Milk, Dairy Products, and Their Functional Effects in Humans: A Narrative Review of Recent Evidence

REVIEW
Milk, Dairy Products, and Their Functional Effects

in Humans: A Narrative Review of Recent Evidence1
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Francesco Visioli2* and Andrea Strata3
2
Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)–Food, CEI UAM+CSIC, Madrid, Spain; and 3Department of Clinical
Nutrition, University of Parma, Parma, Italy
ABSTRACT
Milk is a widely consumed beverage that is essential to the diet of several millions of people worldwide because it provides important macro- and
micronutrients. Milk is recognized as being useful during childhood and adolescence because of its composition; however, its relatively high saturated fat
proportion raises issues of potential detrimental effects, namely on the cardiovascular system. This review evaluates the most recent literature on dairy
and human health, framed within epidemiologic, experimental, and biochemical evidence. As an example, the effects of milk (notably skimmed milk) on
body weight appear to be well documented, and the conclusions of the vast majority of published studies indicate that dairy consumption does not
increase cardiovascular risk or the incidence of some cancers. Even though the available evidence is not conclusive, some studies suggest that milk and
its derivatives might actually be beneficial to some population segments. Although future studies will help elucidate the role of milk and dairy products
in human health, their use within a balanced diet should be considered in the absence of clear contraindications. Adv. Nutr. 5: 131–143, 2014.
Introduction Effects on Body Weight

Milk is an essential component of the diet of ~6 billion Of all the bioactive milk components, calcium and vitamin
people. The world production of milk reaches 730 million D have been chiefly studied for their effects on body weight
tons/y (1,2). Even though mammals produce milk to feed and adipose tissue. Studies have been performed on these
their offspring, in many areas of the world humans con- compounds as either isolated molecules (3–9) or as compo-
tinue to consume milk throughout their life. However, it nents of milk and dairy products (5,7,8,10–12). Proposed
must be emphasized that lactose intolerance is widespread targets include thermogenesis and lipid oxidation (which
throughout the world and that a large proportion of the are enhanced by calcium and vitamin D) (13–15) and in-
world’s population would not benefit from the putative creased lipid fecal excretion (16–19).
benefits of milk. In the past few years, some studies have been published
In addition to milk, several dairy products such as cream, on other milk components and their potential effects on
butter, yogurt, kefir, and cheese have been produced and body weight (20,21). For example, in addition to calcium
consumed worldwide for millennia. Therefore, the impact and vitamin D, dairy proteins are being suggested as re-
of milk and dairy products on human health is quantitatively ducers of adipose mass (namely, visceral fat) and body
relevant and has been the subject of several investigations, on weight (11,14,22,23). These effects have been observed in
both whole products and their isolated components. In partic- healthy participants as well as in overweight, obese (21,24–
ular, the fat portion of milk (largely composed of SFAs) and 27), and diabetic (8,28) patients. In addition to casein,
some of its minor components, notably calcium and oligosac- whey protein appears to be particularly effective (29,30),
charides, are being actively researched for their potential and their actions seem to be mediated by several mecha-
health roles. nisms that include increased satiety and decreased appe-
This review summarizes the most recent studies on milk tite (29). In particular, inhibition of gastric secretion by
and human health and critically discusses the putative actions cholecystokinin (31) and some branched amino acids, the
of milk and principal dairy constituents. abundance of leucine (32), increased secretion of glucagon-
like peptide 1 (GLP-1)4 (33,34) and glucose- dependent
4
Abbreviations used: CVD, cardiovascular disease; GIP, glucose-dependent insulinotropic
1
Author disclosures: F. Visioli and A. Strata, no conflicts of interest. polypeptide; GLP-1, glucagon-like peptide 1; MCP-1, monocyte chemoattractant protein 1;
* To whom correspondence should be addressed. E-mail: francesco.visioli/at/imdea.org. MetS, metabolic syndrome.
ã2014 American Society for Nutrition. Adv. Nutr. 5: 131–143, 2014; doi:10.3945/an.113.005025. 131
insulinotropic polypeptide (GIP) (35), the concomitant sup- receive a follow-up questionnaire with questions about dis-
pression of ghrelin secretion (36), and the potent satiating eases and health-related topics including pregnancy history,
effects of a-lactoalbumin (37) synergistically contribute to menopausal status, smoking habits, and hormone use. The
weight control. first FFQ was collected in 1991 and subsequent FFQs are ad-
The most recent studies in this area include randomized ministered every 4 y. This study reported that dairy intake
clinical trials and meta-analyses. A marked reduction in ad- during high school was inversely associated with the risk
ipose tissue and an increase in lean mass were observed in 90 of developing adult (self-reported) type 2 diabetes. In partic-
overweight and obese premenopausal women after 4 mo of a ular, 2 servings/d were associated with a 38% reduction in
hypocaloric diet that included milk and dairy products. In risk; the association was stronger when dairy consumption
particular, visceral adipose tissue was significantly affected was continued throughout adulthood. A French prospective
(26). A study conducted in 903 healthy adolescents (15–16 y) study (49) conducted in 3435 Parisians followed for 3 y ob-
that included at least 2 servings/d [1 serving = 200 mL of served that a higher intake of dairy products was associated

