In this longitudinal cohort study of individuals at high cardiovascular risk with relatively high nut intake living in a Mediterranean country, the frequency of nut consumption was inversely related to total mortality after 4.8 years of follow-up. Compared to non-consumers, subjects who consumed >3 servings of nuts per week at baseline had a significant 39% lower risk of all-cause mortality. Relative risk reductions were similar for the upper baseline category of non-walnut nuts (34%) or walnut consumption (45%), and when we evaluated the repeated measurements of total nut consumption over time (32%).
Moreover, those in the upper category of baseline nut consumption had a 55% lower risk of cardiovascular mortality and 40% lower risk of cancer mortality compared to those who never consumed nuts. The study subjects participated in the PREDIMED study, a long-term, randomized nutrition intervention trial , and those consuming more nuts at baseline and allocated to intervention with a MedDiet supplemented with nuts showed a significantly reduced total mortality risk of 63%.
The inverse association between baseline nut consumption and total mortality was of borderline significance in participants in the upper category of baseline nut consumption in a MedDiet supplemented with EVOO group, while there was no significant association in those allocated to a low-fat control diet, who were advised to reduce intake of all fatty foods, including nuts. Thus, advice against eating nuts throughout the study might have counterbalanced the protective effect of a lifetime intake of these foods. We assume that the baseline assessment can be considered as a good correlate of lifetime habits in this population.
Our findings concur with those of epidemiological studies showing inverse associations between nut consumption and cardiovascular mortality. Four large prospective studies have reported consistent inverse associations between nut consumption and fatal CHD or sudden cardiac death –. In the Adventist Health Study, subjects who consumed nuts >5 times per week had a 48% reduced risk of fatal CHD . The reduction in death from CHD among women who consumed nuts 2 to 4 times/week in the Iowa Women’s Health Study were 57% . However, a later report from the same study with longer follow-up failed to confirm that nut consumption protected from CHD death . In addition, the Nurses’ Health Study observed that women who consumed nuts ≥5 times/week had a 30% reduced risk of fatal CHD . Finally, the Physicians’ Health Study reported a 47% lower risk of sudden cardiac death and 30% lower risk of total CHD death among men who consumed nuts twice a week or more .
In our study, a reduced risk of cancer mortality has been observed in individuals that frequently consumed total nuts and walnuts. Few epidemiologic studies have been conducted evaluating the association between nut consumption and cancer. An ecological study showed that prostate cancer mortality was inversely associated with nuts and oilseed consumption . Moreover, findings from prospective studies suggest inverse associations between nut consumption and colorectal or endometrial cancer, especially in women –. Some studies showed inverse associations of nut intake and prostate cancer , however the relationship between nuts and cancer incidence and mortality is insufficient and further research is needed . A possible explanation that may account for the inverse relationship between walnuts and cancer mortality but not with other nuts could be that walnuts were richer in free and total polyphenols than all the other nuts . As walnuts are usually consumed raw, and roasting can cause a decline in the efficacy in the antioxidant capacity, it has been shown that raw walnuts, as consumed in the PREDIMED study, had the highest antioxidant efficacy among all the nuts ; this could play a beneficial role in the prevention of cancer.
The present results also support those of prior observational studies suggesting that nut consumption protects against mortality. In the Iowa Women’s Health Study, subjects consuming nuts ≥2 times/week had a significant 12% lower mortality risk than those who ate nuts less than once monthly after a 12-year follow-up . A recent study from a large Dutch cohort followed for 10 years reported that men and women in the 75th percentile of nut intake had 8% and 5% lower risks of all-cause mortality, respectively, compared with subjects in the 25th percentile . Additionally, data from the Nurses’ Health Study, where participants were followed-up for nearly 18 years, showed that consuming nuts ≥2 times/week was associated with a 14% reduced risk of all-cause mortality . It is noteworthy that the protection against total mortality afforded by nut consumption in our study was ≥3 orders of magnitude higher than that observed in studies of non-Mediterranean populations. A likely reason is that PREDIMED participants had a rather high self-selected nut intake before entering the study. Thus, 32% of PREDIMED participants consumed nuts >3 times/week, compared with nearly 10% consuming nuts ≥2 times/week in both the Iowa Women’s Health Study  and the Nurses’ Health Study . In the Dutch study, participants in the 75th percentile of nut consumption had rather low average daily intakes of 11.1 g for men and 6.2 g for women .
The healthy nutritional profile of nuts may account for the inverse association observed between nuts and mortality. Nuts are high in monounsaturated fatty acids, fiber, minerals, vitamins and many bioactive compounds; all these nutrients may partly explain the beneficial effects on health that nuts have been shown to exert [3, 4]. The frequency of nut consumption has been inversely related to several chronic prevalent conditions, such as diabetes, hyperlipidemia, hypertension, obesity, metabolic syndrome, cancer, and CHD, among others [5, 26]. These inverse associations can be influenced by various mechanisms: nuts improve the blood lipid profile  and appear to decrease insulin resistance , and there is also evidence suggesting that they can modulate inflammation , oxidative stress , and endothelial function . As a large body of evidence supports the beneficial effects of frequent nut consumption on many health outcomes, it is plausible that nuts protect as well against all-cause mortality.
Our study has limitations. First, given its observational nature, it is not possible to firmly conclude that the inverse relationship between nut consumption and total mortality reflects cause and effect. Second, even though data were adjusted for all possible confounders, there is still the possibility of residual confounding. However, the enhanced protective effect against all-cause mortality observed in frequent nut consumers at baseline who continued eating nuts during follow-up because they were allocated to the nuts intervention arm supports a causal relationship between increasing dietary exposure to nuts and reduced mortality. However, as the study was conducted in an older Mediterranean population at high cardiovascular risk, the results cannot easily be extrapolated to the general population. Nevertheless, it is relevant to assess these associations in individuals at high cardiovascular risk because this population is the most frequently attended by primary care physicians and the segment of population that can obtain higher benefits with diet or lifestyle changes.
There are also strengths to our study, such as a large sample size, relatively long duration of follow-up, and objective and thorough ascertainment of mortality as outcome in this prospective observational assessment.