Mediterranean diet in the targeted prevention and personalized treatment of chronic diseases: evidence, potential mechanisms, and prospects

Abstract

The prevalence of chronic diseases is currently a major public health issue worldwide and is exploding with the population growth and aging. Dietary patterns are well known to play a important role in our overall health and well-being, and therefore, poor diet and malnutrition are among the most critical risk factors for chronic disease. Thus, dietary recommendation and nutritional supplementation have significant clinical implications for the targeted treatment of some of these diseases. Multiple dietary patterns have been proposed to prevent chronic disease incidence, like Dietary Approaches to Stop Hypertension (DASH) and Diabetes Risk Reduction Diet (DRRD). Among them, the MedDiet, which is one of the most well-known and studied dietary patterns in the world, has been related to a wide extent of health benefits. Substantial evidence has supported an important reverse association between higher compliance to MedDiet and the risk of chronic disease. Innovative strategies within the healthcare framework of predictive, preventive, and personalized medicine (PPPM/3PM) view personalized dietary customization as a predictive medical approach, cost-effective preventive measures, and the optimal dietary treatment tailored to the characteristics of patients with chronic diseases in primary and secondary care. Through a comprehensive collection and review of available evidence, this review summarizes health benefits of MedDiet in the context of PPPM/3PM for chronic diseases, including cardiovascular disease, hypertension, type 2 diabetes, obesity, metabolic syndrome, osteoporosis, and cancer, thereby a working hypothesis that MedDiet can personalize the prevention and treatment of chronic diseases was derived.

Introduction

Chronic diseases represent a diverse group of diseases that can be broadly regraded as those lasting for a year or longer, requiring ongoing medical care and/or restricting daily living or certain activities [1]. Chronic diseases include, but are not restricted to, diseases like cardiovascular disease (CVD), chronic lung disease, cancer, obesity, type 2 diabetes mellitus (T2DM), and renal or liver disease, but may also involve chronic infections, such as HIV and inflammatory bowel disease (Crohn’s disease and ulcerative colitis) [2], and diet is one of the most relevant environmental elements that profoundly affect the onset of these chronic illnesses. Dietary pattern refers to all foods and beverages that an individual habitually eats and drinks, in which the components act synergistically to influence health; hence, dietary patterns may be better than individual nutrients or foods to predict overall health status and disease risk [3]. Therefore, the pros and cons of various dietary patterns need to be extensively and thoroughly assessed in order to guide personalized option for those patterns associated with health prediction and prevention of diet-related diseases [4].

Over the last decade, dietary pattern analysis has been identified as a promising and practical avenue for assessing the association between diet and chronic disease risk. It is important to note that research on dietary patterns shows a growing interest in policy of nutrition, especially as it proves the significance of total diet in promoting health in an integrated way [4]. However, the complexity of interpreting multidimensional dietary data makes it a challenge for the prevention and personalized treatment of various chronic diseases with characteristics of different dietary patterns. The interaction between the human genome and diet has sparked intense research and debate about the efficacy of personalized nutrition, which is a more appropriate method for chronic disease prevention [5]. Overall, diet and nutrition are essential and game-changing components of our daily life and are therefore the basic cornerstone of chronic disease management [2]. In fact, since the early 1970s, numerous researchers have reported the beneficial role of MedDiet, which was initially reported by Keys in the pioneering study of seven countries that focused on the cardiovascular risk factors and the incidence and mortality of CVD [6]. It is now widely accepted that the main components of the MedDiet play a beneficial role in the prevention of CVD and chronic degenerative diseases [7].

Traditional MedDiet, which is based on consuming a large amount of olive oil daily as their main source of fat, is characterized by (a) heavy consumption of fruits, vegetables, whole grains, nuts, seeds, and legumes; (b) regular and moderate consumption of red wine during meals; (c) moderate intake of seafood, fermented milk products (yogurt and cheese), poultry, and eggs; and (d) low intake of meat products, red meat, and confectioneries. In addition, daily physical activity (150–300 min of moderate or 75–150 min of intense aerobic exercise per week), appropriate hydration (about 2 L of water per day), and social diet habits are recommended in the MedDiet pattern [8, 9].

Therefore, this review aims to provide an overview of the effectiveness of MedDiet as a nutritional strategy and provide a theoretical basis for the development of a PPPM/3PM framework for MedDiet in the field of chronic disease prevention and control.

For this, we searched PubMed, Web of Science, and Google scholar from 1986 to 2024. The terms we used for retrieving articles were Mediterranean diet, MedDiet, cardiovascular disease, CVD, hypertension, diabetes, DM, obesity, metabolic syndrome, MetS, osteoporosis, cancer, predictive, preventive, and personalized medicine, with the strategies as follows: ((Mediterranean diet[Title/Abstract]) OR (MedDiet[Title/Abstract])) AND ((((((((((cardiovascular disease[Title/Abstract]) OR (CVD[Title/Abstract])) OR (hypertension[Title/Abstract]) OR (diabetes[Title/Abstract])) OR (DM[Title/Abstract])) OR (obesity[Title/Abstract]) OR (metabolic syndrome[Title/Abstract])) OR (MetS[Title/Abstract])) OR (osteoporosis[Title/Abstract]) OR (cancer[Title/Abstract]) AND ((predictive medicine[MeSH Terms]) OR (preventive medicine[MeSH Terms])) OR (personalized medicine[MeSH Terms]).

