Abstract
Objective
Isoflavones, a group of soybean nutrients, have been found to provide a wide range of benefits to the human body. The prospective cohort study aims to examine the association of dietary intake of isoflavones with all-cause mortality and heart disease mortality in the US.
Materials and methods
In this study, We conducted to explore the potential correlation of isoflavones (total isoflavones, genistein, and daidzein) intake with the risk of all-cause mortality and heart disease mortality. The mortality status and the heart disease cause of death were determined by NHANES-linked National Death Index public access files through December 31, 2019. The association of dietary isoflavones intake with all-cause mortality and heart disease mortality was analyzed by multivariate Cox regression model to compute hazard ratio (HR) and 95% confidence interval (CI), with adjustment for some demographic characteristics, lifestyle factors, and comorbidities. In addition, we employed Kaplan-Meier curves, subgroups and restricted cubic spline models to assess the effect of dietary isoflavones in different circumstances.
Result
The final study population was 11,979 participants, with 1423 participants determined as deceased (7.95%). After adjusting for multiple variables, the study identified an inverse relationship between total isoflavones [Hazard Ratio (HR) 0.85, 95% CI: 0.74–0.99], genistein [HR 0.82, 95% CI: 0.69–0.98], daidzein [HR 0.81, 95% CI: 0.70–0.94] and the incidence of all-cause mortality. Similarly, only high levels of intake daidzein [HR 0.73, 95% CI: 0.53–0.99] were no significantly associated with heart disease mortality. Additionally, a non-linear relationship was observed between dietary isoflavones and all-cause mortality in female participants (p-value for nonlinear < 0.05 and p-value for overall < 0.05).
Conclusion
Our findings suggest dietary intake of total isoflavones, genistein, and daidzein in the right amounts was associated with lower all-cause mortality and exhibited an association of results for mortality from heart disease with daidzein to diminish the chances of heart disease mortality. The present study reveals a U-shaped association between dietary isoflavones and all-cause mortality in female participants.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12889-025-21349-8.
Keywords: Isoflavones, Genistein, Daidzein, Mortality, NHANES, Prospective cohort studies
Introduction
Isoflavones are estrogenic activity non-steroid analogs found in plants [1] (Especially soybeans and other members of the legume) and have been hypothesized to be effective in preventing malignancy [2–5], osteoporosis [6–8], cardiovascular disease [9, 10], and other killer diseases. As a phytoestrogen whose proportion of nutrients in the diet is gradually increasing, isoflavones have been observed to exert its effects through three main subtypes (The proportion of total soy isoflavones accounted for by legume-based foods: genistein [40–60%], daidzein [30–50%] and glycitein [12–13%]) [11] as active forms, while they may also exhibit potential synergistic interactions. In Asian countries [12, 13], the consumption of dietary soy isoflavones is more popular than in European countries and the United States [14, 15]. This disparity may stem from different lifestyles or cooking ways, which exhibit the subtle differences between the consumption of non-fermented soyfoods(tofu and bean sprouts) and fermented soy foods (miso, tempeh, or natto) to affect the absorption of soy isoflavones [16–18].
Dietary isoflavones, as a vital component of diet balance, have shown benefits in the prevention and management of premature death and chronic illnesses. Isoflavones exert their biological effects by binding to estrogen receptors beta (ERβ) and up-regulate ERβ expression at the genetic level [19]. Soy isoflavones have the potential to reduce the risk of coronary heart disease by mitigating inflammation [20] and oxidative stress [21]. These compounds can help prevent the oxidative damage to low-density lipoprotein, which is a key factor in the development of atherosclerosis [22]. By minimizing these processes, soy isoflavones could significantly lower the mortality risk in patients with coronary heart disease. Although several prospective studies have assessed the association between some phytoestrogens intake and the risk of cardiovascular disease [23–27], no prospective study has addressed the association of dietary isoflavone and its subtypes intake with heart disease mortality and all causes of mortality. To tackle population aging, the systematic assessment of the dietary intake of isoflavones is an essential component in dietary adjustment systems and is a primary reference for disease prevention. We utilized the National Health and Nutrition Examination Survey data that was collected from 2007 to 2010 and from 2017 to 2018 to analyze the association between isoflavone intake and heart mortality and all-cause mortality to fill the gap. In addition, some studies consider that isoflavones may be the endocrine disruptor with potential negative influences [28, 29] on the healthy state of a specific demographic. Therefore, we investigated the recommended daily reference intake of soy isoflavones to identify the optimal intake level associated with decreased mortality risk.
Method
Study design and participants
NHANES is a multicenter program implemented nationwide by the National Center for Health Statistics (NCHS). The program was specifically designed to systematically assess the health and nutritional status of the U.S. population using a complex, stratified and cluster multistage, probability sampling method and has been roundly used as a large prospective cohort with a sample that represents the demographic composition of the nation through linkages to a follow-up survey of mortality data [30]. The data acquisition methodology at NHANES encompasses initial in-home interviews, health screenings at mobile screening centers (MEC) [31], and follow-up telephone interviews. The research ethics were ratified by the NHANES review board of the Centers for Disease Control and Prevention, and all participants affirmed their consent in written form. The intake values of isoflavones, assessed to represent the dietary patterns of the United States population, were calculated using the USDA Food and Nutrient Database for Dietary Studies (FNDDS), which is a derived database from the National Health and Nutrition Examination Survey.
