In this meta-analysis there was a 24%, 11%, 19%, 18%, and 19% reduction in the relative risk of coronary heart disease, stroke, cardiovascular disease, total cancer, and all-cause mortality with a higher nut intake, respectively. In the dose–response analysis there was a 29%, 7%, 21%, 15%, and 22% reduction in the relative risk for a one serving per day increase in nut intake (one serving = 28 grams), respectively, although the association for stroke was not statistically significant in the linear dose–response analysis. There was evidence of a nonlinear association between nut intake and coronary heart disease, stroke, cardiovascular disease, total cancer, and all-cause mortality, with most of the reduction in risk observed up to an intake of approximately 15–20 grams per day or 5–6 servings per week for most of the outcomes. In addition, there was a 52%, 39%, and 75% reduction in the relative risk of respiratory disease, diabetes, and infectious disease mortality, respectively, for a one serving per day increase in intake, and non-significant inverse associations were also observed for neurodegenerative disease mortality and kidney disease mortality, although the number of studies was low. The intake of both peanuts and tree nuts was associated with a reduced risk of coronary heart disease, cardiovascular disease, and mortality; however, only the intake of peanuts was associated with reduced risk of stroke, while the intake of tree nuts was associated with reduced cancer risk. Inverse associations were observed in European and American studies as well as in Asian studies of peanuts. Intake of peanut butter was inversely associated with mortality in the high versus low analysis, but not in the dose–response analysis. Although it is possible that the added sugar or salt in peanut butter could counteract any beneficial effects of plain peanuts, the limited number of studies makes the interpretation of those results difficult.

Under the assumption that the observed associations are causal we estimated that approximately 4.4 million premature deaths in the regions covered, including North and South America, Europe, Southeast Asia, and Western Pacific, may be attributable to a nut intake below 20 grams per day. For specific causes of death, we estimated that 1.19 million deaths due to coronary heart disease, 469,000 due to cancer, 1.07 million due to respiratory disease, and 138,000 due to diabetes may be caused by a nut intake below 20 grams per day. However, the appropriateness of these estimates is dependent on the validity of several assumptions, including that of (1) a causal relationship between nut consumption and these outcomes, (2) lack of confounding and measurement error in explaining the results, and (3) the generalizability of the results to the regions covered.

Our meta-analysis provides the most up-to-date summary estimates of the association between nut consumption and cardiovascular disease, cancer, and all-cause and cause-specific mortality and is consistent with previous reviews and meta-analyses that have been published on the topic [29, 31, 61]. Nevertheless, the current meta-analysis contains 1.5–3 times the number of studies compared to the previously published meta-analyses and approximately twice the number of all-cause deaths. For example, in the dose–response analysis of nut intake and all-cause mortality we included 15 studies (85,870 deaths), compared to 5 studies (48,818 deaths) [29], 7 studies (44,636 deaths) [31], and 10 studies (49,232 deaths) in previous meta-analyses [61]. In the dose–response analysis of coronary heart disease, stroke, cardiovascular disease, and total cancer, we included 11, 11, 12, and 8 studies, respectively, compared to 6 and 4 studies for coronary heart disease and stroke in one meta-analysis [30], 7 and 4 studies on coronary heart disease and stroke in another meta-analysis [62], 5 and 3 studies for cardiovascular and cancer mortality in a third meta-analysis [31], and 4 studies on cancer mortality in a fourth meta-analysis [16]. In addition, we found inverse associations between nut consumption and mortality from respiratory disease, diabetes, and infections, although the number of studies in these analyses was low and further studies are needed to confirm these findings.

