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Review

2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) from Polygonum multiflorum Thunb.: A Systematic Review on Anti-Aging

1
College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
2
College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(7), 3381; https://doi.org/10.3390/ijms26073381
Submission received: 7 March 2025 / Revised: 1 April 2025 / Accepted: 3 April 2025 / Published: 4 April 2025
(This article belongs to the Section Molecular Pharmacology)

Abstract

The global rise in aging populations has made healthy longevity a critical priority in medical research. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG), the primary bioactive component of Polygonum multiflorum Thunb. (commonly known as Fallopia multiflora Thunb., He shou wu, Fo-ti, or Polygoni multiflori radix), has emerged as a promising agent for combating aging and age-related diseases. This systematic review evaluates the anti-aging properties of TSG and its protective effects against age-related pathologies. The current evidence demonstrates that TSG exhibits comprehensive anti-aging effects, including lifespan extension, neuroprotection (e.g., ameliorating Alzheimer’s and Parkinson’s diseases), cardiovascular protection (e.g., reducing atherosclerosis and hypertension), delay of gonadal aging, reduction in bone loss (e.g., mitigating osteoporosis), and promotion of hair regrowth. Mechanistically, TSG alleviates oxidative stress, inflammation, and apoptosis while enhancing mitophagy, mitochondrial function telomerase activity, and epigenetic regulation. These multi-target actions align with the holistic principles of traditional Chinese medicine, highlighting TSG’s potential as a multifaceted anti-aging agent. However, further research is required to establish standardized quantitative systems for evaluating TSG’s efficacy, paving the way for its broader clinical application in promoting healthy aging.

1. Introduction

Aging is characterized by the progressive decline of organismic functions in adulthood, leading to increased vulnerability to neurodegenerative diseases, cardiovascular disorders, cancer, and ultimately death [1,2]. In recent years, significant progress has been made in aging research. In 2013, nine hallmarks of aging were proposed, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication [3]. These hallmarks were later expanded to twelve in 2023, with the addition of disabled macroautophagy, chronic inflammation, and dysbiosis [4]. These characteristics are interconnected and contribute to the development of age-related diseases. For instance, DNA damage triggers inflammation through signaling cascades, driving multiple age-related pathologies [5]. Similarly, oxidative stress interacts with the epigenome, further exacerbating age-related conditions [6]. Additionally, factors secreted by senescent cells promote chronic inflammation, which in turn accelerates cellular senescence, creating a vicious cycle that fuels aging and its associated diseases [7]. With aging populations growing worldwide, developing interventions to promote healthy longevity has become a paramount biomedical priority.
2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG, Figure 1), the predominant bioactive component of Polygonum multiflorum Thunb. (P. multiflorum; commonly known as Fallopia multiflora Thunb., He shou wu, Fo-ti, or Polygoni multiflori radix), can be obtained through various extraction and purification approaches. Conventional extraction methods include aqueous decoction and ethanol reflux. Subsequent purification is commonly achieved through chromatographic separation or recrystallization. First documented in the Pharmacopoeia of China (1963) as the primary quality control marker [8], TSG has garnered attention for its potential anti-aging properties. Modern pharmacological studies have demonstrated that TSG exhibits considerable potential in mitigating aging and age-related diseases. However, the mechanisms underlying these effects remain fragmented, and comprehensive reviews focusing on TSG are limited. This review systematically consolidates the latest findings on TSG’s anti-aging properties and its protective effects against age-related pathologies, elucidating its pleiotropic mechanisms and therapeutic potential to inform future research on healthy aging interventions. Additionally, we also briefly evaluate the anti-aging effects of bioactive constituents in P. multiflorum beyond TSG, providing insights into the potential synergistic action of the said compound with other plant constituents.

2. Methods

2.1. Search Strategy

A comprehensive literature search was conducted across five databases, including PubMed, Embase, the Chinese National Knowledge Infrastructure (CNKI), the Chinese Biomedical Database (CBM), and the Chinese Technology Periodical Database, from their inception to 31 December 2024. The search focused on original articles published within the last five years to ensure the inclusion of the most recent findings. The search strategy utilized a combination of MeSH terms and free-text keywords, as detailed in Supplementary Table S1.

2.2. Eligibility and Study Selection

Figure 2 illustrates the study selection process. Following the screening of titles and abstracts, 290 studies were identified for full-text retrieval. After a thorough eligibility assessment, 186 studies were excluded because, e.g., they involved P. multiflorum formulations or were review articles. Consequently, 104 reports were deemed eligible for inclusion in this systematic review, encompassing studies from the inception of the databases to the present. Among these, 48 studies published within the last five years (2020–2024) were included in the final analysis. These studies were categorized by their primary focus: lifespan extension (n = 4), neuroprotection (n = 19), cardiovascular protection (n = 10), reproductive protection (n = 5), bone protection (n = 4), and others (n = 6). This selection ensured a comprehensive and up-to-date evaluation of the potential anti-aging benefits of TSG and other extracts from P. multiflorum.
The study selection process was conducted independently by two or three authors, with any disagreements resolved through discussion and consensus involving the corresponding authors. For studies included in the final analysis, a standardized data extraction form was developed to systematically collect key information from each study.