A total of 29,940 participants were enrolled in the study during the 2007–2010 and 2017– 2018 NHANES cycles. In the present analysis, we restricted our study sample to individuals who were 20 years of age or older at the baseline assessment. Of these, we eliminated 71 participants without mortality data, 3822 participants who lacked complete information on dietary isoflavones intake data, and 1850 participants without relational covariates (including education, hypertension, body mass index (BMI), smoking, hyperlipidemia, alcohol consumption, eating healthy index, diabetes mellitus (DM), etc.). Finally, 11,979 participants with complete covariates were selected for inclusion.(Fig. 1).
Fig. 1.
Flowchart of the participants included in the final analysis
Isoflavones intake
Isoflavone intake in this study was formulated on the consumption of beverages and food and did not take into account the intake of isoflavone medications or supplements. The collected foods were coded using the U.S. Department of Agriculture FNDDS database to calculate six dietary types of primary flavonoid intake for each participant on the initial and subsequent recording date, and take a deep dive into the relationship between isoflavone intake and human health. In this study, we used the average intake of the isoflavones and their subtypes, including genistein and daidzein, through two 24-hour dietary recalls. The first recording of dietary information was captured by skilled interviewers, while the next was collected by telephone 3 to 10 days later.
Total isoflavone intake was defined as the cumulative sum of three subclasses [32] (genistein, daidzein, and glycitein). We collected the results of the dietary frequency questionnaires completed by each participant, and subsequently converted these into estimates of daily isoflavone intake, including its subcategories, using the USDA Database on the Isoflavone Content of Selected Foods [33]. Respondents were categorized into three groups (Low, Medium, High) based on each type of isoflavone intake tertile, including total isoflavones, genistein, and daidzein.
Ascertainment of mortality
With the intention of ascertaining the survival status of the follow-up population. We used a unique study identifier to define all-cause and heart disease mortality, and a match was established with the National Death Index by the National Center for Health Statistics utilizing a probability matching algorithm. If no match was found, it was assumed that the individual was still alive on that date. The follow-up period and person-years were collected from baseline until death or the end of follow-up (December 31, 2019) [34].
In alignment with the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) [35], all-cause and heart deaths were determined. All-cause mortality was characterized as death from heart diseases (codes I00-I09, I11, I13, and I20-I51), malignant neoplasms (codes C00-C97), pneumonia and influenza (J09-J18), and all other causes. Only participants who died from heart-related causes were included in a separate subgroup analysis to determine whether the independent variable had a distinct effect on the cause of heart-related deaths. For comprehensive elucidation of death outcome, the data-supported website for an extensive repository regarding mortality variables is available at the hyperlink: (https://www.cdc.gov/nchs/data-linkage/mortality.htm).
Covariate assessment
Our covariates included age, sex, healthy eating index (HEI) [36–38], ethnicity (Mexican American, other Hispanic, non-Hispanic white, non-Hispanic black, non-Hispanic, other race), body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Education level was classified as Less Than 9th Grade, 9th-11th grade, High school graduate/General equivalency diploma(GED), College Graduate or above, Some college or AA degree. Smoking status was recorded as never smoke, smoke former, or smoke now. Smoking status was classified into three categories: now (smoked over 100 cigarettes in their lifetime and continues to smoke at present), former (smoked over 100 cigarettes in their lifetime but has quit smoking now), and never (smoked below 100 cigarettes in their lifetime). Alcohol consumption status was classified as never; former; mild; moderate; and heavy [39, 40]. Hyperlipidemia was identified as one of three conditions: (1) triglycerides (TG) ≥ 150 mg/dL; (2) total cholesterol (TC) ≥ 200 mg/dL[5.18mmol/L] or low-density lipoprotein (LDL) ≥ 130 mg/dL[3.37mmol/L] or high-density lipoprotein (HDL) ≤ 40 mg/dL[1.04mmol/L] in males, ≤ 50 mg/dL[1.30mmol/L] in females; (3) use of lipid-lowering agents [41]. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg [42] and self-reported diagnosis or use of antihypertensive drugs. Diabetes Mellitus(DM) [43] and related abnormalities [44] are classified as: (1) DM: diabetes mellitus; (2) IFG: impaired fasting glycemia; (3) IGT: impaired glucose tolerance; 4): no. The detailed definitions of general population characteristics, lifestyle habits, and disease conditions will be supplemented in Supplementary Methods.
Statistical analysis
Baseline characteristics were presented as means (SD) for continuous variables or numbers (percentages) for categorical variables, respectively, for three types of isoflavones (total isoflavones, genistein, and daidzein). Tertiles of reliability-adjusted isoflavone compound intake were recorded and calculated into three contiguous groups, respectively (Low, Medium, High). The follow-up person-years were computed from the baseline date to the occurrence of death, loss to follow-up, or the endpoint of date (December 31, 2019), whichever came first. All analyses used the NHANES sampling weights, and the complex multistage cluster survey design of NHANES was taken into reckoning to ensure nationally representative estimates. A value of p < 0.05 was established as a cutoff to demonstrate statistical significance.
We plotted the mean isoflavones intake by age groups (with 12 groups, 20–25 years, 25–30 years, 30–35 years, 35–40 years, 40–45 years, 45–50 years, 50–55 years, 55–60 years, 60–65 years, 65–70 years, 70–75 years, 75–80 years), Education, Body mass index group (with 4 groups, Underweight: <18.5 kg/m2; Normal weight: 18.5–24.9 kg/m2; Overweight: 25–29.9 kg/m2; Obese: ≥30 kg/m2 ), Smoke, Alcohol use status, healthy eating index to examine the trend of isoflavones intake with the age and other different covariate. Differences in characteristics, disease status, and other parameters between tertiles of total isoflavones, genistein and daidzein were respectively tested using the weighted Wilcoxon rank sum test for continuous variables or the weighted Pearson’s Chi-squared test for categorical variables where appropriate.
