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Abstract

Human beings have always pursued a prolonged lifespan, while the aging of the nervous system is associated with a large variety of diseases. Pathological aging of the nervous system results in a series of neurodegenerative diseases and can cause disability and death in the elderly. Therefore, there is an urgent need for the prevention and treatment of nervous system aging. Chinese herbal medicines have a long history, featuring rich and safe ingredients, and have great potential for the development of anti-aging treatment. We searched the publications on PubMed with key words “anti-aging of the nervous system” and “Chinese herbal medicine” in recent 10 years, and found sixteen Chinese herbal medicines. Then by comparing their popularity of use as well as active components based on the research articles, five common Chinese herbal medicines namely Ginseng Radix, Lycii Fructus, Astragali Radix, Coptidis Rhizoma and Ginkgo Folium, were confirmed to be the most related to anti-nervous system aging and neural degenerative diseases. At the same time, the active ingredients, research models, action mechanisms and curative effects of these five common Chinese herbal medicines were reviewed. From the five common Chinese herbal medicines reviewed in this paper, many encouraging effects of Chinese herbal medicines on treating nervous system aging and related diseases were revealed and more potent herbs would be explored with the help of the proposed possible mechanisms.

Keywords

Chinese herbal medicine anti-aging nervous system aging neurodegenerative diseases active ingredient efficacy

Introduction

Aging is a transformational factor in major chronic diseases and a key factor for the development of age-related diseases. Since ancient times, people have pursued health and longevity by delaying aging and improving the quality of life. Aging itself is not a disease but predisposes to senile diseases. Particularly, the aging of the nervous system causes a large number of diseases.¹ Nervous system aging is divided into peripheral nervous system aging and central nervous system aging. Neurodegenerative diseases are conditions that result from the loss of neurons² and/or myelin sheath³ in the brain and spinal cord. Moreover, aging is the strongest risk factor for most neurodegenerative diseases,^4,5 the most common being Alzheimer’s disease⁶ and Parkinson’s disease.⁷ Despite the rising incidence among the elderly, effective drugs for these diseases are still lacking. Due to the rapidly aging population, scientists around the world have been searching for the causes and underlying mechanisms of aging-related diseases, as well as methods to delay aging and prolong lifespan.

Recently, more and more studies have demonstrated the potential of Chinese herbal medicine in anti-aging treatment.^8-10 Chinese herbal medicines typically make use of safe ingredients and offers unique solutions to many intractable diseases.^11,12 Many prescriptions for prolonging lifespan have been described in ancient Chinese medicine books. In contrast, modern medical research has focused on extracting the active ingredients from anti-aging Chinese herbal medicines and studied their anti-drug mechanisms and clinical availability. For example, the main active ingredients astragalus polysaccharides (APS) and Astragaloside IV which contained in Astragali Radix, extracted from astragalus^13,14 have obvious anti-aging effects and can also effectively enhance immunity. A well-known life-prolonging holy product, Ginseng Radix, also exert anti-aging effects through various mechanisms,¹⁵ such as neuroprotective and neuroregulatory effects.¹⁶ After reviewing the references published in the recent 10 years, five most studied Chinese herbal medicines, including Ginseng Radix, Lycii Fructus, Astragali Radix, Coptidis Rhizoma and Ginkgo Folium were summarized in this paper. We proceeded to summarize the active ingredients, research models, mechanisms, and therapeutic effects of these commonly used Chinese herbal medicines.

Nervous System Aging and Neurodegenerative Diseases

Aging is a progression deterioration of fitness caused by deleterious factors, influenced by genetic, environmental, and stochastic processes. From the evolutionary perspective, aging occurs due to the evolutionary restriction maintained by the body, which leads to the accumulation of injuries.¹⁷ Aging is associated with the loss of functional reserves, reduced homeostasis, and decreased regenerative capacity of aging tissues over time. Tissue-specific stem cells, their niches, and regenerative changes in systemic cues regulating stem cell activity contributed to this process.¹⁸ Senescence can be divided into cellular senescence, which involves a permanent state of cell cycle arrest serving as a defence mechanism from unnecessary damage,¹⁹ and individual aging, where the accumulation of the senescent cells leads to overall human senescence.²⁰ Individual senescence is characterized by a gradual decline in bodily function. Aging is a significant risk factor for various common diseases, including nervous system diseases, diabetes, cardiovascular diseases, and cancer²¹ chronic age-related diseases account for approximate half of all human deaths.

Aging has a significant impact on both the central nervous system and peripheral nervous system. The regenerative capacity of the peripheral nerve diminishes with aging, resulting in the emergence of neuropathies, that impede normal bodily function. This decline can be attributed to the diminished ability of Schwann cells to maintain and regenerate the aging nerves.²² Schwann cells play a crucial role in peripheral nerves regeneration and facilitate the repair of various tissues.²³ Brain aging mostly refers to central nervous system aging, which differs from other organs because neurons are highly differentiated cells that can no longer undergo mitosis while still having a limited lifespan.²⁴ In the process of physiological brain aging, a series of structural and functional changes occur, including brain atrophy, a decrease in neurochemical transmitters, loss of neuronal synapses and a decline in cognitive function.²⁵ At cellular and molecular level, Mattson and Arumugam have postulated nine hallmarks of brain aging: mitochondrial dysfunction, oxidative damage, impaired molecular waste disposal, impaired adaptive stress response signalling, impaired DNA repair, aberrant neuronal network activity, dysregulated neuronal calcium homeostasis, stem cell exhaustion, and glia cell activation and inflammation²⁶ (Figure 1).

Figure 1.

Nine hallmarks of brain aging at cellular level and the neurodegenerative diseases.

