Efficacy and safety of Chinese Medicine compounding for anti-aging: A systematic review and meta-analysis of preclinical and clinical studies

Efficacy and safety of Chinese Medicine compounding for anti-aging: A systematic review and meta-analysis of preclinical and clinical studies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of Chinese Medicine compounding for anti-aging: A systematic review and meta-analysis of preclinical and clinical studies Shyanjer Fong, Yufei Li, Yingying Zhai, Jing Li, Xuegong Xu, Zhenhua Li, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6811274/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background: Traditional Chinese Medicine (TCM) compounds, characterized by multi-component, multi-target, and multi-pathway actions, show potential in delaying aging and promoting health. This study aims to systematically evaluate the efficacy and safety of TCM compounds in anti-aging through animal and clinical studies. Methods: A comprehensive search of databases (PubMed, Web of Science, Embase, CNKI, Wan Fang, VIP) was conducted up to July 2024. Study quality was assessed using Cochrane and SYRCLE’s Risk of Bias tools. Meta-analyses, sensitivity, and subgroup analyses were performed in RevMan 5.3, with publication bias assessed via funnel plots. Results: This meta-analysis included 60 animal studies and 19 clinical trials. In animal studies, TCM compounds increased weight, enhanced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, reduced malondialdehyde (MDA), lipid peroxidation (LPO) and Lipofuscin (LPF) levels, improved high-density lipoprotein (HDL) and low-density lipoprotein (LDL) ratios, and elevated estradiol and testosterone levels (P < 0.05). They also boosted spleen and thymus indices and improved cognitive performance in the Morris water maze test (P < 0.05). In clinical studies, TCM compounds significantly improved efficacy, increased SOD activity, reduced MDA level, and enhanced activities of daily living (ADL) scores (P < 0.05). Conclusion: This first meta-analysis of animal and clinical studies on TCM compounds indicates their potential to delay aging, enhance cognition, and reduce cardiovascular risk by modulating oxidative stress, immunity, endocrine function, and lipid metabolism. This study provides evidence-based support for the clinical application of TCM compounds in anti-aging. Systematic review registration: This study has been registered in PROSPERO (CRD42024580741 and CRD42024580853). Traditional Chinese Medicine compounds Anti-aging Efficacy Safety Meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Background Aging results in diminished physiological functions, sensory abilities, neurocognitive deterioration, and ultimately death [1, 2]. It is linked to various diseases, including cancer, cardiovascular issues, and Alzheimer’s [3]. Delaying aging is fundamental for tackling these problems. Investigating aging mechanisms and potential treatments is essential for understanding life processes, prolonging lifespan, and preventing age-related diseases. Currently, anti-aging treatments encompass chemical drugs and biological therapies [4]. However, these drugs can cause side effects, including liver and kidney damage and gastrointestinal issues[5, 6]. This has prompted a search for gentler treatment options with fewer side effects, which has led to widespread interest in Traditional Chinese Medicine (TCM) compounds therapies. TCM compounds are prescriptions made from two or more Chinese herbal medicines, featuring a complex mix of active ingredients that can target multiple aging-related pathways. Researches indicate their effectiveness in combating oxidative stress, enhancing immune function, and regulating endocrine activity through multi-target interventions, thus delaying aging [7, 8]. In conclusion, TCM compounds provide a holistic treatment approach and an innovative option for anti-aging. Many studies [9, 10] have shown that Chinese Medicine has good efficacy in delaying aging. However, the evaluation of the efficacy and safety of TCM compounds remains incomplete. However, these studies lacked tests related to drug safety. Therefore, they could not verify whether long-term use of the drug might lead to liver or kidney damage. Moreover, the lack of comparative evaluations related to drug safety makes it difficult to fully confirm their efficacy and safety. To comprehensively evaluate the efficacy and safety of TCM compounds formulas in delaying aging, we conducted a meta-analysis. This study aims to integrate existing animal and clinical data to provide more reliable evidence of the anti-aging effects of TCM compounds and assess their safety in practical applications. This research provides stronger evidence-based support for TCM compounds in anti-aging treatments, addressing the lack of systematic evidence in this area. Methods Study registration This study protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42024580741 and CRD42024580853). This study was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [11]. Sources of information and search strategy We searched six databases: PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journal Database (VIP), and Wan Fang database. The search period was restricted from the establishment of each database up to July 31, 2024. We conducted searches using a combination of Medical Subject Headings (MeSH) terms and free-text keywords. Literature search strategies are described in Additional file 2. Inclusion criteria Inclusion criteria for animal experimental literature: (a) Study type: animal experimental studies; (b) Intervention: The experimental group only used the TCM compound; (c) Studies subjects: rats or mice; (d) Outcome measures: superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), lipid peroxidation (LPO), lipofuscin (LPF), adverse event effects, weight, testosterone, estradiol, spleen index, thymus index, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and animal behavioral experiments. Inclusion criteria for clinical trial literature: (a) Study type: randomized clinical trials (RCTs); (b) Intervention: The experimental group only used the TCM compound; (c) Studies subjects; Participants aged ≥ 45 years; (d) Outcome measures: clinical efficacy rate, superoxide dismutase (SOD), malondialdehyde (MDA), lipid peroxidation (LPO), mini-mental state examination (MMSE) scale, activities of daily living (ADL) scale. Exclusion criteria (a) Studies evaluating the combined effects of TCM compounds with other TCM treatments or drugs; (b) Original article not available in full text; (c) Incomplete data; (d) Summary literature such as reviews or clinical experience reports; (e) Literature without clearly defined outcome measures. The specific exclusion criteria for animal experiment and clinical trials are as follows. Exclusion criteria for animal experimental literature: (a) Non-animal experimental studies; (b) Studies not involving rats or mice. Exclusion criteria for clinical trial literature: (a) Non-clinical trial studies; (b) Literature without specified diagnostic criteria; (c) Participants aged ≤ 44 years. Study selection and Data extraction Two researchers (Shyanjer Fong, Yufei Li) independently screened the titles and abstracts to identify potential studies that met the inclusion criteria. The full texts of these studies were then imported into EndNote 20 software. Both researchers independently reviewed the full texts and evaluated them based on the aforementioned criteria to determine eligibility. Two researchers independently extracted data from animal experiments, including: (a) Study information: Author(s), publication year, journal of study. (b) Study design: Type of study, sample size, animal species, and model of aging. (c)Intervention: TCM compound, treatment duration, etc. (d) Outcome measures: Primary outcomes: SOD, MDA, GSH-Px, LPO, LPF, adverse event effects. Secondary outcomes: weight, Testosterone, Estradiol, spleen index, thymus index, HDL, LDL, animal behavioral experiments, etc. In cases of disagreement, a third reviewer (Yifan Xia) made the final decision. In addition, we also extracted data from the clinical trials, including basic study information (author, publication year, country, and sample size), study design, interventions, control measures, study duration, outcome measures (Primary outcomes: clinical efficacy rate and adverse event effects. Secondary outcomes: SOD, LPO, MDA, ADL scale, MMSE scale, etc.) and their results. Study quality assessment SYRCLE’s Risk of Bias assessment tool [12] and Cochrane Risk of Bias 2 (RoB 2) tool [13] were utilized to assess the methodological quality of animal experiments and clinical trials, respectively. Two reviewers independently assessed the quality of the research, and any disagreements were resolved through communication with a third reviewer. According to the criteria, the evaluation results were ranked as low risk, unclear risk or high risk. The Animal Experimental Bias Assessment Tool includes 10 criteria for assessing bias: random sequence generation, baseline characteristics, allocation concealment, random housing, blinding of personnel, random outcome assessment, blinding of outcome assessment, incomplete outcome data, selective reporting, other bias. The Clinical Trials Bias Assessment Tool includes the following seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system [14] will be used to assess the strength of evidence by two independent researchers. The quality of evidence will be classified as “high”, “moderate”, “low” or “very low” based on the risk of bias, inconsistency, indirectness, imprecision, and publication bias. Any discrepancies will be resolved through arbitration by a third reviewer. Data analysis All study data were analyzed using Review Manager software (RevMan 5.3) and corresponding forest plots were generated. For continuous data, the standardized mean difference (SMD) and its 95% confidence interval (95% CI ) were used as effect sizes for statistical analysis. In cases of missing data, estimates were made following the Cochrane Handbook for Systematic Reviews of Interventions. The I² statistic was used to assess the heterogeneity between trials. Two types of analysis models were used: fixed-effect and random-effects models. The fixed-effect model was selected when P > 0.1 and I² < 50%, while the random-effects model was chosen when P ≤ 0.1 and I² ≥ 50%. Forest plots were used to estimate the effect of the intervention, and funnel plots were used to assess potential bias in the meta-analysis. A P -value of < 0.05 was considered statistically significant. Sensitivity analysis For outcome measures with high heterogeneity