milk, 125 g of yogurt, or 28 g of cheese (38)] of dairy reported with a lower incidence of (self-reported) type 2 diabetes, re-
a significant weight loss and a reduction in body fat (39,40). duced glycemic tolerance, and metabolic syndrome (MetS).
Male participants also witnessed a protective effect on abdom- An inverse association (14% risk reduction) between milk
inal obesity. From a mechanistic viewpoint, whey protein ad- consumption (especially skimmed or semi-skimmed milk)
ministered before a meal exerted insulinotropic effects and and type 2 diabetes has also been reported by Tong et al.
reduced postprandial insulinemic fluctuations in healthy par- (50), who published a meta-analysis of 7 cohort studies
ticipants (41) and in type 2 diabetic patients (42). In the latter, (328,029 cases). Another recent observational study in
consumption of whey protein before a high-glycemic-load 82,076 postmenopausal women enrolled in the Women‘s
(white bread and potatoes) breakfast or lunch increased insu- Health Initiative Observational Study (which lasted for
lin response by 30–50% and reduced glycemia by ~20%, 8 y) confirmed that consumption of low-fat dairy products
compared with controls (42). This effect is quantitatively was significantly and inversely correlated with a reduced risk
comparable to that of sulfonilureas (43). In agreement with of (self-reported) type 2 diabetes, especially in high-BMI
these studies, Dove et al. (44) reported that the intake of and obese women (51).
600 mL of skimmed milk at breakfast (by 34 overweight Mechanistically, a recent study (52) reported a marked
men and women) had a stronger satiating effect (evaluated amelioration of glycemic variables (i.e., fasting glycemia
4 h later) than that of an isocaloric intake of fruit juice. A sig- and hematic concentrations of glycated hemoglobin in
nificantly lower consumption of foods offered ad libitum at type 2 diabetic patients who consumed fermented dairy
lunch (i.e., after 4 h) was also recorded (44). and yogurt with added vitamin D, with or without calcium)
A recent meta-analysis (45) that reviewed the effect of 29 (53). Finally, data from the EPIC (European Prospective In-
randomized clinical trials comprising 2101 cases confirmed vestigation into Cancer and Nutrition) study relative to
the weight-loss effect of milk and dairy products when in- 16,835 healthy and 12,403 diabetic participants (part of
corporated into hypocaloric diets. However, no beneficial ef- the larger 340,234 participant cohort) of 8 European nations
fect of increasing dairy consumption on body weight and fat confirmed the inverse association between cheese and fer-
loss was seen in long-term studies or in studies without en- mented dairy consumption and incidence of diabetes. In
ergy restriction, which calls for caution in attributing milk to particular, 55 g/d of cheese and yogurt were associated
slimming properties. with a 12% reduction in type 2 diabetes incidence (54).
Finally, a recent study by Mozaffarian et al. (55) in 2617
Diabetes adults enrolled in the Multi-Ethnic Study of Atherosclerosis
A lower incidence of type 2 diabetes and of metabolic dys- (MESA) confirmed the lower (220%) incidence of type 2
function associated with dairy consumption has been re- diabetes associated with dairy use. This association was in-
ported by observational studies (46), but the potential dependent of sex, ethnicity, and other confounders and
mechanisms responsible for these effects have not as yet strengthens the notion that trans-palmitoleic acid might
been elucidated. play important roles via its actions on insulin secretion, tri-
A prospective 10-y study in 37,185 women (i.e., the glyceridemia, and blood pressure (see below). Indeed, the
Women’s Health Study) reported an inverse correlation be- authors hypothesized that, when these beneficial actions
tween milk and dairy consumption and risk of diagnosed di- are confirmed, dairy products could be enriched with this
abetes (28). This association was stronger for skimmed FA (55).
products and led to a 4% risk reduction for 1 additional Interestingly, lactose, as opposed to glucose and fructose,
serving/d. These effects can be hypothetically explained by intake does not appear to be associated with diabetes inci-
increased insulinemic response, decreased glycemic fluctua- dence (56,57). Even though the evidence in favor or against
tions, and increased secretion of GIP and GLP-1 triggered by lactose use by diabetic patients is scant, the American Diabe-
milk proteins, as described above, and by FAs such as trans- tes Association recommends the use of milk and dairy pro-
palmitoleic acid (trans-16:1n–7; see below) (47). ducts. This is partly because milk has a relatively low
The Nurses’ Health Study II (48) was carried out in glycemic index due to dairy proteins, in particular casein,
37,083 women, who were followed for 7 y. Every 2 y, women which exhibit insulinogenic properties and facilitate
132 Visioli and Strata