Under the combined action of some internal and external factors, the nervous system may gradually progresses from physiological aging to pathological aging, which may lead to the development of neurodegenerative diseases²⁷ (Figure 1). Pathological brain aging is characterized by early synaptic destruction and synaptic loss, which leads to abnormal anatomical and functional white-matter connection defects and progressive cognitive decline.²⁸ Neurodegenerative diseases are caused by the entanglement of neuron fibers and the loss of neurons. In addition, the damage and reduced production of neural stem cells (NSCs)²⁹ can also cause neurodegenerative diseases. Alzheimer's disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are three major neurodegenerative diseases.^30,31 Neurodegenerative diseases are characterized by three pathological features. The first is the accumulation of pathological proteins caused by the imbalance of intracellular homeostasis,³² such as A amyloid β-protein in AD³³ and Tau protein tangles,³⁴ etc. The second is neuroinflammation mediated by microglia,³⁵ and the third is neuronal death.³⁶ Most neurodegenerative diseases usually manifest in the elderly, as aging is the most important risk factor for the development of neurodegenerative diseases and the hallmarks of aging are underline the onset of neurodegenerative diseases.⁴

Chinese Herbal Medicines in Nervous System Aging and Related Neurodegenerative Diseases

In traditional Chinese medicine, health and longevity are intricately related to the balance of yin and yang, strong innate endowment and adequate nutrition after birth. The innate origin lies in the kidney, whereas the acquired origin lies in the spleen (stomach). For example, Wang Chong pointed out in The Lunheng Self-discipline: “To keep one’s self-tranquility, to keep one’s self-restraint in due course, to keep one’s mind quiet, to love essence and self-protection, to be guided by appropriate drugs, so that one’s life can be prolonged, and one will not grow old.” In addition, applying Chinese herbal medicines to delay aging and senility can prevent diseases. Many kinds of anti-aging Chinese herbal medicines have been mentioned in ancient books, such as the earliest medical book Shennong Materia Medica. After thousands of years of exploration and research, Chinese medicine scientists have identified numerous anti-aging Chinese herbal medicines. These herbs have been extensively studied and evaluated for their effectiveness in managing neurodegenerative diseases. For example, Yang, Wenting et al.³⁷ analyzed clinical trial data and concluded that Chinese herbal medicine could be recommended for routine use in AD patients, as it may treat AD by enhancing adult hippocampal neurogenesis by activating multi-signal pathways. Therefore, AD patients could benefit from follow-up treatment with Chinese herbal medicine. Chinese herbal medicines can also regulate the signal pathway related to the pathological progress of AD,¹² regulate crosstalk between pathways through a multitarget, and finally improve the cognitive impairment of AD patients. Furthermore, Chinese herbal medicines can also improve Parkinson's disease (PD). Yin, Rong et al.³⁸ summarized the potential targets of bioactive compounds or herbal extracts from Chinese herbal medicines in treating PD, reporting herbs or their bioactive components for drug development. Although the research of Chinese herbal medicines' active ingredients for the treatment of neurodegenerative diseases is still in the preliminary exploration stage,³⁹ Chinese herbal medicine offers a unique theory and rich experience in anti-aging treatment. Exploring the mechanism of Chinese herbal medicine in anti-aging and its role in senile diseases could lead to the development of effective treatments for neurodegenerative diseases.

Five Typical Chinese Herbal Medicines for treating Nervous System Aging and Related Neurodegenerative Diseases

At present, hundreds of anti-aging Chinese herbal medicines have been reported. However, the Compendium of Materia Medica lists about 60 “top grade” anti-aging Chinese herbal medicines, such as Ginseng Radix and Ganoderma lucidum. And, we conducted a comprehensive search for the articles on anti-aging Chinese herbal medicines in PubMed over the past decades. As a result, we identified 25 Chinese herbal medicines with potential anti-aging effects. After reviewing the titles and abstracts, we selected 96 articles related to the treatment of nerve aging and neurodegenerative diseases, involving 15 Chinese herbal medicines. To provide a more visual representation of the popularity of these anti-aging herbs, we created a pie chart (Figure 2) that displays the names of Chinese herbal medicines and the corresponding number of research articles. In addition, we summarized the active components of the top 8 most studied Chinese herbal medicines in Table 1.

Figure 2.

Pie chart with Chinese herbal medicines name and number of documents.

Table 1.

Summary of the Chinese Herbal Medicines and Their Main Active Components With Potential Anti-Aging Effects in Nervous System.

Types of Chinese Herbal Medicines	Plant source	Main active ingredients
Astragali Radix	Astragalus mongholicus Bunge	Polysaccharides and saponins
Lycii Fructus	Lycium barbarum L.	Polysaccharides
Ginkgo Folium	Ginkgo biloba L.	Ginkgo biloba extract
Ginseng Radix	Panax ginseng C.A.Mey.	Glycosides
Coptidis Rhizoma	Coptis chinensis Franch.	Berberine and coptisine
Rhodiolae Crenulatae Radix et Rhizoma	Rhodiola rosea L.	Glycosides
Rehmanniae Radix	Rehmannia glutinosa (gaertn.) DC.	Glycosides
Ganoderma	Ganoderma lucidum (Leyss.ex Fr.) Karst.	Polysaccharides and terpenoids

The most effective compounds which have potential anti-aging effects in nervous system are flavonoids, terpenoids, saponins, and polysaccharides⁴⁰ and berberine.⁴¹ By comparing the number of research articles and their active components of the 15 Chinese herbal medicines, we identified the five Chinese herbal medicines that best aligned the criteria of this review. There herbals are Ginseng Radix, Lycii Fructus, Astragali Radix, Coptidis Rhizoma and Ginkgo Folium. This review summarizes the active ingredients, mechanisms and efficacy of five typical Chinese herbal medicines in anti-nervous system aging and related neurodegenerative diseases.

