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The Journal of Nutrition Vol. 128 No. 9 September 1998,
pp. 1570-1573
Laboratory of Human Nutrition, Massachusetts Institute of Technology, Cambridge, MA 02139
In an Issues and Opinions section, Millward (1997) While these statements by Millward (1997) We accept the view of Millward (1997) It seems as though some confusion may have arisen in Millward's (1997) comparison of the adult rat and human amino acid requirements. When we expressed the requirement pattern in relation to a potentially limiting indispensable amino acid, such as tryptophan or lysine, we found that there was a reasonable similarity between the human values and the average value for the combined nonhuman species within all developmental categories. In this context, the relative requirements for the various indispensable amino acids, one-to-another, might well be similar for rats and humans, as Hegsted (1973) Millward's assertion that the maintenance lysine requirements for rats, pigs and humans, which he summarizes in Table 2 of his paper, are similar is unfounded, in my opinion. First, he uses the human lysine requirement value for the adult as given by FAO/WHO (1973), i.e., 12 mg/(kg··d), which was based on the mean or combined highest estimates of the individual requirement in men and women. A mean requirement for the adult human would be 8.8 mg/(kg·d) (Rose et al. 1955 Now consider Millward's objection to our prediction of initial, tentative amino acid requirements for maintenance, as derived from the amino acid composition of body proteins and modified where data were available from 13C-amino acid tracer studies. Indeed, the approach we adopted meant that we had defined the maintenance pattern with the same amino acid composition of the mixed proteins in the body. Millward considers this unwarranted. It might, however, be pointed out that our tentative values for lysine, as noted above, and for the sulfur amino acids (SAA) and threonine were made with reference to the results of our earlier 13C-tracer studies, despite their limited scope.
Perhaps, three issues may be raised here; first, he has noted elsewhere (Millward 1998 Second, in contrast to the position taken by Millward (1997 and 1998), I would conclude, from the variable data available, that there is an apparent, general similarity between the amino acid pattern of mixed body proteins and the adult maintenance pattern. Indeed, the comparison that we have made previously for the 1985 FAO/WHO/UNU preschool age pattern and body protein shows a close similarity (Young and El-Khoury 1995 Additionally, it is now well appreciated that body protein maintenance in the adult involves depletion of body proteins during the fasting period of the day and their repletion during the fed period of the day. Thus, the pattern of the amino acids liberated from proteins and of that of the retained amino acids must be that of the mixed body proteins. The question then is whether this prandial gain would require, under steady-state conditions of N balance and at requirement of intakes of N, a dietary pattern of IAA that is similar to that of the body mixed proteins. For leucine, our tracer studies indicated that the required amino acid intake needed to achieve body balance, per unit of N intake, was indeed in proportion to leucine in body proteins (El-Khoury et al. 1994a Millward (1997) Millward raises the issue that we have "yet to publish reliable stable isotope studies for lysine, and in my view no other unequivocal studies have been published." We are now exploring the lysine requirements of healthy adults and, with the use of the indicator amino acid oxidation/24-h leucine balance technique, we have now provided initial evidence in favor of our predictions and estimates of the lysine requirements of healthy adults (Kurpad et al. 1998 In his final paragraph, Millward (1997) Millward also makes reference in this final paragraph to the North Carolina wheat study. In this investigation, by Edwards et al. (1971) The tentative amino acid requirement pattern (MIT-AARP) that we have proposed for current application in practical considerations of human protein nutrition is shown in Table 1; it is compared with the 1985 FAO/WHO/UNU preschool child and adult amino acid requirement patterns. The latter were based importantly on experiments of Rose and collaborators that are now no longer considered acceptable or for which the values are nutritionally relevant (Clugston et al. 1996
presented a number of arguments in defense of his position that the comparisons made and conclusions drawn in our (McLarney et al. 1966) article on amino acid requirement patterns among various species and in support of the MIT amino acid scoring pattern, "...are largely irrelevant to human needs after the first 6-12 mo life." In this context, it is curious that Millward also draws similar interspecies comparisons, between and among young and adults, in making his points and developing criticisms of our analysis. This appears to be contradictory. Also, he states, "Young and Pellett (1990) used the MIT scoring pattern to identify a lysine deficiency of cereal-based diets that they say require animal protein supplementation to rectify," which we did not, nor did we (Young and El-Khoury 1995) state that "...growth patterns need not bear any relationship to tissue amino acid content" (Millward 1997). In the first case, we said that it was "...desirable for at least one third of dietary protein to originate from animal sources when total protein is limited," and that "...when animal protein percentages are less than this, the well-known concept of protein complementation should be applied by increasing the availability and consumption of pulse proteins." Indeed, we (Young et al. 1998) fully recognize that "...balanced vegetarian diets can fulfill these higher requirements (i.e., those proposed by Young et al. 1989, Young and El-Khoury, 1995), and so animal foods are not essential from a strictly physiological standpoint." In the second case, the specific point we (Young and El-Khoury 1995) made was that "...the pattern of amino acids required for rat growth does not necessarily resemble any more precisely the amino acid composition of mixed body proteins (or pattern of oxidative amino acid losses) compared with that for maintenance in the preschool child..." or for that matter the adult pig (McLarney et al. 1996).
deserve some comment and clarification, a more important issue is whether the various arguments made by him invalidate our recommendations or minimize their nutritional significance. I think not, as explained below. I shall address his different arguments, largely in the order they were made, beginning with a comment on the reliability of the data used to make our interspecies comparisons (McLarney et al. 1996). Thus, we did make the point that the requirement data used for our analysis depended largely upon the nonhuman species values proposed by various expert groups, recognizing that these values may well differ from those proposed by individual investigators or research groups. This was a rational choice because we also used the recommendations of the international expert groups of the United Nations for human amino acid requirements. Similarly, Millward (1997) used these requirement figures (FAO/WHO/UNU 1985) in developing his reasoning and conclusions.
that there are difficulties in making a precise interspecies comparison, and this is compounded by the uncertainties surrounding the values for human requirements. However, just as he is willing to undertake these comparisons with his selected data, we are also prepared to do so, particularly for purposes of trying to identify whether there are real similarities, distinct differences or even trends that characterize the pattern of amino acid requirements across species and for the different "physiological/developmental" stages that we compared. Millward (1997) appropriately pointed out that the growth rates of animals were far higher than those of humans at any of the life stages used in our comparisons. Indeed, this appeared to us to be a good reason for undertaking our analysis, particularly in light of the less obvious rate of change in the amino acid requirement pattern (mg amino acid/g protein) throughout the growth and developmental stages in the various nonhuman species compared with the rather more distinct change in humans that emerges from the U.N. figures, in spite of the much slower growth rate of humans. Further, Millward (1997) also stated that "...the human data are unlikely to reflect accurately the true developmental change in metabolic demands for amino acids because they have not been systematically studied." Indeed, for this or a quite similar reason, we felt it worthwhile to undertake our analysis so as to expose possible inconsistencies and/or gaps in our knowledge of human amino acid requirements.
has judged. However, our point was that when the pattern is expressed as the requirement for each specific amino acid per unit of protein need, then the international values for the adult human would seem to be much lower when considered in reference to the available estimates in nonhuman adult species (McLarney et al. 1996).
). We have presented arguments previously that this level is likely to be far too low. Second, he then compares estimates of the maintenance lysine requirement in weanling and adult female rats and in young growing and adult pigs. Again, there are problems with this as follows: first, as Millward (1997) appreciates, "these values represent amino acid consumption rates under physiologically unusual circumstances," and second, all of the animal groups used in Millward's comparison still had considerable further growth potential, whereas this is not the case for the human adult. This raises the question of the nutritional/functional meaning of the estimated maintenance needs for the growing organism. "Maintenance" in a growing organism would seem to indicate a metabolic state that is profoundly different from that characterizing maintenance in a fully grown adult. In this context, Millward's concern "for like being compared with like" has also seemingly been violated in his analysis of the lysine requirements of different species. Third, and a point which we can accept, is that Millward draws the conclusion, in comparison with the composition of average tissue protein, that the maintenance lysine requirement is a smaller fraction of total indispensable amino acids (IAA)1; for the human, he sets the lysine requirement (per unit IAA), in relative terms to ~75% of that for the lysine content of mixed body proteins. This value is reasonably comparable to the difference between the lysine requirement, per unit of protein, that we have proposed and that of body mixed proteins, i.e., ~87% (Young and El-Khoury 1995).
