Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2019 / Article
Special Issue

Oxidative Stress in Age-Related Chronic Disease: From Bench to Bedside

View this Special Issue

Review Article | Open Access

Volume 2019 |Article ID 4598167 | https://doi.org/10.1155/2019/4598167

Yanfei Liu, Weiliang Weng, Rui Gao, Yue Liu, "New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach", Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 4598167, 25 pages, 2019. https://doi.org/10.1155/2019/4598167

New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach

Academic Editor: Fiammetta Monacelli
Received21 Apr 2019
Revised28 Sep 2019
Accepted16 Oct 2019
Published12 Dec 2019

Abstract

Aging is a progressive disease affecting around 900 million people worldwide, and in recent years, the mechanism of aging and aging-related diseases has been well studied. Treatments for aging-related diseases have also made progress. For the long-term treatment of aging-related diseases, herbal medicine is particularly suitable for drug discovery. In this review, we discuss cellular and molecular mechanisms of aging and aging-related diseases, including oxidative stress, inflammatory response, autophagy and exosome interactions, mitochondrial injury, and telomerase damage, and summarize commonly used herbals and compounds concerned with the development of aging-related diseases, including Ginkgo biloba, ginseng, Panax notoginseng, Radix astragali, Lycium barbarum, Rhodiola rosea, Angelica sinensis, Ligusticum chuanxiong, resveratrol, curcumin, and flavonoids. We also summarize key randomized controlled trials of herbal medicine for aging-related diseases during the past ten years. Adverse reactions of herbs were also described. It is expected to provide new insights for slowing aging and treating aging-related diseases with herbal medicine.

1. Introduction

Aging, which can be divided into pathological and physiological aging, is a complex biological process characterized by functional decline of tissues and organs, structural degeneration, and reduced adaptability and resistance, all of which contribute to an increase in morbidity and mortality caused by multiple chronic diseases [1, 2]. As fertility declines and life expectancy increases, the proportion of people aged 60 and older is increasing. According to the UNESA population division, approximately 900 million people are 60 years or older worldwide, and this will increase to 21.5% of the global population by 2050 [3] (see Figure 1). As aging progresses, it increases one’s susceptibility to diseases associated with this process, such as vascular aging disorders [46], diabetes [7], muscle dysfunction [8, 9], macular degeneration [10], Alzheimer’s disease (AD) [11, 12], skin diseases [13], and a series of other diseases [1418] (see Figure 2). Aging-related diseases pose a serious threat to human health and reduce the quality of life among elderly people. In addition, it has become a global difficulty to clarify the mechanisms of aging, slow the process of aging, reduce the occurrence of aging-related diseases, and maintain that unfading appearance during the aging process.

Aging is a complex process with complicated mechanisms. At present, one of the accepted theories is related to oxidative stress [1921]. In the process of aerobic metabolism, reactive oxygen species (ROS), including hydroxyl radicals, superoxide anions, and hydrogen peroxide (H2O2), can be produced in cells [2224]. When ROS level exceeds the antioxidant capacity of cells, they react with lipids, proteins, and nucleic acids in cells, resulting in oxidation or peroxide formation. This leads to the destruction of the cell membrane structure, changes in permeability, and a cytotoxic reaction. High levels of ROS can directly damage DNA, proteins, and lipids in cells, causing a DNA damage response [25] and activation of p38MAPK for p16 upregulation. This leads to cell senescence and development of aging-related diseases [26]. DNA damage response also provides an appropriate trigger for the onset of telomere-induced senescence through the p53 pathway [25, 27, 28]. In addition to oxidative stress, various factors play a role in the aging process. Some reviews have reported the mechanisms of aging [26, 2932]; however, only one of the mechanisms was examined; for example, some researchers [29, 30] described the role of miRNAs in aging while others [31, 32] placed an emphasis on autophagy.

In this review article, by mainly retrieving PubMed, here, we identify and critically analyzed nearly 10 years of published studies focusing on the mechanisms of aging and aging-related diseases, while summarizing some herbs and compounds that were more extensively used and studied for slowing aging. Compared with the latest published article describing the efficacy, mechanism, and safety of herbal medicine in slowing aging [33], this review is aimed at discussing the cellular and molecular mechanisms of aging from multiple perspectives, also emphasizing the interaction between exosome and autophagy in aging, and discussing age-related diseases and the progress of herbal medicine as potential therapeutic agents for aging and aging-related diseases. The adverse effects of herbs also get our attention in this review.

2. Cell Types Involved in Aging

2.1. Endothelial Cells

Endothelial cells are an essential part of the heart and vasculature [34]. They possess multiple functions through paracrine and endocrine actions, such as regulating vascular tension, maintaining blood circulation, and mediating inflammation, immune response, and neovascularization [3537]. Endothelial dysfunction caused by endothelial cell senescence is closely linked to the development of aging. Several studies revealed that ROS and inflammation play a role in the apoptosis of endothelial cells [3841]. Oxidative stress combined with thioredoxin-interacting protein (TXNIP) could activate NOD-like receptor family pyrin domain containing 3 (NLRP3) and inflammatory corpuscles during senescence of endothelial cells. In addition, the production of the proinflammatory cytokine, interleukin-1 (IL-1), which is induced by the activation of NLRP3 inflammatory corpuscles, could promote senescence of endothelial cells [42]. In recent years, it has been well established that autophagy and exosomes play significant roles in the course of a disease [43, 44]. Endothelial dysfunction and impaired autophagic activity are associated with age-related diseases [45]. Exosomes containing harbor miRNAs also participate in the regulation of endothelial function [46]. Studies demonstrated that miR-216a, a molecular component of miRNAs, could be induced during endothelial aging and play an important role in aging-related diseases by regulating autophagy-related genes, such as Beclin1 (BECN1) [47].

2.2. Stem Cells

Stem cells are pluripotent cells characterized as undifferentiated and immature with the ability to self-renew. Stem cell therapy is widely used in clinic, especially in cardiovascular regenerative medicine [48]. Under certain conditions, stem cells can be differentiated into various functional cells, with the potential function of regenerating various tissues and organs [49]. Changes in the cell cycle and a decline in the self-renewal ability of stem cells are closely related to aging. Although some changes in their function are intrinsic [50, 51], more external factors can lead to impairment in their function [52]. Studies have shown that the physiological levels of ROS could regulate the balance between self-renewal and stem cell differentiation [53, 54]. Nevertheless, oxidative stress due to high ROS levels could lead to DNA damage, shortening of telomeres [55], and the onset of premature aging markers, such as prelamin A, the lamin A. Nicotinamide adenine dinucleotide phosphate oxidase isoform 4 (Nox4) component of ROS could be localized to promyelocytic leukemia nuclear bodies (PML-NB) related to prelamin A, which could control the aging of stem cells [56]. Additionally, decline in self-renewal factors contributes to stem cell aging [57].

2.3. Vascular Smooth Muscle Cells

There are evidence suggesting that senescent vascular smooth muscle cells (VSMCs) have been observed in aging-related diseases, such as diabetes mellitus and atherosclerosis [58, 59], which indicate that senescent VSMCs contribute to aging. According to a study by Zhan et al. [60], VSMCs pretreated with the AMPK activator and mammalian target of rapamycin (mTOR) inhibitor could delay the replicative senescence of these cells. They revealed that the AMPK/TSC2/mTOR signaling pathway can regulate the replication and aging of VSMCs, which is mainly manifested as inhibition of the AMPK/TSC2/mTOR pathway which can inhibit the replication and aging of VSMCs. Another study showed that miR-34c-5p downregulation promoted VSM aging through a mechanism that might be mediated by the Bcl-2 modifying factor (BMF), which is a functional target of miR-34c-5p. LncRNAES3 was also found to act as a competing endogenous RNA (ceRNA) of miR-34c-5p to enhance BMF expression [61].

3. Molecules or Signal Transduction Pathways in Aging

3.1. Molecules in Aging
3.1.1. MicroRNAs (miRNAs)

MicroRNAs (miRNAs, approximately 20-25 nucleotides) are a class of endogenous noncoding RNAs with regulatory functions found in eukaryotes. Recently, miRNAs were found to play an important role in aging [6282] (see Table 1). According to a study by Du et al. [62], miR-17 extends the lifespan of transgenic mice by upregulating MKP and FoxO3 and downregulating mTOR and JNK through two targets, ADCY5 and IRS1. This study also found that ADCY5 or IRS1 can activate autophagy and inhibit cell aging and apoptosis. Dzakah et al. [63] demonstrated the role of miR-83 in modulating lifespan in Caenorhabditis elegans. Their study found that the deletion of miR-83 extended the lifespan of C. elegans and the expression of miR-83 decreased with age. The life-prolonging effect of miR-83 was achieved by high expression of the transcription factors, daf-16 and din-1. Lyu et al. [64] revealed that the regulation of transforming growth factor-β (TGF-β) signaling promotes senescence via miR-29-induced loss of H4K20me3. Their study found that miR-29 mediated the loss of suv4-20h2, downregulated H4K20me3 expression in mouse fibroblast senescent cells, and promoted cell senescence. Meanwhile, TGF-β accelerated cellular senescence by promoting the miR-29-mediated loss of H4K20me3. Fan et al. [65] observed the role of miR-1292 in cellular senescence of human adipose-derived mesenchymal stem cells (hADSCs). They found that FZD4 downregulation acted as a potential target of miR-1292, leading to overexpression of miR-1292, which promoted hADSC aging and osteogenic differentiation. This event was found to occur via the Wnt/β-catenin signaling pathway. Accumulating evidence suggest that miR-335-3p, which is neuron-enriched, is strongly linked to aging and age-related neurological diseases. Schilling et al. [66] found that statin-associated impairment of cognitive dysfunction is associated with PSD95 decrease, indicating that cholesterol levels are tightly linked to PSD95 levels. According to a study by Raihan et al. [67], overexpression of miR-335-3p, which could suppress cholesterol by inhibiting the expression of 3-hydroxy-3-methylglutaryl-CoA synthase-1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) in astrocyte, led to impaired cognitive function and memory. To add, the decrease in cholesterol levels was associated with the decrease in PSD95. When the miR-335-3p expression was reduced in the hippocampal brain of elderly patients, cognitive impairment and synaptic function could be restored in the aging process.


miR typeModelFunctionTarget geneReference

miR-17H2O2 induced senescent cellsInhibited mTOR and JNK activationADCY5, ISR1[62]
miR-83Caenorhabditis elegansInhibitory activity of miR-83din-1, daf-16[63]
miR-29Senescent embryonic fibroblast cellMediated loss of H4K20me3 promotes senescenceSuv4-20h2[64]
miR-1292hADSCsAccelerated hADSC senescence and restrained osteogenesisFZD4[65]
miR-335-3pMale C57B/6J miceReduced cholesterol and impaired memoryCholesterol[66, 67]
miR-195Neonatal mouse cardiomyocytePromote apoptosis, causing lipotoxic cardiomyopathySIRT1[68]
miR-126HUVECsRegulate high-fat diet-induced endothelial permeability and apoptosisTGF-β[69]
miR-138Aging participantsRegulating the memory function of the elderlyDCP1B[70]
miR-451Streptozotocin-induced diabetic mouse heartParticipated in cardiac fibrosisTGF-β1[71]
miR-34Myocardial infarction (MI) in neonatal and adult miceIts inhibition diminished cell apoptosisBcl2, cyclin D1, Sirt1[72]
miR-146aHuman microvascular endothelial cells (HMVECs)Ameliorates endothelial inflammation and the progression of atherosclerosisReceptor-associated factor 6 (TRAF6)[73]
miR-21Human umbilical vein ECsPromoting endothelial inflammationPPARα[74]
miR-155Human nasopharyngeal cancer and cervical cancer cellsPrevention of an age-induced deleterious decrease in autophagyRHEB, RICTOR, RPS6KB2[75]
miR-24H9C2 cardiomyocytesAttenuate cardiomyocyte apoptosis and myocardial injuryKeap1[76]
miR-181Apolipoprotein E-deficient miceDampen the inflammatory response in the endotheliumNF-κB[77]
miR-18aNaturally aged miceRegulation of extracellular matrix production during aging cardiomyopathyCTGF, TSP-1[78]
miR-377Old skin tissuesPromotes fibroblast senescenceDNA methyltransferase 1 (DNMT1)[79]
miR-9-5pHuman neuroblastoma cell line SH-SY5YSuppression in cell apoptosis, inflammation, and oxidative stressSIRT1[80]
miR-124Normal human epidermal keratinocytesCause skin cell senescenceMEK1, cyclin E1[81]
miR-15Human dermal fibroblastCounteracting senescence-associated mitochondrial dysfunctionSIRT4[82]

3.1.2. Telomere

Telomeres, composed of the telomere DNA sequence and telomere protein, are nucleoprotein structures located at the end of chromosomes, which control the cell division cycle and maintain the genome’s integrity [83]. Studies have shown that decreases in telomere attrition and telomerase activity are two of the main drivers of aging and age-associated damage that lead to cellular senescence [84]. The most well-established driver is the connection between adverse social conditions with DNA damage and accelerated telomere shortening [85, 86]. Epel et al. [87] used standardized questionnaires to assess the previous month’s stress levels of 58 healthy premenopausal women. The control group included women with at least one healthy biological child, and the experimental group included the biological mother of a child with a chronic disease (). Mean telomere length and telomerase activity were measured to evaluate stress-induced changes. The results showed that stress in the experimental group was significantly higher than that in the control group. In addition, women in the experimental group had lower telomerase activity and shorter telomere length than those in the control group. These findings shed light on the cellular level of stress, which can affect one’s health by modulating cell aging, possibly leading to the early onset of age-related diseases. Accumulated evidence indicates that DDR-related protein components are found in senescence-associated DNA damage foci (SDFs) [88]. Once ATM/ATR is activated, phosphorylation occurs in Chk1/Chk2, which further acts on effectors such as p53, leading to cell cycle arrest and failure to continue the cell cycle for a certain period of time, ultimately resulting in cell aging and even apoptosis [89, 90]. Further studies have also confirmed that telomere DNA shortening can induce ATM/ATR-mediated DDR and activate the downstream p53-p21 signal transduction pathway, leading to cell senescence [91].

3.1.3. Sirtuins

Sirtuins containing seven different subtypes (SIRT1-SIRT7), which are members of NAD+ dependent histone deacetylase III, play an important role in cell stress resistance, energy metabolism, apoptosis, and aging [92]. Evidence exists that SIRT1 could deacetylate FOXO, block foxo-dependent transcription and the apoptotic pathway, and promote the survival of senescent cells. This occurs through an increase in SIRT1 expression with age, suggesting that Sirt1 is involved in longevity [93, 94]. SIRT 2 is closely related to age-related diseases, such as Alzheimer’s disease (AD) and Parkinson’s [95]. Studies have shown that inhibition of SIRT2 expression could delay the progression of these diseases. In addition, knockout of SIRT2 and SIRT5 could alleviate the neurodegenerative lesion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The expression of SIRT2 was found to inhibit the dephosphorylation of FOXO3a and increase the level of Bim, leading to apoptosis and acceleration of the process of aging [96]. The mechanism by which SIRT5 deletion reduced apoptosis might be related to the reduction of SOD2 (manganese superoxide dismutase) expression [97]. SIRT3 has been reported to be associated with longevity. It can interact with FOXO3a to remove ROS and inhibit oxidative stress to prolong one’s lifespan [98]. In the latest research by Zhang et al. [99], they found that by performing a whole-body knockout of “longevity gene” SIRT6 in nonhuman primates, they could obtain the world’s first cynomolgus monkey model of longevity gene knockout, thereby revealing the new role of the SIRT6 gene in regulating embryonic development of primates. They could also elucidate the differences in aging and longevity regulation pathways between primates and rodents, laying an important foundation for research on the mechanisms of human development and aging and the treatment of related diseases [99]. SIRT7 could result in antiaging and prolong life by regulating the repair of the nonhomologous DNA damage to maintain the stable heredity of cells [100].

3.1.4. Klotho Gene

The Klotho gene, located on human chromosome 13, contains five exons and exerts antiaging effects. Studies have confirmed that the decrease in Klotho expression with an increase in age leads to aging [101]. Ullah and Sun [102] found that lack of the Klotho gene reduced the activity of telomerase by modifying the expression of TERF1 and TERT, leading to apoptosis of pluripotent stem cells. Sustained exposure to Wnt accelerated cellular senescence both in vitro and in vivo [103]. However, studies revealed that the tissue and organs of Klotho-deficient animals could enhance the Wnt signaling pathway to cause cell senescence [103]. A few other studies showed that Klotho downregulation leads to premature aging of human fibroblasts, which might be achieved by regulating the insulin/IGF-1 pathway to upregulate p53 and p21 protein levels [104106]. According to study by Gao et al. [107], Klotho deficiency could downregulate SIRT1, which reduce activities of AMP-activated protein kinase alpha (AMPKα) and endothelial nitric oxide synthase (eNOS), and upregulate NADPH oxidase activity, ultimately leading to aging-related aortic stiffness.

