The Mediterranean diet is based on food patterns typical of Greece and southern Italy in the 1960s. This dietary pattern, which is traditionally presented as a food pyramid, 14 consists of abundant plant foods (fruit, vegetable, cereals, potatoes, beans, nuts and seeds), olive oil as the principal source of fat, dairy products, fish and poultry consumed in low to moderate amounts, 0 to 4 eggs per week, red meat consumed in low amounts, and wine consumed in low to moderate amounts, normally with meals. This diet is low in saturated fat and has been associated with multiple health benefits, including lower incidence of cardiovascular disease, neurodegenerative diseases, diabetes, and overall cancer, as well as longer survival. 15 - 17 Only a few studies have examined associations between the Mediterranean diet and frailty risk, and the results have been mixed and inconclusive. 11 , 13 Furthermore, to our knowledge, no meta‐analysis has been performed. The objectives of the current study were thus to conduct a systematic review of the literature on prospective cohort studies examining associations between adherence to a Mediterranean diet and incident frailty and to perform a meta‐analysis to synthesize the pooled risk estimates.

Nutrition is considered to play a crucial role in the complex pathogenesis of frailty. 10 Nutrition provides energy and essential nutrients and helps the human body to function properly and maintain homeostasis. The nutrients found in observational and intervention studies to show promising results in relation to frailty are protein and some selected micronutrients, such as carotenoids and vitamins. 11 , 12 Although evidence on individual nutrients or food items is important, when the food is consumed, various micro‐ and macronutrients interact with each other, and may cause synergistic effects. Therefore, instead of focusing on a single dietary component, it may be more reasonable to describe the overall consumption of a diet as a dietary pattern. 13

Frailty is a geriatric syndrome common in older people, and its prevalence is considered to increase with population aging. 1 Although consensus has not been reached on a criterion standard definition, frailty is generally defined as a state of greater vulnerability due to age‐related accumulation of deficits and low physiological reserves across multiple systems. 1 Frailty predicts numerous negative health outcomes in older people, including falls, 2 fractures, 3 hospitalization, 4 nursing home placement, 5 disability, 6 dementia, 7 and premature death, 8 and is associated with poorer quality of life. 9

A meta‐analysis was attempted when there were 3 or more studies providing the same type of effect measures of frailty risk and adherence to a Mediterranean diet was based on the same tool. Adjusted effect measures were preferred to unadjusted ones when a study reported both. The presence and degree of heterogeneity were assessed using the chi‐square test and I 2 statistic, respectively, and I 2 values of 25%, 50%, and 75% were considered to be low, moderate, and high degrees of heterogeneity, respectively. 21 A fixed‐effects model was used if heterogeneity was absent, and a random‐effects model was used if heterogeneity was present, to calculate a pooled risk estimate using the generic inverse variance method. Publication bias was assessed using visual inspection of funnel plots. If significant heterogeneity was observed, sensitivity analysis, subgroup analysis, and random‐effects metaregression analysis would be performed to further explore the cause of the heterogeneity. Review Manager 5, version 5.2 (The Cochrane Collaboration, Copenhagen, Denmark) was used for all analyses, and the level of significance was set at P < .05.

Two reviewers (GK, CA) independently screened titles, abstracts, and full texts to ascertain the eligibility of the studies identified in the literature search. Disagreements were resolved by discussion. Studies were included if they involved community‐dwelling older people with a mean age of 60 and older; assessed adherence to a Mediterranean diet using a tool such as the Mediterranean Diet Score (MDS) 17 ; prospectively examined risk of developing frailty, defined using an original or modified version of validated criteria designed to define frailty, according to adherence to a Mediterranean diet at baseline; and provided odds ratios (ORs), hazard ratios (HRs), or risk ratios (RRs) to quantify risk or sufficient information to calculate these risk estimates.

A systematic search of the literature was conducted on September 14, 2017, based on a protocol generated in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines for systematic reviews. 18 The 5 databases used were Embase, MEDLINE, CINAHL Plus, PsycINFO, and Cochrane Library (Table S1 ). We searched for studies published in 2000 or later, because the most commonly used frailty phenotype criteria were first published in 2001. 19 The search terms used were a combination of Medical Subject Heading (MeSH) and text terms, including “Mediterranean diet” (MeSH) OR “Mediterranean*” AND “Frailty Syndrome” (MeSH) OR “frail*.” We used explosion functions where available and did not restrict the search by language. We reviewed references of included studies and relevant review papers and performed forward citation tracking using Google Scholar for additional studies. We also contacted corresponding authors for additional data necessary for a meta‐analysis.

