Am J Clin Nutr 2000 Cordain 1585 6 (1)

Medium-chain triacylglycerols may not raisecholesterol

Dear Sir:

Although medium-chain triacylglycerols (MCTs; 8:0 and 10:0)historically have been considered nonlipemic for most individuals,the report by Asakura et al (1) suggests that MCTs may be hyper-cholesterolemic in subjects with hypertriglyceridemia. Althoughthe authors emphasized the hypercholesterolemia induced whenMCTs progressively replaced corn oil in the carefully manipu-lated diet of these subjects, an alternative conclusion would bethat the removal of dietary linoleic acid (18:2) was the primarycause of the plasma cholesterol elevation. Patients were adaptedto a low-fat diet (containing 22% of energy as fat) in which 100%corn oil represented about one-half (12%/22%) of the total fatenergy, including �8% of energy from 18:2. Progressive replace-ment of corn oil with MCTs resulted in <2% of energy from 18:2in the final diet period (estimated as 20% of the intrinsic dietaryfat) when 100% MCT was the added fat. This exchange progres-sively increased total cholesterol and triacylglycerol, with VLDLcholesterol and LDL cholesterol contributing equally to the ele-vation in total cholesterol, even though the increase in triacyl-glycerol was not significant. Thus, MCTs increased cholesterol inapolipoprotein B–rich lipoproteins as dietary 18:2 was reducedfrom 8% of energy to <2% of energy, the rise in total cholesterolbeing significant only when all the corn oil was removed. Thebackground carbohydrate and other intrinsic fatty acids were con-stant and tended not to complicate interpretation here, which wasa nice aspect of the study design.

The failure to alter plasma triacylglycerol values in this studylikely reflects the fact that high-carbohydrate diets (22% of energyas fat in this case) are hypertriglyceridemic in their own right. Hadthe total fat provided 30–40% of energy, MCTs might have had amore favorable effect on triacylglycerol. More important is thefact that 18:2 is the principle dietary fatty acid responsible forreducing hepatic fatty acid and triacylglycerol synthesis as well asVLDL secretion induced by carbohydrate, and presumably,induced by MCTs acting like carbohydrate (2). It is well appreci-ated that 18:2 also can enhance impaired LDL receptor activity(3), and carefully controlled fatty acid exchanges showed that pro-gressive decreases in 18:2 per se raise total cholesterol when dietsaturated fatty acids (SFAs) are high but stable, ie, when 18:1replaces 18:2 (4). In the relative absence of dietary cholesterol, theresulting increase in LDL reflects an overproduction of LDL morethan impaired clearance (5). We described these fatty acid interre-lations previously in terms of the 18:2 threshold, wherein a spe-cific amount of 18:2 is required to protect against total cholesterolelevation during consumption of SFAs and cholesterol (6).

Examples of these fatty acid interrelations specifically involvingMCTs were shown in normolipemic women (7) and hamsters (8).In fact, even when women were fed a low-18:2 diet (3% of energy),MCTs proved less cholesterolemic than a source of longer-chainSFAs (trilaurin). Futhermore, the hamster study found MCTs to beas cholesterol lowering as safflower oil in a cholesterol-free dietwhen 18:2 intake was adequate at 5% of energy.

Although the current data support the 18:2 threshold concept,they are not definitive because, as is often the case in such exper-iments, 2 important variables (MCTs and 18:2) were alteredsimultaneously in opposite directions. Thus, it is not clear whichis to blame, rising MCTs or declining 18:2. But substantial evi-dence would argue the latter is most critical (6). A more defini-tive design would have kept 18:2 constant at 5–6% of energy andexchanged MCTs for 18:1 or carbohydrate, which are consideredneutral. Furthermore, the clinical data cited in support of thecholesterol-raising nature of MCTs (9, 10), like the comparisonin normolipemic women (7), suffer the same shortcoming as thepresent study, ie, 18:2 was lower (and below threshold) in theMCT diet period than in the control diet period. The clinicallyrelevant point is that an adequate source of 18:2 needs to be sup-plied when MCTs, or even carbohydrate, replace other long-chain SFAs and monounsaturated fatty acids (5).

In summary, MCTs should not be considered as SFAs thatraise total cholesterol and LDL. Nor do they represent a substi-tute for 18:2 that will effectively reduce circulating apolipopro-tein B–rich lipoproteins in the absence of 18:2.

KC Hayes

Brandeis University, MS-029Waltham, MA 02454-9110E-mail: [email protected]

REFERENCES1. Asakura L, Lottenberg AMP, Neves MQTS, et al. Dietary medium-

chain triacylglycerol prevents the postprandial rise of plasmatriacylglycerols but induces hypercholesterolemia in primary hyper-triglyceridemic subjects. Am J Clin Nutr 2000;71:701–5.

2. Ntambi JM. Regulation of stearoyl-CoA desaturase by polyunsatu-rated fatty acids and cholesterol. J Lipid Res 1999;40:1549–58.

3. Spady DK, Woolett LA, Dietschy JM. Regulation of plasma LDL bydietary cholesterol and fatty acids. Annu Rev Nutr 1993;13:355–81.

4. Pronczuk A, Khosla P, Hayes KC. Dietary myristic, palmitic, andlinoleic acids modulate cholesterolemia in gerbils and hamsters.FASEB J 1994;8:1191–200.

5. Hajri T, Khosla P, Pronczuk A, Hayes KC. Myristic acid-rich fatraises plasma LDL by stimulating LDL production without affect-ing fractional clearance in gerbils fed a cholesterol-free diet. J Nutr1998;128:477–84.

Am J Clin Nutr 2000;72:1583–93. Printed in USA. © 2000 American Society for Clinical Nutrition 1583

Letters to the Editor

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6. Hayes KC. Saturated fats and blood lipids: new slant on an oldstory. Can J Cardiol 1995;11:39G–46G.

7. Tsai YH, Park S, Kovacic J, Snook JY. Mechanisms mediatinglipoprotein responses to diets with medium-chain triglyceride andlauric acid. Lipids 1999;34:895–905.

8. Hayes KC, Lindsey S, Pronczuk A, Trautwein E, Khosla P. Fattyacid modulation of lipoprotein metabolism by natural triglyc-erides in hamsters: lipoprotein turnover and hepatic mRNA abun-dance. In: Christophe A, ed. Structurally modified food fats: syn-thesis, biochemistry, and use. Champaign, IL: AOCS Press, 1998:170–81.

9. Temme EH, Mensink RP, Hornstra G. Effects of medium chain fattyacids (MCFA), myristic acid, oleic acid on serum lipoproteins inhealthy subjects. J Lipid Res 1997;38:1746–54.

10. Cater NB, Heller HJ, Denke MA. Comparison of the effects ofmedium-chain triacylglycerols, palm oil, and high oleic acid sun-flower oil on plasma triacylglycerol fatty acids and lipid andlipoprotein concentrations in humans. Am J Clin Nutr 1997;65:41–5.

Reply to KC Hayes

Dear Sir:

In our study of medium-chain triacylglycerols (MCTs) inhypertriglyceridemic individuals (1), we were disappointed tofind that provision of MCTs as the major source of dietary fatdid not lower plasma triacylglycerol concentrations, which wasthe major objective of the study, and in addition, had the incon-venience of raising plasma cholesterol. Hayes raises the possi-bility that a low-fat diet (carbohydrate- or MCT-rich) may cor-rect the hypertriglyceridemia provided that an ideal proportionof 18:2 is added to the diet. This is an interesting suggestion thatshould be tested experimentally in humans no matter how con-vincing the animal data. Whatever answers one draws fromfuture experiments on these proposed dietary modifications, thebottom line is that MCTs seem useless for the treatment ofhyperlipidemia. In contrast, carbohydrate-induced hyperlipi-demia, which is a well-known phenomenon that occurs in bothhealthy persons and in several cases of moderate hypertriglyc-eridemia, may benefit from Hayes’s interesting proposalbecause it would likely be circumvented by adding the rightamount of 18:2 to a fat-free diet without raising, and probablylowering, plasma cholesterol.

