|Skeletal health
|March 2023
|https://clinicaltrials.gov/ct2/show/NCT04313634
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|December 2022
|https://clinicaltrials.gov/ct2/show/NCT04200911
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|August 2024
|https://clinicaltrials.gov/ct2/show/NCT04629495
|}

== References ==
<references />

Aging and neurodegeneration

2021-10-19T09:36:13Z

Habakuk: /* Aging as a risk factor for neurodegeneration */

{{Draft-article }}[[File:Prevalence of neurodegenerative disease in older individuals.jpg|thumb|485x485px|The prevalence of neurodegenerative diseases increases exponentially in older age. a) The prevalence of Alzheimer's disease per 1000 men and women. b) The prevalence of Parkinson's diseases per 100,000 men and women. 2014 US Data.<ref>Mehta, P., Kaye, W., Raymond, J., Wu, R., Larson, T., Punjani, R., Heller, D., Cohen, J., Peters, T., Muravov, O., & Horton, K. (2018). Prevalence of Amyotrophic Lateral Sclerosis - United States, 2014. ''MMWR. Morbidity and mortality weekly report'', ''67''(7), 216–218. <nowiki>https://doi.org/10.15585/mmwr.mm6707a3</nowiki></ref>]]Aging is the major risk factor for most neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease<ref name=":0">Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. ''Nature Reviews Neurology'', ''15''(10), 565-581. https://www.nature.com/articles/s41582-019-0244-7</ref>. The most common types of neurodegenerative diseases primarily occur in older individuals, and the prevalence of these diseases increases exponentially with age.

In elderly populations, neurodegeneration is common, while brains free of disease are rare. As such, neurodegeneration may be considered part of the same continuum as brain aging.<ref name=":0" />

Very few or no effective treatments are available for neurodegenerative conditions. Therefore, targeting the brain process directly to slow the progression of brain aging may offer a new approach to mitigating neurodegenerative disease.

== Aging as a risk factor for neurodegeneration ==
[[File:Aging as a risk factor for Alzheimer's disease.jpg|thumb|421x421px|A comparison of aging versus other risk factors for Alzheimer’s disease. The risk of Alzheimer’s disease increases approximately 100-fold between the ages of 50 and 75. The combined increase in the risk of Alzheimer’s from genetics (ApoE e4/e4), sex (female), hypertension, smoking, physical inactivity, and diabetes is approximately 10-fold. Data from the CDC. <ref name=":1">Matt Kaeberlein, PhD, Time for a New Strategy in the War on Alzheimer’s Disease, ''Public Policy & Aging Report'', Volume 29, Issue 4, 2019, Pages 119–122, <nowiki>https://doi.org/10.1093/ppar/prz020</nowiki></ref>]]
There are a number of risk factors for neurodegenerative diseases.

=== Aging ===
* Aging:
* Genetic predisposition: the apolipoprotein E (APOE) ε4 allele is a major risk factor for Alzheimer's disease.
* Environmental toxins:
* Early developmental defects:
* Head trauma:

Aging is the most significant risk factor for neurodegenerative disease. Over the age of 65, over 10% of individuals have Alzheimer's disease, and the prevalence continues to increase with age. By the age 95, over 50% of individuals 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 combined (genetics, sex, smoking, diabetes, hypertension and physical inactivity) combined are approximately 10-fold. <ref name=":1" />

=== Genetic risk factors ===
For many of the most prevalent neurodegenerative diseases, there are known genetic risk factors, which explain to varying degrees onset and advance of neurodegenerative diseases. while some neurodegenerative diseases are mediated exclusively by the dysfunction of single genes (such as Huntington's disease), risk factors for other diseases have a more complex relationship with the resulting phenotype.

For Alzheimer's disease and Parkinson's disease, genetic variants with a high penetrance have implicated the production of β-amyloid and α-synuclein in the pathogenesis, respectively. variants with high penetrance lead to familial forms of Alzheimer's disease or Parkinson's disease, which are rare, but have 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 sporadic forms, genome-wide association studies have identified risk-alleles for Alzheimer's disease, such as a mutation in the ''APOE'' gene, and for Parkinson's disease, such as mutations in the ''SNCA'' and ''MAPT'' genes. 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. while the ε2 allele confers a reduced risk for ad (0.56-fold risk for hetero- and homozygous carriers), compared to the most common ε3 allele, ε4 is a major risk factor for ad (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 ===
For various neurodegenerative diseases, exposition to environmental toxins has been described as a risk factor. Metal toxins like Zinc, Copper and Mercury have been implicated in amyloid-β aggregation and τ-hyperphosphorylation, two of the pathological signs of Alzheimer's disease. Biological toxins, leading to oxidative stress and inflammatory responses, have been suggested to play a role in disease development for Alzheimer's disease<ref>Maryam Vasefi, Ehsan Ghaboolian-Zare, Hamzah Abedelwahab, Anthony Osu, Environmental toxins and Alzheimer's disease progression, Neurochemistry International, Volume 141, 2020, ISSN 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 0891-5849, <nowiki>https://doi.org/10.1016/j.freeradbiomed.2021.07.003</nowiki>.</ref>.