The associations between isoflavones intake (total isoflavones, genistein and daidzein) and the risk of all-cause mortality or heart disease mortality were investigated utilizing a multivariate Cox regression model. This approach was employed to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). Then, multiple adjusted models were implemented: model 1 (without any adjustments for covariates except baseline age [years, continuous]), model 2 (adjusted for age, sex, ethnicity, smoke, BMI [kg/m2, continuous], alcohol consumption status), and model 3 (adjusted for all variables in Model 2 as well as other mortality risk factors including Diabetes Mellitus(DM), Hypertension, Smoking status, Hyperlipidemia.). We employed a fundamental age adjustment in Model 1 to account for its effects. Subsequently, in Models 2 and 3, we configured covariates based on the significance level of prognostic risk factors. In addition, the multivariate Cox regression stratified by sex, education, BMI group [45, 46], smoking status, Hyperlipidemia, Diabetes Mellitus, and ethnicity was also conducted. The survey-weighted Likelihood Ratio test was used to examine the significance of interaction effects.
Weighted Kaplan-Meier survival curves were constructed for mortality status with follow-up, stratified by intake levels of total isoflavones, genistein, and daidzein separately to visualize the relationships between isoflavones and risk of mortality. We employed Restricted Cubic Spline RCS regression to examine the dose-response relationship between isoflavone intake and mortality among different genders. Age-standardized death rates were computed referencing the population distribution delineated for the 2000 census. All analyses were performed using the “nhanesR” package(including ‘survey’ package for Cox regression and Kaplan-Meier survival curves) in R version 4.3.2 with a P-value less than 0.05 indicating statistical significance.
Results
Table 1 presents the sample number and weighted percentages with significance levels for differences within variable categories. By the established exclusion criteria, a total of 11,979 participants were covered with a mean age of 47.6 years, which were predominantly Non-Hispanic White, with approximately 10.89% Non-Hispanic Black, 7.86% Mexican American, 5.29% Other Hispanic, and 6.47% Other Race. It represented 163,079,000 non-hospitalized inhabitants of the United States. Notably, significant differences were observed in demographic character and baseline clinical features between participants with lower isoflavones intake and those with higher isoflavones intake. Participants with higher total isoflavones, genistein or daidzein tended to have lower body mass index (P < 0.001) and higher eating healthy index (P < 0.0001). In addition, a total of 1,423 participants (7.95%) were documented as deceased during the follow-up. The participants were recorded as death exhibited significantly higher proportions among lower levels of total isoflavones, genistein, and Daidzein intake. Additionally, we used survival status as a baseline characteristic table for stratification (Supplementary Table 1).
Table 1.
Characteristics of study participants according to tertiles of isoflavones intake
| Characteristica | Total | Total Isoflavones | P | Genistein | P | Daidzein | P | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Low | Medium | High | Low | Medium | High | Low | Medium | High | |||||
| Median (Range) (mg/day) | 0.00 (0.00–0.00) | 0.015 (0,0.035] | 0.31 (0.035,380.83] | 0.00 (0.00–0.00) | 0.01 (0,0.025] | 0.175 (0.025,199.21] | 0.00 (0.00–0.00) | 0.005 (0,0.005] | 0.165 (0.005,147.22] | ||||
| BMI, kg/m2 | 29.1 ± 0.1 | 29.5 ± 0.1 | 29.1 ± 0.1 | 28.7 ± 0.2 | < 0.001 | 29.4 ± 0.1 | 29.2 ± 0.2 | 28.5 ± 0.2 | < 0.001 | 29.4 ± 0.1 | 28.8 ± 0.3 | 28.6 ± 0.2 | < 0.001 |
