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U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111
2To whom correspondence should be addressed at 711 Washington Street. E-mail: rrussell{at}hnrc.tufts.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSpecific problem nutrientsResearch agenda for elderly...REFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSpecific problem nutrientsResearch agenda for elderly...REFERENCES |
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100 elderly individuals who were placed on a
100-g fat diet while in a metabolic unit for a 6-d period (Arora et al. 1989
). During the last 3 d, stools were collected,
and fecal fat was measured. It was found that between the age range of
20–95 y, there was no increase in fecal fat excretion due to age,
thus disproving the commonly held notion of the time that malabsorption
is common in elderly persons. As mentioned, if the system is stressed
(e.g., through the intake of an extremely high fat diet of >120 g/d),
elderly persons begin to show increases in fecal fat, whereas younger
persons do not (Hambraeus 1972). Nevertheless, because
such diets are unphysiologic, such a demonstration is not clinically
pertinent.
A second principle to keep in mind when studying the bioavailability of
nutrients in elderly persons is declining renal function with advancing
age. This has been demonstrated in both men and women (Lindeman 1993, Sokoll et al. 1994
). Renal function
becomes a relevant issue to bioavailability when urinary excretion of a
nutrient or nutrient metabolite is taken as a proxy measure of
absorption and if the excretion of the specific nutrient or nutrient
metabolite occurs primarily via by the kidney. The same holds true if
the blood level of a nutrient or nutrient metabolite is influenced by
renal function. An example of such a nutrient is dxylose:
urinary D-xylose excretion after a 25-g oral load decreases with
advancing age. However, when creatinine clearances are measured, the
decline in the urinary D-xylose excretion due to age can be accounted
for entirely by the decline in renal clearance, rather than by an
intestinal absorptive defect (Arora et al. 1989
).
Similarly, measurement of vitamin B-12 bioavailability by Schilling
tests or measurement of folate bioavailability by urinary excretion
tests (as is done in the classic folic acid absorption test) in elderly
individuals with declining kidney function might give the false
impression of poor absorption, when in fact the intestinal absorption
of these nutrients could be normal. Also, the metabolite homocysteine
in blood is used to reflect folate status. If folate is administered to
an individual with impaired renal function to correct a high serum
homocysteine concentration and the concentration remains elevated, this
might give the false impression that folate bioavailability is impaired
(Hermann et al. 1999
). Homocysteine concentrations must
be interpreted in the light of renal function in the aged person and
not taken as a strict measure of folate or other B vitamin status.
A third principle to keep in mind when judging the bioavailability of
nutrients in elderly persons is that plasma response curves after doses
of fat-soluble substances may not reflect absorption but rather
impaired uptake of the fat-soluble nutrient from chylomicron
remnants. Vitamin A is an example of this. It was shown by
Hollander and Dadufalza (1983) in rats that vitamin A absorption
is increased with advancing age of the animal. Similarly Krasinski et al. (1985)
showed higher plasma response curves of vitamin A
after a physiologic oral dose in older individuals as opposed to
younger control subjects. To define whether these higher response
curves were primarily a result of increased absorption versus decreased
clearance, the following experiment was performed: elderly and young
subjects were fed high fat, vitamin A meals, and several hours later, a
unit of blood was taken for plasmapheresis. Forty-two hours later,
the vitamin A–laden chylomicron remnants were reinfused into
the older and young individuals in the fasting state, and plasma
fall-off curves were determined. It was found that younger persons
cleared vitamin A from the serum approximately twice as fast as did the
elderly persons. Thus, the higher plasma response curves of the elderly
persons that occurred in the original experiment of Krasinski et al. (1985
) is certainly not only due to greater absorption in
the small intestine as was postulated by Hollander and Dadufalza (1983)
] but rather to delayed clearance of the vitamin from
the circulation. In the case of vitamin A, such a delayed clearance of
chylomicron and chylomicron remnants causes a shift of vitamin A into
other lipoprotein compartments, such as LDL. Once vitamin A in the form
of retinyl esters enters these other lipoprotein particles, it is
carried around in blood for a period of days (vs hours) and could
conceivably act as toxin precursors. Thus, to study the true
bioavailability of fat-soluble substances that are absorbed through the
lymphatics, it is not sufficient to know just what the plasma response
curves look like; the plasma clearance curves for the vitamin or
nutrient must also be known.