3.1.5. p16, p53/p21

Cell cycle stagnation is the premise of aging [108]. Although cell aging involves a series of gene expression and cell morphological changes, which are not as simple as cycle stagnation, many experiments have confirmed that the increase in p16 or p53/p21 is enough to cause cell aging [89, 109113]. In mouse embryonic fibroblasts, overexpression of miR-20a increased p16 and upregulated the transcriptional activity of INK4a/ARF, leading to cell senescence [114]. P53 is not only an initiator of cell aging but also a participant in antiaging. These effects of p53 are closely related to its involvement in the regulation of the mTOR pathway, which is closely related to autophagy. P53 can play an antiaging role by inhibiting the activity of mTOR and can also activate mTOR to inhibit the aging process [115]. Meanwhile, p53, through its downstream p53/p21/CDK2 signaling pathway, was found to result in cell cycle arrest and enter the aging state [111]. Studies have found that azithromycin might cause aging of VSMCs by activating the mTOR signaling pathway and increasing the expression of p53/p21/p16. When the activity of mTOR was inhibited, the autophagy level of proteins related to the mTOR signaling pathway increased, leading to a decrease in the expression of p53/p21/p16, thereby delaying the aging of VSMCs [116].

3.2. Signaling Pathway in Aging
3.2.1. Mammalian Target of Rapamycin (mTOR) Pathway

mTOR, activated by growth factors and nutrients, inhibits autophagy and promotes protein synthesis. Over time, mTOR may promote cellular stress, such as protein aggregation, organelle dysfunction, and oxidative stress, which may lead to the accumulation of damage and cell function decline, ultimately promoting the occurrence of age-related diseases [117]. The classical pathway of mTOR is the PI3K/Akt/mTOR signaling pathway. Tan et al. [118] transfected human VSMCs with mTOR siRNA and scrambled siRNA and found that PI3K/Akt/mTOR plays a significant role in VSMC replication and aging, which might be related to the regulation of oxidative stress and telomere function. Additionally, mTOR activation induced stem cell depletion, which reduced tissue repair and aggravated tissue dysfunction. Experimental studies have also shown that by inhibiting the mTOR signaling pathway through gene knockout, rapamycin or dietary restriction can delay aging of various biological models, including yeast, worms, fruit flies, and mice [119].

3.2.2. Nuclear Factor of Activated B-Cell (NF-κB) Signaling Pathway

NF-κB, activation of the transcription factor protein family, is involved in oxidative stress, immunity, inflammation, cell proliferation, apoptosis, and aging of gene transcription regulation. Studies have confirmed that NF-κB has a highly conserved REL homologous domain consisting of 300 amino acids and that its protein family members include p50, p52, REL, REL-A, and REL-B [120]. The NF-κB signaling pathway is activated by senescence-related inflammatory factors. Activated NF-κB enters the nucleus and binds to DNA, thereby participating in cellular immune response [121]. Studies have confirmed that the occurrence of various senile degenerative diseases is closely related to the aging signaling pathway regulated by NF-κB. Postmortem examination revealed an increase in NF-κB activity in brain tissues of Alzheimer disease (AD) patients. In addition, the immunological activity of p65 was detected in neurons and glial cells adjacent to degenerative neurons and senile plaques [122]. The activation of NF-κB is related to the deposition of β-amyloid (Aβ). Studies have found that Aβ deposition could activate NF-κB in cultured neurons with the formation of NO products related to oxidative stress [123]. Autopsy studies found that the number of NF-κB-positive dopaminergic neurons in the brain of patients with Parkinson’s disease was 70 times higher than that of normal people, suggesting that the activation of NF-κB is related to the pathological mechanism of Parkinson’s disease [123, 124].

3.2.3. Nuclear Factor-E2-Related Factor 2 (Nrf2) Signaling Pathway

Nrf2 is a key factor of antioxidant activity in cells. When oxidative stress occurs, Nrf2 is transferred to the nucleus to bind with the antioxidant response element (ARE) and regulates the expression of various antioxidant proteins and detoxification enzymes downstream, ultimately playing a role in endogenous protection [125]. Suh et al. [126] found that total Nrf2 protein and the amount of nuclear Nrf2 protein in rat liver cells significantly decline with an increase in aging. As age increases, the antioxidant capacity of ovarian cells decreases, and the imbalance between oxidation and antioxidants causes gradual apoptosis of ovarian cells, which is one of the important causes of ovarian aging. Studies have found that Nrf2 gene knockout can increase the ovary’s sensitivity to toxic substances and accelerate the aging of ovaries in mice [127]. Chen et al. [128] found that the upregulation of Nrf2 expression could alleviate oxidative stress and DNA damage and inhibit the p53-p21 p16-rb signaling pathway, thereby slowing cell aging. Nrf2 can regulate mitochondrial biogenesis and kinetics to maintain muscle mass and function, and its deficiency with aging increasingly promotes age-related skeletal muscle mitochondrial dysfunction and muscle atrophy [129, 130]. Study also found that Nrf2 activation could inhibit age-related inflammatory responses and oxidative stress and delay the occurrence of aging and age-related diseases [131]. Activation of Nrf2 also improved learning and memory of aging mice administered with D-galactose (D-gal) [132].

3.2.4. Wnt/β-Catenin Signaling Pathway

The Wnt/β-catenin signaling pathway is an evolutionarily, highly conserved signaling pathway with a wide range of biological functions. Studies found that this pathway plays an important regulatory role in cell aging and its activation could lead to senescence changes in mesenchymal stem cells [133]. Studies have also shown that activation of this pathway could lead to DNA damage response and increase the expression of the p53 protein, which might be one of the important mechanisms for stem cell senescence [134]. The p53/p21 pathway and DNA oxidative damage response have been confirmed to play an important role in the aging process of hematopoietic stem/progenitor cells caused by the Wnt/β-catenin signal pathway [135]. Skin aging is the most important external manifestation of human body aging, and the related components of WNT/β-catenin signal pathway are abnormally overexpressed in aged skin tissues [136]. The WNT/β-catenin signal pathway was found to be enhanced in the aging mouse model, and inhibition of the WNT/β-catenin signal pathway could reverse age-related skeletal muscle regeneration injury [137].

3.2.5. Adenosine Monophosphate Protein Kinase (AMPK) Signaling Pathway

AMPK is a highly conserved cellular energy metabolism regulator that plays an important role in regulating cell growth, proliferation, survival, and energy metabolism [138]. AMPK is involved in the regulation of a series of senescence-related signaling pathways, such as SIRT1 and CRTC-1. Studies have shown that AMPK first enhanced the expression of niacinamide phosphoribose transferase and then increased the intracellular concentration of NAD+ to activate SIRT1, which then activates the downstream PGC-1, FoxO1, and FoxO3, ultimately interfering with the aging process [139]. Mair et al. [140] identified that CRTC-1 is the phosphorylation site of AMPK/AAK-2 with the nematode model, and AMPK/AAK-2 prevented its nuclear translocation via CRTC-1 phosphorylation, thereby inhibiting the transactivation of CREB transcriptional regulator crh-1 which extended the nematode’s lifespan. AMPK activates p53 at certain phosphorylation sites and induces cell cycle arrest, leading to cell aging [141].

4.1. Vascular Aging

With an increase in age, the degeneration of vascular structure and function causes vascular sclerosis, which is called vascular aging. The main manifestations of vascular aging are increased arterial stiffness, pulse wave velocity, systolic blood pressure, and central venous pressure [142]. Vascular aging is a major risk factor for atherosclerosis and cardiovascular disease. Vascular aging mainly includes atherosclerosis and arteriosclerotic cardiovascular disease (ASCVD), such as coronary heart disease, hypertension, stroke, cognitive dysfunction, dementia, and peripheral vascular disease [143].

Studies have shown that decreased vasorin magnified the angiotensin II- (Ang II-) mediated increase in the TGF-β1 signaling cascade and caused vascular remodeling, thus leading to vascular aging [144, 145]. Increased Ang II with age led to activation of its downstream molecules MMP, McP-1, and TGF-β. This pathological change made the aortic wall of the elderly present a proinflammatory profile, which could promote atherosclerosis [146, 147]. Vascular endothelial cell senescence is one of the important pathological changes of vascular aging while oxidative stress is one of the main causes of endothelial senescence. eNOS has a significant effect on cardiovascular protection, and oxygenation should stimulate the decreased expression, resulting in a decrease in NO bioavailability, vascular diastolic dysfunction, and arteriosclerosis, ultimately promoting vascular aging [148]. Vascular endothelial cell aging is identified by ROS, the secretion of inflammatory cytokines, eNOS uncoupling, DNA damage, and telomere dysfunction, leading to obstacles in the structure and function of the cardiovascular system. It is also associated with coronary atherosclerotic heart disease [149, 150]. Studies have shown that atherosclerosis is associated with pathological thickening of vascular intima, loss of vascular smooth muscle cells, lipid deposition, and infiltration of macrophages [151]. Senescence was also found to accelerate atherosclerosis by inducing endoplasmic reticulum stress in VSMCs [152].

Complex functional impairment of cerebral microvessels and astrocytes may lead to neurovascular dysfunction and cognitive decline, which results in aging and age-related neurodegenerative diseases [153].

Early intervention of vascular aging can delay the occurrence of ASCVD and protect target organs. Presently, early intervention of vascular aging mainly includes lifestyle improvement and drug therapy. Caloric restriction and low-sodium diet combined with exercise can delay vascular aging. Meanwhile, active control of cardiovascular risk factors, such as hypertension, diabetes, and hyperlipidemia, can also prevent vascular aging. Drug therapy can target structural components of vascular aging, thus delaying development of aging. These mainly include antihypertensive drugs, statins, and hypoglycemic drugs. Antihypertensive drugs such as angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor antagonists (ARBs) have been shown to delay vascular aging due to their antifibrotic effects. Statins can not only regulate fat but also interfere with the process of vascular aging. Hypoglycemic drugs can increase the sensitivity of insulin, improve blood sugar, prevent the reconstruction of blood vessels, and inhibit inflammation of the tube wall.

4.2. Diabetes Mellitus

Diabetes is closely related to aging, and dysfunction of the pancreatic β cells plays an important role in the occurrence and development of diabetes. Aging of β cells in islets is mainly manifested as a decrease in the number of β cells and reduction in their secretion capacity. The mechanisms between islet cell failure in diabetes and aging are complex. Nonetheless, study found that the expression of autophagy signature proteins, LC3/Atg8 and Atg7, was decreased in aging islet cells. Similarly, the autophagy function of islets in aged rats was found to decrease [154]. Upregulation of P16ink4a/p19ARF expression, decrease in bmi-1 and EZH2 levels, and abnormal regulation of platelet-derived growth factor signals are important factors leading to a decline in the proliferation and insulin secretion of age-related β cells [155, 156]. The main interventions for diabetes include diet control, exercise, weight loss, and combination of hypoglycemic drugs.

4.3. Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease that occurs in old age and preold age. Brain aging is the basis and condition for the formation of neurodegenerative diseases. Alzheimer’s disease is characterized by amyloid-β protein (Aβ) deposits that form plaques and by hyperphosphorylation of Tau protein that forms tangles of neurons (NFT). Abnormal mitochondria accumulate in neurons, leading to reduced ATP production, large release of oxygen-free radicals, the production of Aβ, and the intensification of Tau protein phosphorylation [157]. Mutations of PSEN 1 and PSEN 2 cause lysosomal dysfunction, and the presence of lysosomal dysfunction leads to a large number of autophagosomes generated by enhanced mitochondrial autophagy, leading to lysosomal overload and further aggravating brain injury [158]. Chronic activation of the NF-κB pathway can cause the transcription of various inflammatory cytokines and promote glial cells to secrete inflammatory cytokines, leading to nerve cell injury and apoptosis [159, 160]. Currently, drugs used in the clinical treatment of AD are mainly noncompetitive N-methyl-D-aspartic acid receptor antagonists (such as memantine) and cholinesterase inhibitors (such as donepezil and galantamine).

4.4. Skin Aging

Skin aging, which is a part of the overall aging of the body, not only affects its appearance but also reduces its function as the body’s barrier. This can lead to various diseases, such as depression and self-abasement. Tashiro et al. [161] cultured skin fibroblasts from women of different ages to study the relationship between autophagy and skin aging. They found that the autophagy degradation step was inhibited in skin fibroblasts of elderly donors, leading to the accumulation of autophagosomes. This suggests that the impairment of autophagy function in skin fibroblasts of elderly people may impact the skin’s integrity and strength. Some researchers constructed a Drosophila model of skin aging and found that the increased expression of the autophagy marker, Atg7, was associated with skin aging [162]. Another study found that exosome miR-30a can regulate the apoptosis of epidermal cells, and its overexpression led to impaired epidermal differentiation by directly targeting AVEN (encodes a caspase inhibitor), IDH1 (encodes isocitrate dehydrogenase, an enzyme of cellular metabolism), and LOX (encodes lysyl oxidase, a regulator of the proliferation/differentiation balance of keratinocytes), inducing severe barrier dysfunction and skin aging [163]. Treatment for skin aging mainly includes oral antioxidant drugs, topical antiaging agents, and photoelectric and acoustic physical technology.

4.5. Aging-Related Macular Degeneration

Age-related macular degeneration (AMD) is one of the major causes of vision impairment in people older than 60 years of age. AMD can be divided into two types: dry AMD (atrophic), accounting for 85 to 90% of AMD cases and is a pattern of atrophy caused by the absence of retinal pigment epithelial cells and photoreceptor cells, and wet AMD (exudative, neovascular), which is caused by bleeding and exudation of neovascularization into the retina pigment epithelium (RPE) and into the sensory layer of the retina. Accumulating evidence suggests that the abnormal function of autophagy is related to the AMD formation. According to a study by Cai et al. [164], activation of mTOCR1 in aging RPE cells led to impaired lysosomal function and decreased autophagy in RPE cells. When the expression level of miR-29 is increased, the activity of mTORC1 is inhibited to enhance autophagy and remove protein aggregates to delay the occurrence of AMD. Another study found that SQSTM1/p62, a marker of autophagy injury, is deposited in the RPE along with the decrease in autophagy, which activates the inflammatory body, impairs protein clearance, and damages RPE cells, leading to AMD formation [165].

Studies had shown that many herbs had curative effect of slowing aging; selected herbs and compounds that were more extensively used and studied for review include Ginkgo biloba, ginseng, Panax notoginseng, Radix astragali, Lycium barbarum, Rhodiola rosea, Angelica sinensis, Ligusticum chuanxiong, resveratrol, curcumin, and flavonoids. The chemical structural formula of the main active ingredients of herbs and compounds was shown in Figure 3.

5.1. Herbs
5.1.1. Ginkgo biloba (Yinxing)

Ginkgo biloba extract (EGb) has definite pharmacological effects of protecting the vascular endothelium, improving insulin resistance, and preventing atherosclerosis [166]. In addition, EGb exerts a good intervention in various age-related diseases, such as type 2 diabetes mellitus, dementia, cognitive impairment, and coronary heart disease [167]. The first international expert consensus regarding the clinical application of EGb for the treatment of dementia and moderate cognitive impairment was published in 2019 [168]. Dong et al. [169] pretreated senescent endothelial progenitor cells (EPCs) with 10, 25, and 50 mg/L of EGb and found that it could inhibit the senescence of EPCs and increase the activity of telomerase, especially at the concentration of 25 mg/L. The mechanism whereby EGb inhibited the aging of EPCs may be related to the activation of the PI3k/Akt signaling pathway. Zhou et al. [170] administered EGb-761 to aging mice at different doses of 20, 40, 80, and 100 mg/kg once every 3 days for 12 months and found that EGb could reduce ischemic injury and oxidative stress caused by ischemia in aging mice. Its mechanism might be related to the upregulation of protein phosphatase 2 (PP2A) and reduction in extracellular signal-regulated kinase (ERK) activation. Tian et al. [171] administered EGB to streptozotocin- (STZ-) induced diabetic ApoE-/- mice at doses of 200 and 400 mg/kg/day for 12 weeks and found that EGb could regulate glucose and lipid metabolism, reduce arterial plaque, and upregulate autophagy to relieve endoplasmic reticulum stress (ERS). Its mechanisms might be related to the inhibition of ERS through the restoration of autophagy via the mTOR signaling pathway.

5.1.2. Panax ginseng (Renshen)

Ginsenosides are the main active ingredients of Panax ginseng. Studies have shown that ginsenosides display plentiful pharmacological effects such as relieving fatigue, improving immunity, slowing aging, inhibiting metastasis of cancer cells, regulating blood glucose, and protecting liver and kidney functions [172].

Aging mice were intraperitoneally injected with the ginsenoside Rg1, at a dose of 20 mg/kg/day for 28 days continuously. Rg1 could retard testis senescence in mice via antioxidation and the downregulation of the p19/p53/p21 signaling pathway [173]. Zhou et al. [174] cultured aging Sca-1+ hematopoietic stem cells in ginsenoside for 6 h and found that ginsenoside could protect hematopoietic stem cells from aging. Its possible mechanisms of action might involve the regulation of the p16-Rb signaling pathway, the repair of worn telomeres, and maintenance of telomerase activity. Aging mice were fed an experimental diet based on AIN-93G containing 10 g/kg and 30 g/kg ginseng powder for 24 weeks continuously. The results suggested that long-term ginseng feeding could improve aging-related cognitive ability, which was achieved by regulating the cholinergic and antioxidant systems [175]. Other studies found that Rg1 could decrease oxidative stress and downregulate Akt/mTOR signaling to attenuate cognitive impairment in mice and senescence of neural stem cells induced by D-gal [176].