ORs of incident frailty risk according to 3 MDS groups (0–3, 4–5, 6–9) were available from 4 studies 22 - 25 and used for a fixed‐effects meta‐analysis because no significant heterogeneity ( I 2 = 0%, P = .84; I 2 = 16%, P = .31, respectively) was observed. The forest plots are shown in Figure 2 . Greater adherence to a Mediterranean diet was associated with significantly lower incident frailty risks than low adherence (MDS 0–3) (4 studies: pooled OR = 0.62, 95% CI = 0.47–0.82, P = .001 for MDS 4–5; pooled OR = 0.44, 95% CI = 0.31–0.64, P < .001 for MDS 6–9). No obvious asymmetry was observed in the funnel plots for either analysis. We repeated meta‐analyses using a random‐effects model (4 studies: pooled OR = 0.62, 95% CI = 0.47–0.82, P = .001 for MDS 4–5; pooled OR = 0.44, 95% CI = 0.29–0.66, P < .001 for MDS 6–9) and excluding the Chinese study 25 (3 studies: pooled OR = 0.60, 95% CI = 0.44–0.82, P = .001 for MDS 4–5; pooled OR = 0.40, 95% CI = 0.27–0.65, P < .001 for MDS 6–9). These made little difference in our findings. Subgroup analysis and metaregression analysis were not performed because of the low degree of heterogeneity and the small number of included studies.

Figure 1 presents the PRISMA flowchart of the study selection process. Of a total of 125 studies identified, 4 were included (5,789 older people with a mean follow‐up of 3.9 years), all of which met 7 or more of the 9 items of the Newcastle‐Ottawa scale (mean 8.0, range 7–9, Table S2 ). Characteristics of the 4 included studies are summarized in Table 1 . All 4 studies used the MDS, which is a tool used to measure adherence to the traditional Mediterranean diet based on the salient characteristic of this diet; scores range from 0 to 9, with a higher score indicative of greater adherence. 17 Three studies 22 - 24 used modified versions of the Cardiovascular Health Study frailty criteria, which is one of the most widely used measures to define physical frailty based on 5 criteria (unintentional weight loss, self‐reported exhaustion, weakness, slow walking speed, low physical activity). 19 One study 25 used the FRAIL scale, which can measure frailty according to the answers to 5 simple questions about fatigue, resistance, ambulation, illnesses, and loss of weight. 26 Two studies divided their cohort into 3 groups (MDS 0–3, 4–5, 6–9), 23 , 24 and 1 study used sex‐stratified tertiles. 22 Two studies used the MDS as a continuous variable. 24 , 25 All 4 studies included in this review provided ORs of incident frailty risks and used the MDS to measure adherence to a Mediterranean diet, 22 - 25 so ORs according to the MDS were chosen for the meta‐analysis. One of the 4 studies showed results using the Mediterranean Diet Adherence Screener as well. 22 All ORs were adjusted for multiple confounders, which included age, sex, education, marital status, body mass index, smoking, alcohol, living status, energy intake, medication, physical activity, and comorbidities (Table 1 ).

Discussion

This systematic review and meta‐analysis identified 4 studies that included a total of 5,789 community‐dwelling older people followed for a mean 3.9 years and found that greater adherence to a Mediterranean diet was significantly associated with lower risk of incident frailty.

Adherence to a Mediterranean diet was measured using the MDS17 in all the included studies. The MDS is based on intake of food items specific to the traditional Mediterranean dietary pattern: high intake of fruits, vegetables, legumes, nuts, cereals, fish, and olive oil (coupled with low intake of saturated fats); low intake of meat and dairy products; and regular but moderate intake of alcohol, mostly wine.17 The beneficial effects of a Mediterranean dietary pattern on frailty that we observed is consistent with findings from a cross‐sectional study of 923 older Taiwanese adults that explored 79 food items to find the dietary pattern most protective against frailty using reduced rank regression analysis.27 In the dietary pattern identified as best for explaining frailty status, fresh fruits, nuts and seeds, vegetables, whole grains, fish, and breakfast cereals were among the top food items demonstrating protective effects against frailty (factor loading value = −0.48, −0.39, −0.33, −0.27, −0.20, and −0.17, respectively).27 Olive oil and wine were not included, perhaps because this non‐Mediterranean population did not commonly consume them.

