With the improvement of science and technology and living conditions, mankind is gradually moving towards an aging society. According to the United Nations World Population Ageing Report released in 2015 (1), the number of aged people (60 and over) is expected to increase to nearly 2,100 million over the next 35 years. As age increases, the physiological function of the body gradually deteriorates, which is characterized by the decline in the structure and function of organs, cells, and tissues (2). Aging-related diseases are becoming one of the biggest challenges faced by developed and developing countries (3). López-Otínput forwarded nine pathological features of aging, including genomic instability, telomere loss, epigenetic changes, protein homeostasis imbalance, deregulated nutrient sensing, mitochondrial damage, cell senescence, stem cell exhaustion, and intercellular communication changes (4).
Presently, anti-aging methods mainly include diet restriction, gene reprogramming, and drugs (5). A growing number of research data shows that adequate dietary restrictions (DR) have a strong protective effect on obesity, type 2 diabetes, inflammation, hypertension, and cancer-related risk factors under sufficient nutrition (6). In fact, for most people, the duration and degree of the DR program needed for the best benefit are unfeasible and may lead to related side effects. Short term partial reprogramming of Oct4, Sox2, Klf4, and c-Myc (OSKM) improves physiological markers in mice, prolongs their life span, and improves the muscle regeneration ability of the normal old mice (7). However, the feasibility and safety of these two methods need further studies.
Drug therapy is an anti-aging method, and rapamycin, metformin, and spermidine are the typical drugs. Rapamycin, an mTOR inhibitor, can reduce downstream production of mTOR c1 and S6K by inhibiting the mTOR pathway; the life span of mice can be prolonged by up to 60% with 3 months of rapamycin treatment (8). A study was performed to assess whether the mTOR inhibitor RAD001, could improve immune senility to influenza vaccination in elderly volunteers. The results showed that RAD001 enhanced immune response to influenza vaccines and also reduced the percentage of CD4+ and CD8+ T lymphoblastic cells that expressed the programmed death-1 receptor (PD-1) (9). Metformin, a usual drug used in type 2 diabetes mellitus (T2DM) treatment, has been proven to prolong the life span of nematodes (10). Spermidine, a natural polyamine, can prolong the life of mice and play a protective role in the heart by reducing myocardial hypertrophy and protecting the diastolic function of the heart in aged mice (11). Additionally, low dose lithium can prolong the life span of Drosophila melanogaster by 16%; the mechanism may be related to its glycogen synthetase kinase-3 (GSK-3) inhibition and transcription factor nuclear factor erythroid 2-related factor (NRF-2) activation (12).
However, sufficient clinical evidence of the effects of theses drugs on humans is unavailable. In recent years, the anti-aging effect of Chinese herbal medicine (CHM) has been widely and deeply researched. This article is an overview of the progress on elucidating the anti-aging effects of CHM. The research articles of anti-aging CHM published from 2008 to 2018 were retrieved from PubMed. The Clinical Trials (https://clinicaltrials.gov/) and Chinese Clinical Trial Registry (http://www.chictr.org.cn/) databases were searched for registered clinical trials.
The anti-aging role of CHM
Evidence from clinical studies in humans
Nine clinical trials published from 2008 to 2018 were included (Table 1). The types of studies include randomized controlled trials, crossover trials, cohort studies, etc. Resveratrol was the most studied medicine, followed by curcumin. The main outcome indicators of these clinical studies were as follows: general signs, muscle function and structure, cardiovascular and metabolic indicators, cognitive function, aging-related protein or gene, and safety indicators.