MedDiet and CVD

In the twenty-first century, CVD is the most significant threat to the population health [10], including cerebrovascular disease, coronary artery disease, heart failure, and peripheral artery disease, ranking first among the causes of global mortality [4]. Healthy lifestyle and diet in young and middle age are key factors in living without chronic diseases in later life [11]. Numerous preventive medicine evidences have suggested that overall dietary patterns may improve health and prevent CVD to a greater extent than foods or nutrients in isolation [12, 13]. Much attention has been paid to the impact on MedDiet in CVD and its risk factors over the past few decades, with many clinical trials and epidemiological studies emphasizing the beneficial role of diet, in part due to its rich in polyphenols and monounsaturated or polyunsaturated fatty acids [14]. Over the years, there have been several studies on the effects of MedDiet, some of which could further explain the mechanisms underlying the potential benefits of MedDiet for CVD prevention. In this context, the biomolecular mechanisms contributing to MedDiet’s long-term effects on cardiovascular health are as follows: lipid-lowering effect, prevention of inflammation, platelet aggregation, and oxidative stress (Fig. 1) [15–18].

Fig. 1.

Potential mechanisms by which the Mediterranean diet improves chronic diseases of cardiovascular disease, hypertension, type 2 diabetes mellitus, obesity, metabolic syndrome, osteoporosis, and cancer

Currently, the key preventive role of MedDiet in CVD has been highlighted in several studies and randomized trials of dietary interventions, like the Lyon Diet Heart Study, which investigated the positive action of the Mediterranean dietary pattern on the secondary prevention of CVD [19]. The PREDIMED study is the first large-scale randomized controlled intervention trial showing a significant impact of MedDiet as a primary tool to prevent cardiovascular events (e.g., atrial fibrillation, peripheral vascular disease, stroke, and myocardial infarction) [11]. Furthermore, the PREDIMED trial reported that following a personalized medical dietary pattern of MedDiet supplemented with extra virgin olive oil (EVOO) or nuts could decrease cardiovascular events by 30% when compared to the control group of low-fat diet [20], hinting that a preference for ingredients in the MedDiet may have an impact on the preventive efficacy of CVD. The crucial role of diet as a risk factor for CVD was reported in a seven-country research project enrolling over 12,000 males from Greece, Finland, Japan, Italy, Netherlands, former Yugoslavia, and the USA. Of the seven countries, the USA and Finland had the greatest consumption of animal products, saturated fat, and cholesterol and suffered the greatest CVD mortality. Conversely, the opposite trend of cardiovascular events is displayed in the Mediterranean nations and Japan [21]. In a cumulative analysis of a prospective cohort study and randomized controlled trials, a strong inverse correlation between MedDiet adherence and cardiovascular morbidity and mortality was reported (RR 0.71; 95% CI 0.65, 0.78) [22]. Moreover, a meta-analysis of seven observational studies also found strong evidence supporting the positive effects of MedDiet on CVD. Regarding the incidence of both fatal and non-fatal CVD, an eight cohort analysis (534,064 individuals in total) demonstrated that for every 2-point increase in 10 points of MedDiet adherence was related to the significant reduction of incidence or mortality of CVD (RR 0.90; 95% CI 0.87, 0.93) [23]. These studies are highly suggestive of the primary and tertiary prevention effects of the MedDiet on CVD.

Since diet appears to be strongly linked to the prevention of CVD, nutrition epidemiology has been actively advancing the evaluation of the “dietary heart hypothesis” over the past 50 years [24]. In brief, the current evidence based on long-term cohort studies and randomized trials strongly suggests that compliance to MedDiet predicts a decreased cardiovascular events risk. As one of the well-studied dietary models related to preventive medicine of CVD, further randomized controlled trials (RCTs) are warranted to demonstrate the feasibility of MedDiet in other non-Mediterranean countries in the context of 3PM to expand the transferability of MedDiet recommendations.

MedDiet and hypertension

Hypertension is the leading cause of CVD and premature death worldwide, with 10.8 million deaths in 2019. The number of people with hypertension has increased by 90% over the last four decades, primarily in low-income and middle-income countries [25]. According to the current hypertension treatment guidelines issued by the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH), combined with the results of meta-analysis, observational studies, and adult studies, it is practicable to prevent the development of hypertension while reducing cardiovascular risk by changing lifestyle [26]. A healthy lifestyle is a basic strategy to reduce hypertension, among which diet is the most variable factor affecting blood pressure (BP) [27]. Mechanically, MedDiet has been supposed to improve endothelial function [28] and to have considerable benefits on the risk of CVD and hypertension (Fig. 1) [15, 28, 29].