in the analysis, we performed a sensitivity analysis using Stata 18.0. We re-conducted the meta-analysis after excluding studies with relatively low quality from the included research and compared the merged effect sizes before and after exclusion to assess for any significant differences. Additionally, we analyzed other studies to estimate whether the results might be significantly influenced by a single study [15]. Results Study identification and selection process Figure 1 illustrates the results of literature search, collection, and study screening. Following the search, a comprehensive literature retrieval identified 7,971 articles. After removing duplicates, 7,615 papers remained. Subsequently, 7,238 studies were excluded during title and abstract screening. After full-text review and quality assessment, a total of 60 animal studies and 19 clinical studies were included in the meta-analysis. Also, the PRISMA checklist is provided in the Additional file 1. Characteristics of animal studies This meta-analysis included a total of 60 animal studies [16–77], involving a total of 1,560 animals, with 776 assigned to the experimental groups and 784 to the control groups. Among these studies, 26 used Kunming mice, 16 used Sprague-Dawley rats, 10 used Wistar rats, 6 used ICR mice, 1 used NIH mice, 1 used C57BL/6J mice, 1 used BALB/c inbred mice, 1 used APP/PS1 mice, 1 used 3xTg-AD mice, and 1 study did not specify the mouse strain. Among the 60 studies, 26 induced aging naturally, 27 used D-galactose (D-gal) to establish an aging model, and the remaining 7 used hydrocortisone to create a combined aging and Yang-deficiency model, prednisone to induce a Yang-deficiency model, self-designed simple device to establish a Yang-deficiency model, high-fat diet to induce an aging model with hyperlipidemia, the APP/PS1 model, permanent bilateral common carotid artery occlusion to create a vascular dementia model, and scopolamine-induced aging in mice, respectively. All studies employed TCM compounds as the intervention, while the control groups received normal saline, distilled water, CMC-Na solution, starch solution, or soybean oil. The administration period in these studies ranged from 5 days to 4 months. Additional file 3 provides detailed characteristics of the 60 included studies. Characteristics of clinical studies A total of 19 RCTs were included [30, 56, 78–95], published between 1991 and 2023. The sample sizes of the included studies ranged from 46 to 421, a total of 2,390 participants, with 1,466 assigned to the treatment groups and 924 to the control groups. Among these 19 studies, 4 compared TCM compounds with placebos, 8 compared TCM compounds with positive control Western medications, 6 compared TCM compounds with positive control TCM medications, and 1 compared TCM therapy with dietary therapy. The treatment duration varied from 1 to 24 weeks. Additionally, 11 studies reported adverse event effects. Outcome measures included clinical effective rate, adverse event effects, SOD, LPO, MDA, ADL scale, and MMSE scale. Additional file 4 provides detailed characteristics of the 19 included studies. Study quality assessment Based on the GRADE evaluation of the efficacy and safety of TCM compounds, evidence of varying quality levels was reported. Moderate-quality evidence was found for Clinical Effective Rate, SOD, MDA, and ADL scale. However, the “risk of bias” criterion for all outcome measures was rated as “severe”, which limited the evidence strength to a moderate level. Additionally, imprecision was detected in LPO, MMSE scale, and adverse event effects, further reducing the evidence strength to a low level. Inconsistencies, indirectness, and publication bias were not significant. Overall, the evidence strength was assessed as moderate. Additional file 5 provides detailed GRADE assessment. Risk of bias Among the 60 included animal studies, 11 used random number tables for group allocation. The baseline characteristics were generally consistent across all studies, and the data were complete, indicating low risk of bias. None of the studies clarified whether allocation concealment was adequately implemented. 34 mentioned that the breeding conditions and environments for the experimental and control groups were identical, leading us to conclude that animal placement adhered to the principles of randomization. 4 reported the use of random selection during outcome evaluation. However, none of the studies provided sufficient information to determine whether blinding was used for outcome assessment. All studies reported pre-specified outcome measures, which were assessed as low risk of bias. No other issues were identified that could pose a high risk of bias. A risk-of-bias assessment diagram was generated, as shown in Fig. 2 a. Among the 19 included clinical RCT studies, 3 reported the generation of random sequences. 4 conducted allocation concealment, with 2 using numbering systems and another 2 using envelopes for allocation. The remaining 15 did not provide sufficient information to determine whether allocation concealment was performed. Due to the use of TCM compounds, blinding of participants was not feasible; however, for open-label clinical trials, the outcome measures were not influenced by the lack of blinding. Therefore, the trials involving participants and researchers were assessed as low risk for blinding bias. Most studies had complete data and were categorized as low risk of bias. However, 1 had missing cases, leading to incomplete data and was assessed as high risk of bias. None of the studies provided sufficient information to evaluate the risk of reporting bias or other biases. A risk-of-bias assessment diagram was created using RevMan 5.3 software, as shown in Fig. 2 b. Meta-analysis of animal experiments The results of this section were analyzed in terms of antioxidant function indicators, oxidative damage markers Indicators, physiological phenotype indicators, endocrine function indicators, immune function indicators, lipid metabolism function Indicators, spatial learning and memory behavioral indicators. All these indicators are related to the aging process. Antioxidant function indicators SOD The meta-analysis of all studies on serum ( SMD = 1.82, 95% CI [1.47, 2.17]), liver ( SMD = 1.35, 95% CI [0.91, 1.79]), kidney ( SMD = 1.53, 95% CI [0.68, 2.37]), brain tissue ( SMD = 2.29, 95% CI [1.60, 2.98]) SOD levels showed a significant difference in the effects of TCM compounds compared to the aging model group ( P < 0.05), indicating that TCM compounds can significantly enhance SOD levels, as shown in Fig. 3 . Additionally, we conducted a subgroup analysis based on the size, strain, and modeling methods of the rodents. Figure 4 a showed the serum SOD significant difference between mice and rat ( Chi² = 5.22, df = 1, P = 0.02, I² = 80.8%) and among different strains ( Chi² = 10.28, df = 3, P = 0.02, I² = 70.8%) as shown in Fig. 4 b, these findings suggest that rodent size and strain may contribute to the high heterogeneity observed in the analysis. Figure 4 c showed the liver SOD revealed a significant difference among different rodent strains ( Chi² = 4.71, df = 1, P = 0.03, I² = 78.8%), suggesting that variation in rodent strains is a major contributor to the high heterogeneity observed in the analysis. Subgroup analysis of kidney and brain tissue SOD based on rodent size, strain, and modeling methods revealed no significant differences among the subgroups, suggesting that these factors are not major contributors to the high heterogeneity observed in the analysis. GSH-Px The meta-analysis results showed a significant difference in the effects of TCM compounds on GSH-Px compared to the aging model group ( SMD = 1.99, 95% CI [1.37, 2.61], P < 0.05), indicating that TCM compounds can significantly increase GSH-Px levels, as shown in Fig. 5 . Oxidative damage markers indicators MDA The meta-analysis of all studies on serum ( SMD = -1.31, 95% CI [-1.51, -1.11]), liver ( SMD = -1.37, 95% CI [-2.20, -0.54]), kidney ( SMD = -0.94, 95% CI [-1.46, -0.41]), brain tissue ( SMD = -1.39, 95% CI [-1.85, -0.93]) MDA levels showed a significant difference in the effects of TCM compounds compared to the aging model group ( P < 0.05), indicating that TCM compounds can significantly reduce MDA levels. As shown in Fig. 6 . LPO The meta-analysis results showed a significant difference in the effects of TCM compounds on LPO levels compared to the aging model group ( SMD = -1.98, 95% CI [-3.29, -0.67], P < 0.05), indicating that TCM compounds can significantly reduce LPO levels, as shown in Fig. 7 a. LPF The meta-analysis results showed a significant difference in the effects of TCM compounds on LPF levels compared to the aging model group ( SMD = -2.74, 95% CI [-3.76, -1.72], P < 0.05), indicating that TCM compounds can reduce lipofuscin levels, as shown in Fig. 7 b. Physiological phenotype indicators Weight The meta-analysis results indicated a significant difference in the impact of TCM formulas on weight compared to the aging model group (S MD = 0.75, 95% CI [0.27, 1.23], P < 0.05), suggesting that the use of TCM formulas may increase animal weight, as shown in Fig. 8 . Endocrine function indicators Testosterone and Estradiol The meta-analysis results showed a significant difference in the effects of TCM compounds on testosterone levels ( SMD = 2.93, 95% CI [1.69, 4.17]) and estradiol levels ( SMD = 3.22, 95% CI [1.96, 4.49]) compared to the aging model group ( P < 0.05), indicating that TCM compounds can significantly increase testosterone levels and estradiol levels, as shown in Fig. 9 . Immune function indicators Spleen index and Thymus index The meta-analysis results showed a significant difference in the effects of TCM compounds on spleen index ( SMD = 0.93, 95% CI [0.39, 1.47]) and thymus index ( SMD = 0.80, 95% CI [0.40, 1.20]) compared to the aging model group ( P < 0.05), indicating that TCM compounds can significantly improve immune function and increase spleen and thymus index, as shown in Fig. 10 . Lipid metabolism function indicators HDL and LDL The meta-analysis results showed a significant difference in the effects of TCM compounds on HDL levels ( SMD = 1.05, 95% CI [0.65, 1.46]) and LDL levels ( SMD = -0.62, 95% CI [-0.97, -0.27]) compared to the aging model group ( P < 0.05), indicating that TCM compounds can significantly improves lipid metabolism function, as shown in Fig. 11 . Spatial learning and memory behavioral indicators The meta-analysis of all studies on the number of platform crossings ( SMD = 1.39, 95% CI [0.81, 1.97]), time spent in the target quadrant ( SMD = 1.39, 95% CI [0.81, 1.97]) and latency to locate the platform ( SMD = 1.39, 95% CI [0.81, 1.97]) showed a significant difference in the effects of TCM compounds compared to the aging model group ( P < 0.05). This indicates that TCM compounds can increased spatial learning and memory in animals, as shown in Fig. 12 . Additionally, we conducted a subgroup analysis of GSH-Px, MDA, LPO, LPF, weight, testosterone, estradiol, spleen index, thymus index, HDL, LDL, the number of platform crossings, time spent in the target quadrant and latency to locate the platform based on rodent size, strain, and modeling methods revealed no significant differences among the subgroups. Conclusion for animal studies: TCM compounds effectively enhance the body’s antioxidant defense ability by significantly improving antioxidant functional indicators and reducing oxidative stress damage markers. Secondary indicators further confirm its multi-dimensional anti-aging mechanisms: weight improvement suggests metabolic balance regulation, regulation of testosterone and estradiol levels reflect optimized endocrine function, increased spleen and thymus index indicate enhanced immune function, and increased HDL and decreased LDL show improved lipid metabolism. Additionally, the Morris water maze test verifies its protective effects on cognitive function. These findings collectively illustrate that TCM compounds exert comprehensive anti-aging effects through multiple. Meta-analysis of clinical trials The results of this section were analyzed in terms of Clinical Effective Rate, SOD, LPO, MDA, ADL scale, MMSE scale and Adverse Event Effects. All these indicators are related to the aging process. Clinical effective rate The data from the included studies were binary, the Risk Ratio (RR) was used for analysis. The heterogeneity test results showed P < 0.0001, I 2 = 78%, indicating significant heterogeneity among the studies. Therefore, a Random Effects Model (REM) was used to combine and summarize the effect size. The meta-analysis results showed that the Clinical Effective Rate of using TCM compounds to delay aging was higher than that of the control group, with a significant difference between the two groups ( RR = 1.51, 95% CI [1.21, 1.89], P < 0.05), as shown in Fig. 13 a. The 19 studies were subjected to subgroup analysis based on differences in control groups. 4 used a Western medicine control group, and the meta-analysis results showed that the RR value of the TCM compound group compared to the Western medicine control group was 1.28, with a 95% CI [1.12, 1.45] and P < 0.05. 2 used a Placebo control group. The meta-analysis results showed that the RR value of the TCM compound group compared to the blank control group was 3.03, with a 95% CI [1.73, 5.31] and P < 0.05. 3 used other TCM compounds as the control group. The meta-analysis results showed that the RR value was 1.31, with a 95% CI [1.10, 1.55] and P < 0.05. The subgroup analysis results suggest that TCM compounds have anti-aging effects, with the overall clinical effectiveness rate of TCM compounds for delaying aging being higher than that of Western medicine treatments. Additionally, the differences between subgroups were statistically significant ( P = 0.01, I² = 78%), indicating that this subgroup factor may be a major source of heterogeneity among the included studies, as shown in as shown in Fig. 13 b. Antioxidant function indicators SOD The heterogeneity test results were P < 0.00001 and I² = 84%, indicating significant heterogeneity among the studies. Therefore, a REM was selected to aggregate the effect size. The meta-analysis results showed a significant difference in the effect of TCM compounds on SOD levels compared to the control group ( SMD = 0.64, 95% CI [0.32, 0.97], P < 0.05), as shown in Fig. 14 a. Oxidative damage markers indicators LPO The heterogeneity test results were P < 0.0001 and I² = 88%, indicating significant heterogeneity among the studies. Therefore, REM was selected to aggregate the effect size. The meta-analysis results showed no significant difference in the effect of TCM compounds on LPO levels compared to the control group ( SMD = -0.77, 95% CI [-1.55, 0.01], P = 0.05), as shown in Fig. 14 b. MDA The heterogeneity test results were P = 0.03 and I² = 71%, indicating significant heterogeneity among the studies. Therefore, REM was selected to aggregate the effect size. The meta-analysis results showed a significant difference in the effect of TCM compounds on MDA levels compared to the control group ( SMD = -0.61, 95% CI [-1.19, -0.03], P < 0.05), as shown in Fig. 14 c. Cognitive and physical function ADL scale The heterogeneity test results showed P = 0.59, I 2 = 0%, indicating no heterogeneity among the studies, a fixed-effects model (FEM) was used to pool the effect estimates. The meta-analysis results showed a significant difference in ADL scores between the TCM compounds group and the control group ( MD = -1.97, 95% CI [-3.20, -0.74], P < 0.05), as shown in Fig. 14 d. MMSE scale The heterogeneity test results showed P = 0.01, I 2 = 72%, indicating significant heterogeneity among the studies, REM was used to pool the effect estimates. The meta-analysis results showed no significant difference in MMSE scores between the TCM compounds group and the control group ( MD = 0.71, 95% CI [-0.59, -2.02], P > 0.05), as shown in Fig. 14 e. Adverse event effects Among the 19 included studies, 11 reported adverse events during the trials, involving a total of 1,201 participants, including 713 in the treatment group and 488 in the control group. 8 reported no adverse events in either the treatment or control groups. In Cui Jing’s study, two participants in the treatment group experienced subjective dry mouth, and one experienced dry eye, in the control group, one reported dry mouth, one reported dry eye, and one experienced mild constipation, with all symptoms resolving after continued medication. In Gao Ping’s study, no significant adverse events occurred in the treatment group, while in the control group, one participant experienced dizziness, and two experienced mild-to-moderate nausea and reduced appetite. In Sun Yixuan’s study, two participants in the treatment group reported mild loose stools, while one in the control group treated with donepezil hydrochloride experienced nausea. No study reported any participant dropout due to adverse events. Since the data on adverse events were binary, RR was used as the measure. The heterogeneity test results were P = 0.36 and I² = 3%, indicating no heterogeneity among the studies. Therefore, FEM was selected to aggregate the effect size. Meta-analysis results indicated that compared to the control group, the use of TCM compounds to delay aging did not significantly reduce the incidence of adverse events, with no statistically significant difference ( RR = 0.6959, 95% CI [0.2396, 2.0215], P > 0.05), as shown in Fig. 15 . Conclusion for clinical studies: These studies indicate that TCM compounds have effective anti-aging properties and exhibit good safety profiles. Meta-analysis shows that TCM compounds significantly enhance SOD activity and reduce MDA, demonstrating notable antioxidant effects. These improvements in antioxidant markers help reduce oxidative stress, protect cells from damage, and thus delay aging. Furthermore, the ADL scale assessment reveals that TCM compounds significantly improve the quality of life and cognitive function in the elderly. Publication bias of animal experimentation and clinical trials The funnel plot was generated for the included studies to assess publication bias, Fig. 16 and Fig. 17 represent the publication bias of indicators related to animal experimentation and clinical trials, respectively. Asymmetry in the funnel plot suggests mild publication bias. Sensitivity analysis of animal experimentation and clinical trials Figure 18 and Fig. 19 show the sensitivity analysis of indicators related to animal experimentation and clinical trials. The results indicate that removing any single study did not significantly affect the pooled results compared to the original forest plot. This suggests that the study results are stable and reliable, reinforcing the consistency and robustness of the conclusions drawn from the analysis. Discussion This study presents the first meta-analysis combining both clinical and animal experimental data on the anti-aging effects of TCM compounds. Beyond qualitative assessment, it quantitatively evaluates their efficacy in delaying aging. A total of 66 TCM compounds and 122 herbs were analyzed, with the most frequently used being Lycium barbarum (22.1%), Panax ginseng (16.4%), Cuscuta chinensis (13.1%), Poria cocos (13.1%), Astragalus membranaceus (11.5%), Polygonum multiflorum (11.5%), and Epimedium spp. (11.5%). Rich in polyphenols, flavonoids, and saponins, these herbs combat oxidative stress, enhance immunity, regulate endocrine and metabolic functions, and protect tissues—jointly contributing to their anti-aging properties. Regarding the efficacy of TCM compounds, this study demonstrates that TCM compounds exert anti-aging effects through a multi-target, multi-pathway regulatory mechanism. Meta-analysis reveals that these compounds significantly enhance antioxidant enzymes SOD and GSH-Px, while reducing oxidative stress markers MDA and LPO—highlighting their role in mitigating oxidative damage, a key factor in aging. Additionally, TCM compounds modulate the endocrine and immune systems, as well as lipid metabolism, aligning with the TCM principle of holistic regulation. Clinical data further support their efficacy, showing that TCM compounds effectively alleviate aging-related symptoms, with the event incidence rate in the experimental group being 1.51 times higher than in the control group. Regarding the adverse event effects of TCM compounds, there was no significant difference in incidence between the TCM compound and control groups. Reported side effects were generally mild and transient, such as dry mouth and mild gastrointestinal discomfort, which typically resolved with continued use—suggesting a possible adaptive regulatory response by the body. While no harmful effects were identified in the included studies, long-term safety data remain limited, highlighting the need for large-scale, long-term follow-up studies to further evaluate the safety and tolerability of TCM compounds. While the studies generally support the anti-aging effects of TCM compounds, heterogeneity exists—likely due to variations in formulations, treatment durations, study populations, and methodologies. Some studies also had limitations in randomization and blinding, introducing potential bias. Unlike animal models, such as D-galactose-induced aging, which offer controlled conditions