Some studies reported the following adverse reactions: gastrointestinal reactions, dizziness, diarrhea, constipation, muscle cramps, fatigue, memory loss, allergies, difficulty swallowing, rash, headache, etc. In a randomized, double-blind crossover study of resveratrol, three participants treated with 3 g of resveratrol daily experienced severe gastrointestinal symptoms with one requiring hospitalization, but when the dose was lowered to 2 g/d for the remaining participants, no further gastrointestinal symptoms were reported (15). Resveratrol supplementation at doses of 300 and 1,000 mg/day for 90 days does not adversely affect blood chemistry, and is well tolerated in overweight and older individuals; the incidence of adverse events between the treatment and control groups was not statistically significant (13). This study highlights the safety of short-term and low-dose resveratrol administration. In terms of anti-aging, research shows that resveratrol combined with exercise can reduce or reverse sarcopenia in elderly persons (16). Besides, supplementary resveratrol also improves memory performance and increases hippocampal functional connectivity in healthy older adults; improved glucose metabolism may be an underlying mechanism (17). Another study also showed that a single dose of 75 mg of resveratrol improves neurovascular coupling and cognitive function in patients with T2DM (18). However, a prospective study in 783 older community-dwelling adults showed that there was no association between urinary resveratrol metabolites and longevity; total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, cancer, or all-cause mortality (14). Therefore, further clinical research on the anti-aging effect of resveratrol is waranted. On the other hand, curcumin (2,000 mg/day) administration for 12 weeks improves resistance artery endothelial function by increasing vascular nitric oxide bioavailability and reducing oxidative stress (19). A 12-month, randomized, placebo-controlled, double-blind study focused on curcumin and cognition showed that there were no differences in cognitive performance from baseline to the 12-month follow-up between placebo and treatment groups (20). Ganoderma lucidum has been used as a traditional medicine to treat a variety of diseases. A randomized, double-blind, placebo-controlled crossover study on Ganoderma lucidum shows its antioxidation and hepatoprotective efficacy, but the subjects were healthy middle-aged (40–54 years old) volunteers (21), therefore, its efficacy in the elderly should be further studied.
Additionally, we found 10 registered clinical trials (Table 2) from Clinical Trials (https://clinicaltrials.gov) and Chinese Clinical Trial Registry (http://www.chictr.org.cn), the recruiting locations are mainly China and the United States. Generally, large-scale clinical research on the anti-aging effect of CHM remains unavailable. Presently, there are still some shortcomings in clinical research such as fewer cases, short follow-up time, etc.
Evidence from Preclinical Studies
Monomers and Components of CHM
Resveratrol is a natural polyphenolic compound found in several plants, including grapes and Polygonum cuspidatum (79). Studies have shown that it indirectly activates SIRT1 in vivo (80). The life-prolonging metabolic roles of SIRT1 include gluconeogenesis regulation, fatty acid oxidation reduction, fat production reduction, insulin secretion upregulation, and autophagy regulation (81). Additionally, resveratrol can alleviate H2O2-induced oxidative stress injury in endothelial cells, thereby slowing aging (82). Resveratrol can also protect against arterial aging, and this effect is associated with reduced activity of the PRR-ACE-Ang II axis and stimulation of the ACE2-Ang-(1-7)-ATR2-MasR axis (83).
Curcumin is a bioactive substance extracted from the rhizome of Curcuma longa L (84). Curcumin supplementation can increase the survival rate of Drosophila, which may be related to its antioxidant activities and the mitigating effect of heat shock responses (85). Another study showed that curcumin suppresses vascular aging and inflammation triggered by long-term administration of a high-fat diet, which might be a prophylactic food against arteriosclerotic disease (86). Aging is the major risk factor for osteoarthritis and studies have found that curcumin can treat it by inducing autophagy via the Akt/mTOR signaling pathway (87).
Ginsenoside Rg1, an active ingredient of Panax ginseng, can improve the cognitive ability of the D-galactose-induced aging rat model; its mechanism may be related to neural stem/progenitor cell protection, and antioxidant and anti-inflammatory capacity enhancement in the hippocampus (88). Later studies showed that its protective effect may be achieved via downregulation of the p19/p53/p21 signaling pathway (89). Hematopoietic stem cell (HSC) senescence is an important hypothesis accounting for organismal aging; Ginsenoside Rg1 can improve the resistance of Sca-1+ hematopoietic stem/progenitor cells (HSC/HPCs) in aging mice by reducing DNA damage and inhibiting excessive activation of the Wnt/β-catenin signaling pathway (90). The function of the spleen and thymus decreases with aging; Ginsenoside Rg1 can protect the spleen and thymus of D-galactose-induced aging rats via reducing oxidative stress injury and downregulating the expression of aging-related proteins (91).