Eder CR Quintão

University of São Paulo Medical SchoolSão Paulo 01246-903Brazil E-mail: [email protected]

REFERENCE

1. Asakura L, Lottenberg AMP, Neves MQTS, et al. Dietary medium-chain triacylglycerol prevents the postprandial rise of plasma tria-cylglycerol but induces hypercholesterolemia in primary hyper-triglyceridemic subjects. Am J Clin Nutr 2000;71:701–5.

Hunter-gatherer diets—a shore-basedperspective

Dear Sir:

Cordain et al (1) estimated that Paleolithic hunter-gathererswould have consumed as much animal food as possible. I sup-port the inclusion of fish and shellfish in Cordain et al’s estimateof animal food intake because I believe that fish, shellfish, andother shore-based foods were crucial for human brain evolution(2–4). I have 2 comments about the reference values Cordain etal used for plant and animal macronutrient composition.

First, their reference macronutrient values for plant foodswere 62% carbohydrate, 24% fat, and 14% protein. The list offood types for which this reference macronutrient profile wasobtained did not include vegetables (see Table 3 of reference 1).In commonly available databases of the macronutrient contentsof plant foods other than nuts and seeds, the fat content rarelyseems to exceed 1% by weight. Does this imply that Cordain etal’s macronutrient database does not really represent most plantfoods or, alternatively, that nuts and seeds are interpreted to rep-resent most plant foods consumed? Even if plant foods in thePaleolithic period did contain an average of 24% of energy as fatby proximate analysis, this value needs to be corrected down-ward by �30% to yield the content of actual fatty acids that areavailable for energy from plant material other than nuts. Was thiscorrection made?

Second, Cordain et al emphasized the risk of protein toxicityby referring extensively to the outcome of the consumption oflarge amounts of meat containing < 5% fat by weight. Lean mus-cle tissue is 2–3% fat, but animal organs other than muscle,which tend to be 5–10% fat, would also have been consumed.Body fat itself would also have been eaten. Furthermore,hominids would have faced fierce competition from carnivoresfor the copious amounts of meat needed to be eaten to induceprotein toxicity; therefore, protein toxicity probably did notoccur often, and certainly not for extended periods.

As Milton’s (5) editorial points out, it makes empirical sensethat foods of relatively high nutrient and energy densitieswould be consumed when available. However, Milton says that“Hunter-gatherers were not free to determine their diets, ratherit was their predetermined biological requirements for particu-lar nutrients that constrained their evolution. At the same time,these dietary needs apparently allowed for selection to favorincreased brain size in the human lineage and the concomitantdevelopment of technologic, social, and other abilities directedat securing these nutrients” (5). Modern humans in a totallyfree-choice situation ultimately choose a diet that is completein energy and nutrients. Those who cannot choose freely oftendevelop malnutrition or specific nutrient deficiencies. Manyfactors, including climate, competition, and food availabilitywould have been constraints affecting the daily or seasonal dietof hunter-gatherers; in that sense they may not have beentotally free to determine their diets. However, in my view, itwas the discovery of and adaptation to a high-quality shore-based diet that was a major determinant of the rate and extentof human brain evolution, not the other way around as impliedby Milton (5).

We argue that the shore-based ecologic niche was uniquelyable to stimulate expansion of the primate brain because, in addi-tion to being a plentiful supply of dietary energy and protein, it

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provided certain brain-selective nutrients, such as docosa-hexaenoate, iodine, zinc, copper, and iron (2–4). The basis forthis hypothesis is that terrestrial foods are deficient in iodine andcontain little docosahexaenoate (only in animal tissue). Zinc,copper, and iron are more abundant and available from seafoodthan from plants. Dietary or genetically imposed deficiencies ofall of these brain-selective nutrients leaves the modern humanbrain extremely vulnerable to subnormal development. Equallyimportant is the issue of access to reliable sources of foods richin brain-selective nutrients that required minimal effort to locateand consume. Such foods would have to have been available forthousands of years before intelligence had risen sufficiently toconceive of and experiment successfully with true fishing orhunting and trapping of wild animals. The hominid fossil recordshows that at least fish and shellfish—but probably also eggs,amphibians, and plants on lakeshores and seacoasts—providedan abundance of this important dietary stimulus for human brainevolution without special effort or substantial competition frompredators (5).

If the nutrient and energy supplies were consistently inade-quate in some geographic areas over thousands of years, humanbrain evolution would have faltered and long-term colonizationof those areas would have ceased until the appropriate foodswere found or supplements were invented. This is what happenedmost clearly with iodine deficiency, which affects more than abillion mostly vegetarian people in inland areas of all continents.Iodine is essential for energy metabolism, normal brain develop-ment, and fertility (6). People can survive even severe iodinedeficiency but they cannot thrive or reproduce. In contrast,coastal peoples experience no known nutrient deficienciesaffecting brain function. Hence, as we argued (2–4), marine,estuarine, and lacustrine locations probably favored human brainevolution by providing abundant energy and protein but, equallyimportantly, brain-selective nutrients.

Stephen C Cunnane

Department of Nutritional SciencesUniversity of TorontoToronto M5S 3E2CanadaE-mail: [email protected]

REFERENCES1. Cordain L, Brand Miller J, Boyd Eaton S, Mann N, Holt SHA,

Speth JD. Plant-animal subsistence ratios and macronutrient esti-mations in worldwide hunter-gatherer diets. Am J Clin Nutr 2000;71:682–92.

2. Cunnane SC, Harbige LS, Crawford MA. The importance of energyand nutrient supply in human brain evolution. Nutr Health 1993;9:219–35.

3. Broadhurst CL, Cunnane SC, Crawford MA. Rift Valley lakefishand shellfish provided brain-specific nutrition for early Homo. Br JNutr 1998;79:3–21.

4. Crawford MA, Bloom M, Broadhurst CL, et al. Evidence for theunique function of docosahexaenoic acid during evolution of themodern hominid brain. Lipids 1999;34(suppl):S39–47.

5. Milton K. Hunter-gatherer diets—a different perspective. Am J ClinNutr 2000;71:665–7 (editorial).

6. Geelhoed G. Metabolic maladaptation: individual and social conse-quences of medical intervention in correcting endemic hypothy-roidism. Nutrition 1999;15:908–32.

Reply to SC Cunnane

Dear Sir:

Our analysis was based on data derived from historically stud-ied hunter-gatherers (Homo sapiens); hence, it may be inappro-priate to assume, as Cunnane did, that Paleolithic hunter-gather-ers would have maintained identical nutritional patterns characteristicof modern hunter-gatherers. During the Paleolithic period (a timeperiod extending from roughly 2.6 million y ago until 10000 yago), 3 hominid genuses (Australopithecus, Paranthropus, andHomo) that encompassed ≥11 separate species were simultane-ously present (1). There is abundant evidence suggesting that thehominid’s diet was not static but, rather, evolved and variedthroughout the Paleolithic period, depending on the species andthe ecologic niche that was exploited. A common nutritional ele-ment of those hominid species that eventually led to anatomicallymodern humans was the inclusion of more energy-dense animalfoods in their diet (2, 3). There is little or no fossil evidence toindicate that animal foods derived from the aquatic environmentplayed a significant role in the diet of either early or laterhominids until the Upper Paleolithic (35000–40000 y ago)period (4, 5). The fossil record shows that invertebrate shellrefuse piles (middens) and fossilized fish remains associated withhominid occupation sites did not appear until the Upper Pale-olithic period, concurrent with the technologic advent of hooks,lines, weirs, nets, and barbed spears (4, 5). Consequently, the highfish consumption (median: 26–35% of energy) we showed for229 historically studied hunter-gatherers likely would not havebeen representative of Early (2.6 million y ago until 250000 yago) and Middle (250000–40000 y ago) Paleolithic hominids.Hence, fish, shellfish, and other shore-based foods likely wouldhave played a minor role in providing nutrients, including essen-tial fatty acids, that were crucial for the rapid hominid brainexpansion that occurred during the Early Paleolithic.