Some potential limitations of our meta-analysis should be mentioned. There was high heterogeneity in the analysis of cardiovascular disease and all-cause mortality. Some heterogeneity is expected because of differences in the age groups included, geographic location, detail of the dietary assessment, factors adjusted for in the analyses, types of nuts consumed, as well as the distribution of specific causes of death and cancers that contribute to all-cause mortality and total cancer. For cardiovascular disease and all-cause mortality, the heterogeneity was driven more by differences in the strength of the associations than differences in the direction of the association. In the analysis of cardiovascular disease, there was between-subgroup heterogeneity when stratified by sex, with a stronger inverse association among men than women and no heterogeneity within subgroups. However, associations for coronary heart disease and stroke were similar when stratified by sex, thus we cannot exclude the possibility that chance could explain this sex difference for cardiovascular disease. There was also heterogeneity when stratified by adjustment for smoking, hypertension, and whole grains, with stronger associations in studies with adjustment for smoking and hypertension than in studies without such adjustment and a weaker association among studies with adjustment for whole grains than in studies without. In the analysis of all-cause mortality there was little evidence of heterogeneity between subgroups, with the exception of a slightly weaker association among studies with a longer compared to a shorter duration of follow-up. There was no evidence of heterogeneity in the analysis of stroke and total cancer, and moderate heterogeneity in the analysis of coronary heart disease. There was no evidence of heterogeneity when analyses were stratified by geographic location. Although there were some differences among the included studies with regard to the amounts and ranges of nut intake, this was taken into account in the dose–response analyses. Subjects with a high intake of nuts tend to be less likely to smoke, to be slimmer and more physically active, and to have a lower intake of red and processed meat and a higher intake of fruits and vegetables than persons with a low nut intake [13], thus confounding by other lifestyle and dietary factors is a potential source of bias. However, in subgroup analyses we found that the associations observed persisted among studies which adjusted for smoking, alcohol, physical activity, BMI, and dietary factors such as red meat and fruit and vegetables. In addition, in the Nurses’ Health Study and the Health Professionals Follow-up Study the inverse associations persisted when analyses were stratified by these and other potential confounding factors [13]. Measurement errors may have affected the findings, but none of the included studies made corrections for measurement error; however, because of the prospective design of the included studies such errors would most likely attenuate the strength of the observed associations [63].

There was a limited number of studies in the analyses of mortality from respiratory disease, diabetes, infections, neurodegenerative disease, and kidney disease and the potential for selective reporting cannot be entirely excluded. However, it is also possible that most of the included studies may have been too small to have adequate power to investigate these less common causes of death. Further studies are therefore needed on these and other less common causes of death. We did not identify any potentially relevant studies in non-English language, thus language bias is less likely to have influenced the findings. None of the included studies were identified solely from the screening of article references, thus it seems less likely that citation bias has had any influence on the results. Although the initial study selection was performed by one author, two authors independently assessed the potentially relevant studies for inclusion, and all studies included in previous reviews were identified by the search as well as additional studies that were missed by previous reviews, suggesting that selection bias is also less likely to be an issue.

The number of studies that investigated specific types of nuts was limited; thus, any further studies should try to clarify associations between specific subtypes of nuts and cardiovascular disease, cancer, and mortality. However, randomized controlled trials have suggested similar effects of different types of nuts on cardiovascular risk factors [4], which supports our findings with regard to peanuts and tree nuts in relation to coronary heart disease and cardiovascular disease and overall mortality, although only tree nuts were associated with reduced risk of cancer. The PREDIMED study suggested similar associations between walnuts and all other nuts in relation to cardiovascular disease and all-cause mortality; however, walnuts were more strongly associated with cancer mortality than all other nuts [21]. As in any meta-analysis of published studies, publication bias could have influenced the results; however, there was evidence of publication bias only in the analysis of all-cause mortality, but after exclusion of four studies with less than 500 deaths [10, 18, 21, 22], the test for publication bias was not significant, but the summary estimates remained similar, thus publication bias has most likely not substantially influenced the overall findings.