for mechanistic research, clinical studies involve elderly individuals or patients with multiple chronic conditions, adding complexity. Therefore, high-quality, large-scale clinical trials are essential to further confirm efficacy, refine formulations, and establish robust long-term safety assessments. Conclusion In this study, we integrated data from 60 animal experiments and 19 clinical trials, using meta-analysis to quantify the effects of TCM compounds on key outcomes. We found that these TCM compounds significantly enhance antioxidant capacity, improve cognitive function, regulate endocrine activity, boost immunity, and optimize lipid profiles, which are with a favorable safety profile. Therefore, TCM compounds are efficacy and safety, hold potential for delaying aging. Our findings provide evidence-based support for the clinical application of TCM compounds in the field of anti-aging, and may offer more comprehensive strategies for the prevention and treatment of age-related conditions and for promoting healthy aging. Abbreviations ADL Activities of daily living CNKI China National Knowledge Infrastructure database FEM Fixed-effects model GSH-Px Glutathione peroxidase HDL High-density lipoprotein LDL Low-density lipoprotein LPF Lipofuscin LPO Lipid peroxidation MD Mean difference MDA Malondialdehyde MMSE Mini-mental state examination RCTs Randomized controlled trials REM Random effects model RoB Risk of bias RR Relative risk SMD Standardized mean difference SOD Superoxide dismutase TCM Traditional Chinese Medicine VIP Chinese Science and Technology Journal Database Declarations Acknowledgments The authors would like to acknowledge the assistance of all the participants. Authors’ contributions YX and RY contributed to the conceptualization and study design. SF and YL conducted the search. XX, ZL, and LY completed screening. SF, YL, YZ, and JL collected and extracted the data. SF, YL, YX, and RY performed data analysis and interpretation. All authors were involved in the writing or revision of the manuscript and approved the final version. Funding This study was supported by the Technology Project of Beijing University of Chinese Medicine (BUCM-2022-JS-FW-061), the Technology Project of Beijing University of Chinese Medicine (BUCM-2023-JS- FW-064), the Fundamental Research Funds for the Central Universities (2024-JYB-XJSJJ-013), the National Natural Science Foundation of China (81603507), and the project supported by National Administration of Traditional Chinese Medicine (zyyzdxk-2023251). Availability of data and materials The original contributions presented in the study are included in the article/ Supplementary material, further inquiries can be directed to the corresponding author. Declarations Ethics approval and consent to participate This research did not involve any human or animal experiment. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author details 1 National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 10029, China 2 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 10029, China 3 Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, 450007, China References Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019;571(7764):183 − 92. https://doi.org/10.1038/s41586-019-1365-2. Lautrup S, Sinclair DA, Mattson MP, Fang EF. NAD + in brain aging and neurodegenerative disorders. Cell Metab. 2019;30(4):630 − 55. https://doi.org/10.1016/j.cmet.2019.09.001. Li Z, Zhang Z, Ren Y, Wang Y, Fang J, Yue H, et al. Aging and age-related diseases: from mechanisms to therapeutic strategies. 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Supplementary Files highlights.docx Additionalfile1PRISMAchecklist.docx Additional file 1: PRISMA checklist Additionalfile2Searchstrategies.docx Additional file 2: Search strategies Additionalfile3CharacteristicsofAnimalStudies.docx Additional file 3: Characteristics of Animal Studies Additionalfile4CharacteristicsofClinicalStudies.docx Additional file 4: Characteristics of Clinical Studies Additionalfile5GRADEassessment.docx Additional file 5: GRADE assessment Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 11 Aug, 2025 Reviewers agreed at journal 13 Jul, 2025 Reviewers invited by journal 17 Jun, 2025 Editor assigned by journal 11 Jun, 2025 First submitted to journal 03 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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11:06:57","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":275668,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 1: PRISMA checklist\u003c/p\u003e","description":"","filename":"Additionalfile1PRISMAchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-6811274/v1/18fa60da379e0b6744d61513.docx"},{"id":84971170,"identity":"512d2b92-d0fd-4bb4-b55e-919e064f1fe5","added_by":"auto","created_at":"2025-06-19 11:06:57","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":94099,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 2: Search strategies\u003c/p\u003e","description":"","filename":"Additionalfile2Searchstrategies.docx","url":"https://assets-eu.researchsquare.com/files/rs-6811274/v1/dfc632c57fff4e32a0bbd8c7.docx"},{"id":84971947,"identity":"58f16b39-8b7e-4050-81cb-d29172df33c4","added_by":"auto","created_at":"2025-06-19 11:14:56","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":36043,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 3: Characteristics of Animal Studies\u003c/p\u003e","description":"","filename":"Additionalfile3CharacteristicsofAnimalStudies.docx","url":"https://assets-eu.researchsquare.com/files/rs-6811274/v1/3b2bad0edbd4246f31411cff.docx"},{"id":84971164,"identity":"767bb236-32e1-41df-bfa1-895a5c4bdf0c","added_by":"auto","created_at":"2025-06-19 11:06:56","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":21447,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 4: Characteristics of Clinical Studies\u003c/p\u003e","description":"","filename":"Additionalfile4CharacteristicsofClinicalStudies.docx","url":"https://assets-eu.researchsquare.com/files/rs-6811274/v1/c8fdab88766372d1f63547b7.docx"},{"id":84971953,"identity":"cebe0542-0b29-4f8a-ada8-b8819b48730b","added_by":"auto","created_at":"2025-06-19 11:14:57","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":18676,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 5: GRADE assessment\u003c/p\u003e","description":"","filename":"Additionalfile5GRADEassessment.docx","url":"https://assets-eu.researchsquare.com/files/rs-6811274/v1/bb225e5152bd6aab1870e780.docx"}],"financialInterests":"","formattedTitle":"Efficacy and safety of Chinese Medicine compounding for anti-aging: A systematic review and meta-analysis of preclinical and clinical studies","fulltext":[{"header":"Background","content":"\u003cp\u003eAging results in diminished physiological functions, sensory abilities, neurocognitive deterioration, and ultimately death [1, 2]. It is linked to various diseases, including cancer, cardiovascular issues, and Alzheimer\u0026rsquo;s [3]. Delaying aging is fundamental for tackling these problems. Investigating aging mechanisms and potential treatments is essential for understanding life processes, prolonging lifespan, and preventing age-related diseases.\u003c/p\u003e \u003cp\u003eCurrently, anti-aging treatments encompass chemical drugs and biological therapies [4]. However, these drugs can cause side effects, including liver and kidney damage and gastrointestinal issues[5, 6]. This has prompted a search for gentler treatment options with fewer side effects, which has led to widespread interest in Traditional Chinese Medicine (TCM) compounds therapies.\u003c/p\u003e \u003cp\u003eTCM compounds are prescriptions made from two or more Chinese herbal medicines, featuring a complex mix of active ingredients that can target multiple aging-related pathways. Researches indicate their effectiveness in combating oxidative stress, enhancing immune function, and regulating endocrine activity through multi-target interventions, thus delaying aging [7, 8]. In conclusion, TCM compounds provide a holistic treatment approach and an innovative option for anti-aging.\u003c/p\u003e \u003cp\u003eMany studies [9, 10] have shown that Chinese Medicine has good efficacy in delaying aging. However, the evaluation of the efficacy and safety of TCM compounds remains incomplete. However, these studies lacked tests related to drug safety. Therefore, they could not verify whether long-term use of the drug might lead to liver or kidney damage. Moreover, the lack of comparative evaluations related to drug safety makes it difficult to fully confirm their efficacy and safety.\u003c/p\u003e \u003cp\u003eTo comprehensively evaluate the efficacy and safety of TCM compounds formulas in delaying aging, we conducted a meta-analysis. This study aims to integrate existing animal and clinical data to provide more reliable evidence of the anti-aging effects of TCM compounds and assess their safety in practical applications. This research provides stronger evidence-based support for TCM compounds in anti-aging treatments, addressing the lack of systematic evidence in this area.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy registration\u003c/h2\u003e \u003cp\u003e This study protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42024580741 and CRD42024580853). This study was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [11].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSources of information and search strategy\u003c/h3\u003e\n\u003cp\u003eWe searched six databases: PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journal Database (VIP), and Wan Fang database. The search period was restricted from the establishment of each database up to July 31, 2024. We conducted searches using a combination of Medical Subject Headings (MeSH) terms and free-text keywords. Literature search strategies are described in Additional file 2.\u003c/p\u003e\n\u003ch3\u003eInclusion criteria\u003c/h3\u003e\n\u003cp\u003eInclusion criteria for animal experimental literature: (a) Study type: animal experimental studies; (b) Intervention: The experimental group only used the TCM compound; (c) Studies subjects: rats or mice; (d) Outcome measures: superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), lipid peroxidation (LPO), lipofuscin (LPF), adverse event effects, weight, testosterone, estradiol, spleen index, thymus index, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and animal behavioral experiments.