In regard to our estimation of the mean plant-food macronutri-ent profile (62% carbohydrate, 24% fat, and 14% protein), weclearly included vegetables in our estimates. Tubers, roots, bulbs,leaves, and flowers are plant-food categories and are included inTable 3 of our article; these categories would subsume such mod-ern vegetables as potatoes (tubers), radishes (roots), onions(bulbs), lettuce (leaves), and broccoli (flowers). These food cate-gories accounted for 29.3% of our entire wild plant food databaseand have a mean energy density of 4.18 kJ/g. As we mentioned inour article, hunter-gatherers collected plant-food species not ran-domly but in a fashion predicted by optimal foraging theory thatwould tend to maximize the ratio of energy capture to energyexpenditure. Lipid-rich seeds and nuts (mean energy density:13.14 kJ/g) would have been selected preferentially over veg-etable foods when available. Hence, our weighting of the plant-food database in Table 3 of our article reflects the preferential for-aging of these fat-containing plant foods by hunter-gatherers.

In regard to the physiologic protein ceiling, we agree that EarlyPaleolithic hominids such as Homo habilis—because of theirsmall size (male: height = 132 cm, weight = 37 kg), lack of effec-tive weapons, and limited behavioral sophistication—would havebeen unsuccessful hunters of large herbivores and hence wouldhave had only occasional access to “copious amounts of meat” aswell as abdominal organs and depot fat. For the same reasons,these diminutive hominids would also have had little success inconfrontational scavenging and stealing prey from large, carnivo-

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rous predators. The fossil record indicates that the passive scav-enging of the abandoned and defleshed long bones and skulls ofherbivores with their intact contents of marrow and brain wouldhave represented the primary large animal food source for earlyancestral humans (6, 7). Hominids did not become successfulhunters of large game until the Middle to Upper Paleolithic period.

The evolution of a large metabolically active brain in ourspecies required food sources that were energetically dense (2, 3)and that contained docosahexaenoic acid (22:6n�3) (8). AlthoughEast African freshwater fish are good sources of 22:6n�3 (549mg/100 g), they are a poor energy source (498 kJ/100 g) (9) andare less energetically dense than is a mixture of wild, edibleplants (540 kJ/100 g) consumed by hunter-gatherers (10). Scav-enged marrow is a rich energy source (3289 kJ/100 g) and scav-enged brain is a more concentrated source of 22:6n�3 (861mg/100 g) than is East African freshwater fish. Because scav-enged marrow is a more highly concentrated energy source(3289 kJ/100 g) than is freshwater fish (498 kJ/100 g), theenergy return versus the energy expenditure for scavenged mar-row bones would have far exceeded that available from the man-ual capture of freshwater fish. Furthermore, because the energy-protein ratio in African ruminant marrow (477 kJ/g protein) isalmost 20 times greater than for African freshwater fish (27 kJ/gprotein), fish consumption would have been constrained by thephysiologic protein ceiling, whereas marrow consumption wouldnot have been. Thus, when the option was available, scavengedmarrow and the brain that was concurrently present in the skullof the defleshed skeleton would almost always have been cho-sen over active capture of either fish or aquatic invertebrates.Taken together, the data indicate that scavenged marrow fromruminant long bones would have represented the concentratedenergy source required for hominid brain evolution and that thebrains of scavenged skulls would have represented the predomi-nant source of 22:6n�3.

Loren Cordain

Department of Health and Exercise ScienceColorado State UniversityFort Collins, CO 80523E-mail: [email protected]

Janette Brand Miller

Department of BiochemistryUniversity of SydneySydney, NSW 2006Australia

S Boyd Eaton

Departments of Radiology and AnthropologyEmory UniversityAtlanta, GA 30322

Neil Mann

Department of Food ScienceRoyal Melbourne Institute of Technology UniversityGPO Box 2476VMelbourne, VIC 3001Australia

REFERENCES

1. Wood B, Collard M. The human genus. Science 1999;284:65–71.2. Aiello LC, Wheeler P. The expensive tissue hypothesis. Curr

Anthropol 1995;36:199–222.3. Leonard WR, Robertson ML. Evolutionary perspectives on human

nutrition: the influence of brain and body size on diet and metabo-lism. Am J Hum Biol 1994;6:77–88.

4. Yesner DR. Maritime hunter-gatherers: ecology and prehistory. CurrAnthropol 1980;21:727–50.

5. Osborn AJ. Strandloopers, mermaids, and other fairy tales: ecologi-cal determinants of marine resource utilization. In: Binford LR, ed.For theory building in archaeology: essays on faunal remains,aquatic resources, spatial analysis, and systemic modeling. NewYork: Academic Press, 1977:157–205.

6. Blumenschine RJ, Cavallo JA. Scavenging and human evolution.Sci Am 1992;267:90–6.

7. Blumenschine RJ. Carcass consumption sequences and the archaeo-logical distinction of scavenging and hunting. J Hum Evol 1986;15:639–59.

8. Crawford MA, Bloom M, Broadhurst CL, et al. Evidence for theunique function of docosahexaenoic acid during the evolution of themodern hominid brain. Lipids 1999;34(suppl):S39–47.

9. Pauletto P, Puato M, Angeli MT, et al. Blood pressure, serum lipids,and fatty acids in populations on a lake-fish diet or on a vegetariandiet in Tanzania. Lipids 1996;31(suppl):S309–12.

10. Eaton SB, Konner M. Paleolithic nutrition. A consideration of itsnature and current implications. N Engl J Med 1985;312:283–9.

Reply to SC Cunnane

Modern humans are noted for their large brain but factors relatedto the brain’s evolution are imperfectly understood. Cunnane statesthat a “shore-based ecologic niche was uniquely able to stimulateexpansion of the primate brain. . . .” In a previous article, Cunnaneand others (1) described “the African savanna ecosystem of largemammals and primates [as] associated with a dramatic decrease inrelative brain capacity associated with little docosahexaenoic acid”(DHA; 22:6n�3). Abundant long-chain polyunsaturated fatty acids(LCPUFAs), particularly DHA and arachidonic acid (AA; 20:4n�6)are regarded as absolute requirements for advanced neural growthin humans and other mammals (1–3).

Because tropical freshwater fish and shellfish and manymarine fish offer plentiful preformed DHA, Cunnane et al pro-pose that the lacustrine and marine food chain was being exten-sively exploited at the time cerebral expansion took place in theancestral line leading to modern humans (1, 2). I found little evi-dence to support this.

Members of the genus Homo have always been distinguishedby a large brain relative to body size (4, 5). Data suggest that themajor increase in encephalization in Homo occurred during theMiddle Pleistocene, 600–150 thousand years before present (BP)(4). Well before this, overall body size and degree of sexualdimorphism in Homo had arrived at essentially the modern level(5). By 150–100 thousand years BP, absolute brain size in Homoappears to have been within the modern range, whether Homo isviewed as a single or multiple species (4, 5).

The first evidence supporting the systematic use of coastalresources is dated between 127 and 57 thousand years BP (5). Ifconsumption of coastal resources underlies expansion of the mod-



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ern human brain, what factors explain the precipitous increase inbrain size on 3 different continents by members of the genus Homowell before evidence for the exploitation of shore-based resources?If humans in the African Rift Valley consistently utilized lacustrineresources (2), why the long period of stasis in human encephaliza-tion between 1800 and 600 thousand years BP (4)?

Another puzzle concerns the technologic explosion (5)—aburst of creativity in anatomically modern humans that appearsto have begun fairly abruptly in the Late Paleolithic period some40 thousand years BP and involved the dramatic acceleration ofcultural evolution. This technologic explosion was not accompa-nied by any increase in human brain size and thus some otherfactor, possibly the development of fully modern language, hasbeen suggested to underlie it (5).