Nissensohn et al. conducted a systematic review and meta-analysis demonstrating significant reductions in systolic and diastolic BP in individuals with normal or mild hypertension following the consumption of MedDiet. They further noted that MedDiet appeared to have a greater effect on systolic BP (SBP) [30]. The Greek European Prospective Survey of Cancer and Nutrition (EPIC) study investigated 20,343 subjects who were not diagnosed with hypertension, and the results showed a significant negative interrelation between MedDiet score and SBP and diastolic BP (DBP) [31]. Consistently, in the PREDIMED study, 7447 males (55–80 years) and females (60–80 years) were randomly divided into one of three personalized medical dietary intervention groups: MedDiet-EVOO, MedDiet-nuts, and low-fat diet, with over 80% of them had hypertension; after 4 years of follow-up, beneficial changes in BP were exhibited in two MedDiet groups, namely, the DBP of subjects received supplemented MedDiet-EVOO and MedDiet-nuts intervention was lower than that in the low-fat diet group, with reductions of 1.5 and 0.7 mmHg, respectively [32]. In addition, Davis et al. recently conducted an RCT to investigate the effect of increasing MedDiet compliance on BP in Australian participants represented by 166 healthy males and females aged 64 and above. It showed that Australian subjects who persisted to MedDiet had significantly reduced SBP and improved endothelial function after 3 and 6 months compared with volunteers who maintained a habitual diet, strongly illustrating the significant primary prevention function of the MedDiet [33]. The Study of Seguimiento Universidad de Navarra (SUN) investigated the association between MedDiet compliance and hypertension incidence in 9408 male and female populations, all of whom were nurses, college graduates, and other educated adults [34]. After 12 years of following-up, only minor changes in average SBP and DBP were observed to be associated with MedDiet adherence, indicating that the preventive effect of MedDiet on hypertension may be age-dependent [35]. The above results collectively hint that the sensibility of MedDiet to BP is largely dependent on the individual BP background. Several studies focusing on specific dietary components have uncovered that long-term intake of large amounts of VOO characterized by MUFA, with a special focus on oleic acid (OA), promotes BP reduction and hence prevents the development of chronic hypertension [36–39]. To confirm what was described, a study conducted by Teres et al. highlighted that the antihypertensive properties of olive oil may be partially due to the high OA content [40]. Indeed, previous studies have largely ascribed the antihypertensive effect of MedDiet to polyphenols and other phenolic compounds in olive oil, one of the most distinctive ingredients in MedDiet [41–44].

In general, the present studies have shown that MedDiet performs favorable effects in reducing/maintaining BP in mildly hypertensive or healthy subjects, but no sufficient evidence regarding the effects of MedDiet on moderate/severe hypertension or on hypertension with specific diseases can be referred. Thus, the personalized effect of MedDiet on BP needs to be urgently addressed, and far more researches are required to declare whether the antihypertensive efficacy of MedDiet is universal for all grades of hypertension and to reveal the mechanisms of BP changes induced by MedDiet.

MedDiet and T2DM

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, caused by insulin resistance or insufficient insulin secretion, or both. According to the data of the International Diabetes Federation (IDF), 537 million adults (20–79 years old) worldwide have diabetes by 2021, ranking first place among global chronic diseases. The total number of diabetic patients is expected to increase to 643 million by 2030 and to 783 million by 2045 [45]. An epidemiological study has shown that dietary model characterized by reduced intake of starch-based foods, sugary beverages, red and processed meats, and high intake of fruits, vegetables, whole grains, and fish can delay the development of T2DM [46]. Furthermore, given consistent epidemiological and clinical proofs, high dietary fiber consumption (especially cereal fiber), antioxidants, and monounsaturated fatty acids (MUFA), as well as foods containing these compounds, are related to the improvement of insulin sensitivity, capacity of pancreatic β-cells to secrete insulin, and decreased risk of T2DM development (Fig. 1) [46–48]. Therefore, MedDiet, which is rich in these above-mentioned foods and nutrients, has received much attention for its anti-diabetic function. For patients with T2DM, MedDiet is regarded as an effective alternative strategy for blood glucose control when compared with low-fat, high-carbohydrate dietary pattern [49]. Filippatos et al. have revealed moderate and high compliance to MedDiet contributes to the prevention of T2DM primarily by enhancing total antioxidant capacity and reducing inflammation [50]. Similarly, in the latest meta-analysis of prospective cohort studies of 122,810 individuals published between 2007 and 2014, it was hypothesized that grater adherence to MedDiet would significantly reduce the risk of DM by 19% [51]. In recent years, dietary patterns that are high in MUFA have been shown a positive effect on total triglyceride (TG) levels in patients with DM [52] and glycemic control in T2DM [48]. There have also been two prospective studies linking MedDiet adherence to the risks or consequences of gestational diabetes. In a nurses’ health survey that observed 491 cases of incident T2DM aged 22–44 years with a history of gestational diabetes among 4413 females followed for 14 years, those in the highest quartile of adherence to MedDiet had 40% lower risk of T2DM compared with the lowest quartile subjects [53]. Likewise, in a study of 1076 pregnant females from ten countries, compliance to MedDiet was related to a lower prevalence of gestational diabetes and improved glucose tolerance even among females without gestational diabetes [54].