\u003c/p\u003e \u003cp\u003eInclusion criteria for clinical trial literature: (a) Study type: randomized clinical trials (RCTs); (b) Intervention: The experimental group only used the TCM compound; (c) Studies subjects; Participants aged\u0026thinsp;\u0026ge;\u0026thinsp;45 years; (d) Outcome measures: clinical efficacy rate, superoxide dismutase (SOD), malondialdehyde (MDA), lipid peroxidation (LPO), mini-mental state examination (MMSE) scale, activities of daily living (ADL) scale.\u003c/p\u003e\n\u003ch3\u003eExclusion criteria\u003c/h3\u003e\n\u003cp\u003e(a) Studies evaluating the combined effects of TCM compounds with other TCM treatments or drugs; (b) Original article not available in full text; (c) Incomplete data; (d) Summary literature such as reviews or clinical experience reports; (e) Literature without clearly defined outcome measures. The specific exclusion criteria for animal experiment and clinical trials are as follows.\u003c/p\u003e \u003cp\u003eExclusion criteria for animal experimental literature: (a) Non-animal experimental studies; (b) Studies not involving rats or mice.\u003c/p\u003e \u003cp\u003eExclusion criteria for clinical trial literature: (a) Non-clinical trial studies; (b) Literature without specified diagnostic criteria; (c) Participants aged\u0026thinsp;\u0026le;\u0026thinsp;44 years.\u003c/p\u003e\n\u003ch3\u003eStudy selection and Data extraction\u003c/h3\u003e\n\u003cp\u003eTwo researchers (Shyanjer Fong, Yufei Li) independently screened the titles and abstracts to identify potential studies that met the inclusion criteria. The full texts of these studies were then imported into EndNote 20 software. Both researchers independently reviewed the full texts and evaluated them based on the aforementioned criteria to determine eligibility. Two researchers independently extracted data from animal experiments, including: (a) Study information: Author(s), publication year, journal of study. (b) Study design: Type of study, sample size, animal species, and model of aging. (c)Intervention: TCM compound, treatment duration, etc. (d) Outcome measures: Primary outcomes: SOD, MDA, GSH-Px, LPO, LPF, adverse event effects. Secondary outcomes: weight, Testosterone, Estradiol, spleen index, thymus index, HDL, LDL, animal behavioral experiments, etc. In cases of disagreement, a third reviewer (Yifan Xia) made the final decision.\u003c/p\u003e \u003cp\u003eIn addition, we also extracted data from the clinical trials, including basic study information (author, publication year, country, and sample size), study design, interventions, control measures, study duration, outcome measures (Primary outcomes: clinical efficacy rate and adverse event effects. Secondary outcomes: SOD, LPO, MDA, ADL scale, MMSE scale, etc.) and their results.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy quality assessment\u003c/h2\u003e \u003cp\u003eSYRCLE\u0026rsquo;s Risk of Bias assessment tool [12] and Cochrane Risk of Bias 2 (RoB 2) tool [13] were utilized to assess the methodological quality of animal experiments and clinical trials, respectively. Two reviewers independently assessed the quality of the research, and any disagreements were resolved through communication with a third reviewer. According to the criteria, the evaluation results were ranked as low risk, unclear risk or high risk.\u003c/p\u003e \u003cp\u003eThe Animal Experimental Bias Assessment Tool includes 10 criteria for assessing bias: random sequence generation, baseline characteristics, allocation concealment, random housing, blinding of personnel, random outcome assessment, blinding of outcome assessment, incomplete outcome data, selective reporting, other bias.\u003c/p\u003e \u003cp\u003e The Clinical Trials Bias Assessment Tool includes the following seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system [14] will be used to assess the strength of evidence by two independent researchers. The quality of evidence will be classified as \u0026ldquo;high\u0026rdquo;, \u0026ldquo;moderate\u0026rdquo;, \u0026ldquo;low\u0026rdquo; or \u0026ldquo;very low\u0026rdquo; based on the risk of bias, inconsistency, indirectness, imprecision, and publication bias. Any discrepancies will be resolved through arbitration by a third reviewer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eAll study data were analyzed using Review Manager software (RevMan 5.3) and corresponding forest plots were generated. For continuous data, the standardized mean difference (SMD) and its 95% confidence interval (95% \u003cem\u003eCI\u003c/em\u003e) were used as effect sizes for statistical analysis. In cases of missing data, estimates were made following the Cochrane Handbook for Systematic Reviews of Interventions. The \u003cem\u003eI\u0026sup2;\u003c/em\u003e statistic was used to assess the heterogeneity between trials. Two types of analysis models were used: fixed-effect and random-effects models. The fixed-effect model was selected when \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.1 and \u003cem\u003eI\u0026sup2;\u003c/em\u003e \u0026lt; 50%, while the random-effects model was chosen when \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.1 and \u003cem\u003eI\u0026sup2;\u003c/em\u003e \u0026ge; 50%. Forest plots were used to estimate the effect of the intervention, and funnel plots were used to assess potential bias in the meta-analysis. A \u003cem\u003eP\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSensitivity analysis\u003c/h3\u003e\n\u003cp\u003eFor outcome measures with high heterogeneity in the analysis, we performed a sensitivity analysis using Stata 18.0. We re-conducted the meta-analysis after excluding studies with relatively low quality from the included research and compared the merged effect sizes before and after exclusion to assess for any significant differences. Additionally, we analyzed other studies to estimate whether the results might be significantly influenced by a single study [15].\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStudy identification and selection process\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the results of literature search, collection, and study screening. Following the search, a comprehensive literature retrieval identified 7,971 articles. After removing duplicates, 7,615 papers remained. Subsequently, 7,238 studies were excluded during title and abstract screening. After full-text review and quality assessment, a total of 60 animal studies and 19 clinical studies were included in the meta-analysis. Also, the PRISMA checklist is provided in the Additional file 1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of animal studies\u003c/h2\u003e \u003cp\u003eThis meta-analysis included a total of 60 animal studies [16\u0026ndash;77], involving a total of 1,560 animals, with 776 assigned to the experimental groups and 784 to the control groups. Among these studies, 26 used Kunming mice, 16 used Sprague-Dawley rats, 10 used Wistar rats, 6 used ICR mice, 1 used NIH mice, 1 used C57BL/6J mice, 1 used BALB/c inbred mice, 1 used APP/PS1 mice, 1 used 3xTg-AD mice, and 1 study did not specify the mouse strain.\u003c/p\u003e \u003cp\u003eAmong the 60 studies, 26 induced aging naturally, 27 used D-galactose (D-gal) to establish an aging model, and the remaining 7 used hydrocortisone to create a combined aging and Yang-deficiency model, prednisone to induce a Yang-deficiency model, self-designed simple device to establish a Yang-deficiency model, high-fat diet to induce an aging model with hyperlipidemia, the APP/PS1 model, permanent bilateral common carotid artery occlusion to create a vascular dementia model, and scopolamine-induced aging in mice, respectively.\u003c/p\u003e \u003cp\u003eAll studies employed TCM compounds as the intervention, while the control groups received normal saline, distilled water, CMC-Na solution, starch solution, or soybean oil. The administration period in these studies ranged from 5 days to 4 months. Additional file 3 provides detailed characteristics of the 60 included studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of clinical studies\u003c/h2\u003e \u003cp\u003eA total of 19 RCTs were included [30, 56, 78\u0026ndash;95], published between 1991 and 2023. The sample sizes of the included studies ranged from 46 to 421, a total of 2,390 participants, with 1,466 assigned to the treatment groups and 924 to the control groups. Among these 19 studies, 4 compared TCM compounds with placebos, 8 compared TCM compounds with positive control Western medications, 6 compared TCM compounds with positive control TCM medications, and 1 compared TCM therapy with dietary therapy. The treatment duration varied from 1 to 24 weeks. Additionally, 11 studies reported adverse event effects. Outcome measures included clinical effective rate, adverse event effects, SOD, LPO, MDA, ADL scale, and MMSE scale. Additional file 4 provides detailed characteristics of the 19 included studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStudy quality assessment\u003c/h2\u003e \u003cp\u003eBased on the GRADE evaluation of the efficacy and safety of TCM compounds, evidence of varying quality levels was reported. Moderate-quality evidence was found for Clinical Effective Rate, SOD, MDA, and ADL scale. However, the \u0026ldquo;risk of bias\u0026rdquo; criterion for all outcome measures was rated as \u0026ldquo;severe\u0026rdquo;, which limited the evidence strength to a moderate level. Additionally, imprecision was detected in LPO, MMSE scale, and adverse event effects, further reducing the evidence strength to a low level. Inconsistencies, indirectness, and publication bias were not significant. Overall, the evidence strength was assessed as moderate. Additional file 5 provides detailed GRADE assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias\u003c/h2\u003e \u003cp\u003eAmong the 60 included animal studies, 11 used random number tables for group allocation. The baseline characteristics were generally consistent across all studies, and the data were complete, indicating low risk of bias. None of the studies clarified whether allocation concealment was adequately implemented. 34 mentioned that the breeding conditions and environments for the experimental and control groups were identical, leading us to conclude that animal placement adhered to the principles of randomization. 4 reported the use of random selection during outcome evaluation. However, none of the studies provided sufficient information to determine whether blinding was used for outcome assessment. All studies reported pre-specified outcome measures, which were assessed as low risk of bias. No other issues were identified that could pose a high risk of bias. A risk-of-bias assessment diagram was generated, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea.\u003c/p\u003e \u003cp\u003eAmong the 19 included clinical RCT studies, 3 reported the generation of random sequences. 