Salidroside, a phenylpropanoid glycoside, is a potent component isolated from the root of Rhodiola rosea, which can resist immune aging by enhancing humoral and cell-mediated immune responses in aged rats after antigen activation (92). Besides, salidroside can also play a therapeutic role in learning and memory decline by stimulating cAMP response element binding protein (CREB)-dependent functional neurogenesis during aging (93). Aging is the major risk factor for cardiovascular diseases, especially coronary atherosclerosis, which is mainly attributed to the aging of vascular structure and function. Studies showed that salidroside can prevent oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell senescence by promoting the cell cycle and reducing intracellular lipid deposition, inhibiting the expression of senescence-related molecules (94).
Total Flavonoid of Epimedium and Icariin
Epimedium is the dry leaf of Epimedium brevicornu Maxim (95). Its main constituents are the Total Flavonoid of Epimedium (TFE) and Icariin. Oxidative stress is one of the main causes of aging and can induce oxidative DNA damage, causing cell cycle arrest and apoptosis; however, TFE can effectively reduce oxidative stress-induced DNA damage in aging rats by inhibiting p-p53/p21 and chk1/chk2 expression, increasing superoxide dismutase (SOD) activity and decreasing malondialdehyde (MDA) content (96). Icariin alleviates the age-dependent deficit in cognitive function, which may be via activation of neural stem cells (NSCs) in the hippocampus (97). Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Two different damage models of dopamine neurons in rat midbrain induced by neurotoxins of 6-hydroxydopamine (6-OHDA) and lipopolysaccharide (LPS) were employed to investigate the neuroprotective effects of Icariin. The result showed that it could protect dopamine neurons both in vivo and in vitro, and the mechanism may be related to the inhibition of microglia-mediated neuroinflammation (98).
Angelica Sinensis Polysaccharide
Angelica Sinensis (Dang gui) is the dry root of an umbelliferous plant Angelica sinensis (Oliv.) Diels (95). Angelica Sinensis Polysaccharide (ASP) is a major ingredient in Angelica Sinensis. ASP ameliorated stress-induced premature senescence of hematopoietic cells by protecting bone marrow stromal cells against chemotherapeutic injury via alleviating the oxidative damage of stromal cells and improving their hematopoietic function (99).
Astragalus polysaccharides (APS)
APS is a major active ingredient of Astragalus membranaceus. Bone marrow mesenchymal stem cell (BMSCs) dysfunction under pathological stimulation is involved in the development of aging-related diseases such as osteoporosis (100). APS treatment may attenuate apoptosis and senescence in BMSCs, inhibiting the reduction of Nanog, Sox2, and Oct4 expression caused by ferric ammonium citrate (FAC) (100).
ECH is a phenylethanoid glycoside isolated from Cistanche tubulosa, found to extend the life span of worms, increase their tolerance to heat shock and oxidative stress, and modulate the nuclear localization and transcriptional activities of daf-16 (101).
Tetrahydroxystilbene glucoside and emodin
2,3,5,4’-tetrahydoxystilbene-2-O-β-D-glucoside (TSG) is a major bioactive constituent of Polygonum multiflorum Thunb. Several studies have indicated that TSG exerts a marked neuroprotective effect against glutamate-induced hippocampal damage by decreasing ROS production and stabilizing mitochondrial membrane potential (MMP) (102). TSG enhanced hippocampal-dependent contextual fear memory and novel object recognition probably via promoting phosphorylation of ERK1/2, CaMKII, and CREB, upregulation of silent information regulator 1 (SIRT1), and downregulation of miR-134 (103). Emodin, an active component of Polygonum multiflorum Thunb, may exert a significant neuroprotective effect by activating the PI3K/Akt signaling pathway against glutamate-induced apoptosis and improving behavioral function in cerebral ischemia (104). However, attention should be paid to its toxicity, especially hepatic adverse reactions (105).
Other preclinical studies on the anti-aging effects of the monomers and components of CHM are shown in Table 3.