glycemic regulation through a mechanism involving eleva- that the contribution of dietary cholesterol to cardiovascular
tion of certain plasma amino acids and stimulation of risk is being debated and might likely depend on individual
incretins (58). Finally, full-fat milk increases the mean gas- predisposition to synthesize versus absorb cholesterol
tric-emptying time compared with half-skimmed milk, and (74,75). Also, the extent and precise nature of the role of sat-
the low pH in fermented milk may delay gastric emptying. urated fat in cardiovascular disease (CVD) onset and devel-
Therefore, full-fat or fermented milk might aid in glycemic opment are being reexamined (76); likely, SFAs cannot be
control (59). grouped under a single rubric and should instead be consid-
ered individually (77).
Blood Pressure The first review on the effects of dairy products on cho-
Whey proteins have long been studied for their potentially lesterolemia was published in 2000 by St-Onge et al. (78).
positive effects on blood pressure (60,61). For example, The authors cited as a first piece of evidence an old study
Pal and Ellis (62) demonstrated that, in overweight and carried out in the African Maasai ethnic group (79). Maasais

obese participants, the intake of 54 g/d of whey protein consume large quantities of milk, which was inversely corre-
for 12 wk induced a significant reduction in both systolic lated with blood cholesterol concentrations in that study. In-
and diastolic blood pressure, in agreement with Xu et al. deed, milk has even been proposed by the authors as an
(63) who published a meta-analysis of tripeptides and blood inhibitor of cholesterol synthesis. Further studies (80–82)
pressure. The former are bioactive peptides (64–66) that are confirmed the cholesterol-lowering effects of both milk
formed from proteins via the actions of the microbiota and skimmed milk [which was already suggested by Hepner
and gastrointestinal enzymes and which are abundant in et al. (83)]. St-Onge et al. hypothesized that this effect was
fermented dairy products (67). Tripeptides are being inves- due to the intestinal microbial fermentation of indigestible
tigated because of their angiotensin-converting enzyme– carbohydrates, which would alter cholesterol synthesis and
inhibiting activities, which might have important clinical interfere with its enterohepatic circulation, in turn lowering
consequences. In particular, 2 tripeptides, namely isoleucine- cholesterolemia.
proline-proline (Ile-Pro-Pro) and valine-proline-proline More recently, a study by Høstmark et al. (84) conducted
(Val-Pro-Pro) have been incorporated into functional foods in 18,770 participants examined the association between
because of their safety profile and purported beneficial activ- cheese consumption in various age groups and circulating
ities, namely on blood pressure. It is noteworthy that, in ad- concentrations of HDL cholesterol (which was positive)
dition to their activity on blood pressure, other peptides and TGs (which was negative). The authors attributed this
have been isolated and studied for their putative antithrom- effect to the FA composition of cheese and its bacterial con-
botic properties (68). Recently, McGrane et al. (69) reviewed tent. The results led the authors to propose a revision of the
the evidence of the hypotensive effects of milk tripeptides by current guidelines on SFA intake, namely that from cheese.
updating a former 2010 review that 1) examined 223 articles In terms of differential effects of the various dairy pro-
published between 2004 and 2009 (which outlined the in- ducts, 1 study compared the effects of isoenergetic (20%
verse association between milk tripeptide consumption of total calories, normalized for lactose and casein) provi-
and blood pressure) and 2) reviewed 163 studies published sion of milk (2164 mL), cheese (305 g), and butter (93 g) ad-
between July 2009 and December 2010 concerning vitamin ministered in 3 different sessions during 3 wk (85). Cheese
D, calcium, phosphorus, and bioactive peptides in low-fat had the weakest effect on increasing LDL cholesterol, but
dairy as part of low-fat diets. whole milk increased concentrations of LDL cholesterol
A meta-analysis of 7 studies that included ~45,000 partic- similar to butter. These results were confirmed by Biong
ipants, of whom 11,500 were hypertensive (70), reported a et al. (86): the authors reported (in a controlled dietary study
significantly inverse association between low-fat dairy con- in 9 men and 13 women aged 23–54 y) that consumption of
sumption and hypertension risk. Nine other cohort studies cheese induced a lower increase in cholesterol concentra-
(57,256 participants followed for 2–15 y) confirmed this in- tions than that of an identical amount (42 g) of fat from but-
verse correlation; furthermore, those who consumed the ter. Different calcium content was proposed as a potential
highest quantity of low-fat dairy products exhibited the low- explanation for this differential effect. Nestel et al. (87) ad-
est risk of hypertension (71). ministered 40 g/d of either cheese or butter to 14 mildly hy-
A prospective study recently published by Louie et al. percholesterolemic participants. Total and LDL cholesterol
(72), which analyzed 335 Australian children, their milk increased significantly after 4 wk in the butter group as com-
consumption at age 18 mo, and their blood pressure at 8 y pared with the cheese group. Tholstrup et al. (85) also ques-
of age, reported lower blood pressure values in those who tioned the current guidelines on saturated fat consumption
consumed at least 2 servings/d. and suggested the inclusion of modest amounts of cheese in
the diets of mildly hypercholesterolemic participants. In
Cholesterol Concentrations agreement with this suggestion, Hjerpsted et al. (88) recently
Milk and dairy products contain cholesterol (~80 mg/100 g) replaced 13% of total daily calories with 143 g of cheese or
and saturated fat (~15 g/100 g) (73). Therefore, the intake of 47 g of butter (with the same lipid content) for 6 wk in a ran-
these products might theoretically have detrimental effects domized crossover trial in 49 healthy participants. Their
on cholesterol concentrations. However, it is noteworthy data showed that cheese did not increase LDL cholesterol
Functional effects of milk 133