4 conducted allocation concealment, with 2 using numbering systems and another 2 using envelopes for allocation. The remaining 15 did not provide sufficient information to determine whether allocation concealment was performed. Due to the use of TCM compounds, blinding of participants was not feasible; however, for open-label clinical trials, the outcome measures were not influenced by the lack of blinding. Therefore, the trials involving participants and researchers were assessed as low risk for blinding bias. Most studies had complete data and were categorized as low risk of bias. However, 1 had missing cases, leading to incomplete data and was assessed as high risk of bias. None of the studies provided sufficient information to evaluate the risk of reporting bias or other biases. A risk-of-bias assessment diagram was created using RevMan 5.3 software, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eMeta-analysis of animal experiments\u003c/h2\u003e \u003cp\u003eThe results of this section were analyzed in terms of antioxidant function indicators, oxidative damage markers Indicators, physiological phenotype indicators, endocrine function indicators, immune function indicators, lipid metabolism function Indicators, spatial learning and memory behavioral indicators. All these indicators are related to the aging process.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eAntioxidant function indicators\u003c/h2\u003e \u003cp\u003e \u003cem\u003eSOD\u003c/em\u003e The meta-analysis of all studies on serum (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.82, 95% \u003cem\u003eCI\u003c/em\u003e [1.47, 2.17]), liver (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.35, 95% \u003cem\u003eCI\u003c/em\u003e [0.91, 1.79]), kidney (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.53, 95% \u003cem\u003eCI\u003c/em\u003e [0.68, 2.37]), brain tissue (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.29, 95% \u003cem\u003eCI\u003c/em\u003e [1.60, 2.98]) SOD levels showed a significant difference in the effects of TCM compounds compared to the aging model group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that TCM compounds can significantly enhance SOD levels, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eAdditionally, we conducted a subgroup analysis based on the size, strain, and modeling methods of the rodents. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea showed the serum SOD significant difference between mice and rat (\u003cem\u003eChi\u0026sup2;\u003c/em\u003e = 5.22, \u003cem\u003edf\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 80.8%) and among different strains (\u003cem\u003eChi\u0026sup2;\u003c/em\u003e = 10.28, \u003cem\u003edf\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 70.8%) as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb, these findings suggest that rodent size and strain may contribute to the high heterogeneity observed in the analysis. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec showed the liver SOD revealed a significant difference among different rodent strains (\u003cem\u003eChi\u0026sup2;\u003c/em\u003e = 4.71, \u003cem\u003edf\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 78.8%), suggesting that variation in rodent strains is a major contributor to the high heterogeneity observed in the analysis. Subgroup analysis of kidney and brain tissue SOD based on rodent size, strain, and modeling methods revealed no significant differences among the subgroups, suggesting that these factors are not major contributors to the high heterogeneity observed in the analysis.\u003c/p\u003e \u003cp\u003e \u003cem\u003eGSH-Px\u003c/em\u003e The meta-analysis results showed a significant difference in the effects of TCM compounds on GSH-Px compared to the aging model group (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.99, 95% \u003cem\u003eCI\u003c/em\u003e [1.37, 2.61], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that TCM compounds can significantly increase GSH-Px levels, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eOxidative damage markers indicators\u003c/h2\u003e \u003cp\u003e \u003cem\u003eMDA\u003c/em\u003e The meta-analysis of all studies on serum (\u003cem\u003eSMD\u003c/em\u003e = -1.31, 95% \u003cem\u003eCI\u003c/em\u003e [-1.51, -1.11]), liver (\u003cem\u003eSMD\u003c/em\u003e = -1.37, 95% \u003cem\u003eCI\u003c/em\u003e [-2.20, -0.54]), kidney (\u003cem\u003eSMD\u003c/em\u003e = -0.94, 95% \u003cem\u003eCI\u003c/em\u003e [-1.46, -0.41]), brain tissue (\u003cem\u003eSMD\u003c/em\u003e = -1.39, 95% \u003cem\u003eCI\u003c/em\u003e [-1.85, -0.93]) MDA levels showed a significant difference in the effects of TCM compounds compared to the aging model group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that TCM compounds can significantly reduce MDA levels. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eLPO\u003c/em\u003e The meta-analysis results showed a significant difference in the effects of TCM compounds on LPO levels compared to the aging model group (\u003cem\u003eSMD\u003c/em\u003e = -1.98, 95% \u003cem\u003eCI\u003c/em\u003e [-3.29, -0.67], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that TCM compounds can significantly reduce LPO levels, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ea.\u003c/p\u003e \u003cp\u003e \u003cem\u003eLPF\u003c/em\u003e The meta-analysis results showed a significant difference in the effects of TCM compounds on LPF levels compared to the aging model group (\u003cem\u003eSMD\u003c/em\u003e = -2.74, 95% \u003cem\u003eCI\u003c/em\u003e [-3.76, -1.72], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that TCM compounds can reduce lipofuscin levels, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eb.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003ePhysiological phenotype indicators\u003c/h2\u003e \u003cp\u003e \u003cem\u003eWeight\u003c/em\u003e The meta-analysis results indicated a significant difference in the impact of TCM formulas on weight compared to the aging model group (S\u003cem\u003eMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.75, 95% \u003cem\u003eCI\u003c/em\u003e [0.27, 1.23], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), suggesting that the use of TCM formulas may increase animal weight, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eEndocrine function indicators\u003c/h2\u003e \u003cp\u003e \u003cem\u003eTestosterone and Estradiol\u003c/em\u003e The meta-analysis results showed a significant difference in the effects of TCM compounds on testosterone levels (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.93, 95% \u003cem\u003eCI\u003c/em\u003e [1.69, 4.17]) and estradiol levels (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.22, 95% \u003cem\u003eCI\u003c/em\u003e [1.96, 4.49]) compared to the aging model group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that TCM compounds can significantly increase testosterone levels and estradiol levels, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eImmune function indicators\u003c/h2\u003e \u003cp\u003e \u003cem\u003eSpleen index and Thymus index\u003c/em\u003e The meta-analysis results showed a significant difference in the effects of TCM compounds on spleen index (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.93, 95% \u003cem\u003eCI\u003c/em\u003e [0.39, 1.47]) and thymus index (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.80, 95% \u003cem\u003eCI\u003c/em\u003e [0.40, 1.20]) compared to the aging model group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that TCM compounds can significantly improve immune function and increase spleen and thymus index, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e10\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eLipid metabolism function indicators\u003c/h2\u003e \u003cp\u003e \u003cem\u003eHDL and LDL\u003c/em\u003e The meta-analysis results showed a significant difference in the effects of TCM compounds on HDL levels (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.05, 95% \u003cem\u003eCI\u003c/em\u003e [0.65, 1.46]) and LDL levels (\u003cem\u003eSMD\u003c/em\u003e = -0.62, 95% \u003cem\u003eCI\u003c/em\u003e [-0.97, -0.27]) compared to the aging model group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that TCM compounds can significantly improves lipid metabolism function, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e11\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eSpatial learning and memory behavioral indicators\u003c/h2\u003e \u003cp\u003eThe meta-analysis of all studies on the number of platform crossings (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.39, 95% \u003cem\u003eCI\u003c/em\u003e [0.81, 1.97]), time spent in the target quadrant (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.39, 95% \u003cem\u003eCI\u003c/em\u003e [0.81, 1.97]) and latency to locate the platform (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.39, 95% \u003cem\u003eCI\u003c/em\u003e [0.81, 1.97]) showed a significant difference in the effects of TCM compounds compared to the aging model group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). This indicates that TCM compounds can increased spatial learning and memory in animals, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e12\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAdditionally, we conducted a subgroup analysis of GSH-Px, MDA, LPO, LPF, weight, testosterone, estradiol, spleen index, thymus index, HDL, LDL, the number of platform crossings, time spent in the target quadrant and latency to locate the platform based on rodent size, strain, and modeling methods revealed no significant differences among the subgroups.\u003c/p\u003e \u003cp\u003eConclusion for animal studies: TCM compounds effectively enhance the body\u0026rsquo;s antioxidant defense ability by significantly improving antioxidant functional indicators and reducing oxidative stress damage markers. Secondary indicators further confirm its multi-dimensional anti-aging mechanisms: weight improvement suggests metabolic balance regulation, regulation of testosterone and estradiol levels reflect optimized endocrine function, increased spleen and thymus index indicate enhanced immune function, and increased HDL and decreased LDL show improved lipid metabolism. Additionally, the Morris water maze test verifies its protective effects on cognitive function. These findings collectively illustrate that TCM compounds exert comprehensive anti-aging effects through multiple.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eMeta-analysis of clinical trials\u003c/h2\u003e \u003cp\u003eThe results of this section were analyzed in terms of Clinical Effective Rate, SOD, LPO, MDA, ADL scale, MMSE scale and Adverse Event Effects. All these indicators are related to the aging process.