) that oxidative amino acid losses (OAAL) for most amino acids are greater by two or more times than the FAO/WHO/UNU (1985) requirement values, except for the total sulfur amino acids (methionine + cystine) for which the predicted losses and FAO/WHO/UNU (1985) requirement values were quite close. He concludes from this comparison that the SAA "drive" the obligatory nitrogen loss. However, the power of his argument depends, in the first instance, on an assumption of the validity and acceptance of the nutritional significance of the FAO/WHO/UNU (1985) amino acid requirement estimates. Because these can legitimately be questioned, his reasoning becomes problematical in my opinion. Furthermore, it has been shown that the presence of a source of dietary cystine spares the methionine requirement, possibly by as much as 90% (Rose 1957, Williams et al. 1974). Hence, in theory, the OAAL for methionine could be reduced to the equivalent of about one fourth of the methionine loss under conditions of a low cystine intake. I am not aware, however, that dietary cystine, in contrast to methionine (Yoshida, 1986), reduces N excretion when experimental animals are given a protein-free diet. This N-sparing effect is a basis for Millward's suggestion that the SAA losses are rate-limiting for body protein retention. Furthermore, not only are short-term animal feeding studies difficult to interpret for their human nutritional importance, similar experiments in adult humans are lacking. Thus, it is a matter of speculation whether the SAA are rate-determining for mobilization of whole-body proteins under conditions of protein-free or amino acid-inadequate diets.
). I recognize, however, that this comparison may be complicated by the fact that the children used in the studies from which amino acid requirement values have been determined appear to have been retaining body protein at a much higher than normal rate (compare FAO/WHO/UNU 1985 and Pineda et al. 1981). In that case, the dietary retention of indispensable amino acids may well have been more efficient than for a fully repleted, normally growing child. The net effect may have been, therefore, a compensation such that the daily requirement value in the fully replete child and that needed for support of catch-up growth during the late recovery phase from earlier protein-energy malnutrition are similar.
and 1994b). However, because there is a large metabolic capacity to conserve lysine, when intakes are limiting, the question is whether our findings for leucine also apply to lysine. Although, we do not yet have extensive data for lysine, the fasting loss of lysine at a generous [77 mg/(kg··d)] lysine intake appears to be ~70-90% of that predicted from leucine oxidation, depending upon the route (intravenous or oral) of 13C-lysine administration (El-Khoury et al. 1998). In comparison, at a limiting and inadequate intake of lysine [12mg/(kg··d)], the fasting state rate of oxidation appears to be ~50-110% of the rate of leucine loss, when the latter is measured at a low leucine intake (El-Khoury and Young, unpublished results). Hence, it appears that there is some retention, rather than a complete oxidation, of the lysine liberated from proteins during the postabsorptive periods; this "spared" lysine may then be used for retention and replenishment of protein during the prandial phase of amino acid metabolism. Although the differences between measured and leucine-based, predicted oxidative losses of lysine do not seem to be profound, they would support a difference between our proposed lysine requirement (expressed per unit of protein requirement) and the concentration of lysine in whole-body mixed proteins of the magnitude discussed above.