3. Results and Discussion

Table 1 summarizes the recent studies investigating the effects of TSG against aging and age-related diseases. Figure 3 and Figure 4 illustrate the molecular mechanism and therapeutic effects of TSG in promoting healthy longevity.
Table 1. Summary of recent studies (2020–2024) on the effects of TSG against aging and age-related diseases.
Table 1. Summary of recent studies (2020–2024) on the effects of TSG against aging and age-related diseases.
EffectsAging Model (Inducer; Object)TSG Treatment
(Dose; Duration)
Chemical PurityPotential MechanismsAuthor (Year)References
Lifespan extensionH2O2; larval zebrafish25, 50, and 100 μg/mL; 24 h >98%Oxidative stress↓, inflammation↓ (SA-β-gal↓, ROS↓, SOD↑, catalase↑, il-1β↓, il-6↓, cxcl-c1c↓, il-8↓)Xia et al. (2023)[9]
C. elegans100, 200, and 400 μM; until deathUnclear (standard)Mean lifespan↑, mitochondrial function↑ (DAF-16/SKN-1/SIR-2.1 pathways; DAF-16↑, SKN-1↑, SIR-2.1↑, SIRT1↑, Aβ↓, Tau↓, ROS↓, MMP↑) Sun et al. (2024)[10]
NeuroprotectionRadiation; C57BL/6J mice, or Tet2−/− mice40, 80, and 120 mg/kg/d; 5 months 98%Inflammation↓, neurogenesis↑ (AMPK/Tet2 pathway; AMPK↑, Tet2↑, NLRP3↓)Miao et al. (2022)[11]
LPS/ATP + Aβ; BV2, N2a, and SH-SY5Y cells, and primary microglia10, 100 nM, and 1, 10 μM; 24 h>98%Inflammation↓, mitophagy↑, mitosis↑ (AMPK/PINK1/Parkin pathway; AMPK↑, PINK1↑, Parkin↑, NLRP3↓, LC3-II/LC3-I↑, p62↓; iNOS↓, COX-2↓, Drp1↑, MIRO↓, Mfn2↑, MFF↓)Gao et al. (2020)[12]
Okadaic acid; SH⁃SY5Y cells100 μM; 24 hUnclear (standard)Apoptosis↓ (PI3K/AKT pathway; PI3K↑, AKT↑, Bcl⁃2↑, Bax↓)Kang et al. (2024)[13]
High-glucose; HT-22 cells200 µM; 48 hUnclear (standard)Apoptosis↓ (HAT↓, HDAC↑, Bcl-2↑, Bax↓, caspase-3↓)Chen et al. (2022)[14]
Alleviating AD① AD model: APP/PS1 double transgenic mice
② LPS/IFN-γ; BV2 cells
① 40 and 80 mg/kg/d; 5 months
② 25, 50, and 100 μM; 20 h
Unclear (standard) Inflammation↓ (cGAS-STING pathway; cGAS↓, STING↓, NF-κB↓, NLRP3↓; IL-1β↓, IL-6↓, TNF-α↓, IFN-α↓, IFN-β↓, IFIT1↓, IRF7↓)Gao et al. (2023)[15]
AD model: APP/PS1/Tau triple transgenic mice0.033, 0.1, and 0.3 g/kg/d; 60 days ≥70%CDK5↓, MAPK1↓, PP1↑, Tau↓, p39↓Wu et al. (2022)[16]
AD model: Aβ25–35; SD rats 0.033, 0.1, and 0.3 g/kg; 4 or 8 weeks98%Apoptosis↓, improving neuronal morphology (PI3K/AKT/GSK-3β pathway; MKK7/JNK pathway; PI3K↑, AKT↑, GSK-3β↓, Tau↓; MKK7↓, JNK↓) Xia et al. (2023); Li, YB et al. (2023); Li, Y et al. (2023)[17,18,19]
AD model: N2a/APP695swe cells100 μM; 48h98%Apoptosis↓, improving mitochondrial function (MMP↑; PACS-2↓)Wang et al. (2024)[20]
AD model: APP/PS1 mouse 120 mg/kg; 8 weeksUnclear (standard)MAPK pathway, chemokine pathway and autophagy—animalGao et al. (2024)[21]
Ameliorating PD① PD model: MPTP; C57BL/6J mice
② MPP+; mesencephalic DA neurons or SH-SY5Y cells
① 20 mg/kg; 7 days
② unclear
≥98%Apoptosis↓, neurotoxicity↓ (FGF2-Akt, BDNF-TrkB axis; FGF2↑, Akt↑, DA↑, TH↑, BDNF↑, TrkB↑, Bcl⁃2↑, caspase-3↓)Yu et al. (2019)[22]
Mouse neural stem cells10 μM; 2 weeks≥98%DA neuron differentiation (Wnt/β-catenin pathway; Wnt1↑, Wnt3a↑, Wnt5a↑, β-catenin↑, Nurr1↑)Zhang et al. (2021)[23]
Inhibiting ASHigh-fat diet; ApoE-deficient (ApoE−/−) mice0.035 and 0.07 mg/g/d; 8 weeks≥98%Inflammation↓, lipid accumulation↓, AS plaque↓, and regulating intestinal microbiota (TG↓, ox-LDL↓, IL- 6↓, TNF-α↓, VCAM-1↓, MCP-1↓) Li et al. (2020)[24]
① ox-LDL; BMDCs
② ApoE−/− mice
① 40 and 80 µM, 2 h
② 40 mg/kg/d, 5 weeks
≥98%Autophagy↓, DCs maturation↓, Treg differentiation↑, inflammation↓, lipid accumulation↓, (PI3K/AKT/mTOR pathway; PI3K↓, AKT↓, mTOR↓, P62↓; TC↓, TG↓, LDL-C↓; IL-6↓, IL-17A↓, IL-10↑)Yang et al. (2024)[25]
① ApoE−/− mice