Ginseng Radix

Ginseng Radix is a popular herbal medicine that has been used in Chinese herbal medicine for more than 2000 years. Its first use was recorded in Shennong Herbal Classic in ancient China. Ginseng Radix and its components, especially ginsenosides, are not only effective against aging but also beneficial against aging-related neurological diseases. Ginsenoside exhibits anti-apoptosis, anti-oxidation and anti-inflammatory properties, making it effective in protecting the central nervous system against the neurodegenerative diseases associated with aging.⁴² The neural tissue loss and subsequent decline in cognitive function are often observed with advancing age. Ginseng Radix is extensively used and studied due to its enhancement in cognition and stress-relieving effects.⁴³ For example, Ginsenoside Rg1 has been shown to delay cognitive decline caused by the production of Aβ, protein kinase A/cyclic AMP responsive element binding protein (PKA/CREB) activity, and brain-derived neurotrophic factor (BDNF) content in the brain.⁴⁴ Furthermore, Ginsenoside Re was shown to alleviate cognitive impairment in mice.⁴⁵ Additionally, Ginsenosides Rb⁴⁶ and Rd⁴⁷ exhibit robust neuroprotective and regulatory effects. Many Ginsenosides play an active role in anti-aging, especially in the anti-aging of the nervous system,⁴⁸ highlighting Ginseng Radix as the most promising Chinese medicine in the anti-aging field. Studying the active ingredients and anti-aging mechanism of Ginseng Radix is of great significance. Table 2 summarizes the studies on Ginseng Radix in treating nervous system aging and the associated neurodegenerative diseases over the last 10 years.

Table 2.

Summary of the Studies on Ginseng Radix in Treating Nervous System Aging and the Associated Neurodegenerative Diseases Over the Last Ten Years.

Active Ingredients	Experimental model	Possible mechanism	Efficacy	Reference
Ginsenoside Rg2	d-galactose-induced brain aging mice	Maintains mitochondrial function by increasing mitochondrial autophagy flow	Restores D-gal-induced impaired memory function, choline dysfunction, and redox system imbalance	Zhang, Jun-Jie et al.⁴⁹
Ginsenoside Rg1	Amyloid β peptide 25-35 (Aβ25-35) induced AD cell	Inhibits signal transduction pathways of toll-like receptor 3 (TLR3) and TLR4 and reduces inflammatory factors induced by A β	Improves memory impairment associated with Alzheimer's disease (AD)	Zhao, Bao-Sheng et al.⁵⁰
Ginsenoside Rg1	d-galactose-induced aging rats	Promotes the differentiation of neural stem cells/progenitor cells (NSC/NPCs) into neurons, enhances the antioxidant and anti-inflammatory capacity, increases the telomere lengths and telomerase activity and down-regulates cellular senescence-associated gene expression in the hippocampus	Delays the aging of hippocampal cells and improves cognitive ability in aging rats	Zhu, Jiahong et al.⁵¹
Ginsenoside Rg1	d-galactose and AlCl₃-induced aging mice	Restores the decline of fibroblast growth factor (FGF2) and brain-derived neurotrophic factor (BDNF) induced by aging, and reactivates TrkB/Akt signaling pathway to inhibit apoptosis in the hippocampus and prefrontal cortex	Ameliorates cognitive impairment of chemically-induced aging mice	Zhong, Si-Jia et al.⁵²
Ginsenoside Re	Klotho deficient mice	Upregulates nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor/glutathione peroxidase (GPx-1)/extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB) signaling pathway	Alleviates memory impairment in aged mice with Klotho deficiency	Nguyen, Bao Trong et al.⁴⁵
Ginsenoside Rb1	Aged mice with cerebral ischemia	Blocks the oxidative stress and extracellular signal-regulated kinase (ERK) activation in aged mice stimulated by cerebral ischemia	Promotes the recovery of brain injury in aged mice	Dong, Xiao et al.⁵³
Ginsenoside Rd	Adult rats and cultured neural stem cells	①Increases the number of bromodeoxyuridine (BrdU) (+) and doublecortin (DCX) (+) cells in the dentate gyrus of hippocampus ②Promotes the size and number of neurospheres for cultured neural stem cells, and increases the number of BrdU (+) and Ki67 (+) cells	Enhances the proliferation of neural stem cells without affecting the differentiation of neural stem cells in vivo and in vitro	Lin, Tian et al.⁵⁴
Ginseng gintonin	Primary astrocytes	Upregulates autophagy marker LC3 and enhances autophagic flux	Stimulates autophagy in primary cortical astrocytes	Rahman, Md Ataur et al.⁵⁵
Maltol (3-hydroxy-2-methyl-4-pyrone)	d-galactose-induced brain aging mice	Activates PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in the brain	Reduces d-Gal-induced behavioral dysfunction and neurological deficit	Sha, Jiyue et al.⁵⁶
Ginsenoside Rg1	Female C57BL/6J mice	Enhances the activation of mTOR signal and upregulates the synthesis of synaptic plasticity-related proteins	Improve cognitive performance	Yang, Lumeng et al.⁵⁷

Lycii Fructus (Wolfberry)

Lycii Fructus is extracted from the dried fruit of Lycium barbarum L. Lycium barbarum L. has a history of more than 2000 years in China as a traditional herb and food supplement. Lycium barbarum polysaccharide (LBP) is the main active component of Lycii Fructus, which delays nervous system aging by inhibiting the production or aggregation of amyloid β-protein (Aβ), reducing the production of amyloid β-protein (Aβ) peptide, exerting neuroprotection, decreasing neuronal morphology changes, and exerting antioxidative and anti-apoptosis effects.^58-63 Lycium barbarum polysaccharide (LBP) also has a remarkable curative effect on Alzheimer’s disease and Parkinson’s disease.⁶⁴ Furthermore, the fruit extract of Lycii Fructus is an anti-aging ingredient^65-67 that increases the expression of antioxidant-related genes, reduces Aβ deposition and reduces the levels of Aβ oligomer. In addition, the fruitless Lycium barbarum bud extract can also be used to treat Alzheimer’s disease by inhibiting Aβ fibrillation and decomposing Aβ fibers.⁶⁸ The water extract of Lycium barbarum has neuroprotective effects on AD mice by improving cholinergic function.⁶⁹ Table 3 summarizes the studies on Lycii Fructus in treating nervous system aging and the associated neurodegenerative diseases over the last 10 years.