concentrations compared with the run-in period; rather, as 59% (72). A similar association was recorded when diabetes in-
compared with butter, it induced a significantly lower incidence was computed.
crease in total (5.7%) and LDL (6.9%) cholesterol. Finally, a recent meta-analysis (98) of 8 randomized con-
Several potential explanations have been proposed to trolled studies in overweight or obese participants con-
elucidate the differential effects of cheese and butter on cho- cluded that dairy product consumption does not exert
lesterolemia. One hypothesis is that calcium, the concentra- adverse effects on biomarkers of inflammation, even though
tions of which are higher in cheese than in butter, combines further studies specifically designed to assess inflammation-
with FAs in the intestine and forms insoluble detergents as related outcomes should be implemented (98).
suggested by the observation of a higher-fat fecal excretion
in the cheese compared with the butter groups (88). The Cardiovascular Health
higher protein and probiotic content of cheese could also Several scientific societies and regulatory bodies (e.g., the In-
speculatively contribute to its almost neutral effect on plasma ternational Society for the Study of Fatty Acids and Lipids,

cholesterol. As a cautionary note, the study by Tholstrup et al. which is the foremost society; www.issfal.org), the FAO
(85) reported a lack of difference in the cholesterolemic (99), and the European Food Safety Authority (100) recom-
effect of the diets containing whole milk and butter. In mend optimal profiles of FA intake. Even if no consensus has
other words, as mentioned, whole milk did increase LDL- been reached and such guidelines are being constantly
cholesterol concentrations similar to butter and its use by amended according to emerging evidence, some figures
hypercholesterolemic patients should be considered with are being agreed upon. In particular, most societies concur
caution. with regard to adequate intakes (for adults) of >500 mg/d
of long-chain omega-3 FAs and a concomitant limitation
MetS of <8% of energy from saturated fat.
Oxidative stress and inflammation play major roles in the More recently, a workshop entitled “Saturated fatty acids
onset and development of the MetS and its components and cardiovascular disease prevention” (101) gathered sev-
(89–91). MetS diagnosis requires the presence of central eral experts in the area of FAs and CVD, who reached the
obesity and at least 2 of the following 4 additional factors: following consensus that also concerns milk and dairy FA
high TGs, low HDL cholesterol, high blood pressure, or in- profile:
creased fasting plasma glucose concentration (92). 1. Replacing saturated fat (SFAs) with PUFAs lowers cardio-
The Nurses’ Health Study first reported an inverse asso- vascular risk. This effect is not seen when saturates are re-
ciation between a prudent diet that included low-fat dairy placed with carbohydrates, especially those with a high
products and biomarkers of inflammation (93). Similar ob- glycemic index.
servations have been reported by the MESA (94) and
2. Even though replacing SFAs with MUFAs lowers LDL
prompted a series of investigations that explored mecha-
cholesterol, this effect does not translate into lower inci-
nisms of actions and potential causation. Zemel et al.
dence of CVD.
(95,96) supplemented 20 obese patients with skimmed
milk for 28 d and recorded significantly lower oxidative 3. LDL cholesterol is the most widely accepted risk factor for
stress (222% of plasma malondialdehyde and 212% of CVD; however, the HDL:LDL-cholesterol ratio is more pre-
8-iso-PGF2a plasma concentrations) and inflammation dictive than the sole concentrations of LDL cholesterol.
[215% TNF-a, 213% IL-6, 210% monocyte chemoat- 4. Investigating the effects of dietary interventions on just
tractant protein 1 (MCP-1), and +20% adiponectin]. The 1 marker of CVD does not reliably predict clinical outcomes,
same authors (97) studied 40 obese MetS patients and because they depend on several rather than on just 1 factor.
showed that a 12-wk diet that included 3.5 servings/d of 5. The different SFAs exert varied biologic effects and have
milk and/or yogurt reduced oxidative stress markers differential impact on cholesterolemia. As an example, myr-
(235% plasma malondialdehyde) after 7 d, as compared istic and palmitic acids are thought to be noxious, and stea-
with an isocaloric diet that provided 0.5 servings/d of dairy ric acid and short-to-medium-chain (C4–C10) FAs to be
products. After 12 wk, decreased systemic inflammation was neutral; conjugated linoleic acid is so scarce in the diet
also recorded in the dairy group (235% TNF-a, 221% IL- that its metabolic effects are negligible.
6, +55% adiponectin), although not in the control arm.
6. Based on the epidemiologic studies published to date,
The interesting observation that stems from these inter-
there is no evidence to indicate that high intakes of dairy
vention studies is that the observed decrease in oxidative
products increase CVD risk; conversely, the lipidic part of
stress and inflammation markers was independent of body
milk and its byproducts might be beneficial because of its
weight changes and became apparent shortly after the ad-
peculiar FA profile, e.g., rumenic and vaccenic acids and
ministration of dairy products, suggesting causation.
the concomitant presence of calcium, whey proteins, and
Epidemiologically, 1 recent Australian study reported an
other bioactive molecules (101).
inverse association between MetS and type 2 diabetes inci-
dence and dairy consumption in 1807 and 1824 patients, re- It should be noted that, after an initial report that pro-
spectively. In particular, those who had the highest consumption posed the “Alpine paradox” (102), considerable research is
amount of dairy products witnessed a risk reduction in MetS of being undertaken to modulate the FA composition of bovine