② Macrophages in the aorta cells of mice (in ①)
100 mg/kg/d, 8 weeks 99%Atherosclerotic lesions↓, dyslipidemia symptoms↓, and regulating lipid metabolism (Srepb-1c↓, Fasn↓, Scd1↓, Gpat1↓, Dgat1↓, Pparα↑ and Cpt1α↑; Srebp2↓, Hmgcr↓, Ldlr↑, Acat1↓, Acat2↓, and Cyp7a1↑)Li et al. (2024)[26]
① High-fat diet; LDLr−/− mice
② ox-LDL; HAECs
① 50 and 100 mg/kg/d; 12 weeks
② 1, 10, and 100 μM; 24 h
>98%Oxidative stress↓, endothelial senescence↓, telomerase activity↑, mitochondrial damage↓, and improving lipid profiles (PGC-1α pathway; PGC-1α↑, TC↓, TG↓, LDL-c↓, ox-LDL↓; γ-H2AX↓, p53↓, p21↓, p16↓; TERT↑; mitoROS↓, NRF1↑, TFAM↑; ROS↓, MDA↓; β-gal↓, MMP↑, mtDNA↓, SOD↑, CAT↑)Wang et al. (2022)[27]
Cardiovascular protection① Natural aging C57BL/6J mice, Tet2 Mut mice
② IMR-90 fibroblasts
① 120 mg/kg/d; 60 days
② 10 and 100 μM; 48 h
Unclear (standard) HSC aging↓, repopulation potential↑, epigenetic reprograming↑, stemness↑ (AMPK-Tet2 axis; CLPs↑, B lymphocytes↑)Gao et al. (2024)[28]
Ang Ⅱ; HUVECs50 and 100 μM; 24 hUnclear (standard)Endothelial senescence↓ (SA-β-gal↓, p53↓, PAI-1↓, SIRT1↑)Fan et al. (2021)[29]
Anti-hypertensionU46619; superior mesenteric artery of SD ratsConcentration accumulation: 10−5 ∼10−2 M;≥98%Vasodilation (SIRT1/TP pathway; SIRT1↑, TP↓)Chen et al. (2022)[30]
HHcy; C57BL/6 mice40, 80, and 160 mg/kg; 4 weeks98%Inhibiting vasoconstriction (ERK1/2/NF-κB pathway; p-ERK1/2↓, p-p65↓, endothelin-1↓; BP↓, Hcy↓)Jia et al. (2022)[31]
① ZDF rats, OMT−/− mice
② HUVEC and mature adipocyte
co-culture
① 50, 100, and 200 mg/kg/d; 2 weeks
② 100 μM; 24 h
≥98%Oxidative/nitrative stress↓, improving endothelial function (Akt/eNOS/NO pathway; SBP↓, omentin-1↑, Akt↓, eNOS↓, NO↓; NOX2↓, p22phox↓, SOD↓, peroxynitrite anion↓, PPAR-γ↑, Itln-1↑)Dong et al. (2021)[32]
Reproductive protectionH2O2 + FeSO4; rat testicular Leydig cells150 μM; 48 hUnclear (standard)Oxidative stress↓, cell senescence↓ (Insulin/IGF-1pathway; SA-β-gal↓, IRS1↑, IGF-1↑, IRS2↑, INSR↑, IGFBP3↓)Li et al. (2021)[33]
Normal C57BL/6J mice10 mg/kg/d; 32, or 16 weeks95%Oocyte quantity and quality↑, mitochondrial biogenesis↑, steroidogenesis ↑ (AMH↑, PR-B↑, atp6↑, pgc1α↑, cyp11a↑, cyp19↑, er-β↑)Lin et al. (2022)[34]
Estrogenic activityER (+) MCF-7 cells100 nM; 24 h Unclear (standard)Cell proliferation↑, acting as phytoestrogen (ERα↑, ERβ↑, pS2↑) Akter et al. (2023)[35]
Reducing OP① OP model: OVX; SD rats
② H2O2; MC3T3-E1 cells
① 80 mg/kg/d; 3 months
② 10 μM; 24 h
≥98%Oxidative stress↑, apoptosis↓, bone resorption↓ (miR-34a↑, SIRT1↓; Conn.D↑, Tb.N↑, BMD↑, MDA↓, GSH-Px↑; ALP↑, OPN↑, COL-1↑, OCN↑)Wang et al. (2022)[36]
Diabetic OP model: Streptozotocin; C57BL/6J mice 10 and 40 mg/kg; 8 weeks Unclear (standard)Regulating osteogenesis and osteoclast genesis (Ca↑, RUNX-2↑, COL-I↑, OCN↑, β-catenin↑, RAS↓, OPG↑, RANKL↓, sclerostin↓)Zhang et al. (2019)[37]
Bone protectionBMSCs10−6, 10−5, and 10−4 M; 3 or 7 daysUnclear (standard)Cell proliferation↑, osteogenic differentiation↑ (ALP↑, OCN↑, Col1a1↑, Runx2↑, β-catenin↑) Liang et al. (2022)[38]
Note: Arrow symbols denote: (↑) upregulation, (↓) downregulation.
Figure 3. Molecular mechanisms of TSG against aging [25,32]. Arrow symbols denote: (↑) upregulation, (↓) downregulation.
Figure 3. Molecular mechanisms of TSG against aging [25,32]. Arrow symbols denote: (↑) upregulation, (↓) downregulation.
Ijms 26 03381 g003
Figure 4. Mechanisms and therapeutic effects of TSG in promoting healthy longevity. Arrow symbols denote: (↑) upregulation, (↓) downregulation.
Figure 4. Mechanisms and therapeutic effects of TSG in promoting healthy longevity. Arrow symbols denote: (↑) upregulation, (↓) downregulation.
Ijms 26 03381 g004