Table 3.

Summary of the Studies on Lycii Fructus in Treating Nervous System Aging and the Associated Neurodegenerative Diseases Over the Last Ten Years.

Active ingredients	Experimental model	Possible mechanism	Efficacy	Reference
Lycium barbarum polysaccharide (LBPs)	Ovariectomy (OVX) mouse	Downregulates the Toll-like receptor 4 (TLR4)/noncanonical nuclear factor-kappaB (NF-κB) signaling pathway associated mRNAs and proteins, decreases the inflammatory response and reduces neuronal injury	Reduces neuroinflammation and neuronal injury and relieves cognitive impairment of OVX female mice	Zheng, xiaomin et al.⁵⁸
Lycium barbarum polysaccharide (LBP)	Primary cultured rat hippocampal neurons	Increases mitochondrial membrane potential (MMP) and IκB expression, inhibits [Ca²⁺]_i elevation and suppresses apoptotic markers such as NF-κB, IL-6, and Toll-like receptor 4 (TLR4) overexpression	Increases cell ability and decreases impairment of neuronal morphology	Zhao, Peng et al.⁵⁹
Lycium barbarum polysaccharide (LBPs)	Scopolamine-Treated (SCO) rats	Suppresses oxidative stress and neuron apoptosis	Promotes hippocampal neurogenesis and neuron survival and prevents SCO-induced cognitive and memory deficits	Chen, Weiwei et al.⁶⁰
Novel lycium barbarum polysaccharide (LBP-3)	N2a/APP695 cells	Adjusts the activities of β -secretase and γ -secretase to reduce the ratio of Aβ₄₂ to Aβ₄₀	Improves the activity of redox-related enzymes and protects nerves from injury	Wu, Jiaxin et al.⁶¹
Lycium barbarum polysaccharide (LBPs)	Chinese hamster ovary (CHO) cells	Inhibits the production or aggregation of Aβ₄₂	Prevention of neurodegeneration induced by amyloid β-protein (Aβ)	Zhou, Lishuang et al.⁶²
Polysaccharides from Lyciumbarbarum L. (LBP1)	(APP/PS1) transgenic mice	Reduces the production of β-amyloid (Aβ) peptide	Promotes cognitive function and restores synaptic plasticity	Zhou, Yue et al.⁶³
Phenolic compounds in fruit of Lycium ruthenicum Murr.	Network-based pharmacological strategy	Activates succinate dehydrogenase subunit (SDHA, SDHB and SDHC) of mitochondrial electron transfer chain complex II, and ATP5A1 and ATP5B containing mitochondrial electron transfer chain complex V	Maintains the dynamic balance of mitochondrial function and reduces cell apoptosis	Luo, Zhiqiang et al.⁶⁵
Lycii fructus extract (LFE)	Triple transgenic mouse model of Alzheimer's disease (3xTg AD)	Reduces Aβ deposition, increases NeuN positive cells, and up-regulates brain neurotrophic derived factor (BDNF) and tyrosine kinase B (TrkB) expression	Improves learning and memory deficits in AD mouse	Ye, Minsook et al.⁶⁶
Lycium barbarum fruit extract (LBFE) (The active ingredient has not been determined yet)	Drosophila PD model (PINK1B9)	Raises ATP and dopamine levels and increases the expression of antioxidant-related genes	Improves exercise ability, restores muscle morphology and extends life span	Bai, Xiao-Lin et al.⁶⁷
Fruitless wolfberry-sprout extract (FWE)	Alzheimer’s disease transgenic mice (APP/PS1 mice)	Inhibits Aβ fibrillation and decomposes the formed Aβ fibers, reduces glial hyperplasia and inflammatory cytokine release, and improves oxidative stress in the brain	Improves cognitive function of AD mice	Liu, Shu-Ying et al.⁶⁸
Lycium barbarum aqueous extract	Apoptosis cell model of DPC12 cells induced by L-glutamate and AD mice induced by AlCl3 and D-gal	Increases the expression levels of acetylcholine (Ach) and choline acetyltransferase (ChAT) in serum and hypothalamus	Improves learning and memory ability	Hu, Xinyu et al.⁶⁹
Lycium barbarum extracts	Caenorhabditis elegans	Reduces heat shock transcription factor -1(HSF-1) deficiency by deacetylase	Prolongs life and reduces toxic protein accumulation	Zhou, Haitao et al.⁷⁰
Lycium barbarum extract	Caenorhabditis elegans model of Alzheimer's disease	Induces the activation of mtUPR mediated by FSHR-1 and SKN-1-mediated antioxidant system	Inhibit the production of excessive reactive oxygen species, inhibit the production of Aβ, and inhibit mitochondrial damage	Meng, Jiao et al.⁷¹
Lycium barbarum polysaccharide	H2O2-treated PC12 cells in vitro and in CoCl2-treated rats in vivo	Inhibits the H2O2-induced decrease in nuclear factor erythroid 2-related factor 2 (Nrf)2 and heme oxygenase (HO)-1 expression and binding of Nrf2 to the promoters of HO-1	Protects against neurotoxicity	Cao, Shumei et al.⁷²
Lycium barbarum extracts	Triple transgenic mouse model of AD (3xTg-AD)	Decreases both oxidative stress and intracellular calcium influx	Neuroprotection	Liu, Jinfeng et al.⁷³
Lycium ruthenicum polyphenols	PC12 cells	Reduces apoptosis and oxidative stress	Neuroprotection	Gao, Hua et al.⁷⁴
Lycibarbarspermidines A-O	Transgenic fly AD model	Antioxidant	Anti-aging, neuroprotective, anti-AD.	Zhou, Zheng-Qun et al.⁷⁵