5.1.3. Panax notoginseng (Sanqi)

Panax notoginseng contains the notoginseng saponins Rh1, Rh2, Rg1, Rg2, Rgb1, and others, with pharmacological actions such as antitumor activity, enhanced learning and memory, hemolysis, hemostasis, antiaging, and antifatigue [177, 178]. Zhou et al. [179] administered Panax notoginseng saponins (PNS) at 10, 30, and 60 mg/kg/day to natural aging mice and found that it could significantly and dose-dependently inhibit the apoptosis of myocardial cells in senescent rats by attenuating oxidative damage. Li et al. [180] pretreated aging H9c2 cells induced by D-gal with different concentrations of total saponins of Panax notoginseng (5, 25, and 50 g/mL) for 4 h. They found that the number of positive cells stained with galactosidase in the total saponins of the Panax notoginseng group was significantly reduced; SOD activity was found to significantly increase while MDA content and ROS fluorescence intensity were significantly decreased. Results suggest that PNS could resist aging of H9c2 cells induced by D-gal by improving their antioxidant capacity and reducing apoptosis.

5.1.4. Radix astragali (Huangqi)

Radix Astragalus mainly contains astragalus polysaccharides, saponins, flavonoids, and other active components, which have various pharmacological actions such as antioxidation, antiaging, myocardium protection, and enhancement of immune function and hematopoietic function [181].

Ma et al. [182] used different doses (100, 200, 400, and 600 mg/kg) of astragalus extract for intervention in the animal model of sustained myocardial ischemia in vivo. They found that Astragalus can reduce myocardial injury and protect cardiac function, which are related to the reduction of oxidative damage and free radical generation. Ma et al. [182] also conducted in vitro experiments to interfere with the oxidative stress model of cardiac myocytes using Astragalus membranaceus at different concentrations (100, 200, 400, and 600 μg/mL). They found that Astragalus could reduce the number of cell apoptosis by attenuating oxidative injury and arresting Ca2+ influx to block cell death. Li et al. [183] administered different doses (8, 16, and 32 mg/kg) of astragalosides via the intragastric route to the rat model with learning and memory impairment. They found that astragalosides could improve the learning and memory ability and ameliorate the neurodegenerative lesion of hippocampal CA1, which are related to the reduction of intracerebral amyloid precursor protein (APP) and a-secretase and β-secretase mRNA levels. Astragalus polysaccharides can also protect the mitochondria by scavenging ROS, inhibiting mitochondrial permeability transition (PT), and increasing antioxidant enzyme activity to improve aging in mice [184].

5.1.5. Lycium barbarum (Gouqi)

Lycium barbarum has pharmacological actions such as regulating immunity, antitumor activity, nervous system function, liver protection, and slow aging process [185]. Hu et al. [186] administered different doses of Chinese wolfberry, via the intragastric route, to a mouse model of AD induced by the combination of AlCl3 and D-gal. They found that the quantity of horizontal and vertical movements increased while AChE and ChAT levels decreased significantly in mice. These events were related to the modulation of the mitochondrial pathway of apoptosis and the cholinergic system. Jeong et al. [187] used goji berry (150 and 300 mg/kg/day) to interfere with aging rats and found that goji berry could elevate the level of testosterone and reduce the expression of cell apoptosis activators, which are associated with its antioxidant action. Yu et al. [188] used L. barbarum to interfere with oxygen glucose deprivation and reoxygenation-induced injury of neurons. They found that L. barbarum inhibits oxygen glucose deprivation and reoxygenation-induced neuronal cell and autophagic cell death by activating the PI3K/Akt/mTOR pathway.

5.1.6. Rhodiola rosea (Hongjingtian)

Rhodiola rosea contains alkaloids, flavonoids, glycosides, phenolic compounds, volatile oils, coumarins, steroids, and organic acids, plus small amounts of nonorganic elements, which could protect the heart and brain vessels by exhibiting antifibrosis, antioxidation, anti-inflammatory, antivirus, antiapoptosis, and antifatigue activities [189]. Zhou et al. [190] orally administered R. rosea (60 and 120 mg/kg daily) to an atherosclerosis rat model for 9 weeks continuously. The results showed that R. rosea could contribute to antiatherosclerosis via lowering blood lipids, antioxidant, and anti-inflammatory activities and by regulating endothelial function. Schriner et al. [191] demonstrated that R. rosea could prolong the lifespan of Drosophila by perturbing the silent information regulator 2 (SIR2) proteins, insulin and insulin-like growth factor signaling (IIS), and the target of rapamycin (TOR). Furthermore, R. rosea could prolong the life of silkworms by improving antioxidant capacity [192].

5.1.7. Angelica sinensis (Danggui)

The active components of Angelica sinensis mainly include volatile oils (ligustilide, Angelica sinensis ketone), organic acids (ferulic acid, succinic acid, niacin, and azelaic acid), polysaccharides, and flavonoids (ferulic acid, succinic acid, niacin, anisolic acid, and azelaic acid) [193]. Zhang et al. [194, 195] orally administered Angelica polysaccharide (ASP, 200 mg/kg/) to aging mice induced by X-ray whole-body uniform irradiation. HSCs were then separated and purified after mice were sacrificed. The results showed that ASP could significantly reduce the positive rate of SA--gal staining and the proportion of G1 phase in the aging group of HSCs, reduce ROS production, downregulate p16 mRNA, and increase the ability of mixed colony formation and T-AOC. Cheng et al. [196] showed that ASP restored cognitive impairment caused by D-gal administration, promoted neural stem cell (NSC) proliferation, attenuated D-gal-induced NSC senescence, decreased the level of oxidative stress by enhancing antioxidative capacity, and decreased the levels of inflammatory cytokines of NSCs. These events slowed the aging speed by enhancing the antioxidant and anti-inflammatory capacity and downregulating the p53/p21 signaling pathway [197, 198].

5.1.8. Ligusticum chuanxiong (Chuanxiong)

Ligusticum chuanxiong contains tetramethylpyrazine (TMP), ligustrazine, vanillin, emodin, ferulic acid, and other active ingredients which display various pharmacological actions in the cardiac and cerebrovascular system, nervous system, and respiratory system [199]. Chen et al. [200] demonstrated that TMP at different doses of 1, 3, and 10 mg/kg interfered with 6-ohda-induced Parkinson’s disease in mice which confirmed that TMP protects against dopaminergic (DA) neurodegeneration and attenuates DA neuronal apoptosis by activating the PI3K/Akt/GSK3β signaling pathway. Wei and Wang [201] found that ligustrazine alleviated hypoxia-induced HUVEC cell injury, enhanced cell viability, and inhibited cell apoptosis, all of which are related to the upregulation of miR-135b and subsequent activation of JNK/SAPK and PI3K/AKT/mTOR pathways. These events promoted hypoxia-treated HUVEC cell growth. Another study has shown that TMP could inhibit the accumulation of senescent LepR+ mesenchymal stem/progenitor cells in bone marrow, reduce bone loss, and improve the metabolic microenvironment of aging mice via the AMPK-mTOR-Hif1a-VEGF pathway [202]. As a potential treatment, TMP could improve bone diseases related to human age and promote a healthy lifespan.

5.1.9. Other Herbs

Hou et al. [203] selected aging, 24-month-old guinea pigs as the animal experimental models and fed them with a diet containing different doses (75, 100, or 150 mg/kg/day) of water-soluble extract components of Salvia miltiorrhiza Bunge for 28 days continuously. The study found a significant decrease in whole blood viscosity and improvement of blood viscosity and viscoelasticity at the dose of 150 mg/kg/day. Park et al. [204] gave old (20-month-old) specific pathogen-free male Sprague-Dawley rats with magnesium lithospermate B, extracted from Salvia at a dose of 2 or 8 mg/kg/day for 16 consecutive days. The results suggested that it reduces the renal damage of oxidative stress in old rats. After the researchers fed the fruit flies a full or dietary restriction diet supplemented with oregano-cranberry (OC) mixture, the study found that OC could extend the lifespan of fruit flies, especially females, while only OC supplementation at the young age interval increased reproduction in females [205, 206].

After 8 weeks of intraperitoneal injection of 100 mg/kg/d d-galactose to establish a rat model of aging with different doses of Ganoderma lucidum extract, it was found that Ganoderma lucidum could delay the progression of AD by regulating DNA methylation [207]. Lobo et al. [208] gave different concentrations (0.5-5.0 mg/mL) of the Gynostemma pentaphyllum extract to mouse dermal fibroblasts, which were placed under 8-watt ultraviolet C (UVC) light at a distance of 50 cm to induce oxidative stress. The results showed that Gynostemma pentaphyllum extract prolongs viability of mouse dermal fibroblasts damaged by UVC light-induced oxidative stress, especially at 4.5 mg/mL, and it suggested that Gynostemma pentaphyllum extract had potential therapeutic effect on dermal cell aging.

5.2. Compounds
5.2.1. Resveratrol

Resveratrol is a natural polyphenol with anticardiovascular, anticancer, antibacterial, anti-inflammatory, antiaging, antineurodegenerative, and other pharmacological effects [209]. Wu et al. [210] used different doses (30 and 100 mg/kg/day) of resveratrol to intervene in mice with premature ovarian aging caused by chemotherapy. They found that resveratrol could improve premature ovarian aging caused by chemotherapy and ameliorate the renewal ability of oogonial stem cells by attenuating oxidative stress injury via Nrf2 activation.

Dehghani et al. [211] used resveratrol combined with calcitriol to intervene in D-gal-induced aging rats. This combination could protect the heart and its antioxidant status by modulating hemodynamic parameters and increasing the serum level of Klotho, respectively. Du et al. [212] used resveratrol (5, 10, and 50 μM) to intervene in aging cells and found that it could improve cell activity and increase SOD level by regulating autophagy to achieve delayed aging. Amos et al. [213] intervened in damages to Drosophila melanogaster induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with resveratrol (0, 7.5, 15, 30, 60, and 120 mg/kg diet) and found that it could improve the survival rate, prolong the lifespan, and improve the behavioral defects of D. melanogaster; these effects were related to its anti-inflammatory and antioxidant activities.

Posadino et al. [214] treated HUVECs loaded with the ROS probe H2DCF-DA with different concentrations of RES (1–50 μM), and the results showed that low concentrations of RES enhanced PKC activity, promoted DNA synthesis, and reduced apoptosis; high RES concentrations elicit an opposite effect. The results suggested that resveratrol had a biphasic concentration-dependent effect on endothelial cell survival, thus providing a guide for future investigation. Another study by Posadino et al. [215] showed low doses of resveratrol (0.5 μM) effectively acting as an antioxidant agent by significantly reducing the roGFP oxidation state as compared with roGFP-infected control cells. With the increase of resveratrol dose, cell survival and metabolic activity decreased in parallel, suggesting that antioxidant and prooxidation effects were strongly related to dose. In addition, resveratrol was shown to increase skeletal muscle resistance to fatigue in aging mice for the alleviation of age-related skeletal muscle aging [216].

5.2.2. Curcumin

Curcumin, the main component extracted from the rhizome of turmeric and zedoary, has various pharmacological actions, including antiaging, anti-inflammatory, and antioxidant actions [217219].

Shailaja et al. [220] showed that curcumin could reduce the level of C-reactive protein (CRP) and enhance the level of malondialdehyde (MDA), which play a favorable role in slowing aging by inhibiting the expression of age-related inflammatory cytokines. By using concentrations of 1 μM, 5 μM, 10 μM, and 20 μM, Pirmoradi et al. [221] found the intervention effect of curcumin in rat adipose tissue-derived stem cells (rADSC) in vitro. Their results showed that curcumin could promote the proliferation of rADSC and reduce the senescence of adipose stem cells by promoting TERT gene expression. Hu et al. [222] revealed that curcumin could reduce extracellular matrix degradation and interstitial fibrosis induced by hypertension from modulating covalent histone modification and TIMP1 gene activation, thus protecting against hypertension-related vascular damage. Furthermore, curcumin could prolong the lifespan of Drosophila under heat stress conditions by increasing the antioxidant activity and mitigating the effect of heat shock responses [223]. Curcumin could also alleviate aging-related skeletal muscle mass loss and dysfunction [224].

5.2.3. Flavonoids

Flavonoids are a kind of natural polyphenols, mainly including flavonoids, flavanols, flavonoids, anthocyanins, and isoflavones [225]. Studies had shown that flavonoids had definite efficacy in the treatment of age-related neurodegenerative diseases [226], cardiovascular diseases [227, 228], atherosclerosis [229], etc. Some progress has been made in the study of flavonoids in prolonging lifespan [230]. Hung et al. [231] injected 1-methyl-4-phenylpyridinium (MPP+, a Parkinsonian neurotoxin) into the brains of rats and randomly divided them into three groups which received different does (10, 30 mg/kg/day) of baicalein, a phenolic flavonoid for 7 days. The study found that baicalein could inhibit inflammatory activities and MPP+-induced apoptosis and autophagy in the nigrostriatal dopaminergic system of the rat brain. The results suggested that baicalein was of therapeutic significance in Parkinson’s disease. Studies also showed that flavonoids could exert ameliorative antioxidant capacity and reduce Aβ-induced toxicity in Caenorhabditis elegans, thus prolonging lifespan of Caenorhabditis elegans [232, 233].

6. Adverse Effects of Herbal Medicine

Cianfrocca et al. [234] observed that a 49-year-old man received herbal therapy with Ginkgo biloba (40 mg, 3 times daily) for 2 weeks to improve his cognitive abilities, and the patient complained of two palpitations within a month. The 12-lead ECG had a normal morphology but showed sinus rhythm with frequent ventricular premature beats, and with the withdrawal of ginkgo biloba extract, electrocardiographic evidence of ventricular arrhythmias resolved. Erdle et al. [235] reported allergic reactions in two pediatric patients after inhaling and atomizing American ginseng powder, the former with urticaria and respiratory symptoms and the latter with recurrent allergic conjunctivitis, and there was evidence of sensitization to American ginseng on skin prick testing (SPT) ( mm wheal). The researchers concluded that excessive oral administration of astragalus could cause allergy, headache, hypertension, or other symptoms; astragalus injection mainly caused fever, shock, and acute asthma [236]. Larramendi et al. [237] carried out a skin test of goji berry on 30 patients with plant food allergy and found that 24 patients showed positive results, which suggested that goji berries are potentially allergenic to people at high risk of food allergies. Chang et al. [238] reevaluated the postmarketing safety of depside salt injection (made from Radix Salvia miltiorrhiza) based on the real world and found that most common adverse drug reactions were headache, head distention, dizziness, facial flushing, skin itching, thrombocytopenia, and the reversibility of elevated aspartate transaminase. Chaudhari et al. [239] concluded that curcumin commonly used in dermatologic conditions may cause skin allergies, mainly manifested as contact urticaria.

The safety of drug use is one of the important contents of clinical pharmacology; herbal medicine has drawbacks in this respect. Further studies are needed to completely understand these widely used herbs or compounds and their efficacy in aging-related diseases.

7. Conclusion and Perspectives

Aging and aging-related diseases pose a serious threat to human health and reduce the quality of life of elderly people. Therefore, exploring the mechanisms of aging and against the occurrence of aging-related diseases is of great significance. In this paper, we discuss cellular and molecular mechanisms of aging and aging-related diseases, including oxidative stress, inflammatory response, autophagy and exosome interactions, mitochondrial injury, and telomerase damage (see Figure 4). We also discuss the possible mechanisms of age-related diseases (see Figure 5) and modern medical treatment for diseases related to aging. However, modern medicines result in many adverse reactions when used to treat aging-related diseases. Although drug therapy may improve the symptoms of early AD, they are not effective in patients with advanced AD and are associated with gastrointestinal toxicity. Intravitreal injection of antivascular endothelial growth factor is the most effective way to inhibit angiogenesis and control vascular leakage. However, intravitreal injection has many disadvantages which include risk of infection, the requirement of repeated treatment, and high cost. Most importantly, some patients still experience progressive visual impairment after treatment. Exploring the mechanisms of the multitargeted actions of herbal medicine will therefore help establish novel drugs for the treatment of aging-related diseases. In this review, we initially explored the possible mechanisms of herbal medicines in the treatment of aging and aging-related diseases (Table 2). Through in vivo and in vitro studies, various components of herbal medicine have been found to possess the ability to intervene in aging-related diseases by activating telomerase, increasing antioxidant capacity, reducing apoptosis and anti-inflammatory activities, and regulating aging-related pathways and exosomes. We also summarized the clinical randomized controlled trials (RCTs) of herbal medicine in the treatment of aging-related diseases (Table 3) [240250]. These trials found that herbal medicine displays certain clinical efficacy in the treatment of age-related diseases such as type 2 diabetes, vascular dementia, AD, and atherosclerosis. A few clinical studies on AMD exist, but this disorder is considered to be related to the special technique used for intravitreal administration when treating macular lesions. Of note, as shown in Table 3, there are some adverse reactions in the clinical use of herbal medicines, including gastrointestinal discomfort, dry mouth, and abnormal alanine aminotransferase [245247, 250]. Experimental studies had also found that there was a dose-response curve characterized by stimulation at a low dose and inhibition at a high dose. For example, the researchers used different concentrations of the drug to interfere with endothelial cells and found that cell survival rates decreased as the dose of the drug increased [214, 251253]. This indicates that drugs have the effect of dose-dependent bidirectional regulation. When conducting study, attention should be paid not only to the dose-effect relationship but also to the optimal benefit concentration of drugs. Further analysis of the herbs mentioned in the article found that adverse reactions might occur with herbal treatment, such as palpitations, recurrent allergic conjunctivitis, urticaria and respiratory symptoms, fever, shock, and acute asthma [234239]. Researchers should analyze the reasons for the adverse reactions and promote the standard and safe use of herbs.