| Healthy eating index score | 50.6 ± 0.3 | 47.2 ± 0.3 | 51.6 ± 0.4 | 53.8 ± 0.3 | < 0.0001 | 47.8 ± 0.3 | 51.8 ± 0.4 | 53.0 ± 0.3 | < 0.0001 | 48.2 ± 0.3 | 53.2 ± 0.5 | 53.5 ± 0.4 | < 0.0001 |
| Age, years | 47.6 ± 0.3 | 47.8 ± 0.4 | 49.5 ± 0.4 | 45.7 ± 0.4 | < 0.0001 | 47.9 ± 0.4 | 49.2 ± 0.4 | 45.8 ± 0.4 | < 0.0001 | 47.6 ± 0.4 | 51.0 ± 0.6 | 46.6 ± 0.4 | < 0.0001 |
| Energy(kcal/day) | 2104.2 ± 13.3 | 1989.1 ± 18.1 | 2110.7 ± 22.9 | 2226.9 ± 19.3 | < 0.0001 | 1999.7 ± 18.8) | 2071.6 ± 22.0) | 2262.1 ± 7.6) | < 0.0001 | 2050.2 ± 14.9 | 2108.1 ± 37.3 | 2188.1 ± 18.3 | < 0.0001 |
| Alcohol consumptionb, n (%) | < 0.0001 | < 0.0001 | < 0.0001 | ||||||||||
| former | 1779(11.4) | 757(12.9) | 512(10.5) | 510(10.4) | 791(12.1) | 489(10.2) | 499(10.6) | 1073(12.1) | 211(12.7) | 495(10.0) | |||
| heavy | 2421(20.9) | 994(23.4) | 665(20.7) | 762(18.3) | 1037(23.2) | 641(20.6) | 743(18.3) | 1529(23.8) | 210(17.3) | 682(17.3) | |||
| mild | 4265(39.4) | 1485(35.8) | 1250(40.4) | 1530(42.6) | 1588(36.2) | 1214(39.9) | 1463(42.3) | 2218(36.3) | 444(40.9) | 1603(44.4) | |||
| moderate | 1919(17.9) | 683(16.5) | 569(18.7) | 667(18.8) | 719(16.5) | 563(19.5) | 637(18.2) | 1055(17.3) | 194(18.0) | 670(18.8) | |||
| never | 1595(10.2) | 624(11.2) | 465( 9.5) | 506( 9.7) | 656(11.0) | 448( 9.5) | 491( 9.8) | 928(10.6) | 183(10.8) | 484( 9.4) | |||
| Sexb, n (%) | 0.01 | < 0.001 | 0.68 | ||||||||||
| Female | 6152(51.6) | 2359(52.7) | 1839(53.2) | 1954(49.1) | 2481(52.5) | 1807(54.3) | 1864(48.2) | 3473(51.3) | 655(53.3) | 2024(51.6) | |||
| Male | 5827(48.3) | 2184(47.3) | 1622(46.7) | 2021(50.8) | 2310(47.4) | 1548(45.6) | 1969(51.7) | 3330(48.6) | 587(46.6) | 1910(48.3) | |||
| Ethnicityb, n (%) | < 0.0001 | < 0.0001 | < 0.0001 | ||||||||||
| Mexican American | 1887( 7.8) | 564(6.3) | 532(7.6) | 791(9.7) | 586( 6.2) | 461( 6.6) | 840(10.8) | 1164(8.8) | 178(6.9) | 545(6.5) | |||
| Black | 2417(10.8) | 1076(12.9) | 700(10.5) | 641( 8.8) | 1121(12.7) | 697(10.9) | 599( 8.5) | 1454(11.9) | 267(11.3) | 696( 9.1) | |||
| White | 5569(69.4) | 2266(70.8) | 1668(71.4) | 1635(66.2) | 2377(70.9) | 1646(71.9) | 1546(65.6) | 3210(69.1) | 589(70.6) | 1770(69.6) | |||
| Hispanic | 1211( 5.2) | 388(4.5) | 363(5.2) | 460(6.1) | 441(4.9) | 314(4.4) | 456(6.5) | 628(5.0) | 138(5.6) | 445(5.6) | |||
| Other Race | 895( 6.4) | 249(5.2) | 198(5.1) | 448(8.9) | 266(5.1) | 237(6.0) | 392(8.4) | 347(5.0) | 70(5.4) | 478(9.0) | |||
| Educationb, n (%) | < 0.0001 | < 0.0001 | < 0.0001 | ||||||||||
| 9-11th grade | 1711(10.1) | 728(11.7) | 483( 9.8) | 500( 8.6) | 755(11.5) | 449( 9.3) | 507( 9.2) | 1089(11.8) | 172( 9.7) | 450( 7.7) | |||
| College Graduate | 2675(29.9) | 766(23.7) | 797(29.6) | 1112(37.1) | 829(24.2) | 814(30.5) | 1032(36.3) | 1201(24.4) | 291(30.1) | 1183(38.4) | |||
| High school graduate/GED | 2852(24.8) | 1250(28.7) | 817(25.1) | 785(20.2) | 1301(28.4) | 796(24.8) | 755(20.4) | 1765(27.8) | 285(22.8) | 802(20.8) | |||
| Less Than 9th Grade | 1212( 4.7) | 462(5.3) | 342(4.4) | 408(4.1) | 490(5.3) | 288(3.7) | 434(4.7) | 759(5.5) | 149(5.7) | 304(3.0) | |||
| Some college or AA degree | 3529(30.3) | 1337(30.3) | 1022(30.8) | 1170(29.7) | 1416(30.4) | 1008(31.4) | 1105(29.2) | 1989(30.3) | 345(31.5) | 1195(29.8) | |||
| smokeb, n (%) | < 0.0001 | < 0.0001 | < 0.0001 | ||||||||||
| Former | 3010(25.2) | 1130(25.0) | 890(26.3) | 990(24.5) | 1207(25.6) | 856(26.2) | 947(23.9) | 1647(24.4) | 361(27.7) | 1002(25.9) | |||
| Never | 6524(55.8) | 2322(51.8) | 1917(55.9) | 2285(60.1) | 2450(51.7) | 1868(56.0) | 2206(60.6) | 3585(53.2) | 669(56.1) | 2270(59.7) | |||
| Now | 2445(18.9) | 1091(23.1) | 654(17.6) | 700(15.3) | 1134(22.5) | 631(17.7) | 680(15.4) | 1571(22.3) | 212(16.0) | 662(14.2) | |||
| Hypertensionb, n (%) | < 0.0001 | < 0.0001 | < 0.001 | ||||||||||