3.1. Lifespan-Extending Effects of TSG

Under laboratory conditions, the lifespan of Caenorhabditis elegans (C. elegans) is approximately three weeks, making it a widely used model organism for lifespan studies. TSG has demonstrated significant antioxidative and lifespan-extending properties. For instance, in C. elegans, TSG was shown to enhance the resistance to lethal thermal stress and effectively prolong both the mean and maximum lifespan of these organisms [39]. Similarly, in Drosophila melanogaster, TSG extended lifespan and improved climbing ability, further supporting its anti-aging potential [40].
In a study involving H2O2-induced aging in larval zebrafish, TSG pretreatment reduced the activity of senescence-associated β-galactosidase (SA-β-gal), inhibited the accumulation of reactive oxygen species (ROS), and enhanced the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase [9]. Furthermore, TSG suppressed the expression of inflammation-related genes (il-1β, il-6, and il-8), collectively protecting against oxidative-stress-mediated aging in zebrafish [9].
Recent research has further elucidated the mechanisms underlying TSG’s lifespan-extending effects. In C. elegans, treatment with 200 μM TSG increased the mean lifespan by 16.48% and delayed age-associated physiological decline [10]. This effect was mediated through the regulation of mitochondrial quality control processes, involving key pathways such as abnormal dauer formation-16 (DAF-16)/forkhead box O (FOXO), skinhead-1 (SKN-1)/nuclear factor erythroid 2-related factor 2 (Nrf2), and silent information regulator-2.1 (SIR-2.1)/sirtuin 1 (SIRT1), which collectively improve mitochondrial function [10].
As the principal bioactive compound and quality marker of P. multiflorum, TSG’s lifespan-extending effects align with the traditional pharmacological view that P. multiflorum can “prolong lifespan”. These effects are likely attributed to its antioxidative, anti-inflammatory, and mitochondrial function-enhancing properties, thereby providing a scientific basis for the anti-aging effects of P. multiflorum.

3.2. Neuroprotective Effects of TSG

TSG has demonstrated significant neuroprotective effects through multiple mechanisms. In vitro experiments revealed that TSG enhanced mitophagy and mitochondrial function via the AMP-activated protein kinase (AMPK)/PTEN-induced kinase 1 (PINK1)/Parkin pathway, effectively mitigating neuroinflammation induced by lipopolysaccharide (LPS)/ATP and β-amyloid (Aβ) [12]. Additionally, TSG modulated apoptotic pathways by upregulating histone deacetylase (HDAC) and B-cell lymphoma 2 (Bcl-2) while downregulating histone acetyltransferase (HAT), Bcl-2-related X protein (Bax), and caspase-3. These changes improved the survival of mouse hippocampal neuron HT-22 cells under high-glucose conditions [14]. Furthermore, TSG activated the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, leading to increased Bcl-2 levels and reduced Bax expression, thereby attenuating okadaic acid-induced apoptosis in human neuroblastoma SH-SY5Y cells [13]. TSG also delayed cellular senescence in SH-SY5Y cells, potentially through the regulation of apoptosis-related proteins by Gstm3 [41]. Moreover, TSG promoted neurotrophic support by significantly increasing the expression of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) in rat primary astroglia, accompanied by enhanced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 [42]. This suggests that TSG stimulates the release of astroglia-derived neurotrophic factors, highlighting its therapeutic potential for neurological disorders.
In vivo, TSG activated AMPK and modulated the AMPK/ten–eleven translocation methylcytosine dioxygenase 2 (Tet2) pathways, promoting neural precursor cell proliferation and differentiation while suppressing NOD-like receptor protein 3 (NLRP3) inflammasome activation in microglia. These mechanisms collectively contributed to the prevention of radiation-induced cognitive deficits in mice [11].
In summary, TSG exhibits robust neuroprotective properties, enhancing neuronal survival and cognitive function. However, the specific types of neurodegenerative diseases addressed in these studies remain unclear. The following sections will explore the preventive and therapeutic potential of TSG in common neurodegenerative disorders.

3.2.1. Attenuation of Alzheimer’s Disease (AD)

Alzheimer’s disease (AD), one of the most prevalent neurodegenerative disorders, exhibits an age-dependent increase in incidence [43]. TSG demonstrated significant efficacy in enhancing both spatial and non-spatial learning and memory capabilities in APPswe/PS1dE9 (APP/PS1) double transgenic AD model mice. This neuroprotective effect was mediated by the inhibition of microglia activation and inflammatory cytokine expression through the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, both in vitro and in vivo [15]. Furthermore, TSG exerted beneficial effects in APP/PS1/Tau triple transgenic AD mice, primarily through the downregulation of cyclin-dependent kinase 5 (CDK5) and mitogen-activated protein kinase 1 (MAPK1), coupled with the upregulation of protein phosphatase 1 (PP1) and the inhibition of Tau protein phosphorylation [16]. TSG also demonstrated protective effects by downregulating phosphofurin acidic cluster sorting protein-2 (PACS-2), which reduced apoptosis in N2a/APP695swe model cells and enhanced the mitochondrial membrane potential (MMP) [20]. In an Aβ25-35-induced AD rat model, TSG inhibited neuron apoptosis in the hippocampal and cortical regions, improving neuronal morphology. This effect was potentially mediated by the activation of the PI3K/AKT signaling pathway, which inhibited glycogen synthase kinase-3β (GSK-3β), ultimately reducing Tau protein phosphorylation [17,18].
Additionally, TSG’s neuroprotective effects on neuronal injury repair were linked to the downregulation of the MKK7/jun N-terminal kinase (JNK) pathway [19]. TSG also mitigated AD progression by enhancing mitochondrial function, reducing Aβ production, and increasing neurotrophic factor levels [44]. Network pharmacology and molecular docking analyses suggested that TSG’s therapeutic mechanisms in AD primarily involved neuroprotection, anti-inflammatory effects, and the modulation of aging-related processes [45]. Recent research employing data-independent acquisition (DIA)-based quantitative proteomics has identified candidate protein biomarkers in the brain tissues of APP/PS1 transgenic mice following TSG treatment; pathway enrichment analysis identified several biologically relevant pathways associated with these changes, including neurodegenerative disease pathways (AD, PD, and Huntington’s disease), and cellular signaling pathways (MAPK signaling, chemokine signaling, and autophagy regulation) [21].
Accordingly, TSG shows significant potential in alleviating AD by inhibiting inflammation and apoptosis, reducing Aβ production, enhancing mitochondrial function and elevating neurotrophic factor levels, thus improving learning-memory deficits and cognitive impairment.

