One of the effects of their restriction is to inhibit growth, leading to healthier, longer-lived but smaller animals. This stunted growth has been seen as a roadblock to translating the findings to people.
According to the new analysis, however, many of the health benefits also have been demonstrated when sulfur amino acid restriction was initiated in fully grown adult animals, circumventing the problem seen in younger animals. There were no other serious negative effects of dietary sulfur amino acid restriction in the studies.
Studies involving people have associated sulfur amino acids with increased body weight, metabolic syndrome, cardiovascular disease and cancer, suggesting that restricting Met and Cys could protect against these conditions. For now, the evidence in humans is inconclusive. Richie is now overseeing the first tightly controlled feeding study of dietary sulfur amino acid restriction in human subjects, which may provide more direct evidence of health benefits.
Dietary sulfur amino acids are found in protein-containing foods, so restricting them isn't easy. The review, however, points out that many vegan diets are naturally low in Met and Cys. Figure 3 summarizes sulfur balance studies that include L-methionine supplements. Our findings Fig 3 clearly demonstrate that S retention occurs during the consumption of low levels of protein.
When less than 10 mmoles of sulfur derived from dietary proteins are consumed, supplementing the diet with 10 mmoles of L-methionine was accompanied by retention of this amino acid.
At higher levels of dietary protein intake, when the requirements of sulfur are presumably met, essentially all the methionine added to the diet is excreted in the urine. The significant retention of methionine at low levels of protein intake gave the first clues that our dietary supply of sulfur could be borderline or even unsatisfactory for many individuals.
A generalized assessment of diet intake and quality is very difficult to make because of obvious reasons. The heterogeneity of populations cultural, socio-economic, ethnic, geography, occupation, fast-food consumption, advertising, etc all influence food intake. Nevertheless, it seemed important for the purpose of this study to try and generate a profile that would cover various segments of the population, and relate the values obtained to the accepted RDA for SAA and to the alternate higher requirements suggested by others.
To gain further insight we grouped the various individuals evaluated into subgroups Table 1. Even though diets vary periodically we noticed that individuals tend to adopt certain repetitive patterns that in a way facilitated the evaluation. Intake of SAA measured in 32 individuals ranged between 1. For purposes of calculations the cysteine and methionine were combined as SAA.
Dairy products tend to have slightly higher levels of methionine and starch rich foods slightly more cysteine. Eggs contain significantly more cysteine. To estimate molar concentrations a ratio was employed. Some of the lower SAA values recorded in our survey included individuals who tended to be more health conscious and consume no red meet and little animal protein, as well as those consuming "fad diets". Many older people could turn out to be outright deficient group X independent of the criteria used Fig 4.
Obviously these dietary estimates have to be considered very preliminary, but they are meant, at this time, to attempt to shed some light on an area seldom explored. Dietary intake of SAA methionine plus cysteine measured in various subgroups of a population. A solid bar is included at the right of each group, which represents the SAA intake reduced by 0.
Also a column is included, in which the available SAA are reduced by 0. As already noted, this drug, as well as several others, is excreted in great part conjugated with sulfate. Depending on which assumption for minimum requirements are used, only those groups who emerge above the cut-off lines would be receiving an adequate amount of SAA.
Using Tuttle et al estimates [ 6 ] which agree well with our current estimates combined with the estimated loss of sulfate due to acetaminophen conjugation, a large segment of the population, which include those most vulnerable to OA, would appear to be sulfur deficient or receiving marginal intakes.
At this time we cannot draw any solid conclusions from these estimates. We know that renal re-absorption of sulfates increases during periods of deficiency [ 39 ] but not how long such a sparing effect can hold. The values obtained by Tuttle et al are derived from a limited selected VA population. So are ours as well as those of Rose et al. Until these studies are expanded to include simultaneous S and N-Balance determinations and biosynthetic studies in animals, and well controlled S-balance studies in humans are performed we will not be able to clearly answer this important question.
It should be pointed out that we could not find in the recorded literature any studies that effectively measure sulfur balance in human or other animals. All metabolic studies in this connection, even those that focus on the requirements for sulfur amino acids, study nitrogen balance but not sulfur balance. Essentially this means that the role of sulfur amino acids has only been evaluated in herms of protein synthesis, but never in terms of their ability to contribute sulfur to so many important metabolites.
As part of our preliminary investigations we evaluated the dietary intake of SAA, the urinary excretion of inorganic sulfate and of creatinine by a 35 year old male subject consuming a random balanced diet over a 3 day period.