also finds fault with the lysine requirement values reported by Zello et al. (1993), which we have used in support of our position. These values were obtained by using the indicator oxidation method (Zello et al. 1995), but Millward is critical of their studies because no attempt was made to allow for an adaptation of lysine oxidation to the reduced test levels of lysine intake. The dietary design used by Zello et al. (1993), as well as that by Duncan et al. (1996) in a follow-up study, involved giving test intakes of lysine on only 1 d during a dietary period in which subjects were otherwise consuming an experimental diet that supplied a reasonably generous amount of lysine [60 mg/(kg·d)]. Hence, it seems possible that this design would likely lead to a lower, rather than higher, breakpoint on the lysine intake-indicator amino acid oxidation curve. This is because there could be a "replete" or substantial free lysine pool that served as a source of utilizable lysine, in addition to the intake supplied by the six small hourly meals given during the test. Similarly, of possible interest, is that in estimating protein requirements in healthy elderly and young adults, from 13C-leucine balance studies, Millward and his colleagues (Fereday et al. 1997) used an analogous design. In their particular case, 13C-leucine balance estimates were made in subjects who had continued consuming their usual protein intakes until the night before the 9-h tracer infusion protocol was begun the following morning.
).
concludes, "...given 1) the low minimal obligatory needs for indispensable amino acids, 2) the fact that their metabolic demand reflects the extent to which adaptive changes in oxidation occurs and 3) the growing evidence for the availability of indispensable amino acids, including lysine, deriving from colonic microbial de novo amino acid synthesis from salvaged urea..., in my view, definition of adult indispensable amino acid requirements for protein quality scoring is not currently possible or likely to be useful in the future." We (Metges et al. 1997) and others (Gibson et al. 1996, Tanaka et al. 1980, Torrallardona et al. 1994) have obtained evidence for the uptake into body tissues of lysine that is derived from intestinal microbial synthesis. However, the extent to which this source of lysine serves as a net contribution to the total lysine intake is still to be determined. Thus, it is also reasonable to assume that there is a microbial synthesis and uptake of the other IAA, as well as lysine. However, our studies with leucine (El-Khoury et al. 1994a) and those of Millward and his colleagues (Price et al. 1994) suggest that this source of new IAA compensates, in large part, for the losses of IAA that occur via a turnover and secretion of intestinal proteins, and subsequent oxidative catabolism of the amino acids liberated by the activity of the microflora and also intestinal tissues. Hence, although a process of lysine (or IAA) synthesis within the gut lumen and of oxidative catabolism of lumen IAA could be viewed as a metabolic cycle of importance to IAA homeostasis, this would not necessarily complicate estimation of the whole-body kinetics and the oxidation of IAA with the 13C-tracer techniques, as currently employed in our laboratories and those of Millward and his collaborators.
, N balances were measured in adults given a diet, for 15-29 d, that was based largely on wheat protein but supplemented with other plant foods. The total level of lysine in the diet approximated 41 mg/g protein, giving an intake of ~26 mg/(kg··d) [not 17 mg/kg as stated by Millward (1998)]. Their subjects maintained body nitrogen equilibrium; thus it is our judgment that their findings support our conclusions, especially recognizing that the daily lysine intake in this experiment by Edwards et al. (1971) exceeded the FAO/WHO/UNU upper requirement value (12 mg/kg) by about twofold. It also exceeded the mean requirement estimate (8.8 mg/(kg··d)] suggested from the study by Rose et al. (1955) by as much as threefold! On this basis, I do not find a compelling reason to accept Millward's conclusion that the earlier balance studies support the view of low minimal obligatory need for the IAA for human maintenance.
). There is no substantial body of evidence to support a practical use of the FAO/WHO/UNU adult amino acid requirement pattern. Although our own data are still incomplete, in view of the importance of nutrient requirement data for the appropriate planning of world food and protein needs (Young et al. 1998), it seems prudent to accept the MIT-AARP until new evidence leads to a preferred and perhaps more rational alternative.
View this table:
Table 1.
The MIT amino acid requirement pattern (MIT-AARP) compared with the 1985 FAO/WHO/UNU patterns for adults and preschool children.
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FOOTNOTES |
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Manuscript received 8 April 1998. Revision accepted 7 May 1998.
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