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Specific problem nutrients |
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TOPABSTRACTINTRODUCTIONSpecific problem nutrientsResearch agenda for elderly...REFERENCES |
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40% in 
-80-y-old persons (Krasinski et al. 1986
). The prevalence of atrophic gastritis in the Midwest of
the United States as diagnosed by the same pepsinogen assays and
determined in the same laboratory is lower (10% of the elderly
population) (Hurwitz et al. 1997
). Atrophic gastritis
has been related to infection with the bacteria Helicobacter
pylori and is not a result of normal aging; in fact, in normal
aging, there is evidence that elderly persons might secrete more,
rather than less, acid as is seen in atrophic gastritis (Feldman et al. 1996
).
Because the overall prevalence of atrophic gastritis in elderly persons
is estimated to be 20%, this could affect the bioavailability of
specific nutrients, whose absorption is pH dependent, in a considerable
segment of the population. The physiologic consequences of atrophic
gastritis include decreased acid-pepsin digestion in the stomach,
decreased secretion of intrinsic factor (although this decrease is not
sufficient to be rate limiting for vitamin B-12 absorption), bacterial
overgrowth of the stomach and proximal small intestine and elevated
proximal small pH. Nutrients whose absorption has been shown to be
affected by low acid conditions in the stomach include folic acid,
vitamin B-12, calcium, iron and beta-carotene (Russell 1986
, Tang et al. 1996
). Conversely, it has been
shown that small intestinal bacteria in this condition may be a source
of certain vitamins, including vitamin B-6 and folic acid
(Camilo et al. 1996
, Ribaya-Mercado et al. 1987
).
Examples of how atrophic gastritis affects nutrient bioavailability.
Active folic acid intestinal uptake has been shown to reach a maximum
over a narrow pH optimum range of 6.2–6.3 in in vitro studies
(Russell et al. 1979
). A value above or below this range
results in diminished folate uptake by intestinal rings. Using a folate
absorption test, which consists of an oral dose of tritium-labeled
pteroylmonoglutamic acid followed by a parenteral flushing dose and a
24-h urine collection, it has been shown that elderly persons with
atrophic gastritis severely malabsorb folic acid compared with normal
controls (Russell et al. 1986
). Moreover, this folic
acid malabsorption can be corrected by administering folate along with
0.1 N hydrochloric acid to lower gastric and proximal small
intestinal pH.
Atrophic gastritis may also affect the bioavailability of vitamin B-12.
Dietary vitamin B-12 is associated with food proteins, which must be
digested off the vitamin B-12 molecule before it is able to bind to
endogenous R binders or to intrinsic factor. This digestion takes place
under the influence of acid and pepsin. If stomach acid is lacking, the
digestion of protein from the B12 molecule cannot take place, and the
binding of vitamin B-12 to intrinsic factor further down in the small
intestine, therefore, also cannot take place. King et al. (1979
) described a group of five individuals with gastric
atrophy who had diminished absorption of vitamin B-12 when the vitamin
was bound to chicken serum protein. This malabsorption could not be
corrected by giving intrinsic factor along with the protein-bound
vitamin B-12. However, the administration of acid with the
protein-bound vitamin B-12 increased its absorption to within the
normal range in two individuals, and the administration of acid along
with pepsin (with or without intrinsic factor) further increased the
absorption in most of the others. It is interesting that all five of
these individuals were able to normally absorb crystalline vitamin
B-12. It was subsequently shown that the malabsorption of
protein-bound vitamin B-12 in individuals with atrophic gastritis
can also be reversed by lowering bacteria in the proximal small
intestine through the use of antibiotics (Suter et al. 1991
). From these combined studies, it appears that impaired
digestion, and therefore the release of free vitamin B-12 into the
lumen of the small bowel, takes place in atrophic gastritis due to low
acid secretion. The low intraluminal concentrations of free vitamin
B-12, which occur after the feeding of food-bound B12, allow for
bacterial uptake of the free vitamin. However, crystalline vitamin B-12
in a Schilling test can overwhelm the bacterial binding capacity. Thus,
this is an example of a vitamin preparation that is clearly superior to
that of the food-bound vitamin in terms of bioavailability. That
is, persons with atrophic gastritis should consume oral vitamin B-12
supplements or food that has been artificially fortified with vitamin
B-12 to ensure normal vitamin B-12 nutriture.