=== 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, frontotemporal dementia 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 and developmental Factors ===
Early development has been implicated as independent risk factors for neurodegenerative diseases. Alzheimer's disease has been associated with lower education levels<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> and lower general cognitive abilities in childhood<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>. Lower socioeconomic status during early life and childhood trauma has been shown to decrease late-life cognitive abilities, but not directly influence the rate of cognitive decline or Alzheimer's disease<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>.

== Brain aging and functional decline ==
The brain tissue of older adults contains the build-up of protein deposits. These include tau protein and amyloid-β.

== Hallmarks of brain aging ==
[[File:Hallmarks of brain aging.jpg|thumb|552x552px|The nine hallmarks of aging are involved in many neurodegenerative diseases. These include Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), ataxia telangiectasia (AT), Huntington disease (HD), and Parkinson disease (PD).]]
The basic process of neurodegeneration is fundamentally connected to the hallmarks of brain aging.

The nine so-called 'hallmarks of aging' were defined in 2013 and represent the basic biological processes underlying the aging process. These are now widely used in the aging field, and in the context of neurodegenerative diseases.

These are: genomic instability, epigenetic alterations, telomere attrition, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communication. The nine hallmarks of aging have been shown to be linked to brain aging and the main neurodegenerative diseases, as described below.

=== Genomic instability ===
Several types of DNA damage are associated with neurodegeneration. Damage from disruptive molecules known as reactive oxygen species are associated with aging and neurodegenerative disease, and DNA damage leads to genomic instability.

Ongoing damage to the DNA induces a protein called PARP1 to become active, and results in depletion of NAD+. NAD+ is an essential co-factor for sirtuin enzymes that play important roles in health and longevity. DNA damage also causes an increase in cellular senescence and inflammation, which are accelerate brain aging.

=== Telomere attrition ===
Telomeres are the protective 'caps' on the end of chromosomes, composed of protein and DNA. Each time a cell divides, the telomeres generally become shorter. The shortening of telomeres occurs as part of biological aging and causes cellular senescence, and is associated with neurodegeneration and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.

=== Epigenetic alterations ===
Epigenetics describe changes to heritable factors that do not involve changes to the DNA code itself. These include modifications including methylation, by which a methyl group is added to the DNA molecule. Epigenetic changes have been associated with neurodegenerative diseases.

=== Loss of proteostasis ===
Proteostasis refers to the balance of protein production and degradation in cells and tissues. A balance of proteins is crucial for the normal functioning of cells. The misfolding, aggregation or deposition of proteins has been shown to be connected to several neurodegenerative disorders.
=== Mitochondrial dysfunction ===
Neurons are highly metabolically active cells with high energy demands. Mitochondria play a key role in energy production, but become impaired in brain aging and neurodegenerative disease. The production of reactive oxygen species is associated with aging and neurodegenerative diseases. Mitophagy is the process that results in the selective degradation of mitochondria. Growing evidence suggests that defects in mitophagy that occur with aging contribute to the neurodegenerative process. Studies have demonstrated that DNA damage in the cell can contribute to mitochondrial dysfunction. Inducing mitophagy has been suggested as a potential strategy to mitigate brain aging.

=== Cellular senescence ===
Cellular senescence refers to a state of a cell which occurs when dead or dying cells begin releasing inflammatory factors. This can occur as a result of DNA damage to the cell. With age, the number of senescent neurons increases in the brain. Studies in old mice have demonstrated that up to 40% of cortical, hippocampal, and peripheral neurons are senescent. Cellular senescence has been linked with exacerbated age-related brain dysfunction. As such, targeting senescent cells is being considered as a therapeutic strategy for patients with neurodegenerative diseases.

=== Deregulated nutrient sensing and altered metabolism ===
Several nutrient sensing biochemical pathways are linked to aging and longevity. These include insulin-like growth factor 1 (IGF1), mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK) and the sirtuin enzymes. Studies in mice, worm and fly species have demonstrated that modulating these pathways can extend lifespan. Metabolic dysfunction in these pathways is commonly associated with neurological, age-related diseases.