milk toward a purportedly more healthful profile (103). In difficult to disentangle from those of other milk and meat
particular, milk from grass-fed livestock is being proposed components; therefore, more studies are needed to attribute
as being more beneficial than that of corn-fed animals potentially cardioprotective properties to milk FAs. A recent
(104), although appropriate comparative human studies are review by Huth and Park (114) concluded that the con-
lacking. sumption of milk and dairy products cannot, as of today,
In 2002, Tavani et al. (105) published research carried out be positively or negatively associated with cardiometabolic
between 1995 and 1999 in 597 myocardial infarction pa- or stroke risk. Likewise, Kratz et al. (115) recently published
tients, matched with 478 controls. Their data showed that a meta-analysis of 11 studies that concluded that the intake
milk and dairy consumption did not increase myocardial in- of high-fat dairy is inversely associated with the prevalence
farction risk. A meta-analysis of 21 studies that incorporated of obesity and (although modestly) with CVD and meta-
347,747 participants followed for 5–23 y by Siri-Tarino et al. bolic disorders. The conclusions of this article were that
(106) reported no significant association between SFA con- high-fat milk derivatives do not increase CVD risk and ex-

sumption and increased risk of CVD or cerebrovascular dis- plain the diversified and heterogeneous outcomes of the
eases such as stroke. Further to this meta-analysis, the same studies they analyzed by the different animal feed (pasture
authors (107) published an extensive review of the effects of vs. cereal-based feed), that would influence milk composi-
various FAs on CVD risk. Their conclusion was that the re- tion, as already observed by Jenkins et al. (116). This poten-
placement of SFAs with MUFAs and PUFAs reduces both tial confounding factor should be added to other ones such
LDL and HDL cholesterol. Moreover, substituting carbohy- as differences in lifestyle, background diets, etc. which re-
drates for SFAs increased CVD risk. Therefore, the most ef- sults in overall disagreement over the precise role in CVD
fective strategy to prevent CVD, based on this article, would of milk and its products. One notable example of such dis-
be to reduce high-glycemic-index carbohydrates in obesity. agreement can be found in Bonthuis et al. (117), who car-
In a study in 33,625 Dutch participants followed for 13 y, ried out a 16-y prospective study on 1529 Australian
no association between dairy consumption and CVD or participants and concluded that the evidence in favor of a
stroke incidence was observed; conversely, higher intakes CVD-protective role of dairy products (an average of 339
were associated with lower CVD risk, whereas fermented g/d) was scant. Avalos et al. (118) also performed a 16-y pro-
milk products consumption was inversely associated with spective study in 751 men and 1008 women from San Diego,
lower stroke risk (108). CA, and reported a multivariate analysis that showed how
As mentioned, the MetS is multifaceted and greatly in- women who consumed the highest amounts of low-fat dairy
creases CVD risk (109). In this respect, a review of observa- exhibited higher CVD risk. One study, by Goldbohm et al.
tional studies concluded that milk and dairy consumption (119) analyzed 120,852 Dutch men and women (follow-up
might contribute to cardiometabolic syndrome prevention; = 10 y) for their dairy product consumption as related to
namely, 3–4 servings/d have been associated with cardiome- CVD. A neutral association was reported for men, and a
tabolic risk prevention (110). Consequently, based on cur- slight increase in CVD mortality was recorded for women.
rent evidence, the most recent U.S. guidelines suggest to Fermented dairy was associated with modest CVD protec-
“Increase intake of fat-free or low-fat milk and milk pro- tion in both sexes. Opposite results came from a recent study
ducts, such as milk, yogurt, cheese” (111). performed in Costa Rica in 3630 participants (120), in
In terms of mechanisms, Rice et al. (112) recently sum- which dairy consumption was associated with myocardial
marized the most prevalent hypothesis of how milk pro- infarction risk reduction, and from another, larger study
ducts would play preventive roles in cardiometabolism. in 36,636 Swedish women, followed for 11.6 y, that also re-
These products mostly contain TGs with SFAs in the sn-2 ported an inverse association between milk and cheese con-
position; in addition to high proportions of oleic and stearic sumption and myocardial infarction incidence, independent
acids, rumenic and trans-palmitoleic acids are also propor- of fat content (121). These data are in agreement with those
tionally abundant. Moreover, part of the putative effects of Sonestedt et al. (122), who followed 26,445 participants of
might be explained by the presence of several micronutri- Malmö (Sweden) for 12 y and reported the following: 1)
ents such as calcium, vitamin D, whey proteins, and func- dairy consumption is inversely associated with CVD risk,
tional peptides (see above). 2) fermented milk use is significantly inversely associated
In terms of effects of milk FAs on CVD, there might be with CVD risk, and 3) in women, cheese intake is signifi-
important differences between the individual FAs. A total cantly associated with CVD risk. Yet, a meta-analysis by
of 5209 participants who had a daily intake of 10% of total Soedamah-Muthu et al. (123), who analyzed 17 prospective
energy from SFAs were followed for 10 y. Those whose pro- studies, came to the conclusion that milk consumption
portional intake of SFAs from milk had a lower incidence of (200 mL/d) is modestly associated with lower CVD risk and
CVD compared with those who consumed an equivalent that there is no correlation between the intake of milk and
amount of SFAs from bovine meat. In particular, a 5-g/d its derivatives and coronary disease or total mortality, regard-
increase in milk-derived SFAs was associated with a 21% less of their lipid content. Two subsequent studies reached
decrease in CVD risk, whereas the same increase in meat- the same conclusions. In the first (123), 4526 participants
derived SFAs was associated with a 26% increase in CVD were followed for ~10 y; the results indicated an inverse asso-
risk (113). As a cautionary note, the effects of FAs are ciation between fermented milk products use and total