| No | 6962(63.9) | 2525(61.1) | 1950(62.4) | 2487(68.3) | 2670(61.1) | 1900(63.0) | 2392(68.1) | 3856(62.1) | 665(61.2) | 2441(67.6) | |||
| Yes | 5017(36.0) | 2018(38.8) | 1511(37.5) | 1488(31.6) | 2121(38.8) | 1455(36.9) | 1441(31.8) | 2947(37.9) | 577(38.9) | 1493(32.3) | |||
| DMb, n (%) | 0.01 | 0.01 | 0.004 | ||||||||||
| DM | 2257(14.0) | 889(15.2) | 682(14.4) | 686(12.2) | 936(15.2) | 653(14.4) | 668(12.0) | 1316(14.3) | 277(17.2) | 664(12.5) | |||
| IFG | 606( 5.1) | 238(5.5) | 188(5.7) | 180(4.1) | 248(5.6) | 187(5.5) | 171(4.0) | 375(5.7) | 57(4.7) | 174(4.2) | |||
| IGT | 404( 3.0) | 147(2.8) | 131(3.4) | 126(2.8) | 156(2.9) | 126(3.2) | 122(2.9) | 237(2.9) | 39(3.2) | 128(3.0) | |||
| No | 8712(77.8) | 3269(76.4) | 2460(76.4) | 2983(80.7) | 3451(76.1) | 2389(76.8) | 2872(80.9) | 4875(76.8) | 869(74.7) | 2968(80.2) | |||
| Hyperlipidemiab, n (%) | 0.01 | 0.01 | 0.02 | ||||||||||
| No | 3398(30.0) | 1291(29.3) | 907(27.8) | 1200(32.8) | 1364(29.4) | 871(27.7) | 1163(32.9) | 1930(29.7) | 307(24.9) | 1161(32.0) | |||
| Yes | 8581(69.9) | 3252(70.6) | 2554(72.1) | 2775(67.1) | 3427(70.5) | 2484(72.2) | 2670(67.0) | 4873(70.2) | 935(75.0) | 2773(67.9) | |||
| Statusb, n (%) | < 0.0001 | < 0.0001 | < 0.0001 | ||||||||||
| Alive | 10,556(92.0) | 3877(90.1) | 3051(91.7) | 3628(94.4) | 4103(90.3) | 2944(91.5) | 3509(94.7) | 5902(90.8) | 1070(90.1) | 3584(94.4) | |||
| Death | 1423( 7.9) | 666(9.8) | 410(8.2) | 347(5.5) | 688(9.7) | 411(8.4) | 324(5.3) | 901(9.1) | 172(9.8) | 350(5.5) | |||
aCatagorical variables shown as actual number (weighted frequency). Continuous variables normally distributed shown as mean ± standard deviation.
bThe NHANES participants was weighted differently to adjust for the probability of cluster sampling and oversampling of Hispanics and African Americans or aged 60 and above. Therefore the actual number does not match the weighted percentage
We plotted bar charts to examine the trends of total isoflavone intake with age and other variables and spline curves were attached. The total isoflavones increased with education levels. The total isoflavones intake was higher in participants who were at a higher level of education, underweight (BMI < 18·5 kg/m2), non-smokers (smoked below 100 cigarettes in their lifetime), higher healthy eating index, never drink (had < 12 drinks in a lifetime) or mild alcohol consumption (≥ 1 drinks per day for females, ≥ 2 drinks per day for males). In its totality, the trend of total isoflavones intake shows a decreasing fluctuation with age (Fig. 2).
Fig. 2.
The total isoflavones intake by baseline characteristics
Among 11,979 participants, 1,423 instances of mortality were documented throughout the median follow-up duration of 9.9 years (total follow-up of 96,438 person-years), including 330 deaths from heart disease. For all-cause mortality, compared with higher total isoflavones intake participants, higher total isoflavones intake participants had a lower risk of death in model 3 [Hazard Ratio (HR) 0.85, 95% confidence intervals (CI): 0.74–0.99 for higher intake compared with lower intake, P for trend = 0.021], higher genistein [Hazard Ratio (HR) 0.82, 95% confidence intervals (CI): 0.69–0.98, P for trend = 0.025] and daidzein [Hazard Ratio (HR) 0.81, 95% confidence intervals (CI): 0.70–0.94, P for trend = 0.002] had decreased risks of all-cause mortality. A lower hazard ratio typically indicates that increased consumption of isoflavones may be correlated with a decreased risk of mortality. We observed a comparable association of results for mortality from heart disease with daidzein [Hazard Ratio (HR) 0.73, 95% confidence intervals (CI): 0.53–0.99, P for trend = 0.027]. However, the heart disease mortality showed a null association in total isoflavones and genistein, with hazard ratios of 0.85(0.64, 1.15) (Table 2).
Table 2.
