Epigallocatechin-3-Gallate (EGCG): New Therapeutic Perspectives For Neuroprotection, Aging, And Neuroinflammation For The Modern Age Part 4

5. Inflammatory Signaling Pathways Involved in Neurodegeneration

Normal characteristics of aging in the brain are decreased neurogenesis, elevated synaptic damage, increased metabolic stress, cognitive decline, and immunosenescence.

As people age, their brains also age, and this aging affects our thinking ability and memory. But we can't let this fact get us down, because there are things we can do to slow down brain aging while improving our memory.

First, we can help our brains stay young through exercise. Physical exercise promotes brain health by improving blood circulation and increasing the supply of oxygen and nutrients. Furthermore, exercise can also reduce stress and anxiety, states that have negative effects on our brains. Therefore, practicing some light exercise, such as walking, dancing, and yoga, is very helpful in preventing brain aging.

Secondly, we need to maintain a happy attitude. Happiness promotes the release of neurotransmitters in the brain that are important for thinking function. Therefore, we should keep in touch with friends, participate in social activities, try new things and activities, etc., to make us feel better. In addition to this, we can slow down brain aging by changing our diet. Maintain a healthy diet that includes fruits, vegetables, fish, and other foods rich in brain-healthy substances such as Omega-3 fatty acids and vitamins B, E, and C. These substances protect nerve cells and increase the production of neurotransmitters, which improve memory and thinking skills.

Overall, brain aging is inevitable, but there are steps we can take to slow the process. Physical exercise, maintaining a happy attitude, and changing our diet are all good ways to slow down brain aging and enhance memory. Let us actively face brain aging and create a healthy and beautiful life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the many active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in a variety of ways.

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 Aging is also linked to systemic inflammation, increased blood-brain barrier (BBB) permeability, and dysregulated glial cell signaling, influencing chronic inflammation [101]. Normal glial signaling regulating the inflammatory response is the NF-kB, mitogen-activated protein kinase (MAPK), and phosphoinositide-3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathways. The NF-κB pathway has been linked with inflammation related to aging. 

NF-κB can be stimulated by ROS, cytokines, inflammatory agents, growth factors, and synaptic transmission (primarily glutamate). In mice, it was shown that microglia stimulation induces a highly conserved transcriptional signature with aging, characterized by NF-κB expression and neuronal death. 

In rats, elevated NF-κB expression resulted in the generation of neurodegenerative proinflammatory enzymes: cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS). Diabetes has displayed an increased risk of AD by 50% by influencing Aβ pathology by NF-κB upregulation and independent overexpression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). 

Research on primate and rodent models shows that diabetes and obesity drive overexpression of NF-κB in the hypothalamus by promoting a feedback loop of hypertension, overnutrition, and diminished insulin sensitivity [102]. MAPKs consist of serine/threonine kinases triggered via multiple protein kinases in response to extracellular stimuli by dual phosphorylation at conserved threonine and tyrosine residues [103,104]. 

The extracellular signal-regulated kinase (ERK) pathway is a mediator of neuronal function. ERK1/2 activation occurs by various neurotransmitters and neuropeptides through induction of ligand-gated ion channels or GPCRS; ERK1/2 primarily regulates cell proliferation and may regulate calcium signaling [103]. 

The c-Jun N-terminal kinase (JNK) pathway has been shown to promote neurodegeneration or neuroinflammation via the provocation of potentially deleterious stimuli such as hypoxia, free radicals, and ROS. 

The p38 mitogen-activated protein kinase (p38) pathway can be stimulated by various growth factors (platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF)), pro-inflammatory cytokines, and oxidative stress resulting in multiple cellular responses such as inflammation, apoptosis, cell growth, and differentiation [103]. 

IL-6 stimulates Janus kinase (JAK), which activates signal transducer and activator of transcription (STAT), which provoke the regulation of inflammatory response. The phosphoinositide-3-kinase/protein kinase B/mechanistic target of the rapamycin (PI3K-Akt-mTOR) signaling pathway regulates many cellular metabolism and energy homeostatic processes, such as proliferation and survival, which can involve the immune system and CNS. 

It mediates neuronal physiological conditions, such as learning, memory, and neuroprotection. PI3K is activated by phosphorylation due to the coupling of various growth factors, such as epidermal growth factor (EGF) and signaling proteins, i.e., (TLR) ligands bind to receptor tyrosine kinase, which allows for the phosphorylation of phosphatidylinositol 3,4-bisphosphate (PIP2) to PI (3,4,5)-triphosphate (PIP3) triphosphate, which stimulates serine-threonine kinase AKT controlled by phosphoinositide-dependent kinase 1 (PDK1), which can trigger mTOR activation. 