3.2.2. Amelioration of Parkinson’s Disease (PD)

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the mesencephalic substantia nigra [46]. Studies indicated that TSG could restore the fibroblast growth factor 2 (FGF2)/Akt and BDNF/tropomyosin receptor kinase-B (TrkB) signaling axes, as well as protect DA neurons. This neuroprotective effect significantly mitigated neurotoxicity in both the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mouse model and the 1-methyl-4-phenylpyridinium (MPP+)-mediated SH-SY5Y cell line [22]. In experiments involving A53T mutant α-synuclein-transfected cells (A53T AS cells) exposed to MPP+, TSG pretreatment markedly enhanced cell viability and MMP. It also inhibited the overexpression and aggregation of α-synuclein while reducing ROS levels, the Bax/Bcl-2 ratio, and caspase-3 activity [47]. Additionally, TSG exhibited protective effects against DA neurons in 6-hydroxydopamine (6-OHDA)-induced neurotoxicity models by suppressing microglial activation and the subsequent release of pro-inflammatory factors [48]. Moreover, TSG might promote the differentiation of mouse neural stem cells (NSCs) into DA neurons by activating the Wnt/β-catenin signaling pathway, highlighting its potential therapeutic role in PD through NSC transplantation [23].
Therefore, TSG exerts neuroprotective effects by attenuating the neurotoxicity of MPP+, MPTP, or 6-OHDA, suppressing oxidative stress and inflammation, reducing cell apoptosis, and potentially facilitating the differentiation of NSCs into DA neurons. These mechanisms underscore TSG’s potential as a promising therapeutic agent for mitigating PD progression.

3.3. Cardiovascular Protective Effects of TSG

3.3.1. Inhibition of Vascular Senescence and Atherosclerosis (AS)

Epidemiological studies consistently identify age as a major cardiovascular risk factor, with vascular aging closely linked to age-related macrovascular diseases such as atherosclerosis (AS) [49]. AS is characterized by the pathological deposition of lipids, thromboses, connective tissues, and calcium in the vascular system. TSG has been shown to significantly improve endothelial function through enhancement of the NO-cGMP pathway in ApoE-deficient (ApoE−/−) mice, suggesting its potential vasoprotective effects and therapeutic role in endothelial dysfunction-related vascular diseases, including AS [50].
In studies using oxidized low-density lipoprotein (ox-LDL) to stimulate human aortic endothelial cells (HAECs), TSG could alleviate endothelial aging, telomere dysfunction, oxidative stress, and mitochondrial damage, partly through the activation of the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) pathway, as supported by in vivo and in vitro evidence [27]. Furthermore, TSG markedly inhibited AS plaque formation in ApoE−/− mice by improving lipid metabolism, reducing TG and ox-LDL levels, and suppressing inflammation through the downregulation of serum IL-6, tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemotactic protein-1 (MCP-1) [24]. It also modulated intestinal microbiota, influencing Firmicutes, Bacteroidetes, and Helicobacter pylori, which collectively contributed to its anti-AS effects [24].
TSG regulated immune responses by reducing dendritic cell (DC) maturation and promoting Treg differentiation, correcting the Treg/Th17 imbalance via inhibition of the PI3K-AKT-mTOR signaling pathway. This immune modulation was mediated by TSG-induced DC lipophagy, which reduced lipid accumulation and inflammation [25]. In ApoE−/− mice fed a high-fat diet, TSG lowered serum lipids, restored Treg/Th17 balance, and reduced pro-inflammatory cytokines while increasing anti-inflammatory factors, correlating with decreased arterial DC P62 content and plaque area, further supporting TSG’s anti-AS potential [25]. At the metabolic level, TSG restored hepatic lipid metabolism by regulating fatty acid and cholesterol metabolism-related genes, while promoting the polarization of aortic macrophages to the M2 phenotype, further alleviating AS progression [26].
In studies involving angiotensin II (Ang II)-incubated human umbilical vein endothelial cells (HUVECs), TSG pretreatment reduced senescence markers such as SA-β-gal, p53, and plasminogen activator inhibitor-1 (PAI-1), indicating its protective role against Ang II-induced aging, potentially through the regulation of SIRT1 activity [29]. TSG also mitigated TNF-α-mediated cell damage in HUVECs by inhibiting vimentin expression via the TGFβ/Smad signaling pathway [51]. Furthermore, TSG rejuvenated aging hematopoietic stem cells (HSCs), particularly those predisposed to lymphoid differentiation, by modulating the AMPK-Tet2 axis. TSG treatment obviously increased the absolute number of common lymphoid progenitors (CLPs) and B lymphocytes, facilitating the repopulation potential of aging HSCs/CLPs in mice. This rejuvenation was linked to epigenetic reprogramming, which enhanced regenerative abilities and lymphopoiesis [28].
In conclusion, TSG demonstrates significant potential in alleviating vascular senescence and AS through multiple mechanisms, including the inhibitions of inflammation, oxidative stress, and lipid accumulation; the enhancements of telomerase activity, mitochondrial function, and epigenetic reprogramming; and the modulations of intestinal microbiota and immune responses. These findings position TSG as a promising candidate for developing therapies targeting AS and other age-related vascular diseases.

