Alternative Medicine Review Voiume 13, Number 4 2008

Whey ProteinIntroduction

In recent years, milk constituents have become recognized as functional foods, suggesting theiruse has a direct and measurable effect on health outcomes.' Whey, a by-product of cheese and curd manu-facturing, was once considered a waste product. Tlie recognition of whey as a functional food with nutritional applica-tions has elevated whey to a co-product in the manufacturing of cheese,^ The two primary sources of protein in milkare the caseins and whey. Aft:er processing occurs, the caseins are the proteins responsible for making curds, while wheyremains in an aqueous environment. The components of whey include beta-lactoglobulin, alpha-Iactalbumin, bovineserum albumin, lactoferrin, immunoglobulins, lactoperoxidase enzymes, glycomacropeptides, lactose, and minerals.'Today, whey is a popular dietary protein supplement purported to provide antimicrobial activity, immune modulation,improved muscle strength and body composition, and prevention of cardiovascular disease and osteoporosis.

Whey Protein ConstituentsWhey proteins contain all the essential amino acids in higher concentrations than vegetable protein sources.^

Tlie amino acids in whey are efficiently absorbed and utilized, relative to free amino acid solutions.* Whey proteinshave a high concentration of branched-chain amino acids (BCAAs) - leucine, isoleucine, and valine - important fac-tors in tissue growth and repair. Leucine is a key amino acid in protein metabolism.' Whey proteins are also rich in thesulfur-containing amino acids cysteine and methionine, which enhance immune function through intracellular conver-sion to glutathione. Tlie primary whey components and their benefits are Usted in Table 1.

PharmacokineticsWhey proteins do not coagulate under acidic conditions and withstand tbe action of chymosin in the sto-

mach. They are considered to be "fast proteins," as they reach the Jejunum quickly,^ but after reaching the small in-testine, hydrolysis is slower than tbat of casein, allowing for greater absorption over the length ofthe small intestine.Whey's rapid absorption patterns are superior for postprandial protein utilization and overall nitrogen balance inelderly women.*" A randomized, single-blind study examining protein satiety found whey protein exhibits a higherpostprandial level of plasma amino acids than casein.^ A study by Troost et al revealed the lactoferrin component ofwhey survives stomach acid.**

Mechanisms of ActionAntioxidant Effects

Whey has potent antioxidant activity, likely by contributing cysteine-rich proteins that aid in the synthesis ofglutathione (GSH), a potent intracellular antioxidant.' As an antioxidant, glutathione is most effective in its reducedform. As a result of whey's glutathione/antioxidant component, it is being investigated as an anti-aging agent."*

DetoxificationPractitioners use whey protein as a source of cysteine to increase intracellular glutathione levels.'"" Glu-

tathione peroxidase (GSHPx) activity in cow's milk, and presumably whey, is the same as in human milk.'^ As adetoxifying agent, GSHPx, which is derived from selenium and cysteine, is an endogenous antioxidant enzyme that

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Monograph

Table 1. Primary Components of Whey Protein

Whey Component

beta-Lactoglobuiin

Lalpha-Lactalbumm

I[

lmmunoglot)ulins

Lactofenin

Lactoperoxidase

% of Whey Protein Benefits

50-55%

20-25%

iI10-15%

1-2%

t

0.5%

Bovine Serum Albumin 5-10%

Glycomacropeptide 10-15%

Excellent source of essential and branched chain amino acids -spares muscle and glycogen dunng exercise

Binds fat soluble vitamins, increasing bioavailability

Primary protein found in human breast milk

ßicellent source of essential and branched chain amino acids

High in the essential ammo acid tiyptophan, which helps

regulate sleep, mood, stress

IgA. IgO, IgE. IgG, IgM - primarily IgG

Primary protein found in colostrum

ImmunB enhancing benefits to all ages, particularly infants

' AnSoxidant found in breast milk, tears, saliva, blooú

Antiviral, antibacterial, antifungal

Piornotes growth ol beneficial bacteria

R^uiates iron absorption and bioavailability ''

Inhibits growth ol bacteria

La^e-sized prolein with good profiie of essential amino adds i

Fat-binding properües '

Does not contain amino acid phenylalanine. so is often used ininfant fonmulas for infants with phenylketonuria