Coptidis Rhizoma

Coptidis Rhizoma is composed of many alkaloids, including berberine, palmatine, ephedra, cotisin and episcopolamine, among which berberine is the main compound.⁴¹ Berberine can inhibit cholinesterase activity, Aβ production and tau hyperphosphorylation,⁷⁶ thus reducing neuronal damage and apoptosis. Berberine’s small size allows it to effectively cross the blood-brain barrier, acting on a number of molecular targets. Many scholars^77-79 have found that berberine has broad potential in the treatment of neurodegenerative diseases. However, its benefits have only been discovered in recent years, so only a few studies have been performed on the subject. Table 4 summarizes the studies on Coptidis Rhizoma in treating nervous system aging and the associated neurodegenerative diseases over the last 10 years.

Table 4.

Summary of the Studies on Coptidis Rhizoma in Treating Nervous System Aging and Associated Neurodegenerative Diseases Over the Last Ten Years.

Active ingredients	Experimental Model	Possible Mechanism	Efficacy	Reference
Berberine (BBR)	Alzheimer’s disease transgenic mice (TgCRND8 mice)	Reduces the levels of detergent-soluble and -insoluble β-amyloid via inhibiting glycogen synthase kinase (GSK) 3	Ameliorates learning deficits, long-term spatial memory retention, as well as plaque load	Durairajan, Siva Sundara Kumar et al.⁸⁰
Isoquinoline alkaloid	African green monkey epithelial kidney (COS7) cells	Inhibition of acetylcholinesterase	Prevention of Alzheimer's disease	Kaufmann, Dorothea et al.⁸¹
Coptis chinensis Franch polysaccharide (CCP)	CL4176AD transgenic cryptorhabditis elegans	Decreases Aβ protein accumulation and upregulates heat shock protein	Protects against Aβ-induced toxicity	Li, Yujuan et al.⁸²
Coptis chinensis rhizome water extract (CRE) and coptisine (COP)	Neuroblastoma SH-SY5Y cells	Strengthens the thioredoxin defense system against oxidative stress by downregulating thioredoxin-interacting protein (TXNIP) gene expression and reduces the decrease of cell viability, MMP and apoptosis induced by tert butyl hydroperoxide	Neuroprotective effect	Friedemann, Thomas et al.^83,84
Berberine	Triple-transgenic mouse model of Alzheimer's disease	Weakens the hyperphosphorylation of tau	Alleviate cognitive decline	Chen, Ying et al.⁸⁵
Berberine and coptisine	Parkinson’s disease mouse model	Improves mitochondrial function	Neuroprotective effect	Friedemann, Thomas et al.⁸⁶
Coptis chinensis Franch	APPswe/PS1ΔE9 mice	Acts on the intestinal brain axis by regulating short-chain fatty acids	Treats Alzheimer's disease	Xie, Minzhen et al.⁸⁷

Astragali Radix

In recent years, a growing number of studies have focused on the treatment of neurodegenerative diseases by Astragali Radix. The main components of Astragali Radix are Astragalus polysaccharides (APS), astragaloside, flavonoids, saponins, alkaloids, etc.⁸⁸ Astragali Radix polysaccharide⁸⁹ and Astragaloside IV⁹⁰ are the main active ingredients of Astragali Radix in preventing and treating neurodegenerative diseases. Astragalus polysaccharides can inhibit the increase of astrocytes and the activation of microglia, reverse the structural damage of mitochondria, increase the level of reactive oxygen species, promote the formation of autophagy cells against neurodegenerative diseases, and exert antioxidant and anti-aging effects.^91-95 Moreover, Astragaloside IV plays an anti-aging role by inhibiting oxidation and apoptosis, regulating calcium balance and exerting anti-inflammatory properties. In addition, Astragaloside IV promotes mitochondrial autophagy, thus reducing the accumulation of damaged mitochondria and the production of mitochondrial reactive oxygen species.^14,96-103 To conclude, the mechanism of Astragali Radix against aging-related neurodegenerative diseases mainly involves anti-neurotoxicity, anti-neuroinflammation and anti-oxidation. Astragali Radix is a dietary herb, applied with many potential signal regulations, including neurotransmitters and receptors, anti-inflammatory activity, inhibiting amyloid aggregation, inducing myelin repair and neurogenesis, and activating signal pathways related to neurological diseases.¹⁰⁴ Table 5 summarizes the studies of Astragali Radix in treating nervous system aging and the associated neurodegenerative diseases in the recent 10 years.

Table 5.

Summary of the Studies on Astragali Radix in Treating Nervous System Aging and the Associated Neurodegenerative Diseases Over the Last Ten Years.