Hazard ratios (95% CIs) of mortality with weighted isoflavones
| Characteristic | Tertiles of Isoflavones intake | P For Trend | |||
|---|---|---|---|---|---|
| Low | Medium | High | |||
| All-cause Mortality | |||||
| Total Isoflavones | |||||
| Death/person-years | 666/36,951 | 410/27,760 | 347/31,727 | ||
| Model1 | ref | 0.77(0.66,0.89) | 0.70(0.60,0.83) | < 0.0001 | |
| Model2 | ref | 0.83(0.72,0.95) | 0.80(0.69,0.94) | 0.002 | |
| Model3 | ref | 0.86(0.75,0.99) | 0.85(0.74,0.99) | 0.021 | |
| Genistein | Death/person-years | 688/38,883 | 411/26,968 | 324/30,586 | |
| Model1 | ref | 0.82(0.70,0.95) | 0.69(0.57,0.83) | < 0.0001 | |
| Model2 | ref | 0.91(0.78,1.05) | 0.79(0.66,0.95) | 0.009 | |
| Model3 | ref | 0.92(0.80,1.07) | 0.82(0.69,0.98) | 0.025 | |
| Daidzein | Death/person-years | 901/54,576 | 172/10,563 | 350/31,298 | |
| Model1 | ref | 0.77(0.63,0.95) | 0.68(0.58,0.80) | < 0.0001 | |
| Model2 | ref | 0.79(0.64,0.96) | 0.80(0.69,0.92) | < 0.001 | |
| Model3 | ref | 0.80(0.66,0.97) | 0.81(0.70,0.94) | 0.002 | |
| heart disease mortality | |||||
| Total Isoflavones | |||||
| Death/person-years | 163/33,990 | 90/25,836 | 77/30,067 | ||
| Model1 | ref | 0.67(0.45,0.98) | 0.70(0.52,0.93) | 0.009 | |
| Model2 | ref | 0.71(0.48,1.06) | 0.77(0.59,1.02) | 0.052 | |
| Model3 | ref | 0.75(0.51, 1.11) | 0.85(0.64, 1.15) | 0.212 | |
| Genistein | Death/person-years | 168/35,819 | 96/25,025 | 66/29,048 | |
| Model1 | ref | 0.73(0.53,1.01) | 0.63(0.46,0.86) | 0.001 | |
| Model2 | ref | 0.78(0.57,1.09) | 0.69(0.51,0.94) | 0.001 | |
| Model3 | ref | 0.83(0.60, 1.13) | 0.75(0.54, 1.05) | 0.062 | |
| Daidzein | Death/person-years | 218/50,603 | 37/9698 | 75/29,591 | |
| Model1 | ref | 0.61(0.39,0.95) | 0.61(0.45,0.84) | 0.001 | |
| Model2 | ref | 0.60(0.39, 0.93) | 0.68(0.50, 0.91) | 0.001 | |
| Model3 | ref | 0.62(0.41, 0.93) | 0.73(0.53, 0.99) | 0.027 | |
Model 1: Cox proportional hazards regression model adjusted by age
Model 2: Cox proportional hazards regression model adjusted by age, alcohol consumption, sex, ethnicity, smoke, body mass index, education
Model 3: Further adjusted for healthy eating index score, Hypertension, Diabetes mellitus, Hyperlipidemia, total energy
Kaplan-Meir survival analyses showed a statistically significant elevation in all-cause mortality rates (P < 0.001) in participants who observed a lower dietary consumption of total isoflavones, genistein, and daidzein (Fig. 3). The higher intake of total isoflavones, genistein, and daidzein intake demonstrated the most remarkable survival benefit in relation about heart disease compared to the other tertiles (Supplementary Figs. 1–3). We calculated the standardized mortality rate based on the 2000 census; the standardized mortality rate of participants who had higher levels of total isoflavones intake was 5.69%, but those lower levels of total isoflavones intake was 9.02%. Similarly, age-standardized mortality rates for both genistein (Low = 8.78% vs. High = 5.42%) and daidzein (Low = 8.38% vs. High = 5.37%) decreased as their intake levels increased (Fig. 4).
Fig. 3.
Kaplan-Meier survival curves for mortality outcomes. A For Total Isoflavones intake (B) For Genistein intake (C) For Daidzein intake
Fig. 4.
Age-standardized mortality rates vary with isoflavone intake
In the stratified analyses between levels of total isoflavones and risk of all-cause mortality, consistent results were observed when stratifying by sex, ethnicity, BMI group (< 18.5 kg/m2, 18.5–24.9 kg/m2, 25–29.9 kg/m2, ≥ 30 kg/m2), smoking status, education, diabetes mellitus, Hypertension, and Hyperlipidemia after multivariable adjustment (Fig. 5). No significant interaction among these subgroups was observed (p > 0.05). Significant linear trends were observed in the Female subgroup (p = 0.009), the high school graduate/GED subgroup (p = 0.001), and the white race subgroup(p = 0.013) during trend tests. The stratification results of genistein and daidzein were also similar to this (Supplemental Tables 2–3).
Fig. 5.
Associations between levels of total isoflavones and risk of all cause mortality stratified by baseline diabetes, smoke, hypertension, education, BMI, ethnicity. *Covariate adjustment using a fully adjusted model: age, alcohol consumption, sex, ethnicity, smoke, body mass index, education, healthy eating index score, Hypertension, Diabetes mellitus, and Hyperlipidemia
In sensitivity analyses, similar findings were found when further excluding participants within six months of follow-up or further adjusting for categorical variables of age (with group, 20–39 years, 40–59 years, 60–80 years) and BMI group. Excluding par-ticipants with less than six months of follow-up and adjusting for age group and BMI group in the analysis did not significantly or slightly alter the HR. (Supplemental Tables 4–5).
A cubic spline regression (RCS) model with multivariable-adjusted was utilized to demonstrate a dose-response relationship between dietary isoflavones intake and all-cause mortality (Fig. 6). The significantly nonlinear (p-value for nonlinear < 0.05 and p-value for overall < 0.05) associations with total isoflavones, genistein, and daidzein intake and all-cause mortality have been observed in the female group. Based on the inflection point examined in the dose-response curve, we recommended the plan of daily dietary isoflavones intake in females to be as follows: total isoflavones (6.21 mg/day); genistein(3.34 mg/day); daidzein (2.47 mg/day). And no non-linear relationship was detected in the male group (p-value for nonlinear > 0.05). In addition, there were no significant relationships between dietary isoflavones and heart cause death (Supplementary Figs. 4–6).
Fig. 6.