Thus, to date, the overwhelming majority of evidence supports the beneficial role of MedDiet in the DM preventive medicine, and it is even more encouraging that the studies in pregnant women have expanded the applicable population of MedDiet adoption for diabetes prevention. Population-based education about MedDiet may be a safe public health approach that can prevent or delay the onset of T2DM. Future research is required to clarify the mechanisms of reducing diabetes risk independent of weight loss.

MedDiet and obesity

More than two-thirds of adults in Western countries are currently classified as overweight (BMI > 25 kg/m²) or obese (BMI > 30 kg/m²); obesity has been considered an epidemic. Since 1975, the global obesity prevalence has raised nearly threefold, primarily due to the spread of an unhealthy diet and a sedentary lifestyle [55]. Certain evidence has illuminated that MedDiet is effective in weight loss, particularly reduction of central adiposity. Additional study also described the efficacy of polyphenols derived from olive oil in regulating the expression patterns of factors involved in adipocyte proliferation, thereby reducing adipose tissue accumulation (Fig. 1). An analysis of the Spanish cohort from the Spanish European Prospective Survey of Cancer and Nutrition (EPIC) including 17,238 females and 10,589 males who were non-obese at baseline found a significant correlation between an average of 3.3 years of high MedDiet adherence and a decreased obesity morbidity in both male and female [56], implying an outstanding primary prevention effect on obesity of MedDiet. Another SUN program including 10,376 subjects with an average follow-up of 5.7 ± 2.2 years indicated that the individuals with the lowest compliance to MedDiet had the greatest average annual weight gain, whereas those with the highest compliance to MedDiet had the lowest average weight gain [57]. A recent meta-analysis of cohort studies delved into the correlation between compliance to MedDiet and the risk of being overweight and/or obesity, including seven prospective cohort studies, of which six (n = 244,678 adult subjects) displayed the risk for overweight and/or obesity and four cohorts (n = 436,617 subjects) showed the change of weight. Combined six prospective cohort studies, better MedDiet adherence was found to be significantly related to a 9% lower risk of being overweight and/or obese (RR 0.91; 95% CI 0.88, 0.94; I² = 44.7%; P = 0.031) [58]. Similarly, in a random-effect meta-analysis of 19 arms, there was a significant impact of the MedDiet group on body weight (average difference between MedDiet and control diet, − 1.75 kg; 95% CI − 2.86, − 0.64 kg) and BMI (average difference, − 0.57 kg/m²; 95% CI − 0.93, − 0.21 kg/m²) [59]. However, the relatively high-fat content of MedDiet may be conventionally considered to contribute to weight gain and obesity. Given the free access to olive oil and walnuts for participants in the PREDIMED study, this concern was raised at the first publication of the trial [60]. A long-term analysis of the PREDIMED trial, particularly focusing on waist circumference and weight, showed that the adjusted difference after 4.8 years of the MedDiet with olive oil intervention was not significant compared with the control low-fat diet group [61]. In a report from the EPIC study included 373,803 males and females with a median intervention of 5 years, participants with high MedDiet compliance were 10% less likely to become overweight or obese, compared to participants with low compliance, despite only losing 0.16 kg of body weight (95% CI − 0.24, − 0.07 kg) [62]. Hence, long-term intervention using MedDiet with un-restricted calories, high fat, and high plant fat did not appear to have much benefit on weight change and central obesity [63]. However, a prospective descriptive study designed to assess the change in laboratory biomarkers in obese subjects after hypocaloric MedDiet (1400–1600 kcal/day) for 4 months showed a significant reduction in body weight and BMI (both P < 0.001), insulin (P = 0.037), HOMA-IR (P = 0.026), leptin (P = 0.008), and lactate dehydrogenase (P = 0.023) [64], displaying superior tertiary prevention efficacy of MedDiet for mitigating obesity-related complications.

Moreover, a variety of dietary models have been assessed for their effects on weight loss, including low-fat, low-carbohydrate, ketogenic diet, and MedDiet, among others. In addition to its beneficial effects on weight control, the optimal dietary pattern with the best evidence in terms of coordinated benefits of preventing and treating non-communicable diseases (NCDs) and reducing mortality is MedDiet [65–68]. Collectively, MedDiet, specifically MedDiet that restricts energy, may be an alternative tool for weight control. Meanwhile, when targeting obese individuals with other NCDs, MedDiet is the best option for a personalized medical diet. It is worth noting that there is no evidence pointing out the weight gain impact of MedDiet, which dispels opposition due to its relatively high-fat content [59, 64].