Active ingredients	Experimental model	Possible mechanism	Efficacy	Reference
Astragalus polysaccharides (APS)	APP/PS1 mice	Activates Nrf2 channel	Improves the cognitive ability of APP/PS1 mice, reduces apoptosis and Aβ accumulation	Qin, Xiude et al.⁹¹
Astragalus membranaceus-polysaccharides (APS)	Metabolically stressed APPswe/PS1dE9 mice	Reduces the increase of astrocytes and the activation of microglia in the vicinity of plaques, and improves the reactivity of astrocytes with high-fat diet and low-dose injection of streptozotocin (HFSTZ) aggravation in APP/PS1 mice	Ameliorates peripheral metabolic stress, vascular inflammation and neuroinflammation	Huang, Yung Cheng et al.⁹²
Astragalus polysaccharides (APS)	PD mice	Reduces motor dysfunction, increases the proportion of TH-positive cells, reverses the damage to the mitochondrial structure, inhibits reactive oxygen species (ROS), and increase mitochondrial membrane potential	Neurons and mitochondria are protected	Liu, Hong et al.⁹³
Astragalus polysaccharides (APS)	6-Hydroxydopamine (6-HODA) treated PC12 cells	Promotes autophagy in cells, increases the conversion of LC3-I protein to LC3-II protein, down-regulates the protein expression of pAKT and p-mTOR, and up-regulates the protein expression of PTEN.	Activates autophagy for treating PD.	Tan, Yynin et al.⁹⁴
Astragalus polysaccharides (APS)	BV2 microglia	Prevents LPS-induced activation of PKB and NFκ B, resulting in down-regulation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF) and interleukin-1β (IL-1β) in BV2	Anti-inflammation	Luo, Tao et al.⁹⁵
Astragaloside iv	Rats exposed to microwave	Protects the synaptic ultrastructure, maintains synaptic function, increases acetylcholine concentration in the hippocampus, promotes the normalization of electroencephalogram (EEG) signals, and restores brain function	Protects rat hippocampus from microwave-induced structural and functional injuries	Zhao, Li et al.⁹⁶
Astragaloside IV	Long culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium (LPS/MPP)-induced premature senescence model and PD mouse model	Inhibits astrocyte senescence via promoting mitochondrial autophagy	Prevents dopaminergic neurodegeneration in PD.	Xia, mei-Ling et al.¹⁴
Astragaloside IV (AS-IV)	AβO infusion mice with AD-like phenotypes	Inhibits the interaction of tau protein hyperphosphorylation, synaptic defects, neuroinflammation and ptosis via regulating proliferator-activated receptorγ (PPARγ)	Prevents AD-like phenotypes	Wang, Xuncui et al.⁹⁷
Astragaloside IV (AST-IV)	PC12 cells and BV-2 cells	Inhibits TLR4/NF-κB signaling pathway and protects neurons from cell death mediated by microglia by transforming microglia from inflammatory M1 to anti-inflammatory M2 phenotype	Protects neurons from microglia-mediated cell damage	Yu, Jingwen et al.⁹⁹
Astragaloside IV	Hydrogen peroxide (H2O2) induced human neuron cells (SH-SY5Y cells)	Inhibits the expression of α-synuclein through the p38 mitogen-activated protein kinase (MAPK) signaling pathway	Exerts protective effects against neurodegenerative diseases by targeting α-synuclein	Liu, Xiang et al.¹⁰⁰
Astragaloside	SK-N-SH cells	Inhibits mitochondrial permeability transition pore (mPTP) opening and ROS regeneration.	Protects cells from Aβ1-42 neurotoxicity	Sun, Qinru et al.¹⁰¹
Astragaloside IV	Oligomeric Aβ induced AD mouse model	Inhibits activation of microglial cells and expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase	Ameliorates cognitive impairment and neuroinflammation in AD mice	Chen, Fei et al.¹⁰²
Isoastragaloside I (ISO I)	BV2 microglia	Suppresses NF- κB activation via phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling pathways	Prevents LPS-induced microglia activation	Liu, Hongshuai et al.¹⁰³
Astragalus-containing serum (ASMES)	PC12 cells	Reduces 6-hydroxydopamine (6-OHDA) triggered apoptosis and ROS production	Protects PC12 cells from 6-OHDA-caused neuronal toxicity	Guo, Li-Ying et al.¹⁰⁵
17(R),20(R)-3β,6α,16β-trihydroxycycloartanyl-23-carboxylic acid 16-lactone 3-O-β-D-glucopyranoside	In vitro model of 6-hydroxydopamine on isolated rat brain synaptosomes	Inhibition of human recombinant monoamine oxidase type B	Neuroprotective and antioxidant effects	Shkondrov, Aleksandar et al.¹⁰⁶
Astragalus polysaccharides	Caenorhabditis elegans	Reduces oxidative stress, regulates apoptosis pathway and cholinergic system	Prevents neurotoxicity	Li, Haifeng et al.¹⁰⁷
Astragalus polysaccharide	Drosophila melanogaster	Delays the occurrence of Alzheimer’s phenotype induced by Aβ42	Prolongs life and increases exercise ability	Li, Xu et al.¹⁰⁸

Ginkgo Folium

Ginkgo biloba L. is the oldest existing tree species in the world, which can be traced back to the Permian period, about 286 to 248 million years ago. Ginkgo Folium extract has been widely used to treat central nervous system and cardiovascular diseases.^109,110 The active substances of Ginkgo Folium are mainly divided into two categories: EGb761and GBE. The Ginkgo Folium extract EGb761 can prevent neurodegenerative diseases by blocking the mitochondrial-mediated apoptosis signal,^111,112 reducing the hyperphosphorylation of tau protein and increasing the degradation of p-Tau.^113,114 Furthermore, it regulates the phenotype of activated microglia, up-regulating anti-inflammatory cytokines and down-regulating pro-inflammatory cytokines.¹¹⁵ Growing evidence¹¹⁶ shows the therapeutic potential of GBE in Alzheimer's disease (AD). Among herbal extracts, the Ginkgo biloba extract (GBE) is one of the most studied herbs for cognitive impairment and AD. GBE can inhibit the formation of free radicals, exert antioxidant effects, reduce neuronal damage and reduce the occurrence of inflammatory reactions.^117-119 In addition, some scholars extracted a new compound-YY1224, which can inhibit the pro-inflammatory transformation of microglia mediated by Aβ and protect against Aβ toxicity.¹²⁰ Furthermore, Ginkgo biloba L. leaves have high yields, abundant raw materials, low prices and easily available extracts. Therefore, they are suitable for drug development and mass production. Table 6 summarizes the studies on Ginkgo Folium in treating nervous system aging and the associated neurodegenerative diseases over the last 10 years.