The association of all-cause mortality with total isoflavones, genistein and daidzein intake per day by restricted cubic spline
Discussion
In this prospective cohort study conducted as part of the National Health and Nutrition Examination Survey in United States adults, we found that high levels of total isoflavones, genistein, and daidzein intake were associated with a decreased risk of all-cause mortality, with dose-dependent protective effects. In the stratified analyses, a significant association between the highest dietary isoflavones intake in the tertile group and all-cause mortality was found in females but without statistical significance in males. Therefore, we constructed restricted cubic splines to delve into the dose-response relationship between dietary isoflavones and the risk of all-cause mortality stratified by sex and identified a U-shaped dose-response curve for female participants. To our knowledge, the present study is the first large prospective investigation into the correlation between dietary isoflavones and all-cause mortality and heart disease mortality and identify the best protective effects on the point of dietary total isoflavones(6.21 mg/day); genistein(3.34 mg/day); daidzein(2.47 mg/day) on all-cause mortality. The differential outcomes observed between males and females in the dose-response curve may be attributed to a higher sensitivity of women to fluctuations in phytoestrogens compared to men. This increased sensitivity might influence the risk profile for certain diseases [47, 48] that are associated with excessive estrogen levels, some of which are also linked to mortality. When analyzed with heart disease mortality, our data showed that only daidzein had preventive effects on heart disease death. And without nonlinear relationships. In our analysis, the intake of isoflavones and their subgroups serves only as a reference point, representing preliminary conclusions derived from dose-response curve analysis. These findings are subject to variation based on changes in dietary composition and even different dietary patterns.
In addition, we used total isoflavones as an example to demonstrate the intake levels and trends of dietary isoflavones in different demographic groups with distinct characteristics (Fig. 2). In US adults, the total intake of isoflavones gradually increases with a rise in educational background, namely from Less Than 9th Grade to College Graduate or above. In the same way, the trend of total isoflavone intake shows a decreasing fluctuation with age. And participants with high isoflavones intake had healthier characteristics (smoked less, more exercise, lower BMI). In addition, the age-standardized mortality rate based on the 2000 census decreased with a higher intake of total isoflavones; the age-standardized mortality rate was 5.69% among those with the highest intake of total isoflavones. There was a 3.33% reduction compared to the lowest three tertiles of total isoflavone intake.
In the previous study, Nagata et al. [18] demonstrated a significant inverse correlation between natto consumption and the risk of mortality from cardiovascular disease (CVD) in both males and females. 5 prospective cohort studies (3 in Asian populations [49–51], 1 in United States populations [52], 1 in European populations [53]) have investigated the association between soy intake and mortality. In one study [52], participants with nonmetastatic PCa at diagnosis had a lower risk of death due to their adherence to soy-rich dietary patterns. Another study41 reckoned that the point estimate of the hazard ratio for coronary heart disease mortality of participants with soy-rich dietary pattern scores was 20% higher than the general population. The results of this research and their implications lend support to the conclusions drawn by current studies. In addition, a prospective cohort study that collected the total of phytoestrogens exhibited a higher intake of total phytoestrogens (including isoflavones), which revealed a significant association between this factor and a reduced risk of mortality from all causes, cardiovascular disease, and other causes. However, they did not stratify by gender or other demographic characteristic.
In addition to this epidemiological evidence, hypotheses derived from various experimental studies conducted at different levels can also confirm the mechanism by which isoflavone intake provides protective benefits in a wide range of human body systems. As a soybean extract with estrogenic activity, isoflavones adhered to estrogen receptors beta/alpha (ERβ/ERα) in the nucleus of target cells [54], and regulated gene expression by binding estrogen response element or specific target sequences of DNA [55]. In coronary vessels [56], ERβ can change the expression of endothelial nitric oxide-synthase to accelerate vasodilatation of blood vessels by attenuating inflammatory response and oxidative stress in vascular cells [57, 58]. Zhang et al. [59] have unveiled that genistein can lead to a downregulation of cancer stem cell marker CD44 in vitro, markedly suppressing the proliferation of cellular colonies and the development of tumorigenic spheroids in prostate cancer cells. Concurrently, agonists targeting the estrogen receptor beta have been demonstrated to trigger cell apoptosis in conditions of benign prostatic hyperplasia as well as prostate cancer [60, 61]. Of note, isoflavones exhibit activities mediated by both ERα and ERβ at high doses, but the application of low-dose isoflavones has been demonstrated to act selectively in the cardiovascular system [62]. Given the higher intake of legume foods among Asian populations relative to other regions [63], this dietary pattern could potentially result in diverse observational outcomes across various geographical locations.
To date, this is the most extensive population-based study to assess the association between mortality and isoflavones compound (total isoflavones, genistein, and daidzein) intake in adults. This study emphatically examined various effects of dietary isoflavones in different races, sexes, and lifestyles. The advantages of this study are not limited to the aforementioned ones, and we recommended the plan of daily dietary isoflavones intake in females to be as follows: total isoflavones(6.21 mg/day); genistein(3.34 mg/day); daidzein(2.47 mg/day) as for recommended dose for clinical practice, which was developed based on the inflection point examined in the dose-response curve.
