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European University Cyprus Brain Aging: Mechanisms and Prevention Rodothea Savvidi ABSTRACT Impaired Lysosome and Proteasome Function: PREVENTION Structural, cellular, and molecular changes in the Autophagic and proteasomal degradation is impaired. 4- There are some gene variants could be hydroxynonenal (HNE) can disrupt lysosome function in the associated with the development of dementia. brain contribute to aging and cognitive decline. cerebral cortical neurons, leading to the buildup of degraded The ApoE normally breaks down the beta There is brain atrophy, gray and white matter cargo and eventual cell death. amyloid that is associated with Alzheimer’s changes, and loss of synaptic density, alongside disease with the ε4 allele encoding with a less mitochondrial dysfunction, oxidative damage, and Dysregulation of Neuronal calcium Homeostasis: effective ApoE. The use of anti-APOE ε4 impaired protein degradation. Dysregulated Aging impairs the calcium-induced after-hyperpolarisations, thus antibodies in individuals with the ApoE ε4 allele calcium homeostasis, inflammation, and impaired increasing the calcium influx and increasing the calcium release can reduce the amyloid deposition and restore neurogenesis further exacerbate these issues. from the endoplasmic reticulum. Leads an elevation of the the cerebral vessel’s function. Preventive strategies, including genetic, cytoplasmic calcium levels and dysregulation of protein epigenetic, and lifestyle interventions, are phosphorylation, gene expression and cytoskeletal dynamics. Targeting DNA damage can be achieved highlighted as potential ways to delay brain aging. Aberrant Neuronalnflammation Cell Senescence through the inhibition of the DNA damage Promoting healthy habits like exercise, sleep Compromised Activity Attritionere response (DDR) proteins such as ataxia- Stress Responsesr Impaired DNA Impaired Dysregulated telangiectasia mutated and rad3-related, DNA- management, and dietary restrictions, along with Repair Neurogenesis Energy Metabolism targeting molecular mechanisms such as DNA dependent protein kinase, Checkpoint kinase 1, repair and mitochondrial function, may help Compromised Adaptive Cellular Stress Responses: and p53. There are also the regulating preserve cognitive function and prevent deacetylase enzymes. One example is Initiators of adaptive cellular stress responses like ATP activating histone deacetylase 1 with exifone neurodegenerative diseases like Alzheimer’s. consumption, Calcium, and ROS can become impaired during that was shown to have lowered DNA damage. aging, thus the neurons become vulnerable to injury and neurodegenerative disorders (reduced expression of the Regular exercise and managing sleep neurotrophic factors and changed receptor expression or disorders can improve DNA repair. Protective INTRODUCTION downstream signaling limit BDNF, NGF, and IGF-1 signaling). factors against DNA damage include avoiding excessive alcohol consumption, smoking and Aging is a biological process where there is UV exposure. the accumulation of cellular and molecular Aberrant Neuronal Activity: damages over years. As time passes, the The neuronal network activity in the brain regions is disturbed. GABAergic signaling is impaired, causing excitatory imbalances. Maintaining the telomere length can be body is unable to repair this damage thus This is caused by oxidative stress, mitochondrial dysfunction, achieved with therapeutic agents targeting leading to the loss of physiological functions. impaired adaptive stress responses and inflammation. telomerase. Compounds that regulate With that being said, the brain is not immune telomere function include TA-65 that can Impaired DNA repair: to the effects of aging. As we age, the brain activate telomerase. Danazol, 5- undergoes atrophy, where lower white matter ROS damages DNA in the nucleus and mitochondria throughout dihydrotestosterone, and PAPD5 volume and aberrant functional connectivity aging and normal cellular function. In neurons, this damage is demonstrated promise in maintaining telomere exacerbated after excitatory synaptic activation. The coordinated length. are the most prevalent aging-related changes. actions of proteins in DNA repair pathways quickly eliminate damaged DNA bases and replace them with undamaged bases in healthy, young cells. During aging, there is increase in the The regulation of mitochondrial dysfunction damaged mitochondrial and nuclear DNA, decreased expression and oxidative stress can prevent brain aging STRUCTURAL CHANGES and dementia. Dietary restriction