MedDiet and metabolic syndrome (MetS)

The World Health Organization defines MetS as a pathological condition characterized by obesity, insulin resistance, hypertension, hyperlipidemia, and a high waist-to-hip ratio, with the presence of three or more of these criteria being diagnosed as MetS [69]. MetS is increasing in prevalence, affecting nearly a quarter of the global adult population, which is directly associated with the worldwide prevalence of obesity and diabetes [70]. The major risk factors for MetS are sedentary lifestyle and unhealthy western diet, which can be countered by a diet high in grains, vegetables, fruits, fish, and low-fat dairy products, in line with the composition of MedDiet; thus, certain preventive medicine studies have found a positive relationship between MedDiet pattern and the prevention or treatment of MetS [18, 69]. Panagiotakos and colleagues described in the “ATTICA Study” the primary prevention of MetS by MedDiet in 3042 Greek individuals without diabetes and CVD. In their report, subjects who followed MedDiet had a 20% lower risk of evolving MetS, regardless of gender, age, physical activity status, lipid profile, and BP level [71]. Consistently, data from a cross-sectional study of 808 older Spaniards who adhered to MedDiet and were at high cardiovascular risk indicated that individuals following the MedDiet demonstrated a 56% reduction in the risk of developing MetS [72]. These work are further supported by results from a cohort study conducted at Seguimiento University, in which Navarra et al. noted a lower cumulative risk of MetS in subjects with strict adherence to MedDiet after 6 years of follow-up [73]. Subsequently, a 7-year follow-up study of 1918 subjects in the US Framingham Heart Study Offspring cohort uncovered that MedDiet pattern adherence reduced the MetS incidence. Specifically, MedDiet participants showed improvements in MetS characteristics, e.g., abdominal obesity, insulin resistance, and lipid status [74]. Yet, it is worth noting that high-fat conventional MedDiet also has beneficial effects on MetS. In the PREDIMED study, 1224 subjects at high CVD risk were divided into two personalized medical dietary groups: a high-fat MedDiet (supplemented with nuts or EVOO) and the low-fat diet group; at 1-year follow-up assessment, the overall prevalence of MetS in the MedDiet-EVOO and MedDiet-nuts supplemented groups decreased by 6.7% and 13.7%, respectively, compared with a 2.0% decrease in the control group [18]. The above-mentioned evidence highlights the preventive effect of MedDiet on MetS even in individuals with metabolic risks.

In vitro and in vivo studies provide evidence linking the efficiency of MedDiet for MetS with the nutrients they contain, which can improve the metabolic characteristics susceptible to MetS, such as hyperglycemia, dyslipidemia, oxidative stress, and sub-inflammation (Fig. 1) [75]. The case in point is olive oil, which is the most iconic ingredient in the MedDiet and is distinctive in comparison to other dietary patterns. Hydroxytyrosol (HT) and oleuropein (OL), natural molecules from olive oil, have been shown to counteract adiposity by reducing the accumulation of intracellular TG and by suppressing the expression of adipogenesis-associated genes, to alleviate hepatic insulin resistance and steatosis by restraining inflammatory events, oxidative stress, generation of reactive oxygen species (ROS), and lipid peroxidation [76–78]. Extensive concerns on the biological activities and metabolic regulation mechanisms of phenolic substances in olive oil will provide a promising and profound reference for the MedDiet as a prevention diet regarding to the characteristics of MetS [79].

MedDiet and osteoporosis

Osteoporosis (OP) is a progressive bone disease related to age, characterized by microstructure degradation and bone loss, which can lead to severe fractures. OP fractures and OP fracture falls are associated with high dependency, pressure ulcers, lower limb deep vein thrombosis, infections, traumatic ossification, and traumatic osteoarthritis of incidence rate and mortality, posing a great burden on the health care system [80, 81]. It is estimated that OP affects 27.5 million people aged 50–84 worldwide (22 million female and 5.5 million male), and its incidence is projected to increase to 33.9 million by 2025 [82]. Dietary patterns are modifiable lifestyle factors related to bone and muscle health. Interestingly, epidemiological data has revealed a lower prevalence of OP in Mediterranean Europe region, which simultaneously is considered to be explained by diet [83, 84]. In the PREDIMED study, all subjects (n = 870) with a high risk of CVD between the ages of 55 to 80 recruited at the Reus (Spain) center were randomly assigned to personalized medical dietary groups: MedDiet-EVOO, MedDiet-nuts, or a low-fat diet. After a median of 5.2 years of intervention and 8.9 years of follow-up, a higher intake of EVOO was linked to a decreased of OP-related fractures (HR 0.49; 95% CI 0.29–0.81, P = 0.004) [85]. Whereas, in a multicenter RCT of NU-AGE (New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe), individuals (n = 1294) aged 66–74 years who consumed a Mediterranean-style dietary pattern with vitamin D3 supplement (10 IU/day) did not gain any profit on the bone mineral density (BMD) after 1-year intervention. However, those subjects with OP experienced a notable decrease in bone loss at the femoral neck [86]. Circulating level of vitamin K2 (subtype MK-7, menaquinone) is also known to exert a strong beneficial effect in reducing the risk of fractures. MK-7 aids to stimulate the formation of osteoblasts and inhibit the activity of osteoclasts. In osteoblasts, MK-7 facilitates protein synthesis of osteocalcin and various other proteins [87]. Almost all the MKs are synthesized by bacteria in fermented foods, among which MK-7 is rich in nattō, a traditional Japanese dish made from fermented soybeans. Interestingly, a study on the effect of Japanese nattō on serum vitamin K levels found that the ratio of serum MK-7 concentration levels between Eastern Japanese women and British women was 15:1 [88]. As we mentioned, MedDiet pattern recommends heavy consumption of legumes, so nattō appears to be a good option for bone health. Similarly, a prospective European study on cancer and nutrition targeting both males and females (n = 188,795) found that higher MedDiet adherence resulted in a 7% decrease in the incidence of OP hip fracture (HR 0.93; 95% CI 0.89–0.98), especially in males [89]. All these evidences have proposed the competence of MedDiet and its ingredient (EVOO) for tertiary prevention of OP-related complications. Evidence to date, although not extensive, points to a positive impact of MedDiet compliance on preventing OP-related complications, as well as BMD, muscle mass, and body function. The ability to reduce oxidative stress and inflammation of bioactive compounds such as phytochemicals and antioxidants in MedDiet, which are abundant in fruits and vegetables, can be accounted to improving bone and muscle metabolism (Fig. 1) [83]. Therefore, this diet is proposed as a preventive modality that can slow down the incidence of OP and its complications [90].