Taken together, the fossil and archaeologic records suggestthat the modern physical form of our species evolved before themodern capacity for culture (5). Although the question of whereand when anatomically modern humans originated remains unre-solved (5), data do not suggest any causal association betweenthe exploitation of aquatic foods and human brain expansion.

The idea that the African savanna could not support large-brained species (1, 2) seems inaccurate. No evidence suggeststhat primates in this environment have brains smaller for theirbody mass or a lower encephalization quotient (6) than do theircounterparts in tropical forests. In fact, the savanna baboon(Papio spp.) and savanna-woodland vervet (Cercopithecusaethiops) have relatively large brains and high encephalizationquotients compared with most African forest primates (6). Nor isit the case that all large savanna species have small brains rela-tive to their body mass. Elephants, for example, have brains that,over the course of their evolution, “were enlarged even beyondthe extent expected for their large bodies”(6).

Where do humans get the LCPUFAs that are so critical inbrain development? Preformed LCPUFAs can be obtained fromfoods, or LCPUFAs can be synthesized in the mammalian liverfrom dietary precursors, ie, the essential fatty acids linoleic acidand �-linolenic acid. Tissues of the eye and brain can also syn-thesize DHA if the appropriate precursors are available (7). Inhumans, a progressive increase in fatty acid length and degree ofunsaturation from maternal liver to placenta, fetal liver, and fetalbrain has been documented (3). The direct incorporation ofdietary LCPUFAs in the developing brain was also shown (3).Full-term infants can synthesize DHA, and human breast milkcontains both linoleic acid and �-linolenic acid as well as LCP-UFAs, including DHA (8, 9).

Although the conversion of �-linolenic acid to DHA inhumans is stated to be weak (2), “elongation and desaturation of�3 fatty acids in the human liver is very active and capable ofproviding the high levels of long �3 PUFA required by the devel-oping brain” during the crucial stage of brain development (3).Although n�3 deficiency can be induced in humans by a verypoor supply of �-linolenic acid or an excessive supply of linoleicacid relative to �-linolenic acid, the possibility of n�3 fatty aciddeficiency in the wild-food diets of evolving humans seemsunlikely “because of the abundance of these fatty acids in nature,their small minimum requirements and the enzyme preferencefor the linolenate family” (3).

The “aquatic foods argument” also offers no real explanationfor why these foods stimulated human brain expansion. In thisLamarckian scenario, the quiescent brain appears to be waitingpatiently for humans to discover aquatic foods and then, eureka,

the brain is free to enlarge and modern humans result. Not onlyare the selective pressures involved in this scenario unspecified,no information is provided as to how these large-brainedhumans were then able to provide DHA and other brain-specificnutrients for themselves or their developing offspring once theymoved away from lacustrine or shore-based environments.

Dietary pressures appear to have been a major stimulus inhuman evolution (10). The association of stone tools with theearliest evidence for hominid exploitation of meat and marrowfrom large terrestrial ungulates strongly suggests that even theearliest humans used extrasomatic (cultural) innovations to helpthem solve immediate dietary problems (11). The brains, flesh,liver, tongue, marrow, and other parts of wild terrestrial mam-mals would have served as a concentrated source of many essen-tial nutrients required by early humans, including LCPUFAs (12,13). Because wild animals consume diets with very low ratios ofn�6 to n�3 fatty acids, their tissues have relatively high pro-portions of n�3 fatty acids, including eicosapentaenoic acid (aprecursor of DHA) and DHA (12, 13) and wild-plant foodswould provide �-linolenic acid and linoleic acid.

Archaeologic evidence testifies to the increasing technologicproficiency and continuous exploitation of terrestrial mammalsby members of the genus Homo over the course of their evolu-tion (5). Calculations indicate that a diet composed of 35% ter-restrial animal matter and 65% terrestrial plant matter wouldhave provided more than adequate raw material for brain-build-ing purposes, not only sufficient amounts of DHA but also of AAand docosatetraenoic acid (14). As highly opportunistic foragers,ancestral humans likely would have exploited aquatic foodswhenever possible, but such foods seem unnecessary for brainexpansion in the human lineage.

Katharine Milton

Department of Environmental Science, Policy and ManagementDivision of Insect BiologyUniversity of CaliforniaBerkeley, CA 94720-3112E-mail: [email protected]

REFERENCES1. Crawford MA, Bloom M, Broadhurst CL, et al. Evidence for the

unique function of docosahexaenoic acid during the evolution of themodern hominid brain. Lipids 1999;34(suppl):S39–47.

2. Broadhurst CL, Cunnane SC, Crawford MA. Rift Valley lake fishand shellfish provided brain-specific nutrition for early Homo. Br JNutr 1998;79:3–21.

3. Martinez M, Ballabriga A. Effects of parenteral nutrition with highdoses of linoleate on the developing human liver and brain. Lipids1987;22:133–8.

4. Ruff CB, Trinkaus E, Holliday TW. Body mass and encephalizationin Pleistocene Homo. Nature 1997;387:173–6.

5. Klein RC. The human career: human biological and cultural origins.2nd ed. Chicago: University of Chicago Press, 1999.

6. Jerison HJ. Evolution of the brain and intelligence. New York: Aca-demic Press, 1973.

7. Anderson RE, Chen H, Wang N, Stinson A. The accretion of docosa-hexaenoic acid in the retina. World Rev Nutr Diet 1994;75:124–7.

8. Salem N Jr, Wegher B, Mena P, Uauy R. Arachidonic and docosa-hexaenoic acids are biosynthesized from their 18-chain carbon pre-cursors in human infants. Proc Natl Acad Sci U S A 1996;93:49–54.



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9. Budowski P, Druckmann H, Kaplan B, Merlob P. Mature milk fromIsraeli mothers is rich in polyunsaturated fatty acids. World RevNutr Diet 1994;75:105–8.

10. Milton K. A hypothesis to explain the role of meat-eating in humanevolution. Evol Anthropol 1999;8:11–21.

11. de Heinzelin J, Clark JD, White T, et al. Environment and behav-ior of 2.5-million-year-old Bouri hominids. Science 1999;284:625–9.

12. Hayek MG, Reinhart GA. Utilization of �3 fatty acids in compan-ion animal nutrition. World Rev Nutr Diet 1998;83:176–85.

13. Sinclair AJ, Mann NJ. �3 fatty acids in meat raise plasma levels ofeicosapentaenoic and docosapentaenoic acids. World Rev Nutr Diet1998;83:233–4 (abstract).

14. Eaton SB, Eaton SB III, Sinclair AJ, Cordain L, Mann NJ. Dietaryintake of long-chain polyunsaturated fatty acids during the Pale-olithic. World Rev Nutr Diet 1998;83:12–23.

There is still more to learn about soy

Dear Sir:

Teixera et al (1) concluded that “consuming as little as 20 gsoy protein/d instead of animal protein for 6 wk reduces concen-trations of non-HDL cholesterol and apo B by �2.6% and 2.2%,respectively.” This appears to be an incorrect conclusion consid-ering the data and discussion put forth by these authors. In keep-ing with the given protocol of evaluating the effects of variouslevels of soy protein supplementation (soy with or withoutcasein) in moderately hypercholesterolemic adults, their conclu-sion does not match the test. Specifically, the group whoreceived 20 g isolated soy protein (ISP) also received 30 gcasein; additionally, only the groups who received either 50 gISP or casein did not receive a mix of the 2 proteins. Given thatonly the macronutrient and isoflavone contents of the diet werequantified and that actual meat, soy, or other lipid-affectingnutrients were not evaluated, the authors’ conclusions becomeweak. Furthermore, the conclusion that ingesting ≥ 20 g ISP/dinstead of animal protein for 6 wk reduces non-HDL cholesterolis both misleading and inaccurate.