Active ingredientsDosageAdministrationModelPossible mechanismReference

In vitro studies
EGb10, 25, and 50 mg/LPretreatment for 24 hEPCs cultured on fibronectin-coatedculture dishesActivation of telomerase through the PI3k/Akt signaling pathway[169]
Ginsenoside Rg110 μmol/LCultured for 6 hAging Sca-1+ hematopoietic cellsRegulating the p16-Rb signaling pathway, repairing worn telomeres, and maintaining telomerase activity[174]
PNS5, 25, and 50 μg/mLPretreatment for 4 hD-Galactose induced aging H9c2 cellsIncrease antioxidant capacity and reduce apoptosis[180]
Astragalus membranaceus100, 200, 400, and 600 μg/mLPretreatment for 24 hCardiomyocyte model of oxidative stressAttenuating the oxidative injury and arresting the influx of Ca2+ to block cell death[182]
Lycium barbarum15, 30, and 60 μg/mLPretreatment for 24 hPrimary hippocampal neuronsActivating the PI3K/Akt/mTOR signaling pathway[188]
Angelica sinensisAging hematopoietic stem cellsIncrease in the length of telomere and the activity of telomerase, downregulation of the expression of P53 protein[194]
Ligustrazine50, 100, and 200 μMPretreated for 24 hHypoxia-induced injury of HUVECsUpregulation of miR-135b and subsequent activation of JNK/SAPK and PI3K/AKT/mTOR pathways[201]
Gynostemma pentaphyllum extract0.5-5.0 mg/mLMouse dermal fibroblasts induced oxidative stressReduce oxidative stress[208]
Resveratrol5, 10, and 50 μMCultured for 24 hH2O2 induced aging of HUVECsUpregulation of autophagy[212]
Curcumin1, 5, 10, and 20 μMTreatment for 48 hRat adipose tissue-derived stem cellsPromoting TERT gene expression[221]

In vivo studies
EGb-76120,40, 80, and 100 mg/kgi.g. every 3 days, for 12 monthsAged mice (24 months) of middle cerebral artery occlusionUpregulation of phosphatase PP2A and diminished extracellular signal-regulated kinase (ERK) activation[170]
EGb200, 400 mg/kg/dayi.g. 12 weeksStreptozotocin-induced diabetic ApoE-/- miceInhibiting endoplasmic reticulum stress via restoration of autophagy through the mTOR signaling pathway[171]
Ginsenoside Rg120 mg/kg/dayi.p. 28 daysD-Galactose-induced aging miceAntioxidation and downregulation of the p19/p53/p21 signaling pathway[173]
Panax notoginseng saponins10, 30, and 60 mg/kg/dayi.g. 6 monthsNatural aging ratsAttenuating oxidative damage[179]
Astragalus membranaceus100, 200, 400, and 600 mg/kgi.g. twice per day for 7 timesRat model of persistent myocardial ischemiaReducing oxidative damage and free radical generation[182]
Astragalosides8, 16, and 32 mg/kgi.g. 14 daysRats with learning and memory impairmentDownregulate the mRNA levels of APP and β-secretase, decrease expression of APP and Aβ1–40 in hippocampus[183]
Astragalus polysaccharides100, 200, and 300 mg/kg/di.g. 7 weeksD-Galactose induced aging miceScavenging ROS, inhibiting mitochondrial PT, and increasing the activities of antioxidases[184]
Lycium barbarum0.5 or 2.0 g/kgi.g. 4 weeksA mouse model of AD induced by the combination of AlCl3 and D-galactoseModulation of the mitochondrial pathway of apoptosis and the cholinergic system[186]
Goji berry150, 300 mg/kgi.g. 6 weeksNatural aging ratsAntioxidative stress[187]
Rhodiola rosea60, 120 mg/kgi.g. 9 weeksAbdominal aorta of atherosclerosis ratsHypolipemic, antioxidant, and anti-inflammatory activities[190]
Angelica polysaccharide140 mg/kgi.p. 27 daysAging nestin-GFP mice induced by D-galactoseEnhancing the antioxidant and anti-inflammatory capacity, upregulation of p53/p21 signaling pathway[196]
Tetramethylpyrazine1, 3, and 10 mg/kgi.p. 7 or 14 days6-OHDA-induced Parkinson’s disease miceActivation of PI3K/Akt/GSK3β signaling pathway[200]
Resveratrol30, 100 mg/kg/di.g. 2 weeksMice with chemotherapy-induced ovarian agingAttenuating oxidative stress injury by activating Nrf2[210]
Curcumin100, 200, and 400 mg/kg/di.g. 6 monthsNatural aging ratsSuppressing age-related changes in inflammatory indices[220]
Baicalein10, 30 mg/kg/dayi.p. 7 daysMPP+-induced Parkinson’s disease miceInhibit inflammatory activities and MPP+-induced apoptosis and autophagy[231]

Abbreviations: EGb: Ginkgo biloba extract; EPCs: endothelial progenitor cells; HUVECs: human umbilical endothelial vein cells; i.g.: intragastric gavage; i.p.: intraperitoneally injected.

NumberAuthors (year)TargetsConditionsAge (years)Name of herb or formulaDose/durationGroupsMain outcomesAdverse reactions

(1)Liu et al. (2007) [240]Aging vascular dementia≥55Kangxin capsule (Fructus lycii, Herba epimedii, Radix paeoniae alba, Radix Salvia miltiorrhiza, Fructus crataegi, Radix astragali, etc.)0.9 g once and three times per day, for 1 monthI: compound
C: piracetam
CD4, CD4, CD8-1 ↑ ()
HIS index, GDS, ET, E2·T-1 ↓ ()
No adverse reactions were observed
(2)Zhao et al. (2018) [241]Type 2 diabetes mellitus50-75Ginkgo leaf tablets
Liuwei Dihuang pills
2 Ginkgo leaf tablets and 8 Liuwei Dihuang pills, 3 times a day, for 36 monthsI: compound
C: placebos
Plasma CML, 8-IsoP levels ↓ ()
FBG, PBG, BP, HbA1c, TC, TG, LDL-C, HDL-C ()
Drug reaction
(3)Kwok et al. (2014) [242]Atherosclerosis in postmenopausalDG capsules (Danshen and ginseng)Two capsules daily, for 12 monthsI: compound
C: placebos
TC, LDL-C carotid IMT ↓ ()
BP, BMI, Glu ()
No adverse reactions were observed
(4)Dingzhu et al. (2015) [243]Carotid atherosclerosisShoushen granule (Radix Polygoni multiflori, Fructus lycii, Crataegus, and Radix notoginseng)1 tablet once daily for 24 weeksI: compound
C: pravastatin
baPWV, IMTEp, AI, PWVβ ↓ ()Not reported
(5)Lv et al. (2016) [244]Type 2 diabetes mellitus50-80Naoxintong (Radix astragali, Angelica sinensis, Radix paeoniae rubra, and Ligusticum wallichii)1.2 g per day for 3 monthsI: compound
C: blank control
HbA1c ↓ ()
Proliferative effects, migration ability, antiapoptotic function of HUVECs ↑ ()
TC, TG, LDL-C, HDL-C ()
Not reported
(6)Akhondzadeh et al. (2003) [245]Alzheimer’s disease65-80Salvia officinalis extract60 drops daily for 16 weeksI: compound
C: placebos
ADAS-cog, CDR-SB ↓ ()Vomiting, wheezing, nausea
(7)Akhondzade et al. (2010) [246]Alzheimer’s diseaseSaffron15 mg twice per day, for 16 weeksI: compound
C: placebos
ADAS-cog, CDR-SB ↓ ()Dry mouth
(8)Jia et al. (2014) [247]Vascular dementiaSaiLuoTong (Ginkgo biloba, ginsenosides, saffron)360/240 mg daily, for 52 weeksI: compound
C: placebos
VaD Assessment Scale—cognitive subscale scores (, 26 weeks)Mild gastrointestinal intolerance, abnormal alanine aminotransferase, dreaminess
(9)Tajadini et al. (2015) [248]Alzheimer’s disease>50Davaie Loban500 mg, three times daily, for 3 monthsI: compound
C: placebos
ADAS-cog, CDR-SB ↓ ()Without any adverse drug reaction
(10)Uno et al. (2005) [249]Type 2 diabetesGoshajinkigan7.5 g daily for 1 monthI: combined compound and OHAs
C: OHAs
HOMA-R, FBG TC, TG ↓ ()
HbA1c ()
No adverse reactions were observed
(11)Cho et al. (2009) [250]Healthy femaleRed ginseng root extract mixed with Torilus fructus and Corni fructus3 g daily for 24 weeksI: compound
C: placebos
Facial wrinkles ↓
Type I procollagen gene, protein expression ↑
Gastrointestinal discomfort

Abbreviations: GDS: Geriatric Depression Scale; HIS: Hachinski Ischemia Scale; ET: endothelin; E2·T-1: estradiol (E2)·testosterone (T)-1; CML: carboxymethyl lysine; 8-IsoP: 8-isoprostane; FBG: fasting blood glucose; PBG: postprandial blood glucose; HbA1c: glycosylated hemoglobin; TC: total cholesterol; TG: triglyceride; HDL: high-density lipoprotein; LDL: low-density lipoprotein; IMT: intima-media thickness; GLU: glucose; Ep: pressure-strain elastic modulus; Ac: arterial compliance; AI: augmentation index; PWVβ: pulse wave velocity β; HUVECs: human umbilical vein endothelial cells; ADAS-cog: cognitive subscale of Alzheimer’s Disease Assessment Scale; CDR: Clinical Dementia Rating; OHAs: oral hypoglycemic agents.

In conclusion, high-quality RCTs should be carried out to observe the effectiveness and safety of herbal medicine in the treatment of aging and aging-related diseases. It is also important that the intervention of integrated traditional Chinese and western medicine be monitored in aging and aging-related diseases.

Abbreviations

ACEI:Angiotensin-converting enzyme inhibitors
AChE:Acetylcholinesterase
ACS:Acute coronary syndrome
AD:Alzheimer’s disease
ADCY5:Adenylate cyclase 5
Akt:Protein kinase B
AMD:Age-related macular degeneration
AMPK:Adenosine 5-monophosphate-activated protein kinase
AMPKα:AMP-activated protein kinase alpha
ARBs:Angiotensin-receptor antagonists
ARF:Auxin response factor
BECN1:Beclin1
ChAT:Choline acetyltransferase
CRTC-1:CREB-regulated transcription coactivator1
EGb:Ginkgo biloba extract
eNOS:Endothelial nitric oxide synthase
EPCs:Endothelial progenitor cells
EZH2:Enhancer of zeste homolog 2
FOXO:Forkhead box class
FZD4:Frizzled class receptor 4
H2O2:Hydrogen peroxide
hADSCs:Human adipose-derived mesenchymal stem cells
HMGCR:3-Hydroxy-3-methylglutaryl-CoA reductase
HMGCS1:3-Hydroxy-3-methylglutaryl-CoA synthase-1
IL-1:Interleukin-1
INK4:Inhibitors of cyclin-dependent kinase 4
ISR1:Insulin receptor substrate-1
miRNA:MicroRNA
MPTP:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
mTOR:Mammalian target of rapamycin
NAD+:Nicotinamide adenine dinucleotide
NF-κB:Nuclear factor of activated B-cells
NLRP3:NOD-like receptor family pyrin domain containing 3
NO:Nitric oxide
Nox4:Nicotinamide adenine dinucleotide phosphate oxidase isoform 4
Nrf2:Nuclear factor-E2-related factor 2
NSC:Neural stem cells
PML-NB:Promyelocytic leukemia nuclear bodies
PNS:Panax notoginseng saponins
PSEN:Presenilin
ROS:Reactive oxygen species
SIR1:Sirtuins 1
SOD2:Manganese superoxide dismutase
TGF-β:Transforming growth factor-β
TRAF6:Receptor-associated factor 6
TSC2:Tuberous sclerosis complex 2
TXNIP:Thioredoxin-interacting protein
VSMCs:Vascular smooth muscle cells.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Authors’ Contributions

Yanfei Liu put on the reference collection, reference analysis, and writing of the manuscript. Yue Liu and Rui Gao contributed to the topic conception, manuscript revision, and decision to submit for publication and are the cocorresponding authors. Weiliang Weng contributed to reference analysis and helped in the revision of the manuscript.

Acknowledgments

This work was supported by the Special Project for Outstanding Young Talents of China Academy of Chinese Medical Sciences (ZZ13-YQ-001), Beijing Nova Program (No. Z171100001117027), and National Major Scientific and Technological Special Project for “National New Drug Innovation Program” during the Thirteenth Five-Year Plan Period (2017ZX09304003).