MedDiet and cancers

In 2020, 19.3 million new cancer cases and nearly 10 million cancer-related deaths were reported [91]. An estimated 30–40% of cancers can be prevented by physical activity, appropriate diet, and maintaining a proper body weight [92, 93]. Breast cancer has overtaken lung cancer as the most prevalent cancer in the world, with an estimated 2.26 million new cases in 2020, and several studies have underscored a reverse relationship between high compliance to MedDiet and the incidence of breast cancer [91]. A prospective cohort study investigating the correlation between compliance of MedDiet and breast cancer risk in 335,062 women recruited in 10 European countries between 1992 and 2000 found a 6% reduction in breast cancer incidence resulted from high MedDiet adherence after a mean of 11-year follow-up [94]. Besides, a prospective cohort study conducted in the Netherlands, which investigated MedDiet adherence and postmenopausal breast cancer risk in 62,573 females aged 55–69 recruited from 1986 to 2007, revealed that postmenopausal women with high MedDiet compliance had a significant reduced breast cancer risk by 40%, with a hazard ratio (HR) of 0.60 for high versus low adherence to MedDiet [95]. It follows that the MedDiet has a role in primary prevention in reducing the risk of breast cancer. A hospital-based case–control study conducted in Switzerland and Italy with 3034 cases of breast cancer and 3392 control groups with acute, non-neoplastic, and non-gynecologic diseases unfolded similar results in premenopausal and postmenopausal females that is adherence to MedDiet was related to a reduction in breast cancer risk (OR = 0.81, 95% CI 0.70, 0.95, for MedDiet score ≥ 6) [96]. Additionally, MedDiet may be beneficial in decreasing colorectal cancer (CRC) risk, as non-healthy dietary model is supposed to be the most crucial risk factor for the development of this tumor [97, 98]. MCC (multicase-control)-Spain is a multicenter controlled study collecting information on 1629 CRC case events and 3509 population-based controls from 11 provinces in Spain, with findings demonstrating that higher MedDiet adherence was able to reduce CRC risk by roughly 30% and 45% for males and females, respectively (men: OR fourth(Q4) vs. first(Q1) quartile (95% CI), 0.71 (0.55, 0.92); women: ORQ4 vs. Q1 (95%CI), 0.56 (0.40, 0.77)) [99]. Data from three case–control studies of the association between MedDiet and CRC in Italy (including a total of 3745 CRC cases and 6804 hospital controls) by Valentina Rosato et al. has disclosed that the highest MedDiet adherence reduced colon cancer risk by about 50% compared with the lowest MedDiet adherence, confirming the beneficial effect of MedDiet on CRC risk [100]. The high protective ability of MedDiet was also proved in Ratjen’s recent studies, where they demonstrated that high MedDiet adherence could reduce the mortality of CRC patients [101]. Regarding gastric cancer (GC), although there are many pathogenic factors (e.g., Helicobacter pylori) that contribute to its onset, adhering to a healthy lifestyle is still the primary medical strategy for preventing GC. Higher MedDiet adherence significantly decreased the incidence of GC: comparing with subjects in the lowest MedDiet adherence category (0–3), the risk percentages of subjects in the medium (4–5) and high (≥ 6) categories decreased to 22% and 43%, respectively (ORs = 0.78, 0.61, and 0.57 for the corresponding MedDiet score), indicating a significant reversal trend in the risk of GC development after MedDiet [102]. These quality longitudinal studies all highly point to the reliable preventive effect of MedDiet on the incidence of cancer, including breast cancer and gastrointestinal cancer. The positive correlation (beneficial effect) between MedDiet and cancer may be owing to the fact that MedDiet foods (beans, vegetables, fresh fruits or nuts, fish, and olive oil) contain high levels of antioxidants and anti-inflammatory agents disturbing the proliferation and degeneration of cancer cells (Fig. 1) [103]. For instance, it is still the HT in olive oil that is of concern. Bouallagui et al. have declared its cytotoxic effects against MCF-7 breast cancer cells by blocking the cell cycle arrest in the G0/G1 phase [104]. Moreover, in human hepatocellular carcinoma (HCC) cells, HT induced cell cycle arrest and apoptosis through restraining the AKT activation and nuclear factor-kappa B pathway [105]. Therefore, following 3PM principles and further deep investigation is promising, whether in view of MedDiet’s potential as a guiding diet for cancer prevention, or its nutrients as cancer preventive food additive.