and exercise Morphological changes of brain aging include and enzymatic activities of DNA repair proteins. had improved the function of mitochondria cerebral atrophy, grey and white matter changes, and decreased oxidative stress. Hesperidin Inflammation: volume loss, ventricular enlargement and sulci In the aged brain, it was noted that glial cells are in an active was shown to enhance antioxidant defenses, widening. state, thus there is the production of pro-inflammatory cytokines, reducing mitochondrial dysfunction and the Grey matter changes include a reduction in the such as IL-1β, IL-6 and TNF-α. They lead to synaptic de- formation of Aβ plaques. dendritic arborization complexity. Changes in the generation and impairment of the brain function. An unhealthy lifestyle is directly linked to white matter include partial loss of myelin, axons, most dementia cases. High alcohol intake can oligodendroglia cells and reactive astrocytic speed cognitive decline and brain aging. gliosis. As people age, the grooves and folds or Dietary restrictions, increase exercise and ridges in the cerebral cortex's sulci and gyrus, sleep therapy slow brain aging and respectively, get shallower and wider. neurodegeneration. Exercising can help The blood vessels in the brain are also affected regulate histone modification, stabilize the by aging. Specifically, there is arterial mitochondria, reduce neuroinflammation and inflammation and arteriosclerosis. The elastic maintain the blood-brain barrier. fibers, collagen and smooth muscle cells deteriorate over time. DISCUSSION There are several mechanisms associated with brain aging. Gross changes include cerebral CELLULAR AND MOLECULAR atrophy, sulci widening and cerebrovascular changes. Cellular and molecular changes HALLMARKS OF BRAIN mainly occur in the nucleus, mitochondria, AGING lysosomes, calcium homeo-stasis and more. AccumulationImpaired Lysosomesregulation of Figure: Hallmarks of brain aging As we age, DNA expression will change, and Mitochondrial of Oxidativeand ProteasomeNeuronal there will be shortening of telomere length. dysfunction Molecules Function Homeostasis Impaired Neurogenesis: Early prevention and managing the modifiable Mitochondrial Dysfunction: Reductions in the hippocampal and olfactory neurogenesis, which Enlargement or fragmentation, increased lead to cognitive and olfactory deficits. risk factors for brain aging are of outmost importance. Addressing them can help slow oxidative damage to the mitochondrial DNA, Cell Senescence and Telomere Attrition: down cellular and molecular changes impaired function of the electron transport chain, associated with brain aging. It is important to increased numbers of mitochondria with Extensive telomere shortening can trigger apoptosis or cell understand and limit the risk factors to depolarized membranes, impaired calcium senescence. Newly formed neurons are vulnerable to apoptosis handling, and a lower threshold for triggering the caused by telomere damage. As a result, hippocampal neurogenesis promote a better quality of life and healthier is reduced and there is impairment of the hippocampus-dependent brains. formation of mPTPs. spatial learning and memory. REFERENCE Accumulation of Oxidatively Damaged Dysregulated Energy Metabolism: 1. Wrigglesworth J, Ward P, Harding IH, Nilaweera D, Wu Z, Woods RL, et Molecules: al. Factors associated with brain ageing - a systematic review. BMC Aging impairs the brain’s and peripheral tissues’ cells’ ability to Neurology. 2021 Aug 12;21(1). Dysfunctional and aggregated proteins and metabolize lipids and glucose. There is an increase in circulating 2. Lee J, Kim HJ. Normal Aging Induces Changes in the Brain and mitochondria accumulate in the neurons due to glucose due to the inability of cells to increase glucose transport in Metabolic, Cellular, and Molecular Changes. Frontiers in Aging Neuroscience increased production of reactive oxygen species response to insulin, leading to insulin resistance. [Internet]. 2022 Jun 30;14. Available from: (ROS) and low antioxidant defenses. Increased Dyslipidemia may also increase the risk for Alzheimer's Disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281621/ levels of Superoxide anion radical, hydroxyl There is buildup of lipid-laden cells and long-chain ceramides, as well hallmarks, and therapies for brain aging and age-related dementia. Science as a decrease in the amounts of omega-3 fatty acids in brain tissue. Bulletin [Internet]. 2024 Sep 12;69(23):3756–76. Available from: radical and nitric oxide. https://www.sciencedirect.com/science/article/pii/S209592732400639X