Although results from observational studies alone cannot be used to draw conclusions with regards to whether the observed associations are causal, one randomized trial (the PREDIMED study) also found a reduced risk of cardiovascular disease in subjects randomized to a Mediterranean diet with nuts compared to subjects randomized to a control diet [64]; however, it is not clear if this association is due to the Mediterranean diet component, nuts, or a combination of the two. In addition, several mechanisms might explain the beneficial effect observed between nut intake and cardiovascular disease, total cancer, and all-cause mortality. Nuts are good sources of unsaturated fatty acids, protein, fiber, vitamin E, potassium, magnesium, and phytochemicals. Intervention studies have shown that nut consumption reduces total cholesterol, low-density lipoprotein cholesterol, and the ratio of low- to high-density lipoprotein cholesterol, and ratio of total to high-density lipoprotein cholesterol, apolipoprotein B, and triglyceride levels in a dose–response manner [4, 65]. In addition, studies have shown reduced endothelial dysfunction [8], lipid peroxidation [7], and insulin resistance [6, 66] with a higher intake of nuts. Oxidative damage and insulin resistance are important pathogenic drivers of cancer [67, 68] and a number of specific causes of death [69]. Nuts and seeds and particularly walnuts, pecans, and sunflower seeds have a high antioxidant content [70], and could prevent cancer by reducing oxidative DNA damage [9], cell proliferation [71, 72], inflammation [73, 74], and circulating insulin-like growth factor 1 concentrations [75] and by inducing apoptosis [71], suppressing angiogenesis [76], and altering the gut microbiota [77]. Although nuts are high in total fat, they have been associated with lower weight gain [78–80] and lower risk of overweight and obesity [79] in observational studies and some randomized controlled trials [80]. However, the inverse associations observed between nut intake and chronic disease in this meta-analysis persisted among studies that adjusted for BMI, suggesting an association independent of BMI. In addition, it is possible that a high intake of nuts may reduce the severity of disease and progression to death as indicated by studies which found that patients with diabetes, coronary heart disease, and heart failure who consumed more nuts had a reduced risk of cardiovascular disease or all-cause mortality [81–83]. Although we observed similar associations for both incidence and mortality from coronary heart disease and cardiovascular disease, epidemiological studies on nut consumption and type 2 diabetes incidence have largely shown no association [29], while in the present meta-analysis we found a reduced risk of diabetes mortality, which might be due to reduced risk of cardio-metabolic risk factors and complications in diabetes patients with a high nut intake [83–85].

Strengths of the current meta-analysis include the comprehensive and up-to-date search strategy that identified several large additional studies; inclusion of prospective studies, which limits the possibilities for certain biases; the detailed dose–response analyses, which clarified the amount of nut intake needed to reduce the risk of cardiovascular disease, cancer, and all-cause and cause-specific mortality; the consistency and robustness of the findings in a number of subgroup and sensitivity analyses; the high study quality of the included studies; and the large number of participants, which provided statistical power to detect moderate associations between nut consumption and different health outcomes. The observation that nut intake was inversely associated with these outcomes in both men and women and when stratified by geographic location, is a further strength of the analysis.

We estimated that approximately 4.4 million deaths in the regions included may be attributable to nut consumption below 20 grams per day. As shown in the current meta-analysis, nut consumption appears to reduce the risk of coronary heart disease, cardiovascular disease overall, total cancer, all-cause mortality, and mortality from respiratory disease, diabetes and possibly other causes, so using data on nut intake and all-cause mortality will provide a more comprehensive assessment of the mortality burden due to low nut consumption than only analysing mortality from specific diseases (such as coronary heart disease and cancer), at least for regions with a similar distribution of specific causes of death as those included in the meta-analysis. Another limitation is that, for the calculation of the population-attributable risk, we did not find dietary surveys on nut intake from some regions, including Africa, the Middle East and West-Asia, and therefore, in a global context, these estimates are conservative.

These findings support recommendations to increase intake of nuts to reduce risk of chronic diseases and premature mortality in the general population. However, in regions of the world where nuts are a major source of aflatoxin [86], increasing nut intake should only be recommended as long as aflatoxin contamination is avoided in the affected countries. Any further studies should investigate associations with specific types of nuts and the association between nut intake and incidence and mortality from less common diseases, adjust for more dietary confounders, clarify mechanisms underlying non-cardiovascular causes of death, and investigate associations between biomarkers of nut consumption in relation to health outcomes [87, 88]. In addition, further studies from other regions of the world are also needed.