In the apparent zeal of the authors to show the positive effectof small, daily servings of soy on lipid profiles, they mistakenlylabeled non-HDL cholesterol. The authors state that non-HDLcholesterol equates to subtracting HDL from total cholesterol(TC), the error is within the framework of labeling non-HDL asVLDL + LDL cholesterol. Simply stated, the authors had themeans to measure actual VLDL and LDL because they hadmeasured TC, HDL, triacylglycerol, lipoprotein(a), apolipopro-tein A-I, and apolipoprotein B. Thus, with all of the technicalmachinery available to the authors for firsthand measurement ofthese various lipids, it is questionable for them to put forth thatobserved changes in mathematically determined VLDL and LDLare accurate and truly reflective of the non-HDL lipid pool.Although it can be said that 65–70% of TC is carried as LDL,10–15% as VLDL, and 20% as HDL and that there are varioussubfractions of LDL, we cannot accept the conclusion of theauthors as a true measurement of non-HDL cholesterol (2).

Certainly, the role of soy and soy protein as medicinal foodsfor the treatment of mild to moderate hypercholesterolemia

deserves more independent prospective trials to further deter-mine both the risks and benefits of including this food in theWestern diet. However, before we accept generalized conclu-sions such as those made in Teixera et al’s article, we mustinsist on a strong body of evidence. Such a body of evidencemust be in place before we can make recommendations topatients or to the general public. There is still more to learnabout soy.

Douglas S Kalman

Peak Wellness, Inc50 Holly Hill LaneGreenwich, CT 06830E-mail: [email protected]

Carlon M Colker

Department of Internal MedicineGreenwich Hospital6 Perryridge RoadGreenwich, CT 06830-4697

REFERENCES1. Teixeira SR, Potter SM, Weigel R, Hannum S, Erdman JW Jr,

Hasler CM. Effects of feeding 4 levels of soy protein for 3 and 6 wkon blood lipids and apolipoproteins in moderately hypercholes-terolemic men. Am J Clin Nutr 2000;71:1077–84.

2. Fisher DA. Endocrinology: test selection and interpretation. 2nd ed.Teterboro, NJ: Quest Diagnostics Incorporated, 1998:59–62.

Reply to DS Kalman and CM Colker

Dear Sir:

We reassert our conclusion that “as little as 20 g soy protein/dinstead of animal protein for 6 wk reduces concentrations ofnon-HDL cholesterol and apo B by �2.6% and 2.2%, respec-tively” (1). We fully agree with Kalman and Colker that there ismuch more to learn about soy. However, a strong body of evi-dence from several laboratories, including a meta-analysis,already exists on the effects of soy protein on blood lipids (2–4).The Food and Drug Administration (FDA) reviewed the exten-sive literature published on this subject and in October of 1999approved a health claim for foods containing soy protein (5). Thequalifying amount of soy protein approved in this health claim(25 g) is similar to and consistent with the amount of soy proteinshown to decrease blood lipids in our paper (20 g). Therefore,the results of our study, in fact, provide additional support for theFDA-approved health claim.

The comment of Kalman and Colker regarding our conclusionmay have resulted from a misunderstanding on their part of ourstudy design. In our study, the control group received 50 g casein(ie, no replacement). For all other groups, different amounts ofcasein (20, 30, 40, and 50 g) were replaced by equivalentamounts of isolated soy protein, so that the total protein intakeremained constant. Therefore, our conclusion about the replace-



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ment of animal protein with soy protein was indeed consistentwith our data and study design. The comment of Kalman andColker regarding nutrient analysis is also incorrect. Besides theanalysis of macronutrients and isoflavones, we also calculatedtotal cholesterol and saturated, monounsaturated, and polyunsat-urated fat, as stated in the paper. Soy intake was also knownbecause the only form of soy consumed was the one provided inthe test protein (1).

Regarding the non-HDL-cholesterol values, non-HDL choles-terol is by definition any cholesterol that is not associated withHDL particles, and it corresponds to the cholesterol from allapolipoprotein B–containing lipoproteins [ie, VLDL, IDL, LDL,and lipoprotein(a)] (6). We labeled non-HDL cholesterol asVLDL + LDL cholesterol because the traditional definition ofLDL entails LDL + IDL + lipoprotein(a) (7). We chose to reportnon-HDL cholesterol because it has been shown to be a goodindicator of coronary heart disease (6).

We agree that measuring actual concentrations of LDL andVLDL cholesterol separately would provide additional usefulinformation, especially because LDL cholesterol is used histor-ically to determine risk of coronary heart disease (8). LDL cho-lesterol is also commonly determined through use of theFriedewald formula (9). However, it is well known that this for-mula is not accurate if triacylglycerol concentrations are > 4.66mmol/L (400 mg/dL) (10). Moreover, when triacylglycerolconcentrations are between 2.3 and 4.5 mmol/L (200–400mg/dL), LDL-cholesterol values obtained by the Friedewaldformula show considerable variability as compared with thosefrom ultracentrifugation (10). Most patients in our study fellinto 1 of the 2 previous categories, so we chose not to use theFriedewald formula.

Sandra R TeixeiraSandra Hannum

John W Erdman Jr

Division of Nutritional SciencesUniversity of Illinois at Urbana-ChampaignUrbana, ILE-mail: [email protected]

Susan M Potter

Protein Technologies International/DuPontSt Louis, MO

Clare M Hasler

The Functional Foods for Health ProgramUniversity of Illinois at Urbana-ChampaignUrbana, IL

REFERENCES

1. Teixeira SR, Potter SM, Weigel R, Hannum S, Erdman JW Jr,Hasler CM. Effects of feeding 4 levels of soy protein for 3 and 6 wkon blood lipids and apolipoproteins in moderately hypercholes-terolemic men. Am J Clin Nutr 2000;71:1077–84.

2. Carroll KK. Review of clinical studies on cholesterol-loweringresponse to soy protein. J Am Diet Assoc 1991;91:820–7.

3. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis ofthe effects of soy protein intake on serum lipids. N Engl J Med1995;333:276–82.

4. Kritchevsky D. Dietary protein, cholesterol and atherosclerosis:review of the early history. J Nutr 1995;125:589S–93S.

5. Food and Drug Administration. Food labeling: health claims; soyprotein and coronary heart disease. Fed Regist 1999;64:57699–733.

6. Vega G, Grundy S. Does measurement of apolipoprotein B have a placein cholesterol management? Arteriosclerosis 1990;10:668–71 (editorial).

7. Belcher J, McNamara J, Grinstead G, Rifai N, Warnick G, BachorikP. Measurement of low-density lipoprotein cholesterol concentra-tion. In: Rifai N, Warnick G, eds. Laboratory measurement of lipids,lipoproteins and apolipoproteins. Washington, DC: AACC Press,1994:107–24.

8. The Expert Panel. Summary of the second report of the NationalCholesterol Education Program (NECP) Expert Panel on Detection,Evaluation, and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel II). JAMA 1993;296:3015–23.

9. Friedewald W, Levy R, Frederickson D. Estimation of the concen-tration of low-density lipoprotein cholesterol in plasma, without useof the preparative ultracentrifuge. Clin Chem 1972;18:499–502.

10. Schaefer E, McNamara J. Overview of the diagnosis and treatmentof lipid disorders. In: Rifai N, Warnick G, eds. Laboratory measure-ment of lipids, lipoproteins and apolipoproteins. Washigton, DC:AACC Press, 1994:21–42.

Macronutrient estimations in hunter-gathererdiets

Dear Sir:

We disagree with the editorial (1) that accompanied our recentarticle on hunter-gatherer plant-animal subsistence ratios (2).Milton appears to have misinterpreted our findings as well asLee’s (3) original analysis of the Ethnographic Atlas (4).

Within the nutritional community, it is common knowledgethat the quantitative and qualitative lipid composition of domes-ticated meats is vastly different from that found in wild game.Game meat contains lower proportions of fat, especially satu-rated fat, than does meat from grain-fed domesticated animals,even on a whole-carcass basis (5). Nowhere in our article did werecommend that people should eat high-fat, domesticated live-stock. Our take-home messages were that hunter-gatherer dietswere higher in protein and lower in carbohydrate than are currentWestern diets or dietary guidelines and that this macronutrientbalance may provide insight into potentially therapeutic diets. Ifany implication were to be inferred, it would be that dietary fatshould emulate fat sources found in game meat and organs (highin n�3 fats, low in n�6 fats, and high in monounsaturated fats).