References

  1. Q. Bao, J. Pan, H. Qi et al., “Aging and age-related diseases - from endocrine therapy to target therapy,” Molecular and Cellular Endocrinology, vol. 394, no. 1-2, pp. 115–118, 2014. View at: Publisher Site | Google Scholar
  2. C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “The hallmarks of aging,” Cell, vol. 153, no. 6, pp. 1194–1217, 2013. View at: Publisher Site | Google Scholar
  3. UNDESA, Population Division, World Population Prospects the 2015 Revision, United Nations Department of Economic and Social Affairs, 2015.
  4. M. Barton, M. Husmann, and M. R. Meyer, “Accelerated vascular aging as a paradigm for hypertensive vascular disease: prevention and therapy,” The Canadian Journal of Cardiology, vol. 32, no. 5, pp. 680–686.e4, 2016. View at: Publisher Site | Google Scholar
  5. A. Harvey, A. C. Montezano, R. A. Lopes, F. Rios, and R. M. Touyz, “Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications,” The Canadian Journal of Cardiology, vol. 32, no. 5, pp. 659–668, 2016. View at: Publisher Site | Google Scholar
  6. T. W. Buford, “Hypertension and aging,” Ageing Research Reviews, vol. 26, pp. 96–111, 2016. View at: Publisher Site | Google Scholar
  7. A. K. Palmer and J. L. Kirkland, “Aging and adipose tissue: potential interventions for diabetes and regenerative medicine,” Experimental Gerontology, vol. 86, pp. 97–105, 2016. View at: Publisher Site | Google Scholar
  8. C. Domingues-Faria, M. P. Vasson, N. Goncalves-Mendes, Y. Boirie, and S. Walrand, “Skeletal muscle regeneration and impact of aging and nutrition,” Ageing Research Reviews, vol. 26, pp. 22–36, 2016. View at: Publisher Site | Google Scholar
  9. P. Lacolley, V. Regnault, P. Segers, and S. Laurent, “Vascular smooth muscle cells and arterial stiffening: relevance in development, aging, and disease,” Physiological Reviews, vol. 97, no. 4, pp. 1555–1617, 2017. View at: Publisher Site | Google Scholar
  10. W. Ma and W. T. Wong, “Aging changes in retinal microglia and their relevance to age-related retinal disease,” in Retinal Degenerative Diseases, C. Bowes Rickman, M. LaVail, R. Anderson, C. Grimm, J. Hollyfield, and J. Ash, Eds., vol. 854 of Advances in Experimental Medicine and Biology, pp. 73–78, Springer, Cham, 2016. View at: Publisher Site | Google Scholar
  11. C. Cleeland, A. Pipingas, A. Scholey, and D. White, “Neurochemical changes in the aging brain: a systematic review,” Neuroscience & Biobehavioral Reviews, vol. 98, pp. 306–319, 2019. View at: Publisher Site | Google Scholar
  12. I. Maldonado-Lasuncion, M. Atienza, M. P. Sanchez-Espinosa, and J. L. Cantero, “Aging-related changes in cognition and cortical integrity are associated with serum expression of candidate microRNAs for Alzheimer disease,” Cerebral Cortex, vol. 29, no. 10, pp. 4426–4437, 2019. View at: Publisher Site | Google Scholar
  13. A. M. Armenta, E. D. Henkel, and A. M. Ahmed, “Pigmentation disorders in the elderly,” Drugs & Aging, vol. 36, no. 3, pp. 235–245, 2019. View at: Publisher Site | Google Scholar
  14. B. A. Mander, J. R. Winer, and M. P. Walker, “Sleep and human aging,” Neuron, vol. 94, no. 1, pp. 19–36, 2017. View at: Publisher Site | Google Scholar
  15. V. M. Loaiza and A. S. Souza, “An age-related deficit in preserving the benefits of attention in working memory,” Psychology and Aging, vol. 34, no. 2, pp. 282–293, 2019. View at: Publisher Site | Google Scholar
  16. R. Maeso-Díaz, M. Ortega-Ribera, A. Fernández-Iglesias et al., “Effects of aging on liver microcirculatory function and sinusoidal phenotype,” Aging Cell, vol. 17, no. 6, article e12829, 2018. View at: Publisher Site | Google Scholar
  17. J. E. Elliott, C. B. Mantilla, C. M. Pabelick, A. C. Roden, and G. C. Sieck, “Aging-related changes in respiratory system mechanics and morphometry in mice,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 311, no. 1, pp. L167–L176, 2016. View at: Publisher Site | Google Scholar
  18. C. Vicini, A. de Vito, G. Iannella et al., “The aging effect on upper airways collapse of patients with obstructive sleep apnea syndrome,” European Archives of Oto-Rhino-Laryngology, vol. 275, no. 12, pp. 2983–2990, 2018. View at: Publisher Site | Google Scholar
  19. M. De Sá Barreto Da Cunha and S. F. Arruda, “Tucum-do-cerrado (Bactris setosa Mart.) may promote anti-aging effect by upregulating SIRT1-Nrf2 pathway and attenuating oxidative stress and inflammation,” Nutrients, vol. 9, no. 11, article 1243, 2017. View at: Publisher Site | Google Scholar
  20. I. Liguori, G. Russo, F. Curcio et al., “Oxidative stress, aging, and diseases,” Clinical Interventions in Aging, vol. 13, pp. 757–772, 2018. View at: Publisher Site | Google Scholar
  21. R. Wadhwa, R. Gupta, and P. K. Maurya, “Oxidative stress and accelerated aging in neurodegenerative and neuropsychiatric disorder,” Current Pharmaceutical Design, vol. 24, no. 40, pp. 4711–4725, 2019. View at: Publisher Site | Google Scholar
  22. S. I. Liochev, “Reactive oxygen species and the free radical theory of aging,” Free Radical Biology and Medicine, vol. 60, pp. 1–4, 2013. View at: Publisher Site | Google Scholar
  23. S. G. Rhee, “Cell signaling H2O2, a necessary evil for cell signaling,” Science, vol. 312, no. 5782, pp. 1882-1883, 2006. View at: Publisher Site | Google Scholar
  24. L. A. Sena and N. S. Chandel, “Physiological roles of mitochondrial reactive oxygen species,” Molecular Cell, vol. 48, no. 2, pp. 158–167, 2012. View at: Publisher Site | Google Scholar
  25. G. Hewitt, D. Jurk, F. D. M. Marques et al., “Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence,” Nature Communications, vol. 3, no. 1, p. 708, 2012. View at: Publisher Site | Google Scholar
  26. A. Chandrasekaran, M. . P. S. Idelchik, and J. A. Melendez, “Redox control of senescence and age-related disease,” Redox Biology, vol. 11, pp. 91–102, 2017. View at: Publisher Site | Google Scholar
  27. M. Shawi and C. Autexier, “Telomerase, senescence and ageing,” Mechanisms of Ageing and Development, vol. 129, no. 1-2, pp. 3–10, 2008. View at: Publisher Site | Google Scholar
  28. D. Kipling, “Telomeres, replicative senescence and human ageing,” Maturitas, vol. 38, no. 1, pp. 25–37, 2001. View at: Publisher Site | Google Scholar
  29. F. Olivieri, M. Capri, M. Bonafè et al., “Circulating miRNAs and miRNA shuttles as biomarkers: perspective trajectories of healthy and unhealthy aging,” Mechanisms of Ageing and Development, vol. 165, Part B, pp. 162–170, 2017. View at: Publisher Site | Google Scholar
  30. S. Kumar, M. Vijayan, J. S. Bhatti, and P. H. Reddy, “Chapter three - microRNAs as peripheral biomarkers in aging and age-related diseases,” Progress in Molecular Biology and Translational Science, vol. 146, pp. 47–94, 2017. View at: Publisher Site | Google Scholar
  31. A. M. Cuervo and E. Wong, “Chaperone-mediated autophagy: roles in disease and aging,” Cell Research, vol. 24, no. 1, pp. 92–104, 2014. View at: Publisher Site | Google Scholar
  32. A. Plaza-Zabala, V. Sierra-Torre, and A. Sierra, “Autophagy and microglia: novel partners in neurodegeneration and aging,” International Journal of Molecular Sciences, vol. 18, no. 3, p. 598, 2017. View at: Publisher Site | Google Scholar
  33. H. T. Phu, D. T. B. Thuan, T. H. D. Nguyen, A. M. Posadino, A. H. Eid, and G. Pintus, “Herbal medicine for slowing aging and aging-associated conditions: efficacy, mechanisms, and safety,” Current Vascular Pharmacology, vol. 17, 2019. View at: Publisher Site | Google Scholar
  34. C. Sturtzel, “Endothelial cells,” in The Immunology of Cardiovascular Homeostasis and Pathology, S. Sattler and T. Kennedy-Lydon, Eds., vol. 1003 of Advances in Experimental Medicine and Biology, pp. 71–91, Springer, Cham, 2017. View at: Publisher Site | Google Scholar
  35. H. Dib, P. Chafey, G. Clary et al., “Proteomes of umbilical vein and microvascular endothelial cells reflect distinct biological properties and influence immune recognition,” Proteomics, vol. 12, no. 15-16, pp. 2547–2555, 2012. View at: Publisher Site | Google Scholar
  36. S. A. Vielma, R. L. Klein, C. A. Levingston, and M. R. I. Young, “Skewing of immune cell cytokine production by mediators from adipocytes and endothelial cells,” Adipocytes, vol. 3, no. 2, pp. 126–131, 2014. View at: Publisher Site | Google Scholar
  37. E. Suzuki, M. Takahashi, S. Oba, and H. Nishimatsu, “Oncogene- and oxidative stress-induced cellular senescence shows distinct expression patterns of proinflammatory cytokines in vascular endothelial cells,” The Scientific World Journal, vol. 2013, Article ID 754735, 6 pages, 2013. View at: Publisher Site | Google Scholar
  38. J. Zhao, S. Z. Xu, and J. Liu, “Fibrinopeptide A induces C-reactive protein expression through the ROS-ERK1/2/p38-NF-κB signal pathway in the human umbilical vascular endothelial cells,” Journal of Cellular Physiology, vol. 234, no. 8, pp. 13481–13492, 2019. View at: Publisher Site | Google Scholar
  39. W. Wang, C. Shang, W. Zhang et al., “Hydroxytyrosol NO regulates oxidative stress and NO production through SIRT1 in diabetic mice and vascular endothelial cells,” Phytomedicine, vol. 52, pp. 206–215, 2019. View at: Publisher Site | Google Scholar
  40. H. J. Yoon, K. O. Chay, and S. Y. Yang, “Native low density lipoprotein increases the production of both nitric oxide and reactive oxygen species in the human umbilical vein endothelial cells,” Genes & Genomics, vol. 41, no. 3, pp. 373–379, 2019. View at: Publisher Site | Google Scholar
  41. I. Pantsulaia, W. M. Ciszewski, and J. Niewiarowska, “Senescent endothelial cells: potential modulators of immunosenescence and ageing,” Ageing Research Reviews, vol. 29, pp. 13–25, 2016. View at: Publisher Site | Google Scholar
  42. Y. Yin, Z. Zhou, W. Liu, Q. Chang, G. Sun, and Y. Dai, “Vascular endothelial cells senescence is associated with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation via reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP) pathway,” The International Journal of Biochemistry & Cell Biology, vol. 84, pp. 22–34, 2017. View at: Publisher Site | Google Scholar
  43. Y. Ohsumi, “Historical landmarks of autophagy research,” Cell Research, vol. 24, no. 1, pp. 9–23, 2014. View at: Publisher Site | Google Scholar
  44. L. Barile, T. Moccetti, E. Marban, and G. Vassalli, “Roles of exosomes in cardioprotection,” European Heart Journal, vol. 38, no. 18, pp. ehw304–ehw309, 2017. View at: Publisher Site | Google Scholar
  45. A. Salminen and K. Kaarniranta, “Regulation of the aging process by autophagy,” Trends in Molecular Medicine, vol. 15, no. 5, pp. 217–224, 2009. View at: Publisher Site | Google Scholar
  46. T. Saez, P. de Vos, J. Kuipers, L. Sobrevia, and M. M. Faas, “Fetoplacental endothelial exosomes modulate high d-glucose-induced endothelial dysfunction,” Placenta, vol. 66, pp. 26–35, 2018. View at: Publisher Site | Google Scholar
  47. R. Menghini, V. Casagrande, A. Marino et al., “miR-216a: a link between endothelial dysfunction and autophagy,” Cell Death & Disease, vol. 5, no. 1, article e1029, 2014. View at: Publisher Site | Google Scholar
  48. H. Abou-Saleh, F. A. Zouein, A. el-Yazbi et al., “The march of pluripotent stem cells in cardiovascular regenerative medicine,” Stem Cell Research & Therapy, vol. 9, no. 1, p. 201, 2018. View at: Publisher Site | Google Scholar
  49. G. Kolios and Y. Moodley, “Introduction to stem cells and regenerative medicine,” Respiration, vol. 85, no. 1, pp. 3–10, 2013. View at: Publisher Site | Google Scholar
  50. V. Janzen, R. Forkert, H. E. Fleming et al., “Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a,” Nature, vol. 443, no. 7110, pp. 421–426, 2006. View at: Publisher Site | Google Scholar
  51. T. A. Rando, “Stem cells, ageing and the quest for immortality,” Nature, vol. 441, no. 7097, pp. 1080–1086, 2006. View at: Publisher Site | Google Scholar
  52. I. M. Conboy, M. J. Conboy, A. J. Wagers, E. R. Girma, I. L. Weissman, and T. A. Rando, “Rejuvenation of aged progenitor cells by exposure to a young systemic environment,” Nature, vol. 433, no. 7027, pp. 760–764, 2005. View at: Publisher Site | Google Scholar
  53. J. M. Ryu, H. J. Lee, Y. H. Jung et al., “Regulation of stem cell fate by ROS-mediated alteration of metabolism,” International Journal of Stem Cells, vol. 8, no. 1, pp. 24–35, 2015. View at: Publisher Site | Google Scholar
  54. Y. L. Guo, S. Chakraborty, S. S. Rajan, R. Wang, and F. Huang, “Effects of oxidative stress on mouse embryonic stem cell proliferation, apoptosis, senescence, and self-renewal,” Stem Cells and Development, vol. 19, no. 9, pp. 1321–1331, 2010. View at: Publisher Site | Google Scholar
  55. S. Sart, L. Song, and Y. Li, “Controlling redox status for stem cell survival, expansion, and differentiation,” Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 105135, 14 pages, 2015. View at: Publisher Site | Google Scholar
  56. F. B. Francesca Casciaro, M. Zavatti, J. A. Mccubrey et al., “Nuclear Nox4 interaction with prelamin A is associated with nuclear redox control of stem cell aging,” Aging, vol. 10, no. 10, pp. 2911–2934, 2018. View at: Publisher Site | Google Scholar
  57. M. Boyle, C. Wong, M. Rocha, and D. L. Jones, “Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis,” Cell Stem Cell, vol. 1, no. 4, pp. 470–478, 2007. View at: Publisher Site | Google Scholar
  58. B. A. Monk and S. J. George, “The effect of ageing on vascular smooth muscle cell behaviour-a mini-review,” Gerontology, vol. 61, no. 5, pp. 416–426, 2015. View at: Publisher Site | Google Scholar
  59. H. Yin and J. G. Pickering, “Cellular senescence and vascular disease: novel routes to better understanding and therapy,” The Canadian Journal of Cardiology, vol. 32, no. 5, pp. 612–623, 2016. View at: Publisher Site | Google Scholar
  60. J. K. Zhan, Y. J. Wang, S. Li et al., “AMPK/TSC2/mTOR pathway regulates replicative senescence of human vascular smooth muscle cells,” Experimental and Therapeutic Medicine, vol. 16, no. 6, pp. 4853–4858, 2018. View at: Publisher Site | Google Scholar
  61. X. Z. J. Lin, J. Y. Zhong, Y. J. Wang et al., “lncRNA-ES3/miR-34c-5p/BMF axis is involved in regulating high-glucose-induced calcification_senescence of VSMCs,” Aging, vol. 11, no. 2, pp. 523–535, 2019. View at: Publisher Site | Google Scholar
  62. W. W. Du, W. Yang, L. Fang et al., “miR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7,” Cell Death & Disease, vol. 5, no. 7, article e1355, 2014. View at: Publisher Site | Google Scholar
  63. E. E. Dzakah, A. Waqas, S. Wei et al., “Loss of miR-83 extends lifespan and affects target gene expression in an age- dependent manner in Caenorhabditis elegans,” Journal of Genetics and Genomics, vol. 45, no. 12, pp. 651–662, 2018. View at: Publisher Site | Google Scholar
  64. G. Lyu, Y. Guan, C. Zhang et al., “TGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging,” Nature Communications, vol. 9, no. 1, p. 2560, 2018. View at: Publisher Site | Google Scholar
  65. J. Fan, X. An, Y. Yang et al., “miR-1292 targets FZD4 to regulate senescence and osteogenic differentiation of stem cells in TE/SJ/mesenchymal tissue system via the Wnt/β-catenin pathway,” Aging and Disease, vol. 9, no. 6, pp. 1103–1121, 2018. View at: Publisher Site | Google Scholar
  66. J. M. Schilling, W. Cui, J. C. Godoy et al., “Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry,” Behavioural Brain Research, vol. 267, pp. 6–11, 2014. View at: Publisher Site | Google Scholar
  67. O. Raihan, A. Brishti, M. R. Molla et al., “The age-dependent elevation of miR-335-3p leads to reduced cholesterol and impaired memory in brain,” Neuroscience, vol. 390, pp. 160–173, 2018. View at: Publisher Site | Google Scholar
  68. H. Zhu, Y. Yang, Y. Wang, J. Li, P. W. Schiller, and T. Peng, “MicroRNA-195 promotes palmitate-induced apoptosis in cardiomyocytes by down-regulating Sirt1,” Cardiovascular Research, vol. 92, no. 1, pp. 75–84, 2011. View at: Publisher Site | Google Scholar