Inhibits formation of dental plaque and cavities

Antihypertensive/Hypolipidemic Activity

Antihypertenstve peptideshave been isolated in bovine beca-lactoglobulin, suggesting whey reducesblood pressure.-" These peptides pro-vide whey with significant angiotensinI converting enzyme (ACE) inhibitoryactivity, which blocks the conversion ofangiotensin I to angiorensin II, a highlypotent vasoconstrictor molecule.-'

beta-Lactoglobulin has beendescribed by Nagaoka et al as a cho-lesterol-lowering agent. In animalstudies, beta-lactoglobulin inhibitedcholesterol absorption by changingmicellar cholesterol solubility in the

intestme."^

converts lipid peroxides into less harmful hydroxy acids.In addition to the above-mentioned properties, thealpha-lactalbumin component of whey chelates heavymetals" and reduces oxidative stress because of its iron-chelating properties.'''

Immune EnhancementAn in vitro study demonstrated bovine milk-de-

rived IgG at levels as low as 0.3 mg/mL suppresses humanlymphocyte proliferatíve response to T cells. Tbe authorsconclude IgG in bovine milk typically ranges between0.6-0.9 mg/mL and is therefore likely to confer immunitychat could be carried to humans.'^ Studies show raw milkfrom non-immunized cows contains specific antibodiesto human rotavirus, E. coU, Salmonella cnteriditis, S. ty-phimuriutn, and Shigella ßexneri.^'''^^ In a murine study,alpha-lactalbumin, in both the native and hydrolyzedstate, enhanced antibody response to systematic antigenstimulation.'" Alpha-lactalbumin also has a direct effecton B-lymphocyte function, as well as suppressing T cell-dependent and -independent responses.^^

Clinical IndicationsExercise

Wheys amino acid profilemakes it attractive for body composi-tion and to support protein synthesisand muscle growth. In a double-blindtrial, 42 men (ages 18-31) familiarwith weight training followed the

same weight resistance-training program for 12 weekswhile consuming whey protein (1.2 g/kg body wt/day),a multi-ingredient whey protein sports supplement (1.3g/kg body wt/day), or maltodextrin placebo (1.2 g/kgbody wt/day). After 12 weeks, men who received wheyprotein in combination with resistance training showedgreater improvements in at least one of four muscle-strength measurements and in lean tissue mass com-pared to the placebo group.^^

Lands et al examined the effect of three-monthwhey protein supplementation (10 g twice daily) ver-sus the same amount of casein as placebo on muscularperformance in 18 men. When compared to baseline,peak power and 30-second work capacity improvedsignificantly in the treatment group with no chatige inthe placebo group. Body weight remained unchanged inboth groups, but the supplemented group experienceda decrease in percent body fat. Enhanced biosynthesisof intracellular glutathione, shown by an increase oflymphocyte GSH levels in test subjects, is thought to

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be responsible for the improved muscular performanceobserved in this study.^''

Another study examined the effects of caseinand whey proteins on the acute response of muscleprotein balance and synthesis in 25 young men andwomen randomly assigned to receive a 300-mL solutionof whey protein (n-9), casein (n-7), or placebo (n=7)one hour after leg resistance exercise. Subjects in thewhey and casein groups demonstrated a significantlyincreased uptake ot phenylalanine after exercise (casein= 84±10 mg; whey = 62±18 mg; placebo = 5 + 15 mg)as well as stimulation of net muscle protein synthesiscompared to placebo.^^ Cribb et al reported significantimprovements in muscle strength and hypertrophy in26 healthy male body builders supplemented with 1.5 gwhey protein daily for 11 weeks; the control group wasgiven an identical dose of a carbohydrate supplement.̂ **

Two small studies on HIV-positive womenexamined exercise, whey supplementation, and bodycomposition. '̂•^*' In the 2000 study the author notes anincrease in body mass composition with whey supple-mentation; whereas, the 2001 study found no effect.Both studies note an improvement in quality of life withincreased exercise and whey protein intake. Treatmentgroups received 1.0 g/kg daily of undenatured wheyprotein powder.

While moderate exercise enhances immunity,'̂ ^intense athletic training has been shown to stress the im-mune system."^ ' ' Free radical production and increasedinflammatory activity are thought to contribute to im-paired immune activity in over-trained athletes. In highlytrained individuals muscular performance and recoverycan be hindered by oxidative stress." '̂ Lower levels ofsIgA andglutamine''''' have also been observed after in-tense exercise and in over-trained individuals, and havebeen correlated with increased frequency of infection.^"In addition, glutamine deficiency may contribute to gas-trointestinal complaints experienced by highly trainedindividuals." Whey protein is an excellent source ofglutamine and together with its antioxidant and im-mune-enhancing properties suggests supplementationin this population may provide therapeutic benefit.