Milton’s editorial repeated the same error that has occurredcontinually in the anthropologic community since Lee publishedhis work 32 y ago (3). Lee did not report the total food intakesderived from animal sources because he did not sum hunted andfished animal foods. This is one of the reasons our reanalysis ofthe Ethnographic Atlas is original and noteworthy. Although wedid not report it in our article, we analyzed Lee’s sample of58 hunter-gatherer societies as a subset and obtained resultsalmost identical to those of our analysis of the entire sample(n = 229). The dependence on hunted and fished foods for subsis-tence was 86–100% (modal value) and 66–75% (median value).Milton’s statement that “emphasis on hunting occurred only in thehighest latitudes” is also inaccurate because our analysis of Lee’s



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data showed that there is no correlation (Spearman’s rho = 0.01)between dependence on hunting and latitude; on the contrary: asintakes of plant food decrease with increasing latitude, intakes offished food increase and of hunted animal food stay constant—thesame conclusion we reached with our original analysis. The edito-rial deemphasizes the importance of animal foods in hunter-gath-erer diets by citing 2 extreme and nonrepresentative societies, the!Kung and the Hazda, both of which have been shown by theEthnographic Atlas and modern quantitative studies to maintainhigh plant-animal subsistence ratios (67:33 and 56:44, respec-tively). Of the 229 hunter-gatherer societies listed in the Ethno-graphic Atlas, only 1 other society maintains a plant-animal sub-sistence ratio as high as that of the !Kung and only 13% maintaina ratio as high or higher than that of the Hazda. A compilation ofthe few available quantitative dietary studies in hunter-gatherersshowed a plant-animal subsistence ratio of 41:59 (6), which issimilar to the aggregate value (45:55) we reported in our article.

Increases in low-fat dietary protein at the expense of carbohy-drate may have therapeutic effects. Wolfe and Piche (7) showedthat the replacement of dietary carbohydrate with low-fat, high-protein animal foods improved blood lipids (LDL, VLDL, totalcholesterol, triacylglycerol, and the ratio of total to HDL choles-terol). Furthermore, increased dietary protein may reduce therisk of coronary heart disease (8) and reduce serum homocys-teine concentrations (9) while facilitating weight loss (10) andimproving insulin metabolism (11).

Again, we do not recommend increases in intakes of domesti-cated animal fat, only of lean protein from lean animals, prefer-ably protein that may also contain significant amounts of n�3 andmonounsaturated fat such as that found in game meat. Consump-tion of low-fat dietary protein at the expense of carbohydrate is thenutritional pattern that is consistent with our species’ evolutionaryhistory and represents a viable dietary option for improving healthand well-being in modern people. Further research is neededbefore this dietary pattern can be recommended without reserva-tion, particularly in subjects with preexisting kidney disease.

Loren Cordain

Department of Health and Exercise ScienceColorado State UniversityFort Collins, CO 80523E-mail: [email protected]

Janette Brand MillerDepartment of BiochemistryUniversity of SydneySydney, NSW 2006Australia

S Boyd EatonDepartments of Radiology and AnthropologyEmory UniversityAtlanta, GA 30322

Neil MannDepartment of Food ScienceRoyal Melbourne Institute of Technology UniversityGPO Box 2476VMelbourne, VIC 3001Australia

REFERENCES

1. Milton K. Hunter-gatherer diets—a different perspective. Am J ClinNutr 2000;71:665–7 (editorial).

2. Cordain L, Brand Miller J, Eaton SB, Mann N, Holt SHA, Speth JD.Plant-animal subsistence ratios and macronutrient energy estima-tions in worldwide hunter-gatherer diets. Am J Clin Nutr 2000;71:682–92.

3. Lee RB. What hunters do for a living, or how to make out on scarceresources. In: Lee RB, DeVore I, eds. Man the hunter. Chicago:Aldine, 1968:30–48.

4. Murdock GP. Ethnographic atlas: a summary. Ethnology 1967;6:109–236.

5. Eaton SB. Humans, lipids and evolution. Lipids 1992;27:814–20.6. Leonard WR, Robertson ML. Evolutionary perspectives on human

nutrition: the influence of brain and body size on diet and metabo-lism. Am J Hum Biol 1994;6:77–88.

7. Wolfe BMJ, Piche LA. Replacement of carbohydrate by protein in aconventional-fat diet reduces cholesterol and triglyceride concentra-tions in healthy normolipidemic subjects. Clin Invest Med 1999;22:140–8.

8. Hu FB, Stampfer MJ, Manson JE, et al. Dietary protein and risk ofischemic heart disease in women. Am J Clin Nutr 1999;70:221–7.

9. Mann NJ, Li D, Sinclair AJ, et al. The effect of diet on plasmahomocysteine concentrations in healthy male subjects. Eur J ClinNutr 1999;53:895–9.

10. Skov AR, Toubro S, Ronn B, Holm L, Astrup A. Randomized trialon protein vs carbohydrate in ad libitum fat reduced diet for thetreatment of obesity. Int J Obes Relat Metab Disord 1999;23:528–36.

11. O’Dea K, Traianedes K, Ireland P, et al. The effects of diet differingin fat, carbohydrate, and fiber on carbohydrate and lipid metabolismin type II diabetes. J Am Diet Assoc 1989;89:1076–86.

Reply to L Cordain et al

Dear Sir:

In their article in the March 2000 issue of the Journal (1),and now in their letter to the Editor, Cordain et al discussedplant-animal subsistence ratios and likely macronutrient intakes(percentage of energy) in recent hunter-gatherer societies. Theyconcluded that, worldwide, most hunter-gatherer societiesderived > 50% of dietary energy from animal foods and sug-gested that “the universally characteristic macronutrient con-sumption ratios of hunter-gatherers in which protein is elevatedat the expense of carbohydrate” may have therapeutic healtheffects for modern humans.

As discussed in my March 2000 editorial on this topic (2),hunter-gatherer societies, both recent and ancestral, displayed awide variety of plant-animal subsistence ratios, illustrating theadaptability of human metabolism to a broad range of energysubstrates. Because all hunter-gatherer societies are largely freeof chronic degenerative disease, there seems little justificationfor advocating the therapeutic merits of one type of hunter-gath-erer diet over another.

What general features of hunter-gatherer diets might con-tribute to this lack of degenerative disease? One important fea-ture may be that many wild foods consumed by hunter-gatherersare similar or identical to foods consumed by their prehuman



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ancestors. Thus, it could be said that human biology is adaptedto characteristics of a wide range of wild plant and animal foodsbut apparently is less well adapted to characteristics of manycontemporary Western foods.

Most wild foods have a low energy density compared with therefined foods of Western nations. Muscle tissue of wild prey isconsistently low in fat and fat depots tend to be very small inmost wild animals (3). Most wild fruit is hexose dominated (4),and wild plant foods tend to have a low glycemic index (5) and,often, considerable dietary fiber (4, 5). Such features, in combi-nation with the slow transit of ingesta characteristic of humans(4), should make it difficult for hunter-gatherers to digest morethan a limited quantity of these wild foods each day (2). Ineffect, then, most hunter-gatherers have a natural barrier betweenthemselves and chronic dietary or energy excess.

In contrast, contemporary Western populations live sur-rounded by volumetrically concentrated foods that are high insugar and fat and that can be ingested in enormous quantities. Itis extremely easy for individuals in Western nations to consumefar more energy each day than they expend. Although oftenstated, it bears repeating that this Western dietary pattern, incombination with a largely sedentary lifestyle, appears to con-tribute to many chronic degenerative diseases that affect West-ern nations but are largely or completely absent in hunter-gatherer and similar societies (2, 6), regardless of the macronutrientratio or principal energy source.