  69. X. W. Cheng, Y. F. Wan, Q. Zhou, Y. Wang, and H. Q. Zhu, “MicroRNA-126 inhibits endothelial permeability and apoptosis in apolipoprotein E-knockout mice fed a high-fat diet,” Molecular Medicine Reports, vol. 16, no. 3, pp. 3061–3068, 2017. View at: Publisher Site | Google Scholar
  70. J. Schroder, S. Ansaloni, M. Schilling et al., “MicroRNA-138 is a potential regulator of memory performance in humans,” Frontiers in Human Neuroscience, vol. 8, p. 501, 2014. View at: Publisher Site | Google Scholar
  71. C. Liang, L. Gao, Y. Liu et al., “miR-451 antagonist protects against cardiac fibrosis in streptozotocin-induced diabetic mouse heart,” Life Sciences, vol. 224, pp. 12–22, 2019. View at: Publisher Site | Google Scholar
  72. Y. Yang, H. W. Cheng, Y. Qiu et al., “MicroRNA-34a plays a key role in cardiac repair and regeneration following myocardial infarction,” Circulation Research, vol. 117, no. 5, pp. 450–459, 2015. View at: Publisher Site | Google Scholar
  73. S. Ma, X. Y. Tian, Y. Zhang et al., “E-selectin-targeting delivery of microRNAs by microparticles ameliorates endothelial inflammation and atherosclerosis,” Scientific Reports, vol. 6, no. 1, article 22910, 2016. View at: Publisher Site | Google Scholar
  74. J. Zhou, K. C. Wang, W. Wu et al., “MicroRNA-21 targets peroxisome proliferators-activated receptor-α in an autoregulatory loop to modulate flow-induced endothelial inflammation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 25, pp. 10355–10360, 2011. View at: Publisher Site | Google Scholar
  75. G. Wan, W. Xie, Z. Liu et al., “Hypoxia-inducedMIR155is a potent autophagy inducer by targeting multiple players in the MTOR pathway,” Autophagy, vol. 10, no. 1, pp. 70–79, 2014. View at: Publisher Site | Google Scholar
  76. X. Xiao, Z. Lu, V. Lin et al., “MicroRNA miR-24-3p reduces apoptosis and regulates Keap1-Nrf2 pathway in mouse cardiomyocytes responding to ischemia/reperfusion injury,” Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 7042105, 9 pages, 2018. View at: Publisher Site | Google Scholar
  77. X. Sun, S. He, A. K. M. Wara et al., “Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice,” Circulation Research, vol. 114, no. 1, pp. 32–40, 2014. View at: Publisher Site | Google Scholar
  78. G. C. van Almen, W. Verhesen, R. E. W. van Leeuwen et al., “MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure,” Aging Cell, vol. 10, no. 5, pp. 769–779, 2011. View at: Publisher Site | Google Scholar
  79. H. F. Xie, Y. Z. Liu, R. Du et al., “miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1,” Cell Death & Disease, vol. 8, no. 3, article e2663, 2017. View at: Publisher Site | Google Scholar
  80. Z. Wang, L. Sun, K. Jia, H. Wang, and X. Wang, “miR-9-5p modulates the progression of Parkinson’s disease by targeting SIRT1,” Neuroscience Letters, vol. 701, pp. 226–233, 2019. View at: Publisher Site | Google Scholar
  81. M. Harada, M. Jinnin, Z. Wang et al., “The expression of miR-124 increases in aged skin to cause cell senescence and it decreases in squamous cell carcinoma,” Bioscience Trends, vol. 10, no. 6, pp. 454–459, 2017. View at: Publisher Site | Google Scholar
  82. A. Lang, S. Grether-Beck, M. Singh et al., “MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4,” Aging, vol. 8, no. 3, pp. 484–505, 2016. View at: Publisher Site | Google Scholar
  83. K. J. Turner, V. Vasu, and D. K. Griffin, “Telomere biology and human phenotype,” Cell, vol. 8, no. 1, p. 73, 2019. View at: Publisher Site | Google Scholar
  84. H. H. Cheung, X. Liu, L. Canterel-Thouennon, L. Li, C. Edmonson, and O. M. Rennert, “Telomerase protects Werner syndrome lineage-specific stem cells from premature aging,” Stem Cell Reports, vol. 2, no. 4, pp. 534–546, 2014. View at: Publisher Site | Google Scholar
  85. A. O’Donovan, A. J. Tomiyama, J. Lin et al., “Stress appraisals and cellular aging: a key role for anticipatory threat in the relationship between psychological stress and telomere length,” Brain, Behavior, and Immunity, vol. 26, no. 4, pp. 573–579, 2012. View at: Publisher Site | Google Scholar
  86. I. Shalev, T. E. Moffitt, K. Sugden et al., “Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study,” Molecular Psychiatry, vol. 18, no. 5, pp. 576–581, 2013. View at: Publisher Site | Google Scholar
  87. E. S. Epel, E. H. Blackburn, J. Lin et al., “Accelerated telomere shortening in response to life stress,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 49, pp. 17312–17315, 2004. View at: Publisher Site | Google Scholar
  88. T. Van Nguyen, N. Puebla-Osorio, H. Pang, M. E. Dujka, and C. Zhu, “DNA damage-induced cellular senescence is sufficient to suppress tumorigenesis: a mouse model,” The Journal of Experimental Medicine, vol. 204, no. 6, pp. 1453–1461, 2007. View at: Publisher Site | Google Scholar
  89. G. Lossaint, E. Besnard, D. Fisher, J. Piette, and V. Dulić, “Chk1 is dispensable for G2 arrest in response to sustained DNA damage when the ATM/p53/p21 pathway is functional,” Oncogene, vol. 30, no. 41, pp. 4261–4274, 2011. View at: Publisher Site | Google Scholar
  90. D. Churikov and C. M. Price, “Pot1 and cell cycle progression cooperate in telomere length regulation,” Nature Structural & Molecular Biology, vol. 15, no. 1, pp. 79–84, 2008. View at: Publisher Site | Google Scholar
  91. K. Klement and A. A. Goodarzi, “DNA double strand break responses and chromatin alterations within the aging cell,” Experimental Cell Research, vol. 329, no. 1, pp. 42–52, 2014. View at: Publisher Site | Google Scholar
  92. Y. Wang, J. He, M. Liao et al., “An overview of Sirtuins as potential therapeutic target: structure, function and modulators,” European Journal of Medicinal Chemistry, vol. 161, pp. 48–77, 2019. View at: Publisher Site | Google Scholar
  93. Y. Yang, H. Hou, E. M. Haller, S. V. Nicosia, and W. Bai, “Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation,” The EMBO Journal, vol. 24, no. 5, pp. 1021–1032, 2005. View at: Publisher Site | Google Scholar
  94. L. Bordone, D. Cohen, A. Robinson et al., “SIRT1 transgenic mice show phenotypes resembling calorie restriction,” Aging Cell, vol. 6, no. 6, pp. 759–767, 2007. View at: Publisher Site | Google Scholar
  95. S. Fourcade, L. Morato, J. Parameswaran et al., “Loss of SIRT2 leads to axonal degeneration and locomotor disability associated with redox and energy imbalance,” Aging Cell, vol. 16, no. 6, pp. 1404–1413, 2017. View at: Publisher Site | Google Scholar
  96. L. Liu, A. Arun, L. Ellis, C. Peritore, and G. Donmez, “Sirtuin 2 (SIRT2) enhances 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage via deacetylating forkhead box O3a (Foxo3a) and activating Bim protein,” The Journal of Biological Chemistry, vol. 287, no. 39, pp. 32307–32311, 2012. View at: Publisher Site | Google Scholar
  97. L. Liu, C. Peritore, J. Ginsberg, J. Shih, S. Arun, and G. Donmez, “Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson’s disease,” Behavioural Brain Research, vol. 281, pp. 215–221, 2015. View at: Publisher Site | Google Scholar
  98. S. Someya, W. Yu, W. C. Hallows et al., “Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction,” Cell, vol. 143, no. 5, pp. 802–812, 2010. View at: Publisher Site | Google Scholar
  99. W. Zhang, H. Wan, G. Feng et al., “SIRT6 deficiency results in developmental retardation in cynomolgus monkeys,” Nature, vol. 560, no. 7720, pp. 661–665, 2018. View at: Publisher Site | Google Scholar
  100. B. N. Vazquez, J. K. Thackray, N. G. Simonet et al., “SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair,” The EMBO Journal, vol. 35, no. 14, pp. 1488–1503, 2016. View at: Publisher Site | Google Scholar
  101. N. M. Xiao, Y. M. Zhang, Q. Zheng, and J. Gu, “Klotho is a serum factor related to human aging,” Chinese Medical Journal, vol. 117, no. 5, pp. 742–747, 2004. View at: Google Scholar
  102. M. Ullah and Z. Sun, “Klotho deficiency accelerates stem cells aging by impairing telomerase activity,” The Journals of Gerontology: Series A, vol. 74, no. 9, pp. 1396–1407, 2019. View at: Publisher Site | Google Scholar
  103. H. Liu, M. M. Fergusson, R. M. Castilho et al., “Augmented Wnt signaling in a mammalian model of accelerated aging,” Science, vol. 317, no. 5839, pp. 803–806, 2007. View at: Publisher Site | Google Scholar
  104. R. M. De Oliveira, “Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway,” FEBS Letters, vol. 580, no. 24, pp. 5753–5758, 2006. View at: Publisher Site | Google Scholar
  105. Y. Maekawa, M. Ohishi, M. Ikushima et al., “Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway,” Geriatrics & Gerontology International, vol. 11, no. 4, pp. 510–516, 2011. View at: Publisher Site | Google Scholar
  106. H. Miyauchi, T. Minamino, K. Tateno, T. Kunieda, H. Toko, and I. Komuro, “Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway,” The EMBO Journal, vol. 23, no. 1, pp. 212–220, 2004. View at: Publisher Site | Google Scholar
  107. D. Gao, Z. Zuo, J. Tian et al., “Activation of SIRT1 attenuates klotho deficiency-induced arterial stiffness and hypertension by enhancing AMP-activated protein kinase activity,” Hypertension, vol. 68, no. 5, pp. 1191–1199, 2016. View at: Publisher Site | Google Scholar
  108. B. G. Childs, M. Gluscevic, D. J. Baker et al., “Senescent cells: an emerging target for diseases of ageing,” Nature Reviews Drug Discovery, vol. 16, no. 10, pp. 718–735, 2017. View at: Publisher Site | Google Scholar
  109. D. Wu and C. Prives, “Relevance of the p53-MDM2 axis to aging,” Cell Death and Differentiation, vol. 25, no. 1, pp. 169–179, 2018. View at: Publisher Site | Google Scholar
  110. A. Marusyk, L. J. Wheeler, C. K. Mathews, and J. DeGregori, “p53 mediates senescence-like arrest induced by chronic replicational stress,” Molecular and Cellular Biology, vol. 27, no. 15, pp. 5336–5351, 2007. View at: Publisher Site | Google Scholar
  111. Y. Y. Kim, H. J. Jee, J. H. Um, Y. M. Kim, S. S. Bae, and J. Yun, “Cooperation between p21 and Akt is required for p53-dependent cellular senescence,” Aging Cell, vol. 16, no. 5, pp. 1094–1103, 2017. View at: Publisher Site | Google Scholar
  112. M. Gorospe, X. Wang, and N. J. Holbrook, “Functional role of p21 during the cellular response to stress,” Gene Expression, vol. 7, no. 4-6, pp. 377–385, 1999. View at: Google Scholar
  113. F. Yang, M. Yi, Y. Liu, Q. Wang, Y. Hu, and H. Deng, “Glutaredoxin-1 silencing induces cell senescence via p53/p21/p16 signaling axis,” Journal of Proteome Research, vol. 17, no. 3, pp. 1091–1100, 2018. View at: Publisher Site | Google Scholar
  114. L. Poliseno, L. Pitto, M. Simili et al., “The proto-oncogene LRF is under post-transcriptional control of miR-20a: implications for senescence,” PLoS One, vol. 3, no. 7, article e2542, 2008. View at: Publisher Site | Google Scholar
  115. M. Qi, H. Zhou, S. Fan et al., “mTOR inactivation by ROS-JNK-p53 pathway plays an essential role in psedolaric acid B induced autophagy-dependent senescence in murine fibrosarcoma L929 cells,” European Journal of Pharmacology, vol. 715, no. 1-3, pp. 76–88, 2013. View at: Publisher Site | Google Scholar
  116. J. Y. Sung, K. Y. Lee, J. R. Kim, and H. C. Choi, “Interaction between mTOR pathway inhibition and autophagy induction attenuates adriamycin-induced vascular smooth muscle cell senescence through decreased expressions of p53/p21/p16,” Experimental Gerontology, vol. 109, pp. 51–58, 2018. View at: Publisher Site | Google Scholar
  117. T. Weichhart, “mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review,” Gerontology, vol. 64, no. 2, pp. 127–134, 2018. View at: Publisher Site | Google Scholar
  118. P. Tan, Y. J. Wang, S. Li et al., “The PI3K/Akt/mTOR pathway regulates the replicative senescence of human VSMCs,” Molecular and Cellular Biochemistry, vol. 422, no. 1-2, pp. 1–10, 2016. View at: Publisher Site | Google Scholar
  119. D. W. Lamming, L. Ye, D. M. Sabatini, and J. A. Baur, “Rapalogs and mTOR inhibitors as anti-aging therapeutics,” The Journal of Clinical Investigation, vol. 123, no. 3, pp. 980–989, 2013. View at: Publisher Site | Google Scholar
  120. J. A. Didonato, F. Mercurio, and M. Karin, “NF-κB and the link between inflammation and cancer,” Immunological Reviews, vol. 246, no. 1, pp. 379–400, 2012. View at: Publisher Site | Google Scholar
  121. J. Zhao, X. Li, S. Mcgowan, L. J. Niedernhofer, and P. D. Robbins, “NF-κB activation with aging: characterization and therapeutic inhibition,” Methods in Molecular Biology, vol. 1280, pp. 543–557, 2015. View at: Publisher Site | Google Scholar
  122. L. A. J. O'Neill and C. Kaltschmidt, “NF-κB: a crucial transcription factor for glial and neuronal cell function,” Trends in Neurosciences, vol. 20, no. 6, pp. 252–258, 1997. View at: Publisher Site | Google Scholar
  123. F. Dou, X. Chu, B. Zhang et al., “EriB targeted inhibition of microglia activity attenuates MPP+ induced DA neuron injury through the NF-κB signaling pathway,” Molecular Brain, vol. 11, no. 1, p. 75, 2018. View at: Publisher Site | Google Scholar
  124. S. Hunot, B. Brugg, D. Ricard et al., “Nuclear translocation of NF-κB is increased in dopaminergic neurons of patients with Parkinson disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 14, pp. 7531–7536, 1997. View at: Publisher Site | Google Scholar
  125. H. Zhang, K. J. A. Davies, and H. J. Forman, “Oxidative stress response and Nrf2 signaling in aging,” Free Radical Biology and Medicine, vol. 88, Part B, pp. 314–336, 2015. View at: Publisher Site | Google Scholar
  126. J. H. Suh, S. V. Shenvi, B. M. Dixon et al., “Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 10, pp. 3381–3386, 2004. View at: Publisher Site | Google Scholar
  127. X. Meng, H. Chen, G. Wang, Y. Yu, and K. Xie, “Hydrogen-rich saline attenuates chemotherapy-induced ovarian injury via regulation of oxidative stress,” Experimental and Therapeutic Medicine, vol. 10, no. 6, pp. 2277–2282, 2015. View at: Publisher Site | Google Scholar
  128. L. Chen, R. Yang, W. Qiao et al., “1,25-Dihydroxyvitamin D exerts an antiaging role by activation of Nrf2-antioxidant signaling and inactivation of p16/p53-senescence signaling,” Aging Cell, vol. 18, no. 3, article e12951, 2019. View at: Publisher Site | Google Scholar
  129. D. D. Huang, S. D. Fan, X. Y. Chen et al., “Nrf2 deficiency exacerbates frailty and sarcopenia by impairing skeletal muscle mitochondrial biogenesis and dynamics in an age-dependent manner,” Experimental Gerontology, vol. 119, pp. 61–73, 2019. View at: Publisher Site | Google Scholar
  130. Y. Kitaoka, Y. Tamura, K. Takahashi, K. Takeda, T. Takemasa, and H. Hatta, “Effects of Nrf2 deficiency on mitochondrial oxidative stress in aged skeletal muscle,” Physiological Reports, vol. 7, no. 3, article e13998, 2019. View at: Publisher Site | Google Scholar
  131. K. Sahin, C. Orhan, M. Tuzcu et al., “Tomato powder modulates NF-κB, mTOR, and Nrf2 pathways during aging in healthy rats,” Journal of Aging Research, vol. 2019, Article ID 1643243, 8 pages, 2019. View at: Publisher Site | Google Scholar
  132. S. T. Ho, Y. T. Hsieh, S. Y. Wang, and M. J. Chen, “Improving effect of a probiotic mixture on memory and learning abilities in d-galactose-treated aging mice,” Journal of Dairy Science, vol. 102, no. 3, pp. 1901–1909, 2019. View at: Publisher Site | Google Scholar
  133. H. Cui, D. Tang, G. B. Garside et al., “Wnt signaling mediates the aging-induced differentiation impairment of intestinal stem cells,” Stem Cell Reviews and Reports, vol. 15, no. 3, pp. 448–455, 2019. View at: Publisher Site | Google Scholar
  134. Y. Wang, L. Liu, S. K. Pazhanisamy, H. Li, A. Meng, and D. Zhou, “Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells,” Free Radical Biology & Medicine, vol. 48, no. 2, pp. 348–356, 2010. View at: Publisher Site | Google Scholar
  135. D. Y. Zhang, H. J. Wang, and Y. Z. Tan, “Wnt/β-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway,” PLoS One, vol. 6, no. 6, article e21397, 2011. View at: Publisher Site | Google Scholar