mortality, yet not with diabetes or CVD incidence. The sec- negatively with stress in women. Conversely, regular-fat
ond study (52), in 5953 Danish participants aged 30–60 y dairy was associated with increased stress, anxiety, cognitive
who were followed for 5 y, reported a modest beneficial ef- decline, and worse memory. Of note, this study was per-
fect of cheese and fermented milk on glycemic control, yet formed by using questionnaires and not ad hoc tests. The
not on type 2 diabetes incidence. Finally, a recent study same group (137) subsequently examined a subgroup of the
(124) carried out in 1965 Dutch participants (follow-up = Maine-Syracuse Longitudinal Study (which consisted of 5 co-
12.4 y) did not report any association between cardiovascular horts defined by time of entry into the study, i.e., 1975–2000)
and all-cause deaths and milk consumption. Moreover, the and reported, by using neuropsychological tests, that milk
authors recorded an increased CVD risk associated with the use was associated in a dose-dependent fashion with better
use of high-fat foods. For every SD increase, the use of memory and slower cognitive decline. Quantification of
high-fat dairy products increased cardiovascular mortality these effects suggests 200 mL of milk/d as the lowest effective
by 36%. amount that, supposedly, would afford neuroprotection. In

A few years ago, the hypothesis was formulated that, in terms of cognitive development/performance, favorable ef-
France, despite the presence of cardiovascular risk factors fects on cognition and school performance were also ob-
such as a high-fat diet, cardiovascular mortality was lower served in 469 students who were administered 250 mL/d
than that in neighboring countries (125). This apparent in- of milk for 3 mo and who were evaluated by cognitive tests
congruence was attributed to the concomitant use of red (138). Within the context of neuroprotection and cognitive
wine, which is rich in phenolic compounds that act as anti- decline, a recent interesting study by Birnie et al. (139) pro-
oxidants in vitro. Particular attention has been paid to respectively analyzed milk consumption during infancy and
sveratrol, to which several of the alleged healthy effects of cognitive function later in life. The study started in 1930
wine have been attributed, even though very limited human by enrolling 5000 U.K. children and was concluded 65 y later
data are available (126,127). Indeed, the hypothesis that the by assessing the ambulation ability of 405 elderly partici-
antioxidant and anti-inflammatory properties of nonalco- pants. The data showed better (+5%) walking speed and
holic components might determine health effects different balance (+25%) in those who consumed at least 1 glass of
than that of ethanol is intriguing, but is, at present, only sug- milk/d during their childhood.
gested by laboratory data and not by conclusive epidemio-
logic evidence (128,129). Chemoprevention
In summary, the available evidence of an effect (whether Milk contains compounds that might theoretically exert
beneficial or detrimental) of milk and dairy products on chemopreventive actions. In 1994, Kampman et al. (140)
CVD is mixed and does not allow drawing firm conclusions. published an observational study in which 331 men and
Even though milk and its derivatives are apparently able to 350 women were followed for 4 and 8 y, respectively. No as-
positively modulate some risk factors and surrogate markers sociation between milk and fermented milk consumption
of cardiovascular health (e.g., insulin response, dyslipide- and colorectal cancer was reported (141). Subsequent stud-
mias, oxidative stress and inflammation markers, blood ies provided mixed results: although some researchers found
pressure, etc.), the net effect on CVD is as yet to be ascer- positive associations between dairy use and prostate (142–