In addition to the Mediterranean diet, other dietary patterns have been investigated and found to be associated with future frailty risks. A “prudent” dietary pattern characterized by high consumption of olive oil, vegetables, potatoes, legumes, blue fish, pasta, and meat was identified using principal component analysis and was shown to be associated with lower risk of incident frailty over 3.5 years of follow‐up in 1,872 older Spanish adults.28 Another study used the Three‐City Study Bordeaux cohort of 972 older adults and showed that a “healthy” cluster defined according to a hybrid clustering method, which is associated with high intake of fish in men and fruits and vegetables in women, was associated with lower risk of developing frailty during a follow‐up of 12 years.29 A study from the Netherlands found that high adherence to a “traditional” dietary pattern, characterized by a high intake of savory snacks, legumes, eggs, fried potatoes, alcohol, processed meat, and soup, was also associated with less frailty defined according to the Frailty Index 4 years later.30 This effect was observed despite this dietary pattern including foods such as fried potatoes and processed meat, which are associated with higher incidence of cardiovascular disease. Three studies examined associations between quality of diet using the Dietary Quality Index (based on dietary variety; adequacy of vegetables, fruits, grains, fiber, protein, iron, calcium, and vitamin C; moderation of total fat, saturated fat, cholesterol, sodium, and empty calorie foods; and overall balance of macronutrient ratio and fatty acid ratio)25, 31 and the Dutch Healthy Diet index (based on vegetables, fruits, fiber, fish and fish oil, saturated fatty acid, trans‐fatty acids, sodium, and alcohol)30 and subsequent frailty risks and found that higher dietary quality was consistently associated with lower future frailty risks. These findings are at least partially in line with ours in that some dietary components are in common with a Mediterranean diet, such as olive oil, vegetables, fruits, legumes, and fish.

This study's strengths include its robust methodology, including a comprehensive and reproducible search strategy following PRISMA guidelines.18 Two authors independently reviewed the search results and extracted the data. In addition, methodological quality, heterogeneity, and publication bias were assessed. We were able to include all 4 of the studies in the meta‐analysis by obtaining additional data from the authors of the original articles.22, 25 All 4 studies had adequate methodological quality, and there was low degree of heterogeneity in their findings. Furthermore, all the effect measures combined in the meta‐analysis were fully adjusted for multiple confounders, including age, sex and education, which should contribute to the robustness of our synthesized results. Nevertheless, the current study is not without limitations. Only a small number (n = 4) of studies were identified, probably because frailty research in relation to diet has only recently emerged. Further studies are warranted to elucidate associations between the Mediterranean diet and frailty, in particular in non‐Mediterranean countries. In addition, further information on which components of the Mediterranean diet are associated with frailty (e.g. fruit and vegetable, red wine) and which components of frailty are most affected (e.g. measure of muscle strength, exhaustion or weight loss) would give further insight. Adherence to a Mediterranean diet was measured using the MDS in all the studies included. Although the MDS may be a good indicator of adherence to a Mediterranean diet in Mediterranean populations, its relevance to non‐Mediterranean populations is contested.32 Some of the MDS components were based on actual food consumption with cut‐points specific to the study population (e.g., median value of the intake), rather than based on the intake recommended in a traditional Mediterranean diet.17 Therefore the findings based on the MDS may not reflect true adherence to a Mediterranean diet,33 especially in non‐Mediterranean populations.25 Lastly, there may be potentially unmeasured confounding because not all studies adjusted for factors related to a healthier lifestyle in general, such as smoking, alcohol, and physical activity.

There are several potential mechanisms underlying the association between greater adherence to a Mediterranean diet and lower risk of frailty. One possibility is the high intake of foods rich in antioxidants. Fruits and vegetables are rich in carotenoids and vitamins, and red wine contains abundant polyphenols. Oxidative stress is a risk factor for frailty,34 and fruits and vegetables rich in antioxidants may decrease the risk of frailty by counteracting oxidative status. Inflammation is another possible explanation. Frail individuals have higher levels of inflammatory markers, and inflammation is considered to be closely associated with frailty.35 A Mediterranean diet is associated with low levels of inflammatory markers36 and may reduce frailty risk through this mechanism. Adherence to a Mediterranean diet has been associated with better cognitive function, lower rates of cognitive decline, and lower risks of Alzheimer's disease and dementia.37, 38 Moreover, the Mediterranean diet has been associated with lower incidence of cardiovascular disease39 and certain types of cancers, such as colorectal cancer.40 All of the above may contribute to the accumulation of fewer health deficits over time, resulting in a lower incidence of frailty.