In this reanalysis of the data of the PREDIMED trial, we observed a 37% reduction of mortality when comparing extreme quintiles of total polyphenol intake. The dose-response trend for the association between total polyphenol intake and all-cause mortality suggested an L-shaped relationship, with an apparent threshold after the first quintile of polyphenol intake, instead of an inverse linear dose-response relationship. Within the polyphenol subclasses, stilbenes and lignans were inversely associated with total mortality.
In stratified analyses we found a stronger association between total polyphenol intake and mortality risk for women and for those who did not drink alcohol. Although the interaction terms were not significant, the observed trend was suggestive, especially for non-drinkers. The relationship between alcohol intake and polyphenols should be the main focus of future studies.
To our knowledge, though previous studies have investigated the association between intake of specific groups of polyphenols and mortality, this is the first study to investigate the association between total polyphenol intake, as well as that of all polyphenol subgroups with all-cause mortality. In addition, we should acknowledge that the effect of polyphenols and polyphenol-rich foods on chronic degenerative diseases and clinical biomarkers has been broadly studied [19–24]. Previous studies have analyzed the association between polyphenols from wine, tea, chocolate, berries, soy and olive oil with several chronic degenerative disease risk or mortality risk [6, 25–29]. The reported inverse association, specifically for olive oil and red wine, is consistent with the inverse association we found for stilbenes and lignans [29–31]. The suggestion of an inverse association that we found for several flavonoid compounds is also consistent with previous studies of berries, dark chocolate and soy [6, 25, 26]. In many of these previously studied populations, intake of any one polyphenol-rich food was not great enough to reduce mortality, but in our study total polyphenol intake was a wider range, coming from several food sources.
Kuriyama et al. conducted a prospective cohort study among 40,530 healthy Japanese adults and reported that green tea consumption, a polyphenol-rich beverage, was inversely associated with cardiovascular diseases and all-cause mortality, but not with mortality due to cancer . Other studies have also found an inverse association between polyphenol consumption and CVD and CVD-related mortality [20, 25, 26, 32]. Indeed, it has been demonstrated that some polyphenols and their metabolites exert anti-atherosclerotic effects, improve endothelial function and antioxidant status, increase nitric oxide release, and modulate inflammation and lipid metabolism [5, 21, 25, 33–35].
Polyphenols can also act as chemopreventive agents. For example, resveratrol is a well-known stilbene, mostly found in red wine and grapes, with several health benefits, including inhibition of tumorgenesis [8, 36, 37]. In vitro and in vivo studies have shown that epigallocatechin-3-gallate, the major polyphenol of green tea, has anti-carcinogenic effects, such as inhibition of growth proliferation, induction of apoptosis and phase II detoxifying enzymes, and reduction of oxidative damage to DNA [36–38]. Xanthohumol, quercetin, curcumin and genistein are other examples of polyphenols that have shown anticarcinogenic properties due to their capacity to inhibit tumor growth [8, 22, 37, 38].
Available evidence supports that dietary modifications are able to reduce the risk of T2DM, another highly prevalent chronic disease. Wedick et al. found that anthocyanins were inversely associated with the risk of T2DM using data from three US prospective cohorts and Muraki et al. found similar associations for blueberries, grapes and apples [39, 40]. Finally, polyphenols have been proposed as promising phytochemicals for the treatment and prevention of neurogenerative diseases such as Alzheimer’s disease, Parkinson’s disease and other neurological disorders [29, 41].
All of this evidence from chronic disease studies supports the hypothesis that greater polyphenol intake, and the many polyphenol subclasses this represents, serves to extend the life span through multifactorial etiological pathways.
Our study has some limitations. First, we controlled for several confounders in multivariate models, but other unknown or unmeasured confounders may exist. However, if this were the case, we would expect relative risks for all subclasses to be equally over or underestimated and that was not the case. Second, the number of cases of cause-specific deaths was too low to estimate individual relative risks. Others have found the benefits of specific foods are stronger for CVD mortality than cancer or respiratory disease. Future work in this area should include larger studies with estimates of total polyphenol intake. Third, there were limitations with respect to the estimation of polyphenol intake because data were indirectly derived from the FFQs. Although urinary excretion of polyphenols was validated as a biomarker of total polyphenol from the FFQ in two different studies, the values of r were relatively low. The absence of information about some foods in the FFQ could lead to an underestimation of the intake. Moreover, the study did not take into account the bioavailability of these molecules. Finally, these results might be valid only for elderly people at high cardiovascular risk and other studies are needed to generalize the conclusions to other populations.
On the other hand, the main strengths of the study are the prospective design, the large sample size with a relatively long-term follow-up, and comprehensive data on risk factors and confounders. Very importantly, our use of the cumulative average of polyphenol intake across yearly repeated measurements of diet is considered as the best approach to reduce measurement error in nutritional epidemiology  and allowed changes in the diet due to the intervention or other secular trends in intake in Spain to be controlled. We also used the most comprehensive polyphenol database currently available (Phenol-explorer database), which allowed risk estimation related not only to intake of total polyphenol but also all the polyphenol subgroups and subclasses. This comprehensive analysis differentiates our paper from previous related studies.