Table 6.

Summary of the Studies on Ginkgo Folium in Treating Nervous System Aging and the Associated Neurodegenerative Diseases Over the Last Ten Years.

Active ingredients	Experimental model	Possible mechanism	Efficacy	Reference
Ginkgo biloba extract (EGb 761)	Human neuroblastoma cell	Blocks the beginning of the p53-dependent intrinsic mitochondrial apoptosis pathway induced by oxidative stress	Prevents cellular apoptosis induced by oxidative stress	Di Meo, Francesco et al.¹¹¹
Ginkgo biloba extract EGb 761	Aβ 25-35 induced rats	Blocks mitochondria-mediated apoptosis signal in AD.	Reduces cytotoxicity and oxidative stress	Tian, Xiaoqiang et al.¹¹²
Ginkgo biloba extract EGb761	Hyperhomocysteinemia (HHcy) rats	Recovers protein phosphatase 2A subunit (PP2Ac) and glycogen synthase kinase-3beta (GSK3β) activities; reduces hyperphosphorylation of tau and upregulates synapse-associated protein postsynaptic density 95 (PSD95) and synapsin-1 expression	Rescues the spatial memory deficit of HHcy-treated rats and has the potential to treat AD.	Zeng, Kuan et al.¹¹³
Ginkgo biloba extract EGb 761	Human P301S tau mutant-transgenic mice	Increases autophagic activity and p-Tau degradation in neuronal lysosomes	Reduces brain p-Tau levels and prevents AD.	Qin, Yiren et al.¹¹⁴
Ginkgo biloba extract EGb761	APP/PS1 transgenic mice	Upregulates anti-inflammatory cytokines and downregulates pro-inflammatory cytokines by regulating the phenotype of activated microglia	Improves cognitive function and relieves amyloid plaque deposition	Wan, Wenbin et al.¹¹⁵
Ginkgo biloba extract (GBE)	Human neuroblastoma SH-SY5Y	Suppresses the activation of redoxosome-p66Shc induced by glutamate	Attenuates glutamate-induced oxidative toxicity	Wang, ke et al.¹¹⁷
Ginkgo biloba extract (GBE)	Albino rat	Inhibits the formation of free radicals, eliminates reactive oxygen species and enhances the antioxidant capacity	Reduces PD symptoms	Mohammed, Nema A et al.¹¹⁸
Ginkgolide B (GB)	Senescence-accelerated P8 (SAMP8)mice	Mitigates oxidative stress, inflammation and nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 (GPX4) pathway-mediated ferroptosis	Prevents aging and the acceleration of cognitive impairment in SAMP8 mice	Shao, Li et al.¹¹⁹
Ginkgo biloba-supplement (Gb-S)	Rotenone induced mice	Increases Nrf2 immunoexpression and cholinergic enzyme activity, downregulates executioner caspase-3 and attenuates neuron loss	Reduces molecular involvement and pathological attributes associated with Parkinson's disease	Adebayo, Olusegun G et al.¹²¹
Ginkgo biloba L	In silico investigation	Regulates hormone sensitivity, improves endocrine homeostasis, maintains endothelial microvascular integrity and proteolysis of tau protein, especially in amyloid β- protein (Aβ) before plaque formation	Plays a beneficial role in improving mild to moderate dementia in patients with Alzheimer's disease (AD) and other neurological diseases	Li, Hongxiang et al.¹²²
Terpene trilactone-strengthened extract of Ginkgo biloba (YY-1224)	APP/PS1 Tg mice	Downregulates the expression of PAF-acetylhydrolase-1 (PAF-AH-1) and peroxisome proliferator-activated receptor γ (PPARγ) and inhibits Aβ-mediated pro-inflammatory transformation of microglia phenotype by suppressing COX-2 expression	Protective effects against Aβ toxicity	Li, Zhengyi et al.¹²⁰
Ginko biloba leaf extract	Elderly male mice	Increases the number and maturity of newborn Neurons	Enhances adult neurogenesis	Osman, Noura M S et al.¹²³
Ginkgo biloba extract (GBE)	A53T α-synuclein transgenic mice	Reduces oxidative damage and maintains normal dopamine homeostasis	Improves locomotor activity	Kuang, Shaosong et al.¹²⁴

The Similar and Different Cellular Mechanisms of These Five Chinese Herbal Medicines on Anti-Nervous System Aging

At cellular and molecular level, Mattson and Arumugam had postulated certain nine hallmarks of brain aging. In this review, five Chinese herbal medicines are involved in seven of these nine hallmarks (Table 7). Interestingly, these five Chinese herbal medicines all contain ingredients to play roles in repairing mitochondrial dysfunction and reducing oxidative damage. Specially, Ginseng Radix, Lycii Fructus, Astragali Radix and Ginkgo Folium contain ingredients that prevent glia cells activation and neuroinflammation. Moreover, Ginseng Radix, Lycii Fructus and Astragali Radix aid in restoring the transmission of adaptive stress response signals. These common characteristics are observed among the five Chinese herbs discussed in this review. However, each herb also possesses unique properties comparied to the other four. For example, Ginseng Radix can prevent stem cell depletion, Astragali Radix can repair aberrant neuronal network activity, and Lycii Fructus can regulate neural calcium homeostasis.