Nevertheless, some limitations should be considered in the interpretation of our findings. First, dietary isoflavones intake was collected from a 24-hour dietary recall; the potential recall bias was challenging to overcome. Second, many previous studies have mentioned a subtle difference between the consumption of non-fermented soy foods and fermented soy foods to influence the effect of soy isoflavones. Still, we could not incorporate the differential effects between non-fermented soy foods and fermented soy foods into our study and also acknowledge the limitation of not being able to analyze the differential effects of isoflavones based on their various food sources. In addition, our finding is limited to the analysis of dietary intake of isoflavones and does not include an analysis of plasma levels of isoflavones. Finally, due to the inherent limitations of the observational study design, it is not possible to infer definitive causal relationships from our conclusion. Therefore, any generalization of the relationship between isoflavones and effects in vivo should be cautious.
Conclusions
In summary, we found that dietary isoflavones(total isoflavones, genistein, and daidzein) intake levels were inversely associated with the risk of all-cause mortality in US adults. We observed a similar association of results for mortality from heart disease with daidzein to diminish the chances of heart disease mortality. In RCS regression, the female group has observed a significantly nonlinear trend between total isoflavones, genistein, daidzein intake, and all-cause mortality. These findings suggest that these compounds abundant in soybeans may be protective against all-cause mortality and heart disease mortality and recommended intake levels of soy isoflavones for specific populations.
Supplementary Information
Additional file 1: Supplementary methods: as the supplementary to the diagnostic criteria for diseases or lifestyle assessment standards in the methods section.
Additional file 2: Supplementary Table 1: Characteristics of study participants according to survival condition.
Additional file 3: Supplementary Table 2: Associations between levels of Genistein intake and risk of all cause mortality stratified by baseline diabetes, smoke, hypertension, education, BMI, ethnicity.
Additional file 4: Supplementary Table 3: Associations between levels of Daidzein intake and risk of all cause mortality stratified by baseline diabetes, smoke, hypertension, education, BMI, ethnicity.
Additional file 5: Supplementary Table 4: Weighted association between Isoflavones and mortality when excluding participants with less than 6 months of follow-up.
Additional file 6: Supplementary Table 5: Weighted association between Isoflavones and mortality when for categorical variables of age and BMI.
Additional file 7: Supplementary Figure 1: Survival probability by the level of the total isoflavones intake.
Additional file 8: Supplementary Figure 2: Survival probability by the level of the genistein intake.
Additional file 9: Supplementary Figure 3: Survival probability by the level of the daidzein intake.
Additional file 10: Supplementary Figure 4: The association of heart disease mortality with total isoflavones intake per day by restricted cubic spline.
Additional file 11: Supplementary Figure 5: The association of heart disease mortality with genistein intake per day by restricted cubic spline.
Additional file 12: Supplementary Figure 6: The association of heart disease mortality with daidzein intake per day by restricted cubic spline.
Acknowledgements
Thanks to Zhang Jing (Second Department of Infectious Disease, Shanghai Fifth People’s Hospital, Fudan University) for his work on the NHANES database. His outstanding work, nhanesR package and webpage, makes it easier for us to explore NHANES database.
Authors’ contributions
Protocol draft and original paper preparation, Y.Y.; data curation, Y.Y.; formal analysis, Y.Y.; methodology, Y.Y., M.Q. and J.L.; software, Y.Y. and J.L.; supervision, J.L.; writing review and editing, J.L., M.Q. and Y.Y.; visualization, Y.Y.; funding acquisition, J.L. All authors have read and agreed to the published version of the manuscript. Yifei Yan is the first author.
Funding
J.L. received support from the:
Guangdong Medical Science and Technology Research Fund, grant number: A2019319.
Guangdong Medical University Affiliated Hospital Doctoral Fund, grant number: BK201615.
Data availability
Publicly available datasets were analyzed in this study. These data can be found here: https://www.cdc.gov/nchs/nhanes/index.htm and the datasets have analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study was performed using public data from the National Center for Health Statistics and the National Health and Nutrition Examination Survey (NHANES). Prior to enrollment, all participants furnished informed consent. The study requires no further approval and follows ethical guidelines.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Additional file 1: Supplementary methods: as the supplementary to the diagnostic criteria for diseases or lifestyle assessment standards in the methods section.
Additional file 2: Supplementary Table 1: Characteristics of study participants according to survival condition.
Additional file 3: Supplementary Table 2: Associations between levels of Genistein intake and risk of all cause mortality stratified by baseline diabetes, smoke, hypertension, education, BMI, ethnicity.
Additional file 4: Supplementary Table 3: Associations between levels of Daidzein intake and risk of all cause mortality stratified by baseline diabetes, smoke, hypertension, education, BMI, ethnicity.
Additional file 5: Supplementary Table 4: Weighted association between Isoflavones and mortality when excluding participants with less than 6 months of follow-up.
Additional file 6: Supplementary Table 5: Weighted association between Isoflavones and mortality when for categorical variables of age and BMI.
Additional file 7: Supplementary Figure 1: Survival probability by the level of the total isoflavones intake.
Additional file 8: Supplementary Figure 2: Survival probability by the level of the genistein intake.
Additional file 9: Supplementary Figure 3: Survival probability by the level of the daidzein intake.
Additional file 10: Supplementary Figure 4: The association of heart disease mortality with total isoflavones intake per day by restricted cubic spline.
Additional file 11: Supplementary Figure 5: The association of heart disease mortality with genistein intake per day by restricted cubic spline.
Additional file 12: Supplementary Figure 6: The association of heart disease mortality with daidzein intake per day by restricted cubic spline.
Data Availability Statement
Publicly available datasets were analyzed in this study. These data can be found here: https://www.cdc.gov/nchs/nhanes/index.htm and the datasets have analysed during the current study are available from the corresponding author on reasonable request.