3.3.2. Anti-Hypertensive Effects

Hypertension is a leading global risk factor for cardiovascular diseases, strokes, and mortality, affecting approximately 1.28 billion individuals aged 30 to 79 worldwide [52]. Age is a significant contributor to the development of hypertension, cardiovascular diseases, and cognitive impairment [53]. TSG demonstrated vasodilatory effects in U46619-induced contractions of the rat superior mesenteric artery (SMA) by activating the SIRT1 pathway and inhibiting thromboxane prostanoid receptors [30]. Furthermore, TSG partially ameliorated microvascular endothelial dysfunction through the activation of the Akt/mTOR pathway, which suppressed autophagy [54]. This suggests its utility in preventing subclinical vascular alterations associated with prehypertension. In hyperhomocysteinemia (HHcy) models, TSG effectively lowered blood pressure (BP) and decreased plasma Hcy and endothelin-1 (ET-1) levels by inhibiting the ERK1/2/NF-κB/ETB2 signaling pathway, as evidenced by both in vivo and in vitro studies [31].
In studies utilizing Zucker diabetic fatty (ZDF) rats and omentin-1 knockout (OMT−/−) mice, along with co-culture systems of HUVECs and mature adipocytes, TSG reduced systolic BP and improved endothelial vasodilation. Omentin-1 downregulation is associated with endothelial dysfunction and hypertension in obese individuals. TSG treatment increased omentin-1 levels by enhancing peroxisome proliferator-activated receptor-γ (PPAR-γ) binding to the Itln-1 promoter in adipose tissue. This mechanism contributed to endothelial protection by activating the Akt/eNOS/NO pathway and alleviating oxidative and nitrative stress [32].
Taken together, TSG exhibits significant potential as an antihypertensive agent by improving endothelial function, reducing oxidative stress, and modulating key signaling pathways involved in vascular regulation. These properties make TSG a promising candidate for addressing hypertension and related cardiovascular diseases, particularly in the context of aging and obesity.

3.4. Reproductive Protective Effects of TSG

TSG exhibits potential in delaying testicular senescence and protecting male gonadal function. In a rat model of testicular Leydig cell aging induced by H2O2 + FeSO4, TSG significantly downregulated the expression of SA-β-gal and insulin-like growth factor binding protein 3 (IGFBP3), while upregulating levels of IGF-1, insulin receptor (INSR), insulin receptor substrate 1 (IRS1), and IRS2 [33]. These findings suggest that TSG delays Leydig cell aging by modulating the insulin/IGF-1 signaling pathway and exerting antioxidant effects.
Additionally, TSG demonstrates protective effects against ovarian aging. In both young and aged mice, TSG treatment distinctly preserved oocyte quantity and quality, attenuated the decline of cytochrome P450 enzymes (CYP11a and CYP19), which are critical for sex hormone synthesis, and maintained high levels of estrogen receptor beta (ER-β), thereby enhancing estrogen sensitivity. TSG also upregulated mitochondrial biogenesis-related genes (pgc1α and atp6) and increased anti-Müllerian hormone (AMH) levels in aged mice, a key biomarker of ovarian function [34]. Furthermore, studies using an E-screen assay revealed that TSG significantly promoted the proliferation of ER (+) human breast cancer MCF-7 cells and upregulated the expression of estrogen-dependent genes, including ERα, ERβ, and pS2, indicating its estrogenic activity [35].
Collectively, these findings suggest that TSG may serve as a potential phytoestrogen for treating conditions such as premature ovarian failure (POF), premature ovarian insufficiency (POI), diminished ovarian reserve (DOR), and estrogen deficiency-related disorders, including menopausal syndrome and postmenopausal osteoporosis (PMOP). However, further research is needed to confirm these therapeutic potentials.

3.5. Bone Protective Effects of TSG

Osteoporosis (OP) is a systemic skeletal disease characterized by reduced bone mineral density (BMD), increased bone fragility, and a heightened risk of fractures [55]. Aging and estrogen deficiency are primary contributors to OP pathogenesis. In a study utilizing ovariectomized (OVX) rats as an OP model and H2O2 to induce oxidative stress and dysfunction in MC3T3-E1 cells, TSG was found to significantly mitigate bone loss. It increased the levels of bone formation markers, including connectivity density (Conn.D), trabecular number (Tb.N), BMD, and glutathione peroxidase (GSH-Px) in bone tissue. Additionally, TSG enhanced the expression of alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OCN), collagen I, and calcium deposition in MC3T3-E1 cells [36]. These effects are potentially mediated through the inhibition of miR-34a and the upregulation of SIRT1.
Moreover, TSG demonstrated beneficial effects on organ weight and bone length in estrogen-deficient conditions. In OVX mice, TSG treatment increased serum bone alkaline phosphatase (BALP) levels and reduced tartrate-resistant acid phosphatase (TRAP) activity, thereby attenuating bone loss and inhibiting bone destruction [56]. In a streptozotocin-induced diabetic OP mouse model, TSG significantly elevated calcium content in both serum and bone, improved trabecular bone microarchitecture, and increased the osteoprotegerin (OPG) to receptor activator of nuclear factor kappa B ligand (RANKL) ratio, indicating its protective role in diabetic OP [37].
In MC3T3-E1 cells, TSG treatment upregulated the expression of OPG, cyanate, runt-related transcription factor 2 (RUNX-2), osterix, and collagen type I α1, while downregulating RANKL and macrophage colony-stimulating factor (M-CSF). This activation of the PI3K/Akt pathway promoted osteoblast proliferation and differentiation [57]. Furthermore, TSG enhanced ALP activity and OCN content in rat mesenchymal stem cells (MSCs) and protected against bone loss in dexamethasone-induced zebrafish [58]. It also obviously promoted the proliferation of bone marrow MSCs and upregulated osteogenic differentiation markers, including ALP, OCN, Col1a1, RUNX-2, and β-catenin [38].
In summary, TSG exhibits potent anti-osteoporotic effects by reducing bone resorption and enhancing bone formation. These mechanisms may be linked to its estrogenic activity, warranting further investigation.