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eClinical effective rate\u003c/h2\u003e \u003cp\u003eThe data from the included studies were binary, the Risk Ratio (RR) was used for analysis. The heterogeneity test results showed \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, I\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;78%, indicating significant heterogeneity among the studies. Therefore, a Random Effects Model (REM) was used to combine and summarize the effect size. The meta-analysis results showed that the Clinical Effective Rate of using TCM compounds to delay aging was higher than that of the control group, with a significant difference between the two groups (\u003cem\u003eRR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.51, 95% \u003cem\u003eCI\u003c/em\u003e [1.21, 1.89], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e13\u003c/span\u003ea.\u003c/p\u003e \u003cp\u003eThe 19 studies were subjected to subgroup analysis based on differences in control groups. 4 used a Western medicine control group, and the meta-analysis results showed that the \u003cem\u003eRR\u003c/em\u003e value of the TCM compound group compared to the Western medicine control group was 1.28, with a 95% \u003cem\u003eCI\u003c/em\u003e [1.12, 1.45] and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. 2 used a Placebo control group. The meta-analysis results showed that the \u003cem\u003eRR\u003c/em\u003e value of the TCM compound group compared to the blank control group was 3.03, with a 95% \u003cem\u003eCI\u003c/em\u003e [1.73, 5.31] and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. 3 used other TCM compounds as the control group. The meta-analysis results showed that the RR value was 1.31, with a 95% \u003cem\u003eCI\u003c/em\u003e [1.10, 1.55] and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The subgroup analysis results suggest that TCM compounds have anti-aging effects, with the overall clinical effectiveness rate of TCM compounds for delaying aging being higher than that of Western medicine treatments. Additionally, the differences between subgroups were statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 78%), indicating that this subgroup factor may be a major source of heterogeneity among the included studies, as shown in as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e13\u003c/span\u003eb.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eAntioxidant function indicators\u003c/h2\u003e \u003cp\u003e \u003cem\u003eSOD\u003c/em\u003e The heterogeneity test results were \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 and \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 84%, indicating significant heterogeneity among the studies. Therefore, a REM was selected to aggregate the effect size. The meta-analysis results showed a significant difference in the effect of TCM compounds on SOD levels compared to the control group (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.64, 95% \u003cem\u003eCI\u003c/em\u003e [0.32, 0.97], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e14\u003c/span\u003ea.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eOxidative damage markers indicators\u003c/h2\u003e \u003cp\u003e \u003cem\u003eLPO\u003c/em\u003e The heterogeneity test results were \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 and \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 88%, indicating significant heterogeneity among the studies. Therefore, REM was selected to aggregate the effect size. The meta-analysis results showed no significant difference in the effect of TCM compounds on LPO levels compared to the control group (\u003cem\u003eSMD\u003c/em\u003e = -0.77, 95% \u003cem\u003eCI\u003c/em\u003e [-1.55, 0.01], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e14\u003c/span\u003eb.\u003c/p\u003e \u003cp\u003e \u003cem\u003eMDA\u003c/em\u003e The heterogeneity test results were \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03 and \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 71%, indicating significant heterogeneity among the studies. Therefore, REM was selected to aggregate the effect size. The meta-analysis results showed a significant difference in the effect of TCM compounds on MDA levels compared to the control group (\u003cem\u003eSMD\u003c/em\u003e = -0.61, 95% \u003cem\u003eCI\u003c/em\u003e [-1.19, -0.03], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e14\u003c/span\u003ec.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eCognitive and physical function\u003c/h2\u003e \u003cp\u003e \u003cem\u003eADL scale\u003c/em\u003e The heterogeneity test results showed \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.59, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, indicating no heterogeneity among the studies, a fixed-effects model (FEM) was used to pool the effect estimates. The meta-analysis results showed a significant difference in ADL scores between the TCM compounds group and the control group (\u003cem\u003eMD\u003c/em\u003e = -1.97, 95% \u003cem\u003eCI\u003c/em\u003e [-3.20, -0.74], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e14\u003c/span\u003ed.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eMMSE scale\u003c/em\u003e The heterogeneity test results showed \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;72%, indicating significant heterogeneity among the studies, REM was used to pool the effect estimates. The meta-analysis results showed no significant difference in MMSE scores between the TCM compounds group and the control group (\u003cem\u003eMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.71, 95% \u003cem\u003eCI\u003c/em\u003e [-0.59, -2.02], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e14\u003c/span\u003ee.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAdverse event effects\u003c/h3\u003e\n\u003cp\u003eAmong the 19 included studies, 11 reported adverse events during the trials, involving a total of 1,201 participants, including 713 in the treatment group and 488 in the control group. 8 reported no adverse events in either the treatment or control groups.\u003c/p\u003e \u003cp\u003e In Cui Jing\u0026rsquo;s study, two participants in the treatment group experienced subjective dry mouth, and one experienced dry eye, in the control group, one reported dry mouth, one reported dry eye, and one experienced mild constipation, with all symptoms resolving after continued medication. In Gao Ping\u0026rsquo;s study, no significant adverse events occurred in the treatment group, while in the control group, one participant experienced dizziness, and two experienced mild-to-moderate nausea and reduced appetite. In Sun Yixuan\u0026rsquo;s study, two participants in the treatment group reported mild loose stools, while one in the control group treated with donepezil hydrochloride experienced nausea.\u003c/p\u003e \u003cp\u003eNo study reported any participant dropout due to adverse events. Since the data on adverse events were binary, RR was used as the measure. The heterogeneity test results were \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.36 and \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 3%, indicating no heterogeneity among the studies. Therefore, FEM was selected to aggregate the effect size. Meta-analysis results indicated that compared to the control group, the use of TCM compounds to delay aging did not significantly reduce the incidence of adverse events, with no statistically significant difference (\u003cem\u003eRR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6959, 95% \u003cem\u003eCI\u003c/em\u003e [0.2396, 2.0215], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig15\" class=\"InternalRef\"\u003e15\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eConclusion for clinical studies: These studies indicate that TCM compounds have effective anti-aging properties and exhibit good safety profiles. Meta-analysis shows that TCM compounds significantly enhance SOD activity and reduce MDA, demonstrating notable antioxidant effects. These improvements in antioxidant markers help reduce oxidative stress, protect cells from damage, and thus delay aging. Furthermore, the ADL scale assessment reveals that TCM compounds significantly improve the quality of life and cognitive function in the elderly.\u003c/p\u003e \u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003ePublication bias of animal experimentation and clinical trials\u003c/h2\u003e \u003cp\u003eThe funnel plot was generated for the included studies to assess publication bias, Fig.\u0026nbsp;\u003cspan refid=\"Fig16\" class=\"InternalRef\"\u003e16\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig17\" class=\"InternalRef\"\u003e17\u003c/span\u003e represent the publication bias of indicators related to animal experimentation and clinical trials, respectively. Asymmetry in the funnel plot suggests mild publication bias.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis of animal experimentation and clinical trials\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig18\" class=\"InternalRef\"\u003e18\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig19\" class=\"InternalRef\"\u003e19\u003c/span\u003e show the sensitivity analysis of indicators related to animal experimentation and clinical trials. The results indicate that removing any single study did not significantly affect the pooled results compared to the original forest plot. This suggests that the study results are stable and reliable, reinforcing the consistency and robustness of the conclusions drawn from the analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study presents the first meta-analysis combining both clinical and animal experimental data on the anti-aging effects of TCM compounds. Beyond qualitative assessment, it quantitatively evaluates their efficacy in delaying aging. A total of 66 TCM compounds and 122 herbs were analyzed, with the most frequently used being Lycium barbarum (22.1%), Panax ginseng (16.4%), Cuscuta chinensis (13.1%), Poria cocos (13.1%), Astragalus membranaceus (11.5%), Polygonum multiflorum (11.5%), and Epimedium spp. (11.5%). Rich in polyphenols, flavonoids, and saponins, these herbs combat oxidative stress, enhance immunity, regulate endocrine and metabolic functions, and protect tissues\u0026mdash;jointly contributing to their anti-aging properties.