Results are summarized in Fig 5. Urinary excretion of sulfates and creatinine during consumption of a standard diet, over a period of 48 hours. The above figure emphasizes another aspect of the proposed studies, the relationship between S and N excretion. Excretion of creatinine over a 24 hour periods has for a long time been related to muscle mass and used for metabolic calculations.
They are not useful for N- balance studies since they do not follow protein intake [ 40 ]. On the other hand it is clear that sulfate intake and excretion correlate quite well. Free amino acids in general cannot be stored and the SH moiety of cysteine, in particular, is readily oxidized.
Cysteine can be cytotoxic since the reactive thiol-amine structure can combine with aldehydes such as pyridoxal, and can also chelate essential divalent cations. SAA are used to replenish the stores of GSH, which can be considered a storage form for sulfur, and only when this goal is met is the excess oxidized to sulfate.
The excretion of sulfate associated with the administration of methyl prednisolone is included to illustrate how a catabolic event can affect sulfur loss Fig 6. Since steroids are frequently used by patients with joint diseases, the large excretion of sulfate may, among other things, interfere with PG synthesis and other important metabolites such as GSH. This aspect of the catabolic effect of steroids does not seem to have been explored.
Consumption of sparkling mineral water containing 0. Twenty four hour urinary excretion of sulfate by individuals consuming different amounts of protein combined with 10 mmoles of sulfate from a mineral water source, evenly distributed through out the daytime hours, and compared to control case 1, basal diet: 17 mM dietary SAA, case 2, basal diet: 26 mM SAA. These findings support the observation, sometimes disputed, that inorganic sulfates are readily absorbed and excreted in urine, in spite of the osmotic effects that they can generate and which lead to their use as laxatives [ 11 , 41 ].
In our case, steady administration of a dilute solution may have facilitated absorption from the GI tract and enhanced urinary excretion. Levels of sulfates in drinking water vary considerably with their source and location. The water in our studies, San Pellegrino, from an Italian source is stated in the label to contain. Inorganic sulfates are only very minor components of our diet. Some processed or enriched foods contain minute amounts of sulfites as preservatives and certain additives included in flour, for instance, ferric sulfate can contain sulfate.
Garlic, onions, and brussel sprouts contain significant amounts of sulfur. Feedstuffs fed to animals has been investigated for their sulfur content in much more detail than foods for humans, and ranges from 0. As noted earlier the levels of sulfur in the diet can greatly affect the growth and health of livestock. The estimated protein requirements, for all ages, as discussed earlier, has been based on nitrogen equilibrium studies, and aided occasionally by functional indicators such as immune function or muscle strength.
Data from various sources, suggests that the protein requirements for nitrogen equilibrium in the elderly is greater than the 0. Values of around 1. However because of methodological difficulties the data does not allow for a very confident prediction.
As pointed out by Young [ 43 ] our knowledge of the dietary requirements for older individuals are often limited and contradictory, although significant efforts continue to be made to overcome this problem. This amount of protein, would supply approximately 3. Unfortunately these levels of protein intake are infrequently met by the older segment of the population.
The well established sarcopenia associated with older age seems to be associated in part to a decline in protein and energy intake, caused by changes in taste sensation, alterations in dentition, social isolation, depression and economic factors. In addition to the less than optimal food intake, older individuals appear to substitute protein in preference to fat and carbohydrate rich meals, which may again reflect changes in taste [ 44 ].
There is a consensus that in diseases and following trauma these values may be 2 or 3 times higher [ 45 ]. These observations warrant continued attention for the potential supplementation role of SAA supplementation, in the form of additional protein or as has been found useful, N-acetylcysteine in some particular circumstances.
Because of the toxicity of cysteine, and possibly even of methionine supplements given in excess, and the intrinsic problems associated with an induced amino acid imbalance, proteins rich in SAA have been considered as supplements. Although whey proteins contain significantly more cysteine than casein 2.
Cost and availability become another key factor in reducing dietary protein intake in the aged as do perceived intolerance to certain food groups, difficulty tearing and chewing fibrous foods, as well as the fear of consuming too much fat or cholesterol. Unfortunately eggs, which have a amino acid profile considered as a standard against which other proteins are compared, and which are amongst the proteins with a higher SAA content and are amongst the least expensive in terms of cost, are often not included as major ingredients in the diets of older people.
The importance of dietary protein cannot be underestimated in this population since inadequate protein intake contributes, among other things, to a decrease in lung reserve capacity, increased skin fragility, osteoporosis, decreased immune function and muscle mass sarcopenia , poor healing and longer recuperation from illness [ 2 , 47 ].