It is important to note that these hallmarks of brain aging are interconnected and operate within intricate signaling pathways and regulatory systems. Thus, the markers of brain aging do not occur in isolation.²⁶ Considering these interindenpendence of these hallmarks, combination therapies with multiple durgs may be more effective. For example, Shenqi Yizhi granules¹²⁵ are made of Ginseng Radix and Astragali Radix and Ren, Jianting et al. found that Shenqi Yizhi granules significantly increased the expression of proteins in energy metabolism, stress response, cytoskeleton, synaptic transmission, signal transduction, amino acid metabolism and other aspects. However, due to the complex composition and synergistic action of these herbals, the specific mechanism remains to be explored. Liang, Wenyi et al.¹²⁶ discovered that Ginkgo biloba extract increased ginsenoside uptake in the brain of rats through LC-MS/MS analysis. They also found that EGb increased blood-brain barrier permeability by activating A1 adenosine receptor signaling pathway, thus enhancing the uptake of ginsenoside in the brain, and the combination of Ginseng Radix and Ginkgo biloba produced better effects Table 7.

Table 7.

Summary of the Anti-Aging Mechanisms of Five Chinese Herbs That Play a Role in Cellular Aging Hallmarks. (Chinese Herbal Medicine Pictures are Sourced From Network).

Ginseng Radix	Lycii Fructus	Coptidis Rhizoma	Astragali Radix	Ginkgo Folium
①Repair mitochondrial dysfunction.	① Repair mitochondrial dysfunction.	① Repair mitochondrial dysfunction.	① Repair mitochondrial dysfunction.	① Repair mitochondrial dysfunction.
②Reduce oxidative damage.	②Reduce oxidative damage.	② Reduce oxidative damage.	③ Reduce oxidative damage.	②Reduce oxidative damage.
③Prevent the activation of glia cells and prevent neuroinflammation.	③Prevent the activation of glia cells and prevent neuroinflammation.		④ Prevent the activation of glia cells and prevent neuroinflammation.	② Prevent the activation of glia cells and prevent neuroinflammation.
④Restore the transmission of some adaptive stress response signals.	④Restore the transmission of some adaptive stress response signals.		⑤ Restore the transmission of some adaptive stress response signals.
⑤Prevent stem cell exhaustion.	⑤Regulate neural calcium homeostasis.		⑥ Repair aberrant neuronal network activity.

Conclusion and Prospect

Aging is a universal biological process characterized by the accumulation of aging cells,¹²⁷ and is associated with many neurodegenerative diseases.¹⁶ Senescence cells play an important role in the etiology of aging and age-related diseases in mammals.¹²⁸ Slowing down aging by controlling and reducing the number of aging cells is the basis of anti-aging, while pathological aging leads to persistent and harmful changes in organisms. Despite the increasing prevalence of neurodegenerative diseases, no effective treatment is available for these diseases.¹²⁹ However, multiple Chinese herbal medicine compounds present a promising potential in slowing down aging and preventing neurodegenerative diseases. Many Chinese herbal medicines exert their anti-aging effects through multiple mechanisms. Among the five typical Chinese herbal medicines listed in this review, the anti-aging mechanisms mainly involve reducing the production and aggregation of Aβ, preventing tau hyperphosphorylation, anti-neurotoxicity, repairing mitochondrial dysfunction, and reducing oxidative damage, eliminating free radicals to play an antioxidant role, and increasing the formation of anti-neurodegenerative disease cells.

The use of Chinese herbal medicine demonstrates effective control over the early signs of neurodegenerative diseases, and can serve as a preventive intervention. This approach avoids the toxic and side effects associated with western medicine while significantly improves the patient compliance. Moreover, Chinese herbal medicine contains hundreds of compounds, and whether there is synergistic effect between each component has not been well studied. At present, more active components should be separated and screened from Chinese herbal medicine, similar to the discovery of artemisinin for treating malaria. However, this extraction process may lead to the loss of valuable components. In addition, the Ginkgo Folium mentioned in this review highlights that the individual component extracted from plants may not be as effective as the whole extract. Many studies investigating the effective function of Ginkgo Folium primarily focus on the Ginkgo biloba extract (GBE). If the single component is not as effective as the whole extract, the establishment of a comprehensive quality standard system becomes crucial to facilitate the prompt clinical application of herbal medicines. The proposal of quality markers of Chinese medicines¹³⁰ can provide insights to address this issue. Due to the various components responsible for the respective mechanisms, the extraction difficulty of individual compounds also varies. Moreover, among the chemical components of Chinese herbal medicine with anti-aging properties, saponins and polysaccharides are the most prevalent, and the most effective components and mechanisms should be prioritized. Nevertheless, the active components of many extracts have not been identified yet. Further research is required to develop effective treatments for aging and neurodegenerative diseases based on Chinese herbal medicine. In addition, based on the promising outcomes of certain Chinese medicine formulations, combining specific Chinese herbal medicines may yield a more potent and synergistic effect. However, due to the intricate nature of the herbal ingredients and the unclear interactions between them, the development of further research necessitates a more comprehensive solution.

Supplemental Material

Supplemental Material - Anti-Aging of the Nervous System and Related Neurodegenerative Diseases With Chinese Herbal Medicine

Anti-Aging of the Nervous System and Related Neurodegenerative Diseases With Chinese Herbal Medicine by Xiaohui Du, Nanbin Lou, Sinan Hu, Ruopeng Xiao, Chu Chu, Qiankai Huang, Lin Lu, Shanshan Li, Jing Yang in American Journal of Alzheimer’s Disease & Other Dementias®

Footnotes

Authorship Contribution Statement

Jing Yang and Shanshan Li: Conceptualization, Designing, Writing-review and editing. Chu Chu: Revising-the revised manuscript. Nanbin Lou, Sinan Hu, Ruopeng Xiao: Screening and gathering - articles. Qiankai Huang: Drawing the Figure 1. Lin Lu: Revising the language. Xiaohui Du: Writing- original draft, Writing-review and editing, Writing-the revised manuscript.

Declaration of Conflicting Interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the This work was supported by the National Natural Science Foundation of China (Grant number 81901154) and Zhejiang Basic Public Welfare Research Program (Grant number LGD22H250001).

ORCID iD

Jing Yang

Supplemental Material

Supplemental material for this article is available online.

Appendix

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