Pédiatrie Bowel HealthCreating a substitute for mother's milk has

proven challenging. It is well accepted that nursinginfants have a richer gut flora than bottle-fed infants.

particularly with Bifidobacteria and Lactobacilli.^ Suchflora is normally associated with increased resistance tocolonization of the digestive tract with pathogenic bac-teria.'"' In a double-blind study, 102 healthy infants lessthan two weeks old were randomized to receive either astandard cow's mílk formula or an infant formula con-taining partially hydrolyzed whey protein."" The whey-protein fed infants had significantly more Bifidobacteriain their stools, ultimately affording improved gastro-intestinal immunity. It has been observed in previousstudies that higher levels of Bifidobacteria in the diges-tive system decrease the potential for developing atopicconditions in at-risk infants with family history."''

A randomized, double-blind, placebo-con-trolled study of 43 infants with diagnosed infantilecolic compared a hypoallergenic, hydrolyzed whey for-mula to a standard cow's milk formula for one week."*'A clinically relevant result was observed in the wheyformula group, with colic-related crying time reducedto less than one hour per day in the group taking wheyformula - a one-hour greater reduction than the cow'smilk formula group.

Thirty-eight infants with constipation (medianage-1.7 months) were randomized to receive standardinfant formula (n=18) or a partially hydrolyzed wheyformula plus prebiotics (n-20) for three weeks, thencrossed over to the other formula for an additional threeweeks; only 24 subjects completed the crossover portionof the study. Infants on the hydrolyzed whey formulaimproved to softer stools at a higher rate (90 percent)than those consuming the standard infant formula (50percent). Frequency of bowel movements improved sig-nificantly in both groups and similar growth rates werereported in both groups compared to baseline." '̂

A small, randomized, double-blind, crossoverstudy examined the effect of hydrolyzed versus non-hydrolyzed whey protein on growth and developmentof 10 children with short bowel syndrome."'' In chil-dren experiencing bowel resection, food introductionand promotion of normal growth and development isof utmost importance. Tlierefore, the increased transittime of whey proteins in the small intestine makes it anideal protein source for this subset of children. Hydro-lyzation of the whey protein did not have an effect onnitrogen balance, weight gain, or intestinal permeabilitycompared to non-hydrolyzed whey, suggesting patientsshould utilize whichever whey protein is best tolerated.

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ObesityResearch has shown a five-percent reduction

in body £at mass can reduce the risk of obesity-relateddisease. Because high-protein, lower-carbohydrate dietsappear to be the most effective fot promoting weight loss,whey is an attractive source of dietary protein. The aminoacids in whey act as substrates for protein synthesis andmay improve body mass index in individuals participat-ing in exercise and weight reduction programs.''

In a 12-week, randomized, double-blind study,a specialized whey protein high in leucine, bioactivepeptides, and calcium was studied for its effect on fatloss and lean muscle in 106 obese women (ages 25-50)on a restricted 500 calorie/day diet. Subjects receiveda whey protein drink (n=53) or an isocaloric malto-dextrin control beverage (n=53) twice daily, and bodyweight, body fat, and lean muscle mass were measuredat 0, 4, 8, and 12 weeks. Responders were classified assubjects who lost at least 2.25 kg body weight. Bloodsamples were obtained and analyzed at the beginningand end of the study period and chemistry panels, lipidprofiles, insulin, and complete blood counts were mea-sured.'**' Significant weight loss was reported in bothgroups with no statistically significant difference at theend of 12 weeks. However, the whey protein group lostsignificantly more body fat than the control group (2.81kg versus 1.62 kg in the compléter group and 3.63 kgversus 2.11 kg in the responder group), and respondersubjects in the whey-protein group lost significantly lesslean muscle mass than those in the control group (1.07kg versus 2.41 kg, respectively). Overall, subjects in thewhey protein group lost 6.1 percent of their body fatmass. Blood profiles revealed a significant decrease incholesterol, triglycérides, and LDL cholesterol in thetreatment group compared to the control group.*'*'