Conclusions, expert recommendations, and outlook

Predictive medicine

Predictive medicine aims to identify the risks of NCDs, such as cardiovascular disease, diabetes, and cancer, for targeted prevention, while the development of these diseases shares the common initiating events and biological processes of chronic inflammation and oxidative stress, which is therefore a crucial target for the regulation and amelioration of these diseases [106]. Similarly, research on mitochondrial health quality control, general mitigating measures against oxidative mitochondrial damage are based on the antioxidant defense with scavenging activities, personalized lifestyle recommendations, and dietary habits [107]. However, a variety of phytochemicals in MedDiet, especially phenolic substances, have positive anti-inflammatory and antioxidant effects. In addition, it can also reduce the production of mitochondrial ROS and improve mitochondrial damage and cell apoptosis [108]. Therefore, MedDiet, abundant in minimally processed plant-based foods and rich in monounsaturated fat from olive oil, but low in saturated fat from red meats and dairy products, seems to be an ideal nutritional model for mitigating oxidative stress and inflammation and thus is related to a lower risk of many chronic diseases [109].

Fittingly, the above evidence emphasized diet as a protective factor for preventing and treating NCDs and reducing mortality, especially when consuming large quantities of fresh fruits, vegetables, and olive oil, as they have antioxidant and anti-inflammatory properties. The MedDiet can not only prevent the occurrence of T2DM, obesity, MetS, and other diseases by increasing total antioxidant capacity and reducing inflammation to achieve a primary prevention. Evidence derived from prediction analysis of ischemic stroke with unclear etiology has shown that in T2DM individuals and other subpopulations, especially proliferative diabetic retinopathy is an independent predictor of ischemic stroke [110], thereby it can be speculated that the primary prevention effect of MedDiet on T2DM can also prevent the occurrence of ischemic stroke and reduce its incidence. The Lyon Diet Heart Study also investigated the positive effects of the Mediterranean dietary pattern on the secondary prevention of CVD. Moreover, a large number of studies have confirmed that MedDiet can reduce the mortality of CVD, T2DM, and CRC, and obesity-related complications, that is, achieve a tertiary prevention effect. During the data collection, we addedly have got a summary that MedDiet affects the metabolic outcomes (insulin resistance, intrahepatic lipid, hepatic steatosis, and inflammation) of metabolic dysfunction-associated fatty liver disease (MAFLD) [111]. Thus, the combination of a healthy diet with social behavior and lifestyle stands a good chance to make MedDiet a sustainable lifestyle model.

Expert recommendations

The “dietary heart hypothesis” has been actively promoted by experts over the past 50 years, proposing a series of etiological relationships between saturated fat content in diet, serum cholesterol concentration, and disease development of CVD [112]. Strong evidence comes from PREDIMED trial that the MedDiet reduced CVD events by 30%, which is indeed remarkable and strengthens the evidence supporting the recommendation of MedDiet for primary prevention of coronary artery disease (CAD) [113]. Similarly, the Lyon Heart Study is a landmark study examining the efficacy of MedDiet in secondary prevention of CAD. Therefore, in the prevention of CVD-related events, MedDiet plays an essential role and is worthy of widespread application. At the same time, MedDiet pattern is also worth of promoting in the treatment of MAFLD. According to an expert review on the updated AGA Clinical Practice, following a MedDiet pattern is recommended as the preferred dietary pattern for MAFLD patients by minimizing saturated fat, specifically red meat and processed meat, and commercially produced fructose, as well as by consuming dietary fiber, monounsaturated fatty acids, and ω-3 fatty acids and phytosterols, which is conducive to the prevention and treatment of a variety of metabolic diseases (including CVD and diabetes) and is related to the reduction of overall mortality [9]. Nevertheless, the inclusion of MedDiet in the guidelines for the prevention and treatment of various chronic diseases needs to be further advocated.

