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4. The maintenance requirement (MR)

This is a subject on which there is still a difference of opinion. Clearly when growth is rapid the IAA requirement must to a large extent be determined by the pattern of IAAs in the tissue that is being laid down. In the non-growing adult the MR derives from the need to replace IAAs that are consumed in a variety of irreversible pathways (Table 3). There is no a priori reason why this consumption pattern should bear any relation to that of deposition; a view that has been widely held by nutritionists in the past, e.g. Osborne & Mendel (1916, quoted by Millward, 1992) and Said & Hegsted (1970), and which is accepted in principle by Young (personal communication). Thus Fuller et al (1989), in experiments on young pigs, have assessed separately the pattern of requirements for growth and the pattern when there is no growth (maintenance), and found the two patterns to be quite different.

Table 3 Some non-protein pathways of amino acid utilization

From Reeds (1990).

Nevertheless, Young and El Khoury (1995) maintain that in practice in man the maintenance IAA pattern resembles that of tissue protein, on the grounds that there is a close correspondence between the tissue pattern and that of the IAA requirements of pre-school children, as observed by the workers at INCAP (Pineda et al, 1981) (Table 1B). Since in the pre-school child growth represents only some 10% of the requirement, it is reasonable to extrapolate these results to adults.

Is it possible to reconcile these two opposing points of view? On a protein-free diet or fasting the obligatory N loss (ONL) must reflect the pattern of tissue proteins, since the only source of nitrogen is from protein breakdown. In this situation one may suppose that the IAA with the largest consumption pathway 'drives' the obligatory loss. If protein breakdown provides more of a particular IAA than is needed to make good its loss through irreversible pathways, this extra amount must nevertheless be oxidized. When protein is fed, the pattern changes and the IAAs are only needed in a pattern that balances their losses in the consumption pathways. Thus if fasting and feeding occur in a 12 h cycle, 50% of the 24 h requirement will reflect the composition of body protein and 50% that of the consumption pathways.

The picture, however, is complicated by the diurnal cycling of deposition and loss of body protein (see below). Fed state deposition can be regarded as a form of temporary growth, and therefore requires that amino acids should be provided in the concentrations in which they occur in body protein, although Fuller (personal communication) has suggested that temporary protein storage could have a composition quite different from that of body protein as a whole. To a large extent these amino acids must be derived from protein breakdown; if the food intake is, say, one fifth of the flux, four fifths of the amino acids deposited will be derived from breakdown. At maintenance levels of intake, deposition is relatively small, but at higher intakes, when deposition is increased, the rate of protein breakdown is greatly reduced (section 11), so that intake from the diet becomes more important. Millward et al (1991) have discussed whether amino acids liberated from body protein during the fasting period could be held over, as it were, and be available for meeting needs in the fed state. However, the free amino acid pools, particularly those of the branched chain amino acids (BCAs), are too small for this to be likely. Therefore, in the fed state, particularly with generous intakes, the intake from food plays an essential role in topping up the amino acid supply for protein deposition, and to the extent that it is used in this way, this intake probably must have the pattern of tissue protein.

It follows that conceptually the IAA requirement pattern will be some kind of halfway house between the pattern of irreversible losses and the pattern of body protein, and the relative proportions of the two patterns will be influenced by the level of protein intake. It seems to me that the next step must be to measure the individual IAA losses through irreversible pathways. In the meantime, because the two processes of fasting loss and diurnal cycling tend to shift the maintenance pattern towards that of body protein, it may be considered that Young's proposal represents a reasonable working compromise until more direct observations become available. It should be noted that on Young's hypothesis, if the requirement of one IAA is established, those of all the others follow, whereas if an amino acid, e.g. lysine, is differentially conserved, the requirement of each IAA must be determined separately.

5.Diurnal cycling: the Millward-Rivers model

As mentioned in section 2, Millward starts from the position that there are three levels of requirement: optimal, operational and minimal. No attempt is made to put numbers to the optimal requirement, and little more can be said about it, except to emphasize that the minimal requirement, which has engaged so much attention, is not the be-all and end-all.

The operational requirement is the amount needed to secure balance at a range of intakes above the minimal. That such a range exists has long been recognized. The contribution of the new model (Millward & Rivers, 1988; Millward et al, 1989) is to suggest that the oxidative losses of amino acids can be divided into two parts, obligatory losses, L_O and regulatory losses, L_R. The important point is that the regulatory losses are no longer regarded simply as wasted amino acids; rather they have a beneficial and indeed necessary role. This role is the 'anabolic drive', which includes all the effects of amino acids in stimulating the production of hormones such as insulin and in promoting the deposition of protein after a meal (Millward, 1989, 1990). The fact that the replacement of the obligatory losses (50-60 mg N/kg) requires an intake that is almost twice as great (100 mg N/kg) has previously been taken as an effect of inefficiency, the nature and causes of which have never been defined. For Millward, L_R makes a necessary contribution to the control of protein metabolism although he now (personal communication) considers it not very important in adults. Nevertheless a state in which oxidative losses were reduced to a level that exactly compensated for the obligatory loss would not be a desirable one. Thus 'a scoring pattern based on minimal obligatory needs is of little practical use' (Millward, 1992).