To derive their conclusions on hunter-gatherer diets, Cordainet al (1) used Murdock’s Ethnographic Atlas (7). Despite its gen-eral utility, the Atlas provides, at best, a “quantitative overview”(1) of the dietary behaviors of recent (largely 20th century)hunter-gatherers and “in almost all cases represents subjectiveapproximations by Murdock of the ethnographer’s or anthropol-ogist’s original observations” (1).

In his 1968 analysis of hunter-gatherer diets, Lee (8) reclassi-fied some Atlas data and also excluded mounted hunters withguns and “casual” agriculturalists from his database. In Lee’sopinion, only 24 societies from all of Africa, Asia, Australia, andSouth America could be classified as hunter-gatherers, whereasNorth America alone contained > 80% (135) of the 165 “hunt-ing” societies listed in the Atlas.

In contrast, in their analysis, Cordain et al (1) identified229 hunter-gatherer societies in the Atlas; they also combined2 of Lee’s discrete categories (hunting and fishing) to estimatethe total contribution of animal foods to energy subsistence.Given the uneven quality of most dietary data in the Atlas, theoverrepresentation of hunter-gatherer societies from more tem-perate locales and the differences in classification and dataanalysis between these authors, different conclusions seeminevitable and all conclusions appear to merit closer study.

The !Kung and Hazda, dismissed by Cordain et al as “unrep-resentative,” differ from many hunter-gatherers listed in the Atlasprecisely because they have been relatively well studied dietar-ily—in both cases, plant foods contributed the bulk of dailyenergy intake. Examination of the literature suggests that hunter-gatherers throughout the world took full advantage of anydependable sources of dietary energy in their environment(9–11), even devising complex technologies to secure energyfrom potentially toxic plant sources such as acorns and cycads(10, 11). Such dependable plant foods, in turn, tended to berelied on heavily for dietary energy. For this reason, Cordain etal’s comments on the “low carbohydrate content of wild plant

foods” seem largely beside the point—what is key is the steadyavailability of energy from 1 or 2 reliable wild-plant staples. Tosecure a dependable source of dietary carbohydrate, somehunter-gatherers, such as the Mbuti (Africa) and the Maku(South America), established symbiotic trade relationships withindigenous agriculturalists (12).

There seems little doubt that many hunter-gatherer societieshad a high intake of animal protein (and animal foods) by present-day standards (1, 8, 13). However, this does not imply that such adietary pattern is the most appropriate for human metabolism orthat it should be emulated today. Past hunter-gatherers did nothave unlimited dietary options but had to make the best of what-ever was available in a particular habitat. The gut proportions ofhumans do not indicate a highly carnivorous diet; rather, they indi-cate adaptation to a diet made up of high-quality foods of all typesand amenable to digestion primarily in the small intestine (14).Gut proportions of carnivorous mammals differ from those ofhumans (2). Food transit times in humans are very similar to thoseof apes and notably different from those of carnivores (2, 14).

To date, few genetic adaptations to diet have been identified inhumans, suggesting that, in their evolution, humans tended toresolve dietary problems primarily by using technology ratherthan biology. The technologic abilities of humans derive fromtheir unusually large, complex brain, a brain that, under normalconditions, is fueled by a steady supply of glucose. Consumptionof digestible carbohydrate is the most efficient way for humansto obtain glucose for brain function. Potential alternatives—glu-coneogenesis or the use of ketones to fuel the brain—representalternative, more costly metabolic solutions.

Although Cordain et al noted a neutral or therapeutic effectfor high protein intakes in some instances, Hu and Willard (15)recently cautioned application of their findings on heart diseaseand a high protein intake to public dietary advice because “ahigh dietary protein intake is often accompanied by high satu-rated fat and cholesterol intakes.” Given that most Westerners donot have access to wild game, this recommendation seems pru-dent. Certainly the average well-nourished, inactive Americanmight benefit from reaching for 100 g lean protein rather than a100-g cheese danish, but foraging for a 100-g apple might proveto be the most therapeutic of all.

Katharine Milton

Department of Environmental Science, Policy and ManagementDivision of Insect BiologyUniversity of CaliforniaBerkeley, CA 94720-3112E-mail: [email protected]

REFERENCES1. Cordain L, Brand Miller J, Eaton SB, Mann N, Holt SHA, Speth JD.

Plant-animal subsistence ratios and macronutrient energy estima-tions in worldwide hunter-gatherer diets. Am J Clin Nutr 2000;71:682–92.

2. Milton K. Hunter-gatherer diets—a different perspective. Am J ClinNutr 2000;71:665–7.

3. Naughton JM, O’Dea K, Sinclair AJ. Animal foods in traditionalAustralian Aboriginal diets: polyunsaturated and low in fat. Lipids1986;21:684–90.

4. Milton K. Nutritional characteristics of wild primate foods: do thenatural diets of our closest living relatives have lessons for us?Nutrition 1999;15:488–98.



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5. Brand-Miller JC, Holt SHA. Australian Aboriginal plant foods: aconsideration of their nutritional composition and health implica-tions. Nutr Res Rev 1998;11:5–23.

6. Walker ARP. Are health and ill-health lessons from hunter-gathererscurrently relevant? Am J Clin Nutr (letter; in press).

7. Murdock GP. Ethnographic atlas: a summary. Ethnology 1967;6:109–236.

8. Lee RB. What hunters do for a living, or, how to make out on scarceresources. In: Lee RB, DeVore I, eds. Man the hunter. Chicago:Aldine, 1968:30–48.

9. Hall GD. Pecan food potential in prehistoric North America. EconBotany 2000;54:103–12.

10. Kuhnlein HV, Turner NJ. Traditional plant foods of Canadianindigenous peoples. Philadelphia: Gordon and Breach, 1991.

11. Smyth RB. The Aborigines of Victoria. Vol I. London: Trubner andCo, 1878.

12. Milton K. Protein and carbohydrate resources of the Maku indiansof northwestern Amazonia. Am Anthropol 1984;86:7–27.

13. Flodin NW. Nutritional influences in the geographic dispersal ofPleistocene man. Ecol Food Nutr 1999;38:71–99.

14. Milton KM. Primate diets and gut morphology: implications forhuman evolution. In: Harris M, Ross EB, eds. Food and evolution:toward a theory of human food habits. Philadelphia: Temple Uni-versity Press, 1978:93–116.

15. Hu FB, Willard WC. Reply to TC Campbell. Am J Clin Nutr 2000;71:850–1 (letter).

No advantage of using ferrous bisglycinate asan iron fortificant

Dear Sir:

In the June 2000 issue of the Journal, Bovell-Benjamin et al(1) compared the absorption of iron from ferrous sulfate, ferrousbisglycinate, and ferric trisglycinate added to a whole-maizemeal. They concluded that iron absorption was better from fer-rous bisglycinate than from ferrous sulfate or ferric trisglycinateand that ferrous bisglycinate was an effective and safe source ofiron that was particularly useful as an iron fortificant in diets richin phytate. Their other main conclusion was that iron from fer-rous bisglycinate does not exchange in the intestinal nonheme-iron pool with the iron from maize or ferrous sulfate.