=== Stem cell exhaustion ===
Stem cells are required for the creation of new cells in later life. However, stem cell function declines over an organism's lifespan, due to several other hallmarks including DNA damage, defective proteostasis, and epigenetic deregulation. The loss of stem cells is linked to age-related neurodegeneration.

=== Altered intercellular communication ===

Changes to levels of hormones such as insulin and IGF1 occur with age and are linked with neurodegeneration. In addition, loss of regulation of the immune system with age is implicated in neurodegenerative diseases. For example, inflammation, a protective response to injury, becomes chronically upregulated with age and high levels of inflammation are related to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

== Interconnectedness of the hallmarks ==
The hallmarks of aging are highly interconnected and occur in a complex process that is part of neurodegeneration. For example, the loss of proteostasis is strongly linked to inflammation and senescence. The metabolic dysfunction that occurs with age and is present in neurodegenerative diseases is associated with mitochondrial dysfunction and oxidative stress. The reduction in number of stem cells is linked to almost all the other hallmarks, such as genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence and telomere attrition.
== Aging and Alzheimer's disease ==

== New treatments for neurodegenerative diseases ==
Current efforts to develop evidence-based treatments for neurodegenerative diseases are ongoing, but no highly effective treatment approaches have been discovered. Given the complexity of age-related neurodegenerative diseases, the current approach of targeting single pathways may be inadequate. Instead, broader therapeutic approaches that target the brain aging process directly may be considered as a new approach to treating neurodegenerative diseases. Further research into understanding nine hallmarks of aging and targeting these processes may be required to create effective new therapies for neurodegeneration. Some approaches being explored are described below:
==== Supplementing NAD+ ====
NAD+ is an essential molecule involved in energy metabolism in the body. A sufficient supply of NAD+ is necessary for maintenance of mitochondrial health, DNA repair, energy homeostasis and brain health. Levels of NAD+ decline with age in humans, but supplementation can increase levels of NAD+. Supplementation with molecules that turn into NAD+, known as NAD+ precursors, include nicotinimide riboside (NR) and nicotinimide mononucleotide (NMN). These supplements may help to extend healthy lifespan and slow brain aging, thereby delaying or protecting against neurodegeneration. Studies in mice have shown that NR reduces plaque accumulation and improves cognition, as well as including learning and memory. NMN has similarly demonstrated beneficial effects in mice. Clinical trials evaluating the potential benefits of NAD+ in humans are currently underway.

==== Inhibition of cellular senescence ====
Senescence of the astrocytes and microglial cells - cells that support neurons in the brain - accumulate in normal brain aging and patients with Parkinson's disease and Alzheimer's disease. The elimination of these cells may represent a new strategy for extending the healthspan of the brain and treating neurodegenerative diseases. Strategies using have shown beneficial effects in animal models:

* Rapamycin has been shown to delecerate cellular senescence as one of perhaps several neuroprotective effects
* Metformin has been shown to suppress cellular senescence via activation of microRNA-processing proteins that reduce plaque build-up in Alzheimer's disease and Parkinsons's disease.

== Clinical trials targeting age-related mechanisms of neurodegenerative disorders ==
{| class="wikitable"
|+
!Hallmark of aging targeted
!Drug(s)
!Mechanism of action
!Disease
!Actual or Estimated trial completion date
!ClinicalTrials.gov Link
|-
|Altered intercellular communication
|Niacin
|Reducing inflammation
|Parkinson's disease
|April 2020
|https://clinicaltrials.gov/ct2/show/NCT03462680
|-
|Deregulated nutrient sensing
|Resveratrol
|Reducing insulin resistance
|Mild cognitive impairment
|June 2022
|https://clinicaltrials.gov/ct2/show/NCT02502253
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Alzheimer's disease or MCI
|July 2022
|https://clinicaltrials.gov/ct2/show/NCT03061474
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Parkinson's disease
|March 2024
|https://clinicaltrials.gov/ct2/show/NCT03568968
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Alzheimer's disease
|August 2023
|https://clinicaltrials.gov/ct2/show/NCT04063124
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|July 2031
|https://clinicaltrials.gov/ct2/show/NCT04685590
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|June 2023
|https://clinicaltrials.gov/ct2/show/NCT04785300
|-
|Cellular Senescence
|Dasatinib plus Quercetin, Fisetin
|Removing senescent cells
|Skeletal health
|March 2023
|https://clinicaltrials.gov/ct2/show/NCT04313634
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|December 2022
|https://clinicaltrials.gov/ct2/show/NCT04200911
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|August 2024
|https://clinicaltrials.gov/ct2/show/NCT04629495
|}

== References ==
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