DiabetesWbey protein reduces postprandial glycemia and

promotes insulin release in healthy subjects.''' In one trial,blood glucose and insulin response were measured in 14type 2 diabetic men and women (ages 27-69) after con-sumption of a high-glycemic-index meal witb or withoutwhey protein supplementation. Insulin levels after break-fast were 31-percent higher when whey was added to themeal, an effect even more pronounced after lunch, as evi-denced by a 57-percent increase in the insulin responseand 21-percent reduction in blood glucose with wheycompared to no whey. Glucose-dependent insulinotropic

polypeptide responses were also higher after supplemen-tation with whey protein. These results demonstrate thatwhey protein added to meals with a high glycémie indexstimulates insulin release and reduces postprandial glu-cose levels in type 2 diabetic pati

Cardiovascular DiseaseWhey protein tnay provide benefit for nor-

malizing blood pressure and lipid levels. A study on agroup of 20 healthy adult males investigated whethera fermented milk supplement containing Lactohacilluscasei and Streptococcus thermophHus with added wheyprotein concentrate would affect serum lipids and bloodpressure.'''^ When volunteers consumed 200 mL of fer-mented milk with whey protein concentrate or placebo(non-fermented rnilk without added whey protein)twice daily for eight weeks, the whey-protein group hadsignificantly higher HDL cholesterol and lower triglyc-érides and systolic blood pressure than the non-wheygroup. Tlie difference in total- and LDL-cholesterollevels between groups was not statistically significant.

Human Immunodeficiency Virus (HIV)Glutathione deficiency is common in individu-

als infected with HIV. A study by Micke et al demon-strated significantly elevated glutathione levels in 30subjects with HIV supplemented with 45 g whey pro-tein daily for two weeks.^" The satne researchers, in asubsequent six-month study, again found significantlyincreased glutathione levels compared to baseline.^'

CancerWhey protein concentrates have been re-

searched extensively with respect to cancer preventionand treatment. Glutathione stimulation is thought tobe the primary immune-modulating mechanism. In areview of whey protein concentrates in the treatmentof cancer, Bounous discusses the antitumor and anti-carcinogenic potential. The amino acid precursors toglutathione in whey might increase glutathione concen-tration in relevant tissues, stimulate immunity, and de-toxify potential carcinogens.^^ Other authors concludethe iron-binding capacity of whey might also contributeto anticancer potential, as iron may act as a mutagenicagent causing oxidative damage to tissues."

Many animal studies have examined the ef-fects of whey and its immune-enhancing components,

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including lactoferrin and beta-lactoglobulin.^'''^^ Inan animal model of colon cancer, animals given wheycomponents demonstrated significantly lower incidenceof tumors and fewer aberrant crypts."'̂ '̂ '̂ ^ A hamsterstudy demonstrated fractionated whey has the ability toprevent and treat 5-fluorouracÍl chemotherapy-inducedoral mucositis." This protection is thought to occurvia induction of tumor growth factor-beta (TGF-ß),which reduces basal epithelial cell prohferation. An invitro study by Kent et al demonstrated that an isolateof whey protein, when compared to a casein-based pro-tein, increased glutathione synthesis and protected hu-man prostate cells against oxidant-induced cell death.^

Other Uses of Whey ProteinTlic wide range of essential and non-essential

umino acids, minerals, fats, and biologically active pro-teins in whey provide extensive application in clinical nu-trition. Adequate protein intake is essential for post-sur-gical wound healing, and protein depletion delays healingtime.^' Surgery stresses the body, altering natural de-fenses and leading to various post-surgical complications.Zimecki et al demonstrated the lactoferrin componentof whey protein regulates the immune response and pro-vides protective measures in post-surgical patients.^^

Human studies demonstrate whey protein im-proves cognitive function and coping ability in highlystressed individuals.^''^ Because a rise in serotonin isthought to improve adaptation to stress,^^ the authorspropose tryptophan in whey provides a substrate to in-crease brain serotonin levels. Tlie treatment groups forboth studies received alpha-lactalbumin-enriched wheyprotein because it has the highest tryptophan concen-tration of whey protein fractions.

Side Effects and ToxicityFor individuals with frank milk allergies, whey

products may not be suitable. On the other hand, manydairy-sensitive individuals find that casein is the culpritand they can tolerate whey, particularly if it is partiallyhydrolyzed and therefore less allergenic. Other dairy-sensitive individuals are lactose-intolerant. Most wheyproteins are processed to remove lactose, with finishedproducts only containing trace amounts. A challengetest with a small pordon of a particular whey supple-ment for an individual with dairy sensitivities is indi-cated before beginning therapeutic amounts.

DosageDosages of whey protein published in clinical

trials range from 30-90 g daily, depending on the condi-tion heing treated.

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