tained. Potential confounding factors such as fat content 145) and ovary (146) cancers, others found the opposite
and FA profile, background diets, lifestyles, and coingestion when colorectal (147), lung (148,149), or breast (150) can-
of other beneficial or noxious dietary components likely cers were investigated. What is possibly the largest prospec-
contribute to this unclear picture. Future studies will add ev- tive cohort study in this field was published in 2009 by Park
idence to help resolve this issue. et al. (151), who analyzed, via the use of a questionnaire,
diets and cancer incidence in 293,907 men and 198,903
Cognitive Function women, with a follow-up of 7 y. Their data showed that cal-
Cognitive function can be modulated, to some extent, by cium and dairy intake was inversely associated with gastro-
food (130), and its decline can be slowed down by adopting intestinal (especially colorectal) cancer incidence. The
appropriate diet and lifestyle (131). Among all dietary com- multivariate analysis showed a calcium-associated reduction
ponents, relatively little attention has been paid to milk and in gastrointestinal cancer risk of 16% for men and 23% for
its derivatives. Some studies reported amelioration of cogni- women. Other cancers were also inversely associated with
tive decline linked to augmentation of vascular function milk and cheese intake, namely those of the head and
brought about by dairy consumption (132–134). However, neck, esophagus, stomach, colon, and bladder. This puta-
specific studies have been performed only recently. A recent tively protective effect of dairy intake has been ascribed to
systematic review (135) identified 8 observational studies the milk content of potentially chemopreventive com-
that reported a direct association between dairy con- pounds such as calcium, vitamin D, conjugated linoleic
sumption and better cognitive function. Crichton et al. acid, etc. (152). In particular, calcium has been suggested
(136) published a study in ~1000 Australian adults, in to inhibit cell proliferation, stimulate differentiation and ap-
whom consumption of low-fat yogurt was positively associ- optosis in the gastrointestinal tract and in the mammalian
ated with memory and socialization in men and low-fat gland, and bind to FAs and biliary salts in the intestine,
cheese was associated positively with socialization and therefore lessening their potentially noxious effects on the

mucosa. However, calcium would also interact with vitamin have been proposed to explain this hypothetical effect
D and with insulin-like growth factor 1, in turn increasing (142–144,169,170). The lay public is familiar with the
the risk of prostate cancer (142,153). Indeed, Park et al. “China Study” (which was actually a book rather than a
(151) did report increased prostate cancer risk linked to peer-reviewed article), which concluded that animal protein,
higher dairy and calcium consumption. In 2 European stud- namely casein given to laboratory animals, provoked tumors
ies (154,155), the inverse association between milk use and such as prostate cancer. On the basis of current evidence, the
colorectal cancer was confirmed. In the first study (154), effects of casein—particularly isolated casein, separated
45,241 participants were followed for 12 y and their intake from other components of dairy that often work synergisti-
of yogurt was monitored (mean: 85 g/d for men and 98 g/d cally—cannot be generalized to all forms of milk protein,
for women) and plotted against colorectal cancer incidence, much less all forms of animal protein. In fact, experiments
showing an inverse association that was stronger in men. A in rodents suggest some antitumor activity of dairy protein
systematic review by Aune et al. (155) took into account 19 fraction and, more specifically, of the whey protein compo-