Animal and human studies have demonstrated that adequate protein nutrition is crucial for the maintenance of GSH homeostasis [ 48 ]. Elevated levels of GSH inhibit prostaglandin production by a direct interaction with COX enzymes, of potential significance in the progression of inflammatory or degenerative states [ 36 ].
It is of particular interest, as discussed earlier that prostagandins synthesized from PUFA and most of the non-steroidal anti-inflammatory drugs share this same locus of involvement.
It is also relevant that some recent studies have found that on occasions the pain reduction in OA associated with the administration of chondroitin sulfate, a source of sulfur, was found to be equivalent to that provided by NSAID. The reasons for such unpredictable results, we suspect could be associated with differences in levels of protein in the diet, the better responders consuming higher amounts of SAA.
This hypothesis will have to be evaluated in future clinical studies. As discussed neither cysteine nor methionine are stored in the body. Even in extreme situations, such as when tryptophane deficiency leads to a general catabolic effect, the organism tries to spare the loss of sulfur by continuing to store any available sulfur as GSH in the liver. GSH values are subnormal in a large number of wasting diseases and following certain medications, and by supplying SAA many of these changes can be reversed [ 49 ].
Whether dietary supplements containing sulfur display similar effects has not been evaluated systematically. Documented improvements in OA and joint pains associated with sulfurated water hydrotherapy, many times accompanied by the simultaneous ingestion of such waters has also been related to the GSH involvement in the antioxidant cascade.
In spite of the apparent complexity associated with evaluating the dietary intake of a population as a whole a pattern seems to emerge, even when evaluating small groups of individuals. The major means by which methionine metabolism is regulated are 1 allosteric regulation by SAM and 2 regulation of the expression of key enzymes. In the liver, SAM exerts powerful effects at a variety of loci. The liver-specific MAT has a high K m for methionine and, therefore, is well fitted to remove excess dietary methionine.
It exhibits the unusual property of feedback activation; it is activated by its product, SAM This property has been incorporated into a computer model of hepatic methionine metabolism, and it is clear that it renders methionine disposal exquisitely sensitive to the methionine concentration Therefore, elevated SAM promotes transsulfuration methionine oxidation and inhibits remethylation methionine conservation.
In addition to its function in methionine catabolism, the transsulfuration pathway also provides cysteine for glutathione synthesis. Cysteine availability is often limiting for glutathione synthesis, and it appears that in a number of cells e. Transsulfuration is sensitive to the balance of prooxidants and antioxidants; peroxides increase the transsulfuration flux, whereas antioxidants decrease it It is thought that redox regulation of the transsulfuration pathway occurs at the level of CBS, which contains a heme that may serve as a sensor of the oxidative environment Taurine is remarkable, both for its high concentrations in animal tissues and because of the variety of functions that have been ascribed to it.
Taurine is the most abundant free amino acid in animal tissues. The magnitude of the intracellular taurine pool deserves comment. For example, skeletal muscle contains In addition to its role in the synthesis of the bile salt taurocholate, taurine has been proposed, inter alia, to act as an antioxidant, an intracellular osmolyte, a membrane stabilizer, and a neurotransmitter. It is an essential nutrient for cats; kittens born to mothers fed taurine-deficient diets exhibit retinal degeneration Taurine is found in mother's milk, may be conditionally essential for human infants, and is routinely added to most infant formulas.
Recent work has begun to reveal taurine's action in the retina. It appears that taurine, via an effect on a glycine receptor, promotes the generation of rod photoreceptor cells from retinal progenitor cells Taurine concentrations in rat tissues 22 , The numbers in parentheses give taurine as a percentage of the total free amino acid pool in each tissue.
The sulfur-containing amino acids present a fascinating subject to the protein chemist, the nutritionist, and the metabolic scientist, alike. They play critical roles in protein synthesis, structure, and function.
Their metabolism is vital for many critical functions. SAM, a remarkably versatile molecule, is said to be second, only to ATP, in the number of enzymes that require it. Vitamins play a crucial role in the metabolism of these amino acids, which, in turn, play a role in folic acid assimilation. Despite the great advances in our knowledge of the sulfur-containing amino acids, there are important areas where further work is required.
These include methionine transamination and the molecular basis for the many functions of taurine. We wish to thank Dr. Methionine residues as endogenous antioxidants in proteins.
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In animals, the great bulk of S-adenosylmethionine is used in methylation reactions.
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