  136. C. Zhang, P. Chen, Y. Fei et al., “Wnt/β-catenin signaling is critical for dedifferentiation of aged epidermal cells in vivo and in vitro,” Aging Cell, vol. 11, no. 1, pp. 14–23, 2012. View at: Publisher Site | Google Scholar
  137. A. Suzuki, R. Minamide, and J. Iwata, “WNT/β-catenin signaling plays a crucial role in myoblast fusion through regulation of nephrin expression during development,” Development, vol. 145, no. 23, article dev168351, 2018. View at: Publisher Site | Google Scholar
  138. R. Ruiz, E. María Pérez-Villegas, and Á. Manuel Carrión, “AMPK function in aging process,” Current Drug Targets, vol. 17, no. 8, pp. 932–941, 2016. View at: Publisher Site | Google Scholar
  139. M. Y. Kim, J. H. Lim, H. H. Youn et al., “Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice,” Diabetologia, vol. 56, no. 1, pp. 204–217, 2013. View at: Publisher Site | Google Scholar
  140. W. Mair, I. Morantte, A. P. C. Rodrigues et al., “Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB,” Nature, vol. 470, no. 7334, pp. 404–408, 2011. View at: Publisher Site | Google Scholar
  141. D. H. Lee, T. H. Lee, C. H. Jung, and Y. H. Kim, “Wogonin induces apoptosis by activating the AMPK and p53 signaling pathways in human glioblastoma cells,” Cellular Signalling, vol. 24, no. 11, pp. 2216–2225, 2012. View at: Publisher Site | Google Scholar
  142. B. Jani and C. Rajkumar, “Ageing and vascular ageing,” Postgraduate Medical Journal, vol. 82, no. 968, pp. 357–362, 2006. View at: Publisher Site | Google Scholar
  143. X. Xu, B. Wang, C. Ren et al., “Recent progress in vascular aging: mechanisms and its role in age-related diseases,” Aging and Disease, vol. 8, no. 4, pp. 486–505, 2017. View at: Publisher Site | Google Scholar
  144. L. Jiang, M. Wang, J. Zhang et al., “Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells,” PLoS One, vol. 3, no. 5, article e2231, 2008. View at: Publisher Site | Google Scholar
  145. G. Pintus, R. Giordo, Y. Wang et al., “Reduced vasorin enhances angiotensin II signaling within the aging arterial wall,” Oncotarget, vol. 9, no. 43, pp. 27117–27132, 2018. View at: Publisher Site | Google Scholar
  146. M. Wang, J. Zhang, L. Q. Jiang et al., “Proinflammatory profile within the grossly normal aged human aortic wall,” Hypertension, vol. 50, no. 1, pp. 219–227, 2007. View at: Publisher Site | Google Scholar
  147. M. Wang, D. Zhao, G. Spinetti et al., “Matrix metalloproteinase 2 activation of transforming growth Factor-β1 (TGF-β1) and TGF-β1–type II receptor signaling within the aged arterial wall,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 7, pp. 1503–1509, 2006. View at: Publisher Site | Google Scholar
  148. K. G. Soucy, S. Ryoo, A. Benjo et al., “Impaired shear stress-induced nitric oxide production through decreased NOS phosphorylation contributes to age-related vascular stiffness,” Journal of Applied Physiology, vol. 101, no. 6, pp. 1751–1759, 2006. View at: Publisher Site | Google Scholar
  149. C. Sepulveda, I. Palomo, and E. Fuentes, “Mechanisms of endothelial dysfunction during aging: predisposition to thrombosis,” Mechanisms of Ageing and Development, vol. 164, pp. 91–99, 2017. View at: Publisher Site | Google Scholar
  150. R. P. Brandes, I. Fleming, and R. Busse, “Endothelial aging,” Cardiovascular Research, vol. 66, no. 2, pp. 286–294, 2005. View at: Publisher Site | Google Scholar
  151. F. D. Kolodgie, A. P. Burke, G. Nakazawa, and R. Virmani, “Is pathologic intimal thickening the key to understanding early plaque progression in human atherosclerotic disease?” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 5, pp. 986–989, 2007. View at: Publisher Site | Google Scholar
  152. M. R. Hamczyk, R. Villa-Bellosta, V. Quesada et al., “Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells,” EMBO Molecular Medicine, vol. 11, no. 4, article e9736, 2019. View at: Publisher Site | Google Scholar
  153. S. Tarantini, C. H. T. Tran, G. R. Gordon, Z. Ungvari, and A. Csiszar, “Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline,” Experimental Gerontology, vol. 94, pp. 52–58, 2017. View at: Publisher Site | Google Scholar
  154. L. Yamani, B. Li, and L. Larose, “Nck1 deficiency improves pancreatic β cell survival to diabetes-relevant stresses by modulating PERK activation and signaling,” Cellular Signalling, vol. 27, no. 12, pp. 2555–2567, 2015. View at: Publisher Site | Google Scholar
  155. A. V. Molofsky, S. G. Slutsky, N. M. Joseph et al., “Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing,” Nature, vol. 443, no. 7110, pp. 448–452, 2006. View at: Publisher Site | Google Scholar
  156. H. Chen, X. Gu, I. H. Su et al., “Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus,” Genes & Development, vol. 23, no. 8, pp. 975–985, 2009. View at: Publisher Site | Google Scholar
  157. F. M. Menzies, A. Fleming, A. Caricasole et al., “Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities,” Neuron, vol. 93, no. 5, pp. 1015–1034, 2017. View at: Publisher Site | Google Scholar
  158. R. M. Barrientos, M. M. Kitt, L. R. Watkins, and S. F. Maier, “Neuroinflammation in the normal aging hippocampus,” Neuroscience, vol. 309, pp. 84–99, 2015. View at: Publisher Site | Google Scholar
  159. H. Zhang, X. Sun, Y. Xie, J. Zan, and W. Tan, “Isosteviol sodium protects against permanent cerebral ischemia injury in mice via inhibition of NF-κB-mediated inflammatory and apoptotic responses,” Journal of Stroke and Cerebrovascular Diseases, vol. 26, no. 11, pp. 2603–2614, 2017. View at: Publisher Site | Google Scholar
  160. C. Fang, L. Xie, C. Liu et al., “Tanshinone IIA improves hypoxic ischemic encephalopathy through TLR-4-mediated NF-κB signal pathway,” Molecular Medicine Reports, vol. 18, no. 2, pp. 1899–1908, 2018. View at: Publisher Site | Google Scholar
  161. K. Tashiro, M. Shishido, K. Fujimoto et al., “Age-related disruption of autophagy in dermal fibroblasts modulates extracellular matrix components,” Biochemical and Biophysical Research Communications, vol. 443, no. 1, pp. 167–172, 2014. View at: Publisher Site | Google Scholar
  162. C. Scherfer, V. C. Han, Y. Wang, A. E. Anderson, and M. J. Galko, “Autophagy drives epidermal deterioration in a Drosophila model of tissue aging,” Aging, vol. 5, no. 4, pp. 276–287, 2013. View at: Publisher Site | Google Scholar
  163. C. Muther, L. Jobeili, M. Garion et al., “An expression screen for aged-dependent microRNAs identifies miR-30a as a key regulator of aging features in human epidermis,” Aging, vol. 9, no. 11, pp. 2376–2396, 2017. View at: Publisher Site | Google Scholar
  164. J. Cai, H. Zhang, Y. F. Zhang, Z. Zhou, and S. Wu, “MicroRNA-29 enhances autophagy and cleanses exogenous mutant αB-crystallin in retinal pigment epithelial cells,” Experimental Cell Research, vol. 374, no. 1, pp. 231–248, 2019. View at: Publisher Site | Google Scholar
  165. E. Korhonen, N. Piippo, M. Hytti, J. M. T. Hyttinen, K. Kaarniranta, and A. Kauppinen, “SQSTM1/p62 regulates the production of IL-8 and MCP-1 in IL-1β-stimulated human retinal pigment epithelial cells,” Cytokine, vol. 116, pp. 70–77, 2019. View at: Publisher Site | Google Scholar
  166. J. Tian, Y. Liu, Y. Liu, K. Chen, and S. Lyu, “Cellular and molecular mechanisms of diabetic atherosclerosis: herbal medicines as a potential therapeutic approach,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 9080869, 16 pages, 2017. View at: Publisher Site | Google Scholar
  167. W. Zuo, F. Yan, B. Zhang, J. Li, and D. Mei, “Advances in the studies of Ginkgo biloba leaves extract on aging-related diseases,” Aging and Disease, vol. 8, no. 6, pp. 812–826, 2017. View at: Publisher Site | Google Scholar
  168. N. Kandiah, P. A. Ong, T. Yuda et al., “Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: expert consensus on the use of Ginkgo biloba extract, EGb 761®,” CNS Neuroscience & Therapeutics, vol. 25, no. 2, pp. 288–298, 2019. View at: Publisher Site | Google Scholar
  169. X. X. Dong, Z. J. Hui, W. X. Xiang, Z. F. Rong, S. Jian, and C. J. Zhu, “Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity,” Journal of Cardiovascular Pharmacology, vol. 49, no. 2, pp. 111–115, 2007. View at: Publisher Site | Google Scholar
  170. X. Zhou, Y. Qi, and T. Chen, “Long-term pre-treatment of antioxidant Ginkgo biloba extract EGb-761 attenuates cerebral-ischemia-induced neuronal damage in aged mice,” Biomedicine & Pharmacotherapy, vol. 85, pp. 256–263, 2017. View at: Publisher Site | Google Scholar
  171. J. Tian, M. S. Popal, Y. Liu et al., “Ginkgo biloba leaf extract attenuates atherosclerosis in streptozotocin- induced diabetic ApoE-/- mice by inhibiting endoplasmic reticulum stress via restoration of autophagy through the mTOR signaling pathway,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 8134678, 19 pages, 2019. View at: Publisher Site | Google Scholar
  172. C. Mancuso and R. Santangelo, “Panax ginseng and Panax quinquefolius: from pharmacology to toxicology,” Food and Chemical Toxicology, vol. 107, Part A, pp. 362–372, 2017. View at: Publisher Site | Google Scholar
  173. Z. L. Wang, L. B. Chen, Z. Qiu et al., “Ginsenoside Rg1 ameliorates testicular senescence changes in D-gal-induced aging mice via anti‑inflammatory and antioxidative mechanisms,” Molecular Medicine Reports, vol. 17, no. 5, pp. 6269–6276, 2018. View at: Publisher Site | Google Scholar
  174. Y. Zhou, J. Liu, S. Cai, D. Liu, R. Jiang, and Y. Wang, “Protective effects of ginsenoside Rg1 on aging Sca-1+ hematopoietic cells,” Molecular Medicine Reports, vol. 12, no. 3, pp. 3621–3628, 2015. View at: Publisher Site | Google Scholar
  175. M. R. Lee, J. Y. Ma, and C. K. Sung, “Chronic dietary ginseng extract administration ameliorates antioxidant and cholinergic systems in the brains of aged mice,” Journal of Ginseng Research, vol. 41, no. 4, pp. 615–619, 2017. View at: Publisher Site | Google Scholar
  176. L. Chen, H. Yao, X. Chen et al., “Ginsenoside Rg1 decreases oxidative stress and down-regulates Akt/mTOR signalling to attenuate cognitive impairment in mice and senescence of neural stem cells induced by D-galactose,” Neurochemical Research, vol. 43, no. 2, pp. 430–440, 2018. View at: Publisher Site | Google Scholar
  177. C. Xu, W. Wang, B. Wang et al., “Analytical methods and biological activities of Panax notoginseng saponins: recent trends,” Journal of Ethnopharmacology, vol. 236, pp. 443–465, 2019. View at: Publisher Site | Google Scholar
  178. H. Zhao, Z. Han, G. Li, S. Zhang, and Y. Luo, “Therapeutic potential and cellular mechanisms of Panax notoginseng on prevention of aging and cell senescence-associated diseases,” Aging and Disease, vol. 8, no. 6, pp. 721–739, 2017. View at: Publisher Site | Google Scholar
  179. Z. Zhou, J. Wang, Y. Song et al., “Panax notoginseng saponins attenuate cardiomyocyte apoptosis through mitochondrial pathway in natural aging rats,” Phytotherapy Research, vol. 32, no. 2, pp. 243–250, 2018. View at: Publisher Site | Google Scholar
  180. J. Li, L. Yang, J. Z. Wang et al., “Study on protective effect of Panax notoginseng total saponins on H9c2 cells senescence against D-galactose,” Zhong Yao Cai, vol. 37, no. 8, pp. 1421–1424, 2014. View at: Google Scholar
  181. Z. Guo, Y. Lou, M. Kong, Q. Luo, Z. Liu, and J. Wu, “A systematic review of phytochemistry, pharmacology and pharmacokinetics on Astragali radix: implications for Astragali radix as a personalized medicine,” International Journal of Molecular Sciences, vol. 20, no. 6, p. 1463, 2019. View at: Publisher Site | Google Scholar
  182. X. Ma, K. Zhang, H. Li, S. Han, Z. Ma, and P. Tu, “Extracts from Astragalus membranaceus limit myocardial cell death and improve cardiac function in a rat model of myocardial ischemia,” Journal of Ethnopharmacology, vol. 149, no. 3, pp. 720–728, 2013. View at: Publisher Site | Google Scholar
  183. W. Z. Li, W. Y. Wu, D. K. Huang et al., “Protective effects of astragalosides on dexamethasone and Aβ25-35 induced learning and memory impairments due to decrease amyloid precursor protein expression in 12-month male rats,” Food and Chemical Toxicology, vol. 50, no. 6, pp. 1883–1890, 2012. View at: Publisher Site | Google Scholar
  184. X. T. Li, Y. K. Zhang, H. X. Kuang et al., “Mitochondrial protection and anti-aging activity of Astragalus polysaccharides and their potential mechanism,” International Journal of Molecular Sciences, vol. 13, no. 2, pp. 1747–1761, 2012. View at: Publisher Site | Google Scholar
  185. Y. Gao, Y. Wei, Y. Wang, F. Gao, and Z. Chen, “Lycium barbarum: a traditional Chinese herb and a promising anti-aging agent,” Aging and Disease, vol. 8, no. 6, pp. 778–791, 2017. View at: Publisher Site | Google Scholar
  186. X. Hu, Y. Qu, Q. Chu, W. Li, and J. He, “Investigation of the neuroprotective effects of Lycium barbarum water extract in apoptotic cells and Alzheimer’s disease mice,” Molecular Medicine Reports, vol. 17, no. 3, pp. 3599–3606, 2018. View at: Publisher Site | Google Scholar
  187. H. C. Jeong, S. H. Jeon, Z. G. Qun et al., “Lycium chinense Mill improves hypogonadism via anti-oxidative stress and anti-apoptotic effect in old aged rat model,” The Aging Male, pp. 1–10, 2018. View at: Publisher Site | Google Scholar
  188. Y. Yu, X. Wu, J. Pu et al., “Lycium barbarum polysaccharide protects against oxygen glucose deprivation/reoxygenation-induced apoptosis and autophagic cell death via the PI3K/Akt/mTOR signaling pathway in primary cultured hippocampal neurons,” Biochemical and Biophysical Research Communications, vol. 495, no. 1, pp. 1187–1194, 2018. View at: Publisher Site | Google Scholar
  189. H. Tao, X. Wu, J. Cao et al., “Rhodiola species: a comprehensive review of traditional use, phytochemistry, pharmacology, toxicity, and clinical study,” Medicinal Research Reviews, vol. 39, no. 5, pp. 1779–1850, 2019. View at: Publisher Site | Google Scholar
  190. Q. Zhou, X. Han, R. Li et al., “Anti-atherosclerosis of oligomeric proanthocyanidins from Rhodiola rosea on rat model via hypolipemic, antioxidant, anti-inflammatory activities together with regulation of endothelial function,” Phytomedicine, vol. 51, pp. 171–180, 2018. View at: Publisher Site | Google Scholar
  191. S. E. Schriner, K. Lee, S. Truong et al., “Extension of Drosophila lifespan by Rhodiola rosea through a mechanism independent from dietary restriction,” PLoS One, vol. 8, no. 5, article e63886, 2013. View at: Publisher Site | Google Scholar
  192. C. Chen, J. Song, M. Chen et al., “Rhodiola rosea extends lifespan and improves stress tolerance in silkworm, Bombyx mori,” Biogerontology, vol. 17, no. 2, pp. 373–381, 2016. View at: Publisher Site | Google Scholar
  193. W.-L. Wei, R. Zeng, C.-M. Gu, Y. Qu, and L.-F. Huang, “Angelica sinensis in China-a review of botanical profile, ethnopharmacology, phytochemistry and chemical analysis,” Journal of Ethnopharmacology, vol. 190, pp. 116–141, 2016. View at: Publisher Site | Google Scholar
  194. X. P. Zhang, J. Liu, C. Y. Xu et al., “Effect of Angelica sinensis polysaccharide on expression of telomere, telomerase and P53 in mice aging hematopoietic stem cells,” China Journal of Chinese Materia Medica, vol. 38, no. 14, pp. 2354–2358, 2013. View at: Publisher Site | Google Scholar
  195. X. P. Zhang, Q. X. Wang, B. Chen et al., “Angelica sinensis polysaccharides delay aging of hematopoietic stem cells through inhibitting oxidative damge,” China Journal of Chinese Materia Medica, vol. 38, no. 3, pp. 407–412, 2013. View at: Publisher Site | Google Scholar
  196. X. Cheng, H. Yao, Y. Xiang et al., “Effect of Angelica polysaccharide on brain senescence of Nestin-GFP mice induced by D-galactose,” Neurochemistry International, vol. 122, pp. 149–156, 2019. View at: Publisher Site | Google Scholar