The consequence of different patterns for growth and maintenance (section 4) is that in the fed state, even at minimal levels of protein intake, some IAAs may be provided in excess of needs. Millward et al (1990, 1991) have pointed out that the branched chain and aromatic IAAs are potentially toxic; their concentrations cannot be allowed to rise and any excess has to be disposed of by oxidation, through high capacity highly regulated oxidative pathways. One might suppose that although the oxidative enzymes are readily inducible, teleologically it would be inadvisable for the expression of them ever to be reduced to zero. This could be regarded as a further reason for the so-called inefficiency of amino acid utilization.

A second contribution of the Millward-Rivers model is that it emphasizes the importance of the diurnal cycle of fasting and feeding. Clugston & Garlick (1982) originally showed that deposition of protein during feeding is balanced by loss in the fasted state. Millward predicted from his model that the amplitude of the fasted-fed swings would increase with increasing protein intake, and his recent studies have shown that this is indeed the case, as shown in Figure 2 (Pacy et al, 1994). As Millward (1992) has said 'The increasing fasting loss with increasing protein intake generates an increasing demand for fed-state protein deposition to balance these losses'. Thus it is impossible to define any particular figure for the operational requirement. However, his dictum 'the more you eat the more you need' seems to imply that the intake can never catch up with the need, which is the logic of Achilles and the tortoise. This must be regarded as artistic license - the intake certainly can overtake the need. Millward's own 24 h balances are positive at high intakes; the same problem that has always plagued conventional nitrogen balance studies (Hegsted, 1976).

Although the mechanism is not understood by which the balance of body protein is maintained over the cycle of feeding and fasting, a good deal is known about the kinetic changes that characterize the cycle. In the original studies of Clugston & Garlick (1982) feeding appeared to cause an increase in whole body synthesis, but it was later suggested that this was an artefact resulting from recycling of amino acids during a prolonged 24 h infusion. The subject has been reviewed by Pacy et al (1994) and by McNurlan & Garlick (1989), and is discussed further in section 12. Most workers (e.g. Nissen & Haymond, 1986) now believe that the main effect of food is to decrease the rate of protein degradation through the combined influences of amino acids, insulin and perhaps other hormones (Millward et al, 1990).

The other component of the diurnal cycle is amino acid oxidation. The fasting oxidation rate is influenced by the preceding diet, as shown in Figure 3, from Price et al (1994). It increased almost 2-fold when the intake rose from 0.36 to 2.3 g/kg/d. There has been some disagreement over fasting oxidation. The MIT group, in their early studies, took the view that it remained constant when the habitual amino acid intake varied. It is apparent from Figure 3 that the change in fasting oxidation rate is only about 7.5 mmol/kg/h when the change in protein intake is 1 g/kg/d. The MIT group were working over a narrower range of leucine intakes than Price et al (section 8) so that, given the variability, the relation to habitual intake was not apparent. The difference between fed and fasted oxidation rates in Figure 3 represents the effect of food. As Millward predicted from his model, the difference increases with increasing intake.

This work on the diurnal cycle is important and relevant It firmly implicates the processes of protein synthesis and breakdown in the regulation of protein balance. Previously it would have been possible to regard the twin cycles (synthesis-breakdown and input output) as operating to a large extent independently (Waterlow, 1994), but not any more.

6. Theoretical basis of the MIT tracer balance studies

So far we have been concerned more with ideas than with numerical estimates of requirements. We come now to the tracer balance studies of Young and coworkers (Young et al, 1989). The new MIT pattern was supported by two general propositions. The first is that the amount of the IAA requirement is determined by the obligatory N loss (ONL) and that the pattern reflects the composition of body protein. 'The oxidation rates of individual amino acids occur in proportion to the pattern or concentration of amino acids in mixed body protein' (Young et al, 1989). Thus, if the ONL is 54 mg/kg/d (FAO/WHO/UNU, 1985), equivalent to 0.34 g protein, and if the leucine content of body protein is 80 mg/g, then the loss of leucine will be 27 mg/kg/d. Of course, a factor also has to be applied for the efficiency with which dietary amino acids are able to replace this loss. I have already argued (section 4) that this reasoning is doubtful and that the adult requirement pattern of the IAAs cannot be determined simply by the composition of body protein.

The second general proposition is that the ONL represents that proportion of total protein turnover that is not recycled back into protein synthesis. We know from tracer studies that, at intakes in the region of maintenance, recycling is about 90% (Waterlow, 1968). If the ONL of 54 mg/kg/d represents the 10% of protein turnover that is not recycled, then total protein turnover must be 540 mg N or about 3.4 g protein/kg/d. This estimate fits well with actual values obtained by various methods (Waterlow, 1984). However, the argument tends to be circular, because although it is consistent with what we know about protein turnover, it is still based, as before, on the ONL and the composition of body protein. It is therefore not surprising that the two approaches give identical results, give or take a milligram or two for rounding off, as shown in Tables 7 and 8 of Young et al (1989).

These criticisms, like the arguments themselves, are really irrelevant. The MIT pattern stands or falls by the extensive body of well planned and well executed studies that have been carried out by Young and his colleagues over more than a decade. The original tracer balance studies of 1986 were followed by others designed to eliminate possible sources of error and to extend the data base.

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