3.6. Other Protective Effects of TSG

TSG has demonstrated potential in improving the physiological functions of aged mice subjected to excessive caloric intake and in delaying the onset of senescence-related symptoms. The anti-aging effects of TSG were mediated, at least partially, through the AMPK/SIRT1/PGC-1α pathway. This mechanism leads to significant improvements in motor function, bone mineral density, and the mitigation of high-calorie-induced organ pathology, such as liver and kidney damage, as well as the enhancement of mitochondrial function [59]. These findings suggest that TSG could serve as a promising therapeutic candidate for addressing aging-related disorders and complications arising from excessive caloric intake.
In a cisplatin-induced myelosuppressive rat model, TSG was found to promote the proliferation of BMSCs and increase peripheral white blood cell counts following chemotherapy. This effect might be attributed to the inhibition of cyclin-dependent kinase inhibitor 1A (CDKN1A) overexpression and the upregulation of cyclinE1 [60]. In vitro study further supported TSG’s protective role against cisplatin-induced injuries, preserving both osteogenic and adipogenic differentiation in BMSCs [60].
Additionally, TSG exhibits significant effects on hair regrowth. Depilated mice treated with TSG demonstrated marked hair regrowth, which was associated with the inhibition of apoptotic factors, including Fas, p53, Bax, active caspase-3, and procaspase-9 activities [61]. Furthermore, a systematic review showed that TSG might act as a key molecular component of P. multiflorum in protecting against age-related hearing loss [62].
Despite the growing body of evidence highlighting TSG’s anti-aging properties and potential therapeutic applications, the intricate pharmacological mechanisms underlying these effects remain incompletely understood. Further research is needed to elucidate these mechanisms and expand the clinical significance of TSG in addressing aging-related conditions.

3.7. Effects of Other P. multiflorum Extracts Against Aging and Age-Related Diseases

3.7.1. Identified Compounds

Emodin, an anthraquinone in P. multiflorum, also demonstrates neuroprotection by modulating apoptosis-related proteins (Bcl-2, Bax, caspase-3) and inhibiting the HDAC4/JNK pathway, thereby alleviating diabetic cognitive impairment [14,63]. It also exhibits anti-atherosclerotic effects via PI3K/AKT/mTOR suppression [64] and promotes hair darkening through MITF-mediated upregulation of tyrosinase [65]. Physcion, another anthraquinone, inhibits 5α-reductase, improving hair follicle regeneration in androgenic alopecia [66]. Mito-TSGs (TSG derivatives) enhance mitochondrial function, showing promise in AD models by reducing oxidative stress [67]. Polydatin attenuates bone loss by suppressing MAPK signaling [68], while polysaccharides extend the lifespan in C. elegans via oxidative stress mitigation [69].

3.7.2. Ethanol Extract

The 75% ethanol extract from P. multiflorum regulates DNA methylation [70] and improves lipid metabolism [71] in D-gal-stimulated aging mice. And it also alleviates glucocorticoid-induced OP by enhancing autophagy in aging mice [72]. A 50% ethanol extract ameliorates vascular dementia by restoring vitamin B6 and taurine metabolic pathways [73], while a 60% fraction extends C. elegans lifespan via DAF-16/SIR-2.1/SKN-1 activation [74]. Additionally, an 80% methanol extract exhibits phytoestrogenic activity, boosting MCF7 proliferation [35].

3.7.3. Aqueous Extract

The aqueous extract from P. multiflorum significantly mitigates diabetic encephalopathy by inhibiting HDAC4/JNK-induced apoptosis [63] and enhances cognition in aging mice via oxidative stress reduction [75]. It also displays estrogen-like effects, promoting uterine growth [76], and improves androgenic alopecia with mechanisms linked to reduced androgen levels and enhanced Wnt/β-catenin signaling [77]. An unidentified P. multiflorum component delays skin aging by enhancing collagen synthesis and mitophagy [78].
Supplementary Table S2 summarizes the recent studies (2020–2024) investigating the effects of other P. multiflorum extracts against aging and age-related diseases. While these P. multiflorum extracts also show broad anti-aging potential, the specific bioactive components warrant further isolation and mechanistic validation.

4. Conclusions and Future Perspectives

The aging population represents a significant global challenge, underscoring the urgent need for the development of anti-aging therapeutics aimed at extending healthy lifespans. This issue is of paramount importance to both the medical community and society at large. TSG, the primary quality marker of P. multiflorum, demonstrates unique potential in preventing and treating aging and age-related diseases. Our findings reveal that TSG exhibits a broad spectrum of anti-aging effects, including lifespan extension, neuroprotection (e.g., ameliorating AD and PD), cardiovascular protection (e.g., alleviating vascular senescence, AS, and hypertension), delay of gonadal aging, reduction in bone loss (e.g., mitigating OP), and promotion of hair regrowth, among others. Mechanistically, TSG exerts its anti-aging effects by mitigating oxidative stress and inflammation, suppressing cellular apoptosis, promoting mitophagy, enhancing mitochondrial function and telomerase activity, and regulating methylation and intestinal flora. This study further demonstrates that TSG therapeutically targets multiple hallmarks of aging, including cellular senescence, chronic inflammation, impaired macroautophagy, mitochondrial dysfunction, telomere attrition, epigenetic alterations, deregulated nutrient sensing, and dysbiosis, thereby slowing, halting, or even reversing senescence. Other P. multiflorum extracts exhibit similar effects and mechanisms. These effects align with the holistic principles of traditional Chinese medicine.
However, several limitations must be addressed to advance this field. (1) Limited clinical evidence: Most current studies are preclinical, relying on animal or cell models. This lack of robust clinical evidence hinders the translation of TSG’s potential into practical applications. Future research should prioritize high-quality, multicenter, large-sample clinical trials to validate the efficacy and safety of TSG, thereby facilitating its clinical adoption and guiding interventions for aging and age-related diseases. (2) Scope of research: While TSG has shown efficacy in improving conditions such as AD, PD, AS, and OP, its protective effects against other age-related diseases, such as DOR and PMOP, remain underexplored and require further investigation. (3) Compositional complexity: Beyond TSG and a few well-identified compounds, the complex composition of P. multiflorum complicates pharmacological studies. Incomplete component analyses obscure active constituents and their mechanisms. Further research should identify key components and their interactions with aging hallmarks to reveal therapeutic targets. (4) Regional bias: Although this review included randomized controlled trials without regional restrictions, the majority of the studies analyzed were conducted in China. This may introduce regional biases, potentially due to the limited global promotion and application of TSG. A critical challenge is how to effectively integrate TSG into the clinical management of aging and age-related diseases on a global scale. Addressing these limitations through the proposed research directions (points 1–3) is expected to establish a quantitative system for evaluating TSG’s efficacy. Such efforts will systematically elucidate the scientific basis of TSG’s anti-aging effects, promote its widespread application, and contribute to the goal of achieving healthy longevity.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/ijms26073381/s1.