  197. X. Mu, Y. Zhang, J. Li et al., “Angelica sinensis polysaccharide prevents hematopoietic stem cells senescence in D-galactose-induced aging mouse model,” Stem Cells International, vol. 2017, Article ID 3508907, 12 pages, 2017. View at: Publisher Site | Google Scholar
  198. Q. Wang, Y. Huang, C. Qin et al., “Bioactive peptides from Angelica sinensis protein hydrolyzate delay senescence in Caenorhabditis elegans through antioxidant activities,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 8956981, 10 pages, 2016. View at: Publisher Site | Google Scholar
  199. Z. Chen, C. Zhang, F. Gao et al., “A systematic review on the rhizome of Ligusticum chuanxiong Hort. (Chuanxiong),” Food and Chemical Toxicology, vol. 119, pp. 309–325, 2018. View at: Publisher Site | Google Scholar
  200. L. Chen, L. Cheng, X. Wei et al., “Tetramethylpyrazine analogue CXC195 protects against dopaminergic neuronal apoptosis via activation of PI3K/Akt/GSK3β signaling pathway in 6-OHDA-induced Parkinson’s disease mice,” Neurochemical Research, vol. 42, no. 4, pp. 1141–1150, 2017. View at: Publisher Site | Google Scholar
  201. S. Wei and H. Wang, “Ligustrazine promoted hypoxia-treated cell growth by upregulation of miR-135b in human umbilical vein endothelial cells,” Experimental and Molecular Pathology, vol. 106, pp. 102–108, 2019. View at: Publisher Site | Google Scholar
  202. B. Gao, X. Lin, H. Jing et al., “Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti-inflammatory and angiogenic environment in aging mice,” Aging Cell, vol. 17, no. 3, article e12741, 2018. View at: Publisher Site | Google Scholar
  203. W.-C. Hou, H.-S. Tsay, H.-J. Liang, T.-Y. Lee, G.-J. Wang, and D.-Z. Liu, “Improving abnormal hemorheological parameters in aging guinea pigs by water- soluble extracts of Salvia miltiorrhiza Bunge,” Journal of Ethnopharmacology, vol. 111, no. 3, pp. 483–489, 2007. View at: Publisher Site | Google Scholar
  204. C. H. Park, S. H. Shin, E. K. Lee et al., “Magnesium lithospermate B from Salvia miltiorrhiza Bunge ameliorates aging-induced renal inflammation and senescence via NADPH oxidase-mediated reactive oxygen generation,” Phytotherapy Research, vol. 31, no. 5, pp. 721–728, 2017. View at: Publisher Site | Google Scholar
  205. S. Zou, J. R. Carey, P. Liedo, D. K. Ingram, B. Yu, and R. Ghaedian, “Prolongevity effects of an oregano and cranberry extract are diet dependent in the Mexican fruit fly (Anastrepha ludens),” The Journals of Gerontology: Series A, vol. 65A, no. 1, pp. 41–50, 2010. View at: Publisher Site | Google Scholar
  206. S. Zou, J. R. Carey, P. Liedo, D. K. Ingram, and B. Yu, “Prolongevity effects of a botanical with oregano and cranberry extracts in Mexican fruit flies: examining interactions of diet restriction and age,” Age, vol. 34, no. 2, pp. 269–279, 2012. View at: Publisher Site | Google Scholar
  207. G. Lai, Y. Guo, D. Chen et al., “Alcohol extracts from Ganoderma lucidum delay the progress of Alzheimer’s disease by regulating DNA methylation in rodents,” Frontiers in Pharmacology, vol. 10, p. 272, 2019. View at: Publisher Site | Google Scholar
  208. S. N. Lobo, Y. Q. Qi, and Q. Z. Liu, “The effect of Gynostemma pentaphyllum extract on mouse dermal fibroblasts,” ISRN Dermatology, vol. 2014, Article ID 202876, 6 pages, 2014. View at: Publisher Site | Google Scholar
  209. Y.-R. Li, S. Li, and C.-C. Lin, “Effect of resveratrol and pterostilbene on aging and longevity,” BioFactors, vol. 44, no. 1, pp. 69–82, 2018. View at: Publisher Site | Google Scholar
  210. M. Wu, L. Ma, L. Xue et al., “Resveratrol alleviates chemotherapy-induced oogonial stem cell apoptosis and ovarian aging in mice,” Aging, vol. 11, no. 3, pp. 1030–1044, 2019. View at: Publisher Site | Google Scholar
  211. A. Dehghani, Z. Hafizibarjin, R. Najjari, F. Kaseb, and F. Safari, “Resveratrol and 1,25-dihydroxyvitamin D co-administration protects the heart against D-galactose-induced aging in rats: evaluation of serum and cardiac levels of klotho,” Aging Clinical and Experimental Research, vol. 31, no. 9, pp. 1195–1205, 2019. View at: Publisher Site | Google Scholar
  212. L. Du, E. Chen, T. Wu, Y. Ruan, and S. Wu, “Resveratrol attenuates hydrogen peroxide-induced aging through upregulation of autophagy in human umbilical vein endothelial cells,” Drug Design, Development and Therapy, vol. 13, pp. 747–755, 2019. View at: Publisher Site | Google Scholar
  213. A. O. Abolaji, A. O. Adedara, M. A. Adie, M. Vicente-Crespo, and E. O. Farombi, “Resveratrol prolongs lifespan and improves 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced oxidative damage and behavioural deficits in Drosophila melanogaster,” Biochemical and Biophysical Research Communications, vol. 503, no. 2, pp. 1042–1048, 2018. View at: Publisher Site | Google Scholar
  214. A. M. Posadino, R. Giordo, A. Cossu et al., “Flavin oxidase-induced ROS generation modulates PKC biphasic effect of resveratrol on endothelial cell survival,” Biomolecules, vol. 9, no. 6, p. 209, 2019. View at: Publisher Site | Google Scholar
  215. A. M. Posadino, A. Cossu, R. Giordo et al., “Resveratrol alters human endothelial cells redox state and causes mitochondrial-dependent cell death,” Food and Chemical Toxicology, vol. 78, pp. 10–16, 2015. View at: Publisher Site | Google Scholar
  216. L. Toniolo, P. Fusco, L. Formoso et al., “Resveratrol treatment reduces the appearance of tubular aggregates and improves the resistance to fatigue in aging mice skeletal muscles,” Experimental Gerontology, vol. 111, pp. 170–179, 2018. View at: Publisher Site | Google Scholar
  217. A. A. Momtazi-Borojeni, E. Abdollahi, B. Nikfar, S. Chaichian, and M. Ekhlasi-Hundrieser, “Curcumin as a potential modulator of M1 and M2 macrophages: new insights in atherosclerosis therapy,” Heart Failure Reviews, vol. 24, no. 3, pp. 399–409, 2019. View at: Publisher Site | Google Scholar
  218. M. B. Naeini, A. A. Momtazi, M. R. Jaafari et al., “Antitumor effects of curcumin: a lipid perspective,” Journal of Cellular Physiology, vol. 234, no. 9, pp. 14743–14758, 2019. View at: Publisher Site | Google Scholar
  219. S. Tasneem, B. Liu, B. Li, M. I. Choudhary, and W. Wang, “Molecular pharmacology of inflammation: medicinal plants as anti-inflammatory agents,” Pharmacological Research, vol. 139, no. 139, pp. 126–140, 2019. View at: Publisher Site | Google Scholar
  220. M. Shailaja, K. M. D. Gowda, K. Vishakh, and N. S. Kumari, “Anti-aging role of curcumin by modulating the inflammatory markers in albino Wistar rats,” Journal of the National Medical Association, vol. 109, no. 1, pp. 9–13, 2017. View at: Publisher Site | Google Scholar
  221. S. Pirmoradi, E. Fathi, R. Farahzadi, Y. Pilehvar-Soltanahmadi, and N. Zarghami, “Curcumin affects adipose tissue-derived mesenchymal stem cell aging through TERT gene expression,” Drug Research, vol. 68, no. 4, pp. 213–221, 2018. View at: Publisher Site | Google Scholar
  222. J. Hu, T. Shen, J. Xie, S. Wang, Y. He, and F. Zhu, “Curcumin modulates covalent histone modification and TIMP1 gene activation to protect against vascular injury in a hypertension rat model,” Experimental and Therapeutic Medicine, vol. 14, no. 6, pp. 5896–5902, 2017. View at: Publisher Site | Google Scholar
  223. Y. Chen, X. Liu, C. Jiang et al., “Curcumin supplementation increases survival and lifespan in Drosophila under heat stress conditions,” BioFactors, vol. 44, no. 6, pp. 577–587, 2018. View at: Publisher Site | Google Scholar
  224. C. Receno, C. Liang, D. Korol et al., “Effects of prolonged dietary curcumin exposure on skeletal muscle biochemical and functional responses of aged male rats,” International Journal of Molecular Sciences, vol. 20, no. 5, p. 1178, 2019. View at: Publisher Site | Google Scholar
  225. L. Wen, Y. Jiang, J. Yang, Y. Zhao, M. Tian, and B. Yang, “Structure, bioactivity, and synthesis of methylated flavonoids,” Annals of the New York Academy of Sciences, vol. 1398, no. 1, pp. 120–129, 2017. View at: Publisher Site | Google Scholar
  226. P. Maher, “The potential of flavonoids for the treatment of neurodegenerative diseases,” International Journal of Molecular Sciences, vol. 20, no. 12, p. 3056, 2019. View at: Publisher Site | Google Scholar
  227. A. M. Mahmoud, R. J. Hernández Bautista, M. A. Sandhu, and O. E. Hussein, “Beneficial effects of citrus flavonoids on cardiovascular and metabolic health,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 5484138, 19 pages, 2019. View at: Publisher Site | Google Scholar
  228. D. Maaliki, A. A. Shaito, G. Pintus, A. El-Yazbi, and A. H. Eid, “Flavonoids in hypertension: a brief review of the underlying mechanisms,” Current Opinion in Pharmacology, vol. 45, pp. 57–65, 2019. View at: Publisher Site | Google Scholar
  229. T. De Bruyne, B. Steenput, L. Roth et al., “Dietary polyphenols targeting arterial stiffness: interplay of contributing mechanisms and gut microbiome-related metabolism,” Nutrients, vol. 11, no. 3, p. 578, 2019. View at: Publisher Site | Google Scholar
  230. K. Pallauf, N. Duckstein, and G. Rimbach, “A literature review of flavonoids and lifespan in model organisms,” The Proceedings of the Nutrition Society, vol. 76, no. 2, pp. 145–162, 2017. View at: Publisher Site | Google Scholar
  231. K.-C. Hung, H.-J. Huang, Y.-T. Wang, and A. M.-Y. Lin, “Baicalein attenuates α-synuclein aggregation, inflammasome activation and autophagy in the MPP+-treated nigrostriatal dopaminergic system in vivo,” Journal of Ethnopharmacology, vol. 194, pp. 522–529, 2016. View at: Publisher Site | Google Scholar
  232. E. Lashmanova, N. Zemskaya, E. Proshkina et al., “The evaluation of geroprotective effects of selected flavonoids in Drosophila melanogaster and Caenorhabditis elegans,” Frontiers in Pharmacology, vol. 8, p. 884, 2017. View at: Publisher Site | Google Scholar
  233. T. Yang, L. Fang, T. Lin et al., “Ultrasonicated sour Jujube seed flavonoids extract exerts ameliorative antioxidant capacity and reduces Aβ-induced toxicity in Caenorhabditis elegans,” Journal of Ethnopharmacology, vol. 239, article 111886, 2019. View at: Publisher Site | Google Scholar
  234. C. Cianfrocca, F. Pelliccia, A. Auriti, and M. Santini, “Ginkgo biloba-induced frequent ventricular arrhythmia,” Italian Heart Journal, vol. 3, no. 11, pp. 689–691, 2002. View at: Google Scholar
  235. S. C. Erdle, E. S. Chan, H. Yang, B. A. Vallance, C. Mill, and T. Wong, “First-reported pediatric cases of American ginseng anaphylaxis and allergy,” Allergy, Asthma & Clinical Immunology, vol. 14, no. 1, p. 79, 2018. View at: Publisher Site | Google Scholar
  236. S. Lu, K.-j. Chen, Q.-y. Yang, and H.-r. Sun, “Progress in the research of Radix Astragali in treating chronic heart failure: effective ingredients, dose-effect relationship and adverse reaction,” Chinese Journal of Integrative Medicine, vol. 17, no. 6, pp. 473–477, 2011. View at: Publisher Site | Google Scholar
  237. C. H. Larramendi, J. L. García-Abujeta, S. Vicario et al., “Goji berries (Lycium barbarum): risk of allergic reactions in individuals with food allergy,” Journal of Investigational Allergology & Clinical Immunology, vol. 22, no. 5, pp. 345–350, 2012. View at: Google Scholar
  238. Y. Chang, W. Zhang, Y. Xie et al., “Postmarketing safety evaluation: depside salt injection made from Danshen (Radix Salviae Miltiorrhizae),” Journal of Traditional Chinese Medicine, vol. 34, no. 6, pp. 749–753, 2014. View at: Publisher Site | Google Scholar
  239. S. P. Chaudhari, A. Y. Tam, and J. A. Barr, “Curcumin: a contact allergen,” The Journal of Clinical and Aesthetic Dermatology, vol. 8, no. 11, pp. 43–48, 2015. View at: Google Scholar
  240. X. Liu, J. Du, J. Cai et al., “Clinical systematic observation of Kangxin capsule curing vascular dementia of senile kidney deficiency and blood stagnation type,” Journal of Ethnopharmacology, vol. 112, no. 2, pp. 350–355, 2007. View at: Publisher Site | Google Scholar
  241. Y. Zhao, X. An, J. Liu et al., “The improvement of oxidative stress by two proprietary herbal medicines in type 2 diabetes,” Complementary Therapies in Medicine, vol. 40, pp. 120–125, 2018. View at: Publisher Site | Google Scholar
  242. T. Kwok, P. C. Leung, C. Lam et al., “A randomized placebo controlled trial of an innovative herbal formula in the prevention of atherosclerosis in postmenopausal women with borderline hypercholesterolemia,” Complementary Therapies in Medicine, vol. 22, no. 3, pp. 473–480, 2014. View at: Publisher Site | Google Scholar
  243. S. Dingzhu, X. Sanli, C. Chuan, S. Rui, and L. Danfei, “Effect of Shoushen granule on arterial elasticity in patients with carotid atherosclerosis: a clinical randomized controlled trial,” Journal of Traditional Chinese Medicine, vol. 35, no. 4, pp. 389–395, 2015. View at: Publisher Site | Google Scholar
  244. P. Lv, X. Tong, Q. Peng et al., “Treatment with the herbal medicine, naoxintong improves the protective effect of high-density lipoproteins on endothelial function in patients with type 2 diabetes,” Molecular Medicine Reports, vol. 13, no. 3, pp. 2007–2016, 2016. View at: Publisher Site | Google Scholar
  245. S. Akhondzadeh, M. Noroozian, M. Mohammadi, S. Ohadinia, A. H. Jamshidi, and M. Khani, “Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: a double blind, randomized and placebo-controlled trial,” Journal of Clinical Pharmacy and Therapeutics, vol. 28, no. 1, pp. 53–59, 2003. View at: Publisher Site | Google Scholar
  246. S. Akhondzadeh, M. S. Sabet, M. H. Harirchian et al., “Saffron in the treatment of patients with mild to moderate Alzheimer’s disease: a 16-week, randomized and placebo-controlled trial,” Journal of Clinical Pharmacy and Therapeutics, vol. 35, no. 5, pp. 581–588, 2010. View at: Publisher Site | Google Scholar
  247. J. Jia, C. Wei, S. Chen et al., “Efficacy and safety of the compound Chinese medicine SaiLuoTong in vascular dementia: a randomized clinical trial,” Alzheimer's & Dementia: Translational Research & Clinical Interventions, vol. 4, pp. 108–117, 2018. View at: Publisher Site | Google Scholar
  248. H. Tajadini, R. Saifadini, R. Choopani, M. Mehrabani, M. Kamalinejad, and A. A. Haghdoost, “Herbal medicine Davaie Loban in mild to moderate Alzheimer’s disease: a 12-week randomized double-blind placebo-controlled clinical trial,” Complementary Therapies in Medicine, vol. 23, no. 6, pp. 767–772, 2015. View at: Publisher Site | Google Scholar
  249. T. Uno, I. Ohsawa, M. Tokudome, and Y. Sato, “Effects of Goshajinkigan on insulin resistance in patients with type 2 diabetes,” Diabetes Research and Clinical Practice, vol. 69, no. 2, pp. 129–135, 2005. View at: Publisher Site | Google Scholar
  250. S. Cho, C.-H. Won, D. H. Lee et al., “Red ginseng root extract mixed with Torilus fructus and Corni fructus improves facial wrinkles and increases type I procollagen synthesis in human skin: a randomized, double-blind, placebo-controlled study,” Journal of Medicinal Food, vol. 12, no. 6, pp. 1252–1259, 2009. View at: Publisher Site | Google Scholar
  251. R. Giordo, A. Cossu, V. Pasciu, P. T. Hoa, A. M. Posadino, and G. Pintus, “Different redox response elicited by naturally occurring antioxidants in human endothelial cells,” The Open Biochemistry Journal, vol. 7, pp. 44–53, 2013. View at: Publisher Site | Google Scholar
  252. V. Pasciu, A. M. Posadino, A. Cossu et al., “Akt downregulation by flavin oxidase–induced ROS generation mediates dose-dependent endothelial cell damage elicited by natural antioxidants,” Toxicological Sciences, vol. 114, no. 1, pp. 101–112, 2010. View at: Publisher Site | Google Scholar
  253. A. M. Posadino, A. Cossu, R. Giordo et al., “Coumaric acid induces mitochondrial damage and oxidative-mediated cell death of human endothelial cells,” Cardiovascular Toxicology, vol. 13, no. 3, pp. 301–306, 2013. View at: Publisher Site | Google Scholar

Copyright © 2019 Yanfei Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views2825
Downloads1206
Citations

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.