Current research has shown the relevance of this pathway to aging and, coupled with AD, can alter normal AKT and mTOR activity since both are controlled by oxidative stress, decreased nutrient concentration, and innate immune signals. 

Further, AD upregulates this pathway resulting in neurodegeneration. The PI3K-AKT-mTOR signaling pathway is linked to insulin regulation (particularly cerebral insulin), reduced in aging individuals making them more susceptible to AD [105,106].

6. Contributing Determinants to the Incidence of AD: Health Disparities, Sex, and Gender

Health inequality involves differences in quality healthcare due to living conditions, race/ethnicity, socioeconomic status, pollutant exposure, diet, comorbidities, gender, and family health history [107]. Other noteworthy factors are cognitive reserve, genetic differences in pathological resilience, and educational level. 

There is a dearth of research into health inequality effects on minorities, i.e., African Americans (AAs), Latinos, and Hispanics, related to AD [20,108]. A research article by McDonough [109] introduces the Weathering hypothesis deduced by Geronimus [110], which states "the cumulative impact of those mentioned above social, physical, and economic adversities faced by AAs lead to early health deterioration and advanced biological aging," which can be used to evaluate social stressor effects on minority neurological health. 

Powell et al. [111] evaluated community effects involved in AD, a cross-sectional investigation of autopsy samples from 447 decedents living in a disadvantaged neighborhood at the time of death. 

They found that it was correlated with a heightened risk of Alzheimer's disease neuropathology when adjusted for age, sex, and year of death. Another relevant study was conducted by Saadi et al. [112], who showed that AAs and Hispanics were less likely (30% to 40%) to see an outpatient neurologist than Caucasians, respectively.

Furthermore, AAs were prone to being cared for in an emergency room, having frequent hospital stays, and paying more for inpatient care than Caucasians. 

Other research has illustrated how social stressors can exacerbate the risks for AD neuropathy [112,113]. A research area that has not garnered enough attention is the sex and gender differences observed in neurodegenerative disorders. 

Men and women have different outcomes concerning neurodegenerative disease arising from socioeconomic status, level of education, genetics, and hormonal differences [114–116]. Current studies show that sex differences exist in a cognitive decline concerning AD [117,118]. 

Bloomberg et al. [119] evaluated cognitive decline and performance correlated to aging and education and found that women had stronger memory and lesser memory decline than men regardless of education level. However, education did play a factor in the fluency tests, in which women who were higher educated and in the later cohort had higher scores than the men. Still, there were no sex differences in fluency decline [119]. 

Androgens (testosterone) and estrogens may serve to prevent and treat neurodegenerative diseases due to their many anti-inflammatory properties, such as halting proinflammatory cytokine production, protection from oxidative stress, and modulation of Aβ production [120,121]. 

Several investigations show that estrogen's neurological roles in regulating the effects of the trophic factors in the brain heighten cerebral blood flow, restrain atrophy of cholinergic neurons, and adjust BBB glucose transporter expression and membrane translocation [122,123]. 

Aging is liable to cause a loss of sex hormones (androgens and estrogens), which induce muscle loss, muscle weakness, diminished functional performance, and reduced life span [124,125]. 

Postmenopausal women (age 65 and over) are more susceptible to AD than men [122]. Immunological sex differences exist in microglia, as shown in microglial transcriptomic and proteomic studies that change with age [126,127].

7. Preventive Measures for Neurodegenerative Disease: Nutraceutical and Phytochemical Use in Neurodegenerative Disease

Regarding AD, there have been no new FDA-approved drugs since 2003 and no authorized disease-modified treatment (DMT), although there have been many extensive clinical trials [32,33,128]. Considering this fact, the advent of nutraceuticals has led to a possible new form of control of this disease. 

Nutraceuticals are a broadly defined term that comprises many products that arise from the food industry, herbal and dietary supplement trade, pharmaceutical, and hybrid agribusiness/nutrition enterprises that may have potential medicinal value in treating disease [96]. 

Nutraceuticals have gained tremendous interest due to their long history of use and providing a natural alternative to the current pharmaceutical drugs in the market [96]. Nutraceuticals have been shown to have anti-inflammatory, antioxidative, and anti-aging properties. 

The anti-inflammatory/antioxidative processes carried out by nutraceuticals are as follows: (a) hinder NFκB activation, (b) inhibit overexpression of proinflammatory cytokines, (c) downregulation of the overexpression of calcium/calmodulin (CAM) and enzymes, (d) block enzymatic action of COX-2 and iNOS, (e) arrest ROS enzymatic production, and (f) elevate ROS scavenging [129].

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