Future of personalized medicine

PPPM/3PM is by far the most beneficial to health care and suitable for the management of chronic diseases, such as diabetes and cancer [114, 115]. Following the principles of PPPM/3P medicine, which adopts predictive diagnosis, carries out medical dietary prevention and treatment tailored to individual disease characteristics, is safe, healthy, effective, cost-effective, and suitable for individuals with chronic diseases [116]. For example, as a systemic multifactorial disease, the occurrence of prostate cancer (PCa) can be contributed by inflammatory reactions, MetS, abnormal BMI, and other factors. A study on the PCa management highlights the importance of personalized nutrition in PCa prevention, including strongly recommended consumption of fish, cruciferous vegetables, berries, etc. [117]; hence, from the above-recommended foods, it can be speculated that MedDiet may also be applicable for the prevention of PCa and can provide personalized nutritional support. Furthermore, certain personalized medicine studies have looked at the effects of the MedDiet on specific states of disease or specific populations of disease, or the disparate effects of the tilt of the dietary components themselves on disease. Regarding the role of MedDiet in obesity control, although the results are currently mixed, some evidence also pointed out that energy-restricted MedDiet in particular can reduce adiposity and has the advantage of concurrent chronic disease management over certain dietary patterns (e.g., low-fat, low-carbohydrate). MedDiet is therefore considered the best option for personalized medical diets targeting obese individuals with other NCDs. Meanwhile, the evidence with pregnant women supports the beneficial role of MedDiet in the gestational diabetes preventive medicine, and MedDiet adherence may help prevent age-related changes in BP. More refined and personalized dietary patterns, such as MedDiet-EVOO and MediDiet-nuts, have been discussed in several studies, for instance, MedDiet-EVOO intervention is superior to MedDiet-nuts intervention in decreasing OP-related fractures. Therefore, personalized medical diets should be orientated to different diseases, which may be more conducive to preventing or treating complications related to chronic diseases [118]. Public health policies and appropriate nutrition recommendations are also required to promote MedDiet or other healthy plant-based diet and healthy lifestyles at different levels (such as primary care centers, universities, schools, and hospitals), which should be the cornerstone of chronic disease prevention at the national and international level. It is important to note that despite high-quality evidence highlighting the health benefits of MedDiet, there are still a number of obstacles that often impede compliance to this pattern, including lack of cooking skills, time, availability, and financial constraints. Therefore, promoting the adoption of MedDiet and adapting its features to food supply as well as country-specific and culturally appropriate differences are crucial [119].

Over the last decades, there has been a growing awareness that dietary patterns affect health, especially as many studies have showed significant effects of nutrients on human metabolic function and disease processes. Of several dietary patterns, MedDiet is widely considered to be a pattern of “healthy eating” due to its contribution to health status and its positive impact on quality of life. As discussed in this review, strict adherence to MedDiet benefits in preventing chronic diseases, delaying or countering their incidence, and reducing their mortality or complications. In the future, it is believed that following MedDiet can become a part of personalized nutrition to improve people’s health. From this perspective, 3PM can help identify problems and find solutions to alleviate inflammation and oxidative-stress-related complications of chronic diseases through the concept of “food as medicine” [120].

Abbreviations

AGA

America Gastroenterological Association

BP

Blood pressure

BMI

Body mass index

BMD

Bone mineral density

CI

Confidence interval

CVD

Cardiovascular disease

CRC

Colorectal cancer

CAD

Coronary artery disease

DASH

Dietary Approaches to Stop Hypertension

DRRD

Diabetes Risk Reduction Diet

DM

Diabetes mellitus

DBP

Diastolic BP

EVOO

Extra virgin olive oil

ESC

European Society of Cardiology

ESH

European Society of Hypertension

EPIC

European Prospective Survey of Cancer and Nutrition

GC

Gastric cancer

HT

Hydroxytyrosol

HR

Hazard ratio

HCC

Human hepatocellular carcinoma

IDF

International Diabetes Federation

MUFA

Monounsaturated fatty acids

MetS

Metabolic syndrome

MAFLD

Metabolic dysfunction-associated fatty liver disease

MCF-7

Michigan Cancer Foundation-7

NCDs

Non-communicable diseases

OA

Oleic acid

OL

Oleuropein

OP

Osteoporosis

OR

Odds ratio

PPPM/3PM

Predictive, preventive, and personalized medicine

PCa

Prostate cancer

RCTs

Randomized controlled trials

ROS

Reactive oxygen species

RR

Relative risk

SBP

Systolic BP

SUN

Seguimiento Universidad de Navarra

TG

Triglyceride

T2DM

Type 2 diabetes mellitus

VOO

Virgin olive oil

Author contribution

YX and XX collaborated on writing the original manuscript and the figure design. XZ, DY, TL, QH, and FZ reviewed the manuscript. NW and XL designed the study and revised the manuscript. All authors have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Funding

This work is supported by National Natural Science Foundation of China (Grant No. 82003476) and Dalian Medical University Interdisciplinary Research Cooperation Project Team Funding (Grant No. JCHZ2023012).

Data availability

Not available.

Code availability

Not available.

Declarations

Ethical approval

Not available.

Consent to participate

Not applicable.

Consent for publication

All authors had accepted responsibility to submit for publication.

Competing interests

The authors declare no competing interests.

Conflict of interest

The authors declare no competing interests.