Extracts of CHM
Ganoderma lucidum (Ling Zhi)
Ganoderma lucidum is the dried fruiting body of Ganoderma lucidum (Leyss. ex Fr.) Karst. or Ganoderma sinense (95). Ganoderma lucidum extracts play a role in ameliorating DNA damage (106), which is a major causes of aging. Since oxidative stress also plays an important role in the aging process, researchers accessed its ability to protect bladder function from ischemia/reperfusion (I/R)-mediated oxidative damage, and found that Ganoderma lucidum, prior to I/R, can completely inhibit the negative effects of I/R (107).
Cistanches herba (Rou Cong Rong)
Cistanches is the dry-sliced fleshy stem of Cistanche deserticola Y.C. Ma or Cistanche tubulosa (Schenk) Wight. Cistanche deserticola can improve the age-related behavioral decline and pathological manifestations of cataract and retinopathy in rats (108). Cistanche tubulosa extends the lifespan and increases the flies’ resistance to oxidative stress, and enhances memory formation in young flies (109).
Cynomorium songaricum (Suo Yang)
Cynomorium songaricum (CS) is a dry fleshy stem of Cynomorium songaricum Rupr (95). Research shows that it extends both the mean and maximum lifespan of adult female flies by improving antioxidant stress ability (110). The ethyl acetate fraction of CS attenuated staurosporine-induced SK-N-SH neuroblastoma cell death (111). The flavonoid extract of CS shows antioxidant and anti-fatigue effects on the swimming endurance of rats; free radical scavenging enzymes increase after treatment with the flavonoid extract (112).
Alpiniae oxyphyllae fructus (Yi Zhi)
Alpiniae oxyphyllae fructus is the dried and ripe fruit of Zingiberaceae plant Alpinia oxyphylla Miq. (95). Cardiac hypertrophy is a pathophysiological phenomenon associated with aging. Research has proven that Alpiniae oxyphyllae fructus (AOF) can improve aging-related cardiovascular diseases such as myocardial remodeling and cardiac hypertrophy. It inhibits apoptosis in the cardiac tissue of SD rats by regulating apoptosis-related genes and activating the longevity factor SIRT1 (113). Further research shows that AOF protects against cardiac hypertrophy in the D-galactose-induced senescent rat model via downregulation of both concentric and eccentric hypertrophy signaling pathways such as ERK1/2/JNK (114).
Other preclinical studies on the anti-aging effect of CHM extracts are shown in Table 4.
Researchers studied the anti-aging effect and mechanism of eight kinds of CHM compounds (Liu Wei Di Huang Wan, Qi Bao Mei Ran Dan, Shi Quan Da Bu Wan, Sheng Mai Yin, Er Chen Wan, Huan Shao Dan, Qin Jiao Wan, and Tian Ma Wan) on Caenorhabditis elegans and found that their mechanism was partially related to antioxidative and thermal stress effect (115). Researchers firstly focused on the expression of related proteins (STUB1, CaMKIIα, AMFR) in Alzheimer’s disease (AD), and then studied the effect of CHM compounds on their expression (116-118).
Liu Wei Di Huang
Liu Wei Di Huang (LW) is a typical traditional Chinese medicine (TCM) prescription, consisting of six herbs. It has long been clinically used to treat many kinds of aging-related diseases. It was demonstrated to ameliorate the decline of learning and memory in senescence-accelerated mouse/prone 8 (SAMP8); improvement of the synaptic plasticity via inhibiting voltage-dependent calcium channels and promoting N-Methyl-d-aspartate receptor function may be one of the mechanisms (119). Senescence-accelerated mouse/prone 8 (SAMP8) is considered a robust experimental model for AD. LW-AFC was prepared from Liu Wei Di Huang decoction and included polysaccharides, glycosides, and oligosaccharides. Research shows it can ameliorate cognitive impairment by altering gene expressions and regulating pathways in the hippocampus (120). Aqueous LW extract shows potential benefits for PD treatment in both primary mesencephalic neuron cells and MPTP-treated C57BL/6 mice (121).