cohort studies and reported a significantly inverse association nent of milk because of its glutathione-increasing effects
between milk (200 mL/d) and total dairy (400 g/d), yet (171). In short, even though a cancer-promoting effect of
not cheese (50 g/d), consumption and colorectal cancer casein and other milk proteins cannot be ruled out, the ev-
incidence. idence in favor or against such effect is still too limited to
With regard to breast cancer, after the first report by draw firm conclusions.
Knekt et al. (156) of a significantly inverse association be-
tween milk use and breast cancer incidence in 4697 Finnish Milk Components with Putative Functional
women, Shin et al. (157) published a cohort study in which Properties
they did not find any association between dairy, calcium, or Recently, several oligosaccharides have been categorized in
vitamin D consumption and breast cancer incidence in post- milk and have been suggested as potentially bioactive in-
menopausal women. Conversely, in premenopausal women, gredients. Even though bovine milk contains only trace
a significant reduction in breast cancer risk associated with amounts of these beneficial components (172), some re-
low-fat dairy products was reported. Of note, a subsequent searchers are working toward producing human milk oligo-
meta-analysis (158) of >20 studies (that included a total of saccharides in transgenic animals (173). Due to the lack of
351,041 women with a follow-up of 15 y) did not find any suitable commercial standards for bovine oligosaccharides,
association between these 2 variables. In agreement with we can only identify >70 fully annotated oligosaccharides
these data, a successive review (150) did not find convincing in human milk and ~40 in bovine milk, of which 24 contain
evidence that milk consumption is associated with lower sialic acid (172). Oligosaccharides are composed of a lactose
breast cancer incidence. Conversely, Dong et al. (159) con- core bound to lactose-amine units via b1–3 or b1–6 links
ducted a meta-analysis in 1,063,471 participants in 18 pro- and carrying fucose or sialic acid in their terminal position
spective cohort studies and reported an inverse association (172,174,175). It is noteworthy that these molecules are abun-
between dairy, although not milk, use and breast cancer, no- dant in human milk and have been proposed as important for
tably in premenopausal women and when low-fat products child development. Neutral oligosaccharides—namely the
were separately analyzed (160,161). In summary, there is no monomer N-acetylglucosamine and fucose—are essential
evidence that milk and dairy use increases or reduces the in- to the development of the microbiota of breast-fed neonates
cidence of breast cancer. because of their immunomodulating actions (176). Con-
A similar picture is shown with milk and bladder cancer. versely, acidic oligosaccharides (where the monomer is sialic
One meta-analysis by Mao et al. (162) (who analyzed 19 acid) help to prevent the adhesion of pathogens to the intes-
cohort case-control studies totaling 7867 bladder cancer pa- tinal mucosa (177). Bovine milk also contains these oligo-
tients) reported that high milk consumption was associated saccharides, which are abundant in colostrum (178,179).
with a 16% reduction in bladder cancer risk; this inverse as- Oligosaccharides are prebiotics and help to create a healthy
sociation was stronger in Asian participants than in North microbiota (180–182). Even though a thorough discussion
American participants and was not seen in Europeans. Fi- on the role of the microbiota in human health goes beyond
nally, the statistical significance depended on the type of the aim of this article, this is an important and dynamic field
dairy product that was analyzed. Another meta-analysis of research that is attracting considerable attention and is
(163) examined 14 studies on milk (4879 cases of bladder being addressed from several viewpoints (183–185). Even
cancer) and 6 studies on dairy products (3087 cases) con- though many fruits and vegetables contain oligosaccharides
ducted in a total of 324,241 participants. No correlations be- and some of them have been synthesized, those from milk
tween variables were found. are remarkable in that they exhibit a branched rather than
With regard to other cancers, no clear evidence emerges a linear structure. Moreover, they contain fucose and sialic
from most of the studies that have been published thus acid, which are almost absent in other oligosaccharides.
far, including lung (149), ovary (146), esophagus and stom- This structural difference might confirm that milk oligosac-
ach (164–166), and oropharyngeal (167,168) cancers. Posi- charide activities are different than oligosaccharides of syn-
tive associations between dairy use and prostate cancers thetic or vegetal origin. It must be underscored that the
have been published, and several mechanisms of action concentration of oligosaccharides in bovine milk decreases

in a time-dependent fashion: ad hoc investigations are be- far as its putative health effects are concerned, there are efforts
ing carried out to formulate these compounds as nutra- to increase its concentrations in bovine milk (103)], phos-
ceuticals or as probiotic components of functional foods pholipids (200), tripeptides, calcium, phosphorus, lactoferrin
(172). (201), and oligosaccharides might exert useful, although as yet
Finally, it is noteworthy that some kinds of cheeses, unproven, physiologic actions. Furthermore, milk has been
namely those infected with Penicillium such as Roquefort, shown to be an efficient vehicle for lipid-soluble nutrient ab-
Stilton, or Gorgonzola, exhibit high concentrations of an- sorption (187) because milk fat appears to be highly dispersed
drastins A–D, which are potent inhibitors of farnesyltrans- in very small micelles (202).
ferase, a key enzyme in cholesterol synthesis (186). Other In conclusion, whereas future studies will help to eluci-
peptides formed during ripening-induced proteolysis might date the role of milk and dairy products in human health,
further contribute healthful, albeit as yet unexplored, prop- their use within a balanced diet should be considered in
erties that would partially explain the relatively low inci- the absence of clear contraindications.

dence of CVD in high-cheese-consumption countries.
Milk is also often fortified, e.g., with vitamin D or omega- Acknowledgments
3 FAs (187), because it provides an excellent vehicle for fat- Both authors read and approved the final version of the
soluble molecules (see below) and can be marketed to target manuscript.
population groups after appropriate regulatory evaluation
(188). In summary, either fortified or “natural” milk and
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