Author Contributions

Conceptualization, C.Z.; Supervision, C.Z. and C.Y.; Resources, Y.L., C.L. and D.P.; Methodology, C.Y.; Investigation, J.L. and W.T.; Formal analysis, C.Y.; Writing—original draft, Y.L., C.L. and D.P.; Writing—review and editing, C.Z., J.L., W.T. and C.Y.; Funding acquisition, C.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (grant No. 82360952); and the Guizhou Provincial Health Commission Science and Technology Fund Project (grant No. gzwkj2021-543).

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
β-Amyloid
ADAlzheimer’s disease
AKTProtein kinase B
Ang IIAngiotensin II
APPAmyloid precursor protein
ASAtherosclerosis
BALPBone alkaline phosphatase
Bcl-2B-cell lymphoma-2
BaxBcl-2-associated X protein
BDNFBrain-derived neurotrophic factor
BMDBone mineral density
BMSCsBone mesenchymal stem cells
BPBlood pressure
CDKN1ACyclin-dependent kinase inhibitor 1A
C. elegansCaenorhabditis elegans
cGASCyclic GMP-AMP synthase
CLPsCommon lymphoid progenitors
Conn.DConnectivity density
DADopaminergic
DAF-16Abnormal dauer formation-16
DCsDendritic cells
DEDiabetic encephalopathy
D-galD-galactose
DORDiminished ovarian reserve
ERKExtracellular signal-regulated kinase
ET-1Endothelin-1
FGF2Fibroblast growth factor 2
FOXOForkhead box O
GSH-PxGlutathione peroxidase
GSK-3βGlycogen synthase kinase-3β
HAECsHuman aortic endothelial cells
HDACHistone deacetylase
HHcyHyperhomocysteinemia
HSCsHematopoietic stem cells
HUVECsHuman umbilical vein endothelial cells
IGFInsulin-like growth factor
IRS1Insulin receptor substrate 1
JNKJun N-terminal kinase
LPSLipopolysaccharide
MAPKMitogen-activated protein kinase
MCP-1Monocyte chemotactic protein-1
MMPMitochondrial membrane potential
MPTP1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine
MPP+1-Methyl-4-phenylpyridinium
mTORMechanistic target of rapamycin
NLRP3Nod-like receptor protein 3
Nrf2Nuclear factor erythroid 2-related factor 2
NSCsNeural stem cells
OCNOsteocalcin
OPGOsteoprotegerin
OPNOsteopontin
OVXOvariectomized
PACS-2Phosphofurin acidic cluster sorting protein-2
PAI-1Plasminogen activator inhibitor-1
PDParkinson’s disease
PGC-1αProliferator-activated receptor γ coactivator 1α
PI3KPhosphatidylinositol-3-kinase
PMOPPostmenopausal osteoporosis
POFPremature ovarian failure
POIPremature ovarian insufficiency
P.multiflorumPolygonum multiflorum Thunb.
PPAR-γPeroxisome proliferator-activated receptor-γ
RANKLReceptor activator for nuclear factor kappa B ligand
ROSReactive oxygen species
RUNX-2Runt-related transcription factor 2
SA-β-galSenescence-associated β-galactosidase
SIRT1Silent information regulator 1
SKN-1Skinhead-1
SODSuperoxide dismutase
STINGStimulator of interferon genes
Tb.NTrabecular number
TCTotal cholesterol
TGTriglyceride
TNF-αTumor necrosis factor-α
TRAPTartrate-resistant acid phosphatase
TrkBTropomyosin receptor kinase-B
TSG2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside
VaDVascular dementia
VCAM-1Vascular cell adhesion molecule-1
ZDFZucker diabetic fatty
6-OHDA6-Hydroxydopamine

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Figure 1. Chemical structure of TSG.
Figure 1. Chemical structure of TSG.
Ijms 26 03381 g001
Figure 2. PRISMA 2020 flow diagram for new systematic reviews.
Figure 2. PRISMA 2020 flow diagram for new systematic reviews.
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MDPI and ACS Style

Zhu, C.; Li, J.; Tang, W.; Li, Y.; Lin, C.; Peng, D.; Yang, C. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) from Polygonum multiflorum Thunb.: A Systematic Review on Anti-Aging. Int. J. Mol. Sci. 2025, 26, 3381. https://doi.org/10.3390/ijms26073381

AMA Style

Zhu C, Li J, Tang W, Li Y, Lin C, Peng D, Yang C. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) from Polygonum multiflorum Thunb.: A Systematic Review on Anti-Aging. International Journal of Molecular Sciences. 2025; 26(7):3381. https://doi.org/10.3390/ijms26073381

Chicago/Turabian Style

Zhu, Can, Jinhong Li, Wenchao Tang, Yaofeng Li, Chang Lin, Danhong Peng, and Changfu Yang. 2025. "2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) from Polygonum multiflorum Thunb.: A Systematic Review on Anti-Aging" International Journal of Molecular Sciences 26, no. 7: 3381. https://doi.org/10.3390/ijms26073381

APA Style

Zhu, C., Li, J., Tang, W., Li, Y., Lin, C., Peng, D., & Yang, C. (2025). 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) from Polygonum multiflorum Thunb.: A Systematic Review on Anti-Aging. International Journal of Molecular Sciences, 26(7), 3381. https://doi.org/10.3390/ijms26073381

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