\u003c/p\u003e \u003cp\u003eRegarding the efficacy of TCM compounds, this study demonstrates that TCM compounds exert anti-aging effects through a multi-target, multi-pathway regulatory mechanism. Meta-analysis reveals that these compounds significantly enhance antioxidant enzymes SOD and GSH-Px, while reducing oxidative stress markers MDA and LPO\u0026mdash;highlighting their role in mitigating oxidative damage, a key factor in aging. Additionally, TCM compounds modulate the endocrine and immune systems, as well as lipid metabolism, aligning with the TCM principle of holistic regulation. Clinical data further support their efficacy, showing that TCM compounds effectively alleviate aging-related symptoms, with the event incidence rate in the experimental group being 1.51 times higher than in the control group.\u003c/p\u003e \u003cp\u003eRegarding the adverse event effects of TCM compounds, there was no significant difference in incidence between the TCM compound and control groups. Reported side effects were generally mild and transient, such as dry mouth and mild gastrointestinal discomfort, which typically resolved with continued use\u0026mdash;suggesting a possible adaptive regulatory response by the body. While no harmful effects were identified in the included studies, long-term safety data remain limited, highlighting the need for large-scale, long-term follow-up studies to further evaluate the safety and tolerability of TCM compounds.\u003c/p\u003e \u003cp\u003eWhile the studies generally support the anti-aging effects of TCM compounds, heterogeneity exists\u0026mdash;likely due to variations in formulations, treatment durations, study populations, and methodologies. Some studies also had limitations in randomization and blinding, introducing potential bias. Unlike animal models, such as D-galactose-induced aging, which offer controlled conditions for mechanistic research, clinical studies involve elderly individuals or patients with multiple chronic conditions, adding complexity. Therefore, high-quality, large-scale clinical trials are essential to further confirm efficacy, refine formulations, and establish robust long-term safety assessments.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this study, we integrated data from 60 animal experiments and 19 clinical trials, using meta-analysis to quantify the effects of TCM compounds on key outcomes. We found that these TCM compounds significantly enhance antioxidant capacity, improve cognitive function, regulate endocrine activity, boost immunity, and optimize lipid profiles, which are with a favorable safety profile. Therefore, TCM compounds are efficacy and safety, hold potential for delaying aging. Our findings provide evidence-based support for the clinical application of TCM compounds in the field of anti-aging, and may offer more comprehensive strategies for the prevention and treatment of age-related conditions and for promoting healthy aging.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eADL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eActivities of daily living\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCNKI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChina National Knowledge Infrastructure database\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFEM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFixed-effects model\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGSH-Px\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGlutathione peroxidase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHigh-density lipoprotein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLow-density lipoprotein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLPF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLipofuscin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLPO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLipid peroxidation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMean difference\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMDA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMalondialdehyde\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMMSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMini-mental state examination\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRCTs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRandomized controlled trials\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eREM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRandom effects model\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRoB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRisk of bias\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRelative risk\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eStandardized mean difference\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSuperoxide dismutase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTCM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTraditional Chinese Medicine\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVIP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChinese Science and Technology Journal Database\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to acknowledge the assistance of all the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYX and RY contributed to the conceptualization and study design. SF and YL conducted the search. XX, ZL, and LY completed screening. SF, YL, YZ, and JL collected and extracted the data. SF, YL, YX, and RY performed data analysis and interpretation. All authors were involved in the writing or revision of the manuscript and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Technology Project of Beijing University of Chinese Medicine (BUCM-2022-JS-FW-061), the Technology Project of Beijing University of Chinese Medicine (BUCM-2023-JS- FW-064), the Fundamental Research Funds for the Central Universities (2024-JYB-XJSJJ-013), the National Natural Science Foundation of China (81603507), and the project supported by National Administration of Traditional Chinese Medicine (zyyzdxk-2023251).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/ Supplementary material, further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not involve any human or animal experiment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eNational Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 10029, China\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eSchool of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 10029, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eZhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, 450007, China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. 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CLINICAL RESEACH ON WENSHEN ANTI-LAW SHOULD INTERFERE WITH A WEAK MIDDLE-AGED DEFICIENCY [Masters]: Nanjing University of Chinese Medicine; 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Ming Z, Yimiao L, Huichan W, Yu C, Lina M, Hui P, et al. Guilingji capsule for Alzheimer's disease: secondary analysis of a randomized non-inferiority-controlled trial. Journal of Traditional Chinese Medicine. 2023;43(05):1019-25. https://doi.org/10.19852/j.cnki.jtcm.20230404.006.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Zhong Y, Zhu B, Zheng S. Clinical Research of Yishou Tiaozhi Tablet in Anti-Senility. Chinese Journal of Integrative Medicine on Cardio-Cerebrovascular Disease. 2001(05):14\u0026thinsp;\u0026minus;\u0026thinsp;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Traditional Chinese Medicine compounds, Anti-aging, Efficacy, Safety, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-6811274/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6811274/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eTraditional Chinese Medicine (TCM) compounds, characterized by multi-component, multi-target, and multi-pathway actions, show potential in delaying aging and promoting health. This study aims to systematically evaluate the efficacy and safety of TCM compounds in anti-aging through animal and clinical studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA comprehensive search of databases (PubMed, Web of Science, Embase, CNKI, Wan Fang, VIP) was conducted up to July 2024. Study quality was assessed using Cochrane and SYRCLE’s Risk of Bias tools. Meta-analyses, sensitivity, and subgroup analyses were performed in RevMan 5.3, with publication bias assessed via funnel plots.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThis meta-analysis included 60 animal studies and 19 clinical trials. In animal studies, TCM compounds increased weight, enhanced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, reduced malondialdehyde (MDA), lipid peroxidation (LPO) and Lipofuscin (LPF) levels, improved high-density lipoprotein (HDL) and low-density lipoprotein (LDL) ratios, and elevated estradiol and testosterone levels (P \u0026lt; 0.05). They also boosted spleen and thymus indices and improved cognitive performance in the Morris water maze test (P \u0026lt; 0.05). In clinical studies, TCM compounds significantly improved efficacy, increased SOD activity, reduced MDA level, and enhanced activities of daily living (ADL) scores (P \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e This first meta-analysis of animal and clinical studies on TCM compounds indicates their potential to delay aging, enhance cognition, and reduce cardiovascular risk by modulating oxidative stress, immunity, endocrine function, and lipid metabolism. This study provides evidence-based support for the clinical application of TCM compounds in anti-aging.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystematic review registration:\u003c/strong\u003e This study has been registered in PROSPERO (CRD42024580741 and CRD42024580853).\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of Chinese Medicine compounding for anti-aging: A systematic review and meta-analysis of preclinical and clinical studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-19 11:06:51","doi":"10.21203/rs.3.rs-6811274/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-08-11T13:15:33+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-07-13T19:45:03+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-17T10:16:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-12T03:59:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"Systematic Reviews","date":"2025-06-03T08:27:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ffef77bf-ccec-47c0-b0fe-ea316a5080cd","owner":[],"postedDate":"June 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-20T12:03:36+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-19 11:06:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6811274","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6811274","identity":"rs-6811274","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}