Milk, Fruit and Vegetable, and Total Antioxidant Intakes in Relation to Mortality Rates

Cohort Studies in Women and Men

Karl Michaëlsson; Alicja Wolk; Håkan Melhus; Liisa Byberg

Disclosures

Am J Epidemiol. 2017;185(5):345-361. 

In This Article

Discussion

In 2 independent population-based cohorts, mortality rates were highest in persons with high consumption of milk combined with low consumption of fruits and vegetables or a low ORAC. However, the gradient of risk with increasing milk consumption was more pronounced in women, and an additive interaction for mortality rates between milk consumption and fruit and vegetable consumption was found only in women.

The findings of our observational investigation should not be evaluated in isolation and have to be interpreted cautiously. A recent attempt to perform a meta-analysis demonstrated substantial heterogeneity in nonfermented milk consumption among cohort studies in relation to mortality from all causes.[43] Heterogeneity among studies was observed in most subgroups defined by sex, country, and study quality.[43] Besides methodological differences, a potential explanation for the inconsistent findings may be related to the variability in the range of milk consumption in different populations and, as also indicated by our present study, by different patterns of intake of antioxidant-rich foods in the populations. To our knowledge, no randomized trial has examined the association of milk intake with incidence of mortality, and this study design is unlikely to ever be implemented. Another possible analytical approach might be the use of genetic variation in lactase persistence within a Mendelian randomization study design, but this specific genetic variant is probably weak as an instrumental variable,[44] with conceivable pleiotropic effects.[45,46]

The present study extends our previous finding of higher mortality rates with high milk consumption.[1] Our postulated mechanism is that milk consumption induces oxidative stress by way of the galactose component of lactose, because galactose supplementation results in premature aging in animals through induction of oxidative stress and inflammation.[2–5] Oxidative stress induced by galactose is a consequence of an imbalance between prooxidant and antioxidant defenses, which causes accumulation of advanced glycation end-products and reactive oxygen species, especially superoxide radicals and hydrogen peroxide.[2–5] Indeed, we have previously noted higher concentrations of oxidative stress and inflammation markers in human urine and serum with high consumption of milk.[1]

Mortality rates were increased at more moderate levels of milk consumption in women as compared with men; excess mortality was seen with 1–2 glasses of milk per day in women, while twice that amount was necessary for the observation of excess mortality in men. A sex difference in sensitivity to galactose exposure has been identified experimentally,[6–8] and galactose elimination capacity is also higher in men than in women, but it declines with increasing age.[47–49]

Galactose is used in the endogenous production of human breast milk. Most lactose in human breast milk is synthesized from galactose taken up from the blood, and only one-third is made from endogenous synthesis.[50] Liver glycogen in infants is formed mainly from breast milk–derived galactose,[51] and it acts as a reservoir for subsequent hepatic glucose release to the circulation during times of fasting.[52,53] A lower female degradation of galactose might have been an evolutionary survival mechanism for the child. Specifically, the enzyme galactose-1-phosphate uridylyltransferase (GALT) in the Leloir breakdown pathway of galactose (Figure 4) has a higher activity in male animals than in female animals.[7,54,55] GALT deficiency is also the main cause of galactosemia, an inborn error of metabolism resulting in early death without avoidance of galactose intake. With lower capacity of galactose degradation to glucose by the Leloir pathway, an alternative route is the polyol pathway, where galactose is converted to galactitol by aldose reductase, secondarily leading to free-radical formation.[56,57] In addition, galactose reacts nonenzymatically with amino groups in proteins and peptides, forming advanced glycation end-products.[3] Although the exact mechanisms are not known, galactose-treated rodents, flies, and tissue culture cells also display evidence of lower-than-expected antioxidant enzyme activities, suggesting that the normal defenses might be compromised.[2,5,58]

Figure 4.

Overview of galactose metabolism. The major pathway of galactose metabolism (the Leloir pathway) operates via the enzymes galactokinase (GALK), galactose-1-phosphate uridylyltransferase (GALT), and uridine diphosphate (UDP) galactose 4-epimerase (GALE), resulting in UDP-glucose. The conversion to galactitol by aldose reductase via the polyol pathway results in decreased availability of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, with increased production of free radicals (56). By way of a nonenzymatic reaction with amino groups in proteins, lipids, and nucleic acids, galactose is converted to advanced glycation end products (AGEs).

By reducing oxidative stress and inflammation processes, higher fruit and vegetable intake has convincingly been shown to promote longevity[17,59] and reduce the risk of cardiovascular disease[13,17,60] and some cancers.[61] Intriguingly, and supporting our results in women, there is experimental evidence that fruits and vegetables or extracts of them can rescue animals from the premature aging phenotype induced by galactose supplementation.[20–24,62,63]

We found no clear interaction between milk intake and fruit and vegetable intake in men. This failure to find an interaction could have several explanations. The association between milk and mortality was more modest in men, and a clear excess mortality rate was observed in men only above ≥3 glasses/day, which limited our possibility to detect an interaction pattern with fruit and vegetables. Furthermore, the gene expression and activity of antioxidant enzymes (such as mitochondrial glutathione peroxidase and superoxide dismutase) in animals seem to be higher in females than in males, giving females an enhanced capacity to provide mitigation of oxidative damage through an increased intake of antioxidants.[64]

The main strengths of this study were the use of data from 2 large population-based cohorts and the comprehensive FFQ administered in a setting with a wide range of milk intakes and intakes of antioxidant foods. We found consistency in the results irrespective of whether fruit and vegetable consumption or ORAC was used as the effect measure modifier. Loss to follow-up was negligible, because we used the individual personal identification number for linkage to the death registry. Through the use of time-updated information and with a larger number of outcomes in the SMC, we observed stronger estimates compared with use of a single assessment of exposure. Questions regarding fruit and vegetable intake were more diversified in the second FFQ, administered in 1997, but still the mortality rate patterns with a threshold at 5 servings/day were similar (Figure 1B). Our results might not apply to people of other ethnic origins, such as those with a high prevalence of lactose intolerance, or to children and adolescents.

Our observational results in this population of Swedish adults question the value of recommending high consumption of milk, especially in women not meeting the recommended requirements for fruit and vegetable intake (≥5 servings/day).

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