Dang Gui Shao Yao San
Dang Gui Shao Yao San (DSS) was originally described in Dong Han Dynasty, ancient China. JD-30 is a fraction extracted from DSS and is able to improve synaptic plasticity and ameliorate deterioration of cognition by blocking and disrupting Aβ aggregation (122). Simultaneously, the elevation of estradiol, NO, and glycine levels in blood plasma may contribute to the cognitive improvement effects of DSS (123). Systems pharmacology research indicated that DSS treats neurodegenerative diseases and other diseases, as determined through research on the same pathological proteins involved in these diseases (124). Additionally, DSS has been proven to promote angiogenesis and neurogenesis after ischemic stroke (125). In conclusion, DSS has great potential in the treatment of neurodegenerative diseases, especially AD, and needs further study.
Zuo Gui Yin
Zuo Gui Yin/Wan is one of the TCM prescriptions from a classical TCM book named “Jing Yue Quan Shu”. Bone mineral density was enhanced markedly in ovariectomized mice and naturally aged mice after Zuo Gui Wan administration. This result shows that it has an anti-aging activity (126). In terms of neuroprotection, Zuo Gui Wan promoted the recovery of neurological function by abrogating inflammation via regulating NogoA, NgR, and RhoA levels, and other neurotrophic factors (127).
Bu Shen Yi Zhi formula
Bu Shen Yi Zhi (BSYZ) formula, a traditional CHM compound composed of Fructus Cnidii (She Chuang Zi), Panax ginseng (Ren Shen), Polygonum multiflorum (Shou Wu), Cortex moutan (Mu Dan Pi), Ligustrum lucidum (Nv Zhen Zi), and Fructus lycii (Gou Qi Zi), has been well-researched by Chinese research teams, especially its neuroprotection effect. Neuroinflammation is considered to be an important mediator in the pathogenesis and progression of PD. BSYZ is thought to alleviate 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced neuroinflammation by inhibiting the activation of NLRP3 inflammasome in microglia (128). Additionally, the acetate extract components of BSYZ provide neuroprotection against scopolamine (SCOP)-induced cognitive dysfunction by inhibiting oxidative stress and apoptosis (129). In a recent study, the team used a systems pharmacology approach to investigate the active ingredients of BSYZ and potential targets in AD, and on this basis established the APPswe/PSEN1dE9 transgenic mouse model to validate the proposed mechanisms for BSYZ. The results showed that the effects of BSYZ on cognitive dysfunction may be related to the regulation of amyloid-β metabolism and neuronal apoptosis (130).
Other preclinical studies on the anti-aging effect of CHM compounds are shown in Table 5.
In summary, no theory can fully explain the complex process of aging as it is multifactorial. In recent years, research on the anti-agining effect of CHM has developed rapidly, but no CHM has been proven to have a clinically effective anti-aging effect. In this review, CHM has been shown to have several anti-aging biological activities in vivo and in vitro, beneficial neuroprotective effects in neurodegenerative diseases like AD, PD, and skin photoaging, and cardiovascular disease protective effects. Research has mainly focused on the components, extracts, and compounds of CHM, whose mechanisms include clinical symptom improvement, anti-oxidation, free radical scavanging, neuroendocrine level regulation, vascular endothelial function improvement, immunity and apoptosis regulation, DNA damage prevention, etc. Among these, anti-oxidation and free radical scavenging are the most common. However, compared with a large number of preclinical studies, there are relatively few related clinical studies and a lack of long-term follow-up studies for endpoint events. Therefore, more convincing clinical trials are needed to confirm the efficacy of CHM, and elucidate the detailed pharmacokinetics, toxicity, standardization, and therapeutic dosage in humans. In conclusion, as a multitarget anti-aging drug, future research should pay more attention to CHM.
Funding: This work was supported by grants of National Key R&D Program of China (2017YFC1700301), the Fundamental Research Funds for the Central public welfare research institutes (ZZ13-024-4) and Qihuang Scholar of “Millions of Talents Project” (Qihuang Project) of Traditional Chinese Medicine Inheritance and Innovation to Fengqin Xu.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm.2020.04.09). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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