In comparisons of iron absorption from meals, the percent-age absorption, based on tracer methodology, needs to be mul-tiplied by the amounts of iron present in the correspondinglabeled pools. Bovell-Benjamin et al concluded that iron fromferrous bisglycinate does not exchange with the iron frommaize or ferrous sulfate. This conclusion was based on obser-vations that, when the same amounts of iron as ferrous sulfateand ferrous bisglycinate were given separately together withthe maize meal, iron absorption was 1.7% and 6.0%, respec-tively; when the same amounts of iron were added to the samemaize meal, absorption of the tracers was 1.0% and 6.8%,respectively. The authors combined the mean percentageabsorption in their studies 1A and 1B, which were then 1.3%and 6.4%, respectively, indicating a 4.7 times greater absorp-tion of iron from ferrous bisglycinate (P < 0.05). It is not clearhow the conclusion of “no exchange” was drawn between thelabels in the intestinal pool in study 1B. However, because the

absorption studies were done in the same subjects, the data canbe analyzed in a way that is more sensitive and specific bycomparing the absorption in the same subjects and not in2 groups of subjects. The mean absorption of iron from thetracer for ferrous sulfate given alone with maize was 1.7%(study 1A); when ferrous sulfate was given together withmaize and ferrous bisglycinate (study 1B) the absorption waslower (1.0%). These mean values suggest that the absorptionwas different in the 2 studies. When we compared more cor-rectly the individual ratios in absorption of the ferrous sulfatetracer in studies 1A and 1B, this mean ratio was 1.653(t = 2.436, P = 0.0375). A corresponding comparison of fer-rous bisglycinate in studies 1A and 1B showed that the absorp-tion was the same when ferrous sulfate was given alone instudy 1A and when given together with the same amount offerrous sulfate in the same meals in study 1B (mean ratio:0.956, t = �0.299, P = 0.77). This implies 1) that the absorp-tion of iron from the nonheme-iron pool dropped by �40%(1/1.65) when ferrous sulfate was given together with ferrousbisglycinate and 2) that the percentage absorption of iron froma hypothetical chelate pool of ferrous bisglycinate was notinfluenced. The most obvious explanation is that some ironmoved from “the ferrous bisglycinate pool” to the “maizepool,” which we know from several previous studies is uni-formly labeled by the added ferrous sulfate.

All this implies that the iron absorption from ferrous sulfategiven with maize in study 1A was measured correctly. However,the absorption of iron from ferrous bisglycinate in study 1A can-not be calculated because we do not know 1) how much ironmoved from ferrous bisglycinate to the nonheme-iron pool inmaize, and thus 2) how much iron remained in chelate form. Weknow from study 2A that iron in ferrous bisglycinate is less wellabsorbed than is ferrous sulfate when given alone. It may beassumed that ferrous bisglycinate is partly dissociated and thatan unknown, but possibly considerable, amount of iron isreleased into the nonheme-iron pool (maize-meal pool). Anabsolute condition in these kinds of tracer studies is to know thespecific activity of the iron.

This would imply that it is impossible to estimate the totalamounts of iron absorbed. Actually, the only way to correctlyanalyze the isotopic exchange between an iron compound andiron in a food is by comparing iron absorption from a biosyn-thetically radioiron-labeled food (eg, maize) and the iron com-pound to be tested. An incomplete isotopic exchange betweeniron in another iron chelate, FeNaEDTA, and biosyntheticallyradioiron-labeled maize was observed by several investigators(3–5). In unpublished studies in our laboratory we found anabsorption ratio of 0.58 ± 0.044 between biosynthetically radio-iron-labeled maize and the iron in FeNaEDTA (n = 10). All theseresults suggest that a fraction of iron chelates may form a sepa-rate pool, that some iron is dissociated and exchanges with thenonheme-iron pool, and that some unknown fraction is absorbedfrom a kind of possible mucosal-iron pool.

An interesting part of the discussion in the present study (1)addressed the process of absorption of iron from the intestineswhen strong iron chelates are also present. Our assumption isthat there is a pool at the intestinal mucosal surface from whichiron is taken up by special nonheme-iron receptors. This mucosalpool is directly connected with the nonheme, intraluminal non-heme-iron pool. In that pool, ferric iron is probably reduced toferrous iron to be absorbable. Iron chelates such as ferrous bisg-



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lycinate and FeNaEDTA are present initially in an iron chelatepool that is connected both with the common nonheme intralu-minal pool (where an isotopic exchange may take place) anddirectly with the mucosal nonheme-iron pool, where its iron maybe released and absorbed. In this way, iron status influences theabsorption from both the iron in the chelate pool (as reportedhere) and the iron in the usual intraluminal nonheme-iron pool.Such a hypothesis might explain many of the seemingly contra-dictory results.

On the basis of our analysis of the data presented, we cannotaccept the main conclusions drawn by Bovell-Benjamin et al.There is no evidence to support the conclusion that ferrous bis-glycinate is useful as an iron fortificant.

Leif HallbergLena Hulthén

Institute of MedicineDepartment of Clinical NutritionSahlgrenska University HospitalAnnedalsklinikernaS-41345 GöteborgSweden

REFERENCES

1. Bovell-Benjamin A, Viteri FE, Allen LH. Iron absorption from fer-rous bisglycinate and ferric trisglycinate in whole maize is regulatedby iron status. Am J Clin Nutr 2000;71:1563–9.

2. Hallberg L. Bioavailability of iron from different meals. In: Nutri-tion in health and disease and international development. New York:Alan R Liss, Inc, 1981;333–43.

3. Layrisse M, Martinez-Torres C. Fe(III)-EDTA complex as iron for-tification. Am J Clin Nutr 1977;30:1166–74.

4. Martinez-Torres C, Romano EL, Renzi M, Layrisse M. Fe(III)-EDTA complex as iron fortification. Further studies. Am J Clin Nutr1979;32:809–16.

5. MacPhail AP, Bothwell TH, Torrance JD, et al. Factors affecting theabsorption of iron from Fe(III)EDTA. Br J Nutr 1981;45:215–27.

Reply to L Hallberg and L Hulthén

Dear Sir:

Hallberg and Hulthén question the interpretation of our data thatshowed that ferrous bisglycinate is absorbed better from wholemaize than is ferrous sulfate. Specifically, they question our conclu-sion that there was no exchange in the intestinal pool between ironfrom ferrous bisglycinate and iron from ferrous sulfate.

The basis of our conclusion is that absorption of iron from fer-rous sulfate and ferrous bisglycinate was the same whether the

labeled forms of these compounds were given separately or mixedtogether in the same meal. Our data were analyzed correctlybecause it is appropriate to control for the repeated-measures natureof the design. Also, because a log transformation was used, in effectthe absorption ratios were compared, not the absolute values. Asstated in our article, the average absorption of iron from ferrous sul-fate was about one-fifth that of its absorption from ferrous bisglyci-nate (P < 0.0001).

What we did not do was use the repeated-measures procedureto examine the interaction between study and iron source. We havesince used that procedure and found the interaction to be signifi-cant (P = 0.01). It is therefore appropriate to make a comparisonof iron sources between studies. This comparison showed that ironabsorption from the bisglycinate was the same in each trial(P = 0.77, Tukey’s test) but, as noted by Hallberg and Hulthén, theabsorption from ferrous sulfate differed between studies 1A and1B (P = 0.04). However, the results do not support their interpre-tation that there is an exchange between iron from ferrous bisgly-cinate and the nonheme-iron pool.

If the iron from these sources had exchanged in the intesti-nal pool there would have been a similar trend in iron absorp-tion from both iron sources in studies 1A and 1B. In fact, theopposite occurred. As the geometric mean absorption ratio ofiron from ferrous sulfate between studies 1A and 1B droppedto 0.59, a significant difference, it increased to 1.13 for ferrousbisglycinate, which was not significant. If, as Hallberg andHulthén suggest, the explanation is that some iron moved fromthe ferrous bisglycinate into the “maize pool,” which is equili-brated with the ferrous sulfate iron, less label from bisglyci-nate would have been absorbed in study 1B, and there wouldhave been less of a difference between the geometric absorp-tion means. However, the means became more separated: theratio of absorption of iron from ferrous bisglycinate to absorp-tion of iron from ferrous sulfate in study 1A was 3.5 andincreased to 6.8 in study 1B. In addition, even if the cause ofthe 41% lower absorption of iron from ferrous sulfate in study1B was dilution with iron from ferrous bisglycinate, it stillcould not explain this amount of divergence. Importantly, carewas taken to provide the same amount of iron as sulfate or bis-glycinate, or both, so that the size of the intestinal iron poolwas similar in the 2 studies.

Lindsay H Allen

Department of NutritionUniversity of CaliforniaDavis, CA 95616E-mail: [email protected]

Fernando E Viteri

Department of Nutritional SciencesUniversity of CaliforniaBerkeley, CA 94720



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Am J Clin Nutr 2000 Cordain 1585 6 (1)