Iron and calcium are other nutrients whose bioavailability is affected
by atrophic gastritis. Decreased iron absorption has been reported in
old age, but many studies were not well controlled for iron status or
for the presence of gastrointestinal disease. It has been demonstrated
that the absorption of ferric iron is diminished in achlorhydric
subjects (Choudhurry and Williams 1959
). Acid serves to
keep the ferric iron in solution until it reaches the absorptive sites
of the duodenal mucosa. Ferric iron is insoluble above pH 5, although
ferrous iron and heme iron remain in solution at neutral or slightly
alkaline pH values. Substances that ligand ferric iron, such as
ascorbate, increase the absorption of ferric iron at a neutral or
slightly alkaline pH range. However, chelation must occur when the iron
is in solution, that is, when the iron is in acid milieu. Thus, acidity
is needed for the chelation of ferric iron to take place, which will
then be kept in solution at the higher pH of the proximal small
intestine, so iron will be available for absorption. Heme iron does not
appear to be affected by lack of acid and thus is normally absorbed in
individuals with atrophic gastritis.
Elderly persons show reduced absorption of calcium, in general, which
is related to age-related changes in vitamin D metabolism. For
example, decreased skin synthesis, decreased vitamin D absorption,
decreased vitamin D receptors in the intestinal epithelial cell and
impaired conversion of 25-hydroxy vitamin D to the active hormonal form
1,25-dihydroxy vitamin D have all been demonstrated (Barragry et al. 1978
, Ebeling et al. 1992
, Holick et al. 1989
, Tsai et al. 1984
). In addition,
elderly individuals show a reduced ability to adapt to low calcium
diets by increasing the efficiency of calcium absorption, whereas
younger individuals are able to make such an adaptation (Ireland and Dordtran 1973
). As previously mentioned, atrophic gastritis
can also affect calcium absorption. Calcium carbonate reacts with
hydrochloric acid to form soluble calcium chloride, which is
subsequently absorbed in the proximal small bowel. In atrophic
gastritis due to the absence of acid, calcium may not be solubilized or
absorbed.
Finally, it was recently shown by Tang et al. (1996
)
that gastric acidity increases a blood response to a beta-carotene
dose, thereby implicating a negative effect of atrophic gastritis with
reduced gastric acid levels on beta-carotene absorption.
In considering bioavailability, one is talking not only about
absorption but also about activation and metabolism of the nutrient in
the body. This should also be considered in elderly subjects, although
very little is known about this for most nutrients. For vitamin D, as
has been already mentioned, there is impaired conversion in elderly
persons of 25-dihydroxy vitamin D to 1,25-hydroxy vitamin D after
parathyroid hormone stimulation. Elderly persons have also been shown
to have an increased vitamin B-6 requirement compared with younger
persons, although the reason for this is obscure (Ribaya-Mercado et al. 1991
). The higher vitamin B-6 requirement does not
appear to be due to a malabsorptive problem, but rather there may be a
problem in metabolism of the vitamin after absorption has occurred.
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Research agenda for elderly persons |
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TOPABSTRACTINTRODUCTIONSpecific problem nutrientsResearch agenda for elderly...REFERENCES |
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For all fat-soluble substances, to determine bioavailability not only in terms of absorption but also in terms of clearance from the circulation into peripheral tissues.
Do all fat-soluble substances that are absorbed in chylomicrons act similar to vitamin A?
To study the bioactivation and metabolism of nutrients in the elderly.
There are changes in vitamin D metabolism with aging, but it is not clear whether there are similar changes in the conversion of provitamin A carotenoids to vitamin A or for the activation of vitamin B-6, as mentioned here. Such knowledge may determine the form of a nutrient that is in a supplement.
To use stable isotope techniques to determine the bioavailability of nutrients and other bioactive components.
This is a highly useful technique that yields more exact results than the techniques that are presently used to assess bioavailability (e.g., plasma response curves).
To broaden study from that of the known vitamins and minerals (for which we have at least some knowledge) to that of the bioavailability and metabolism of other bioactive substances, such as isoflavones, polyphenols and carotenoids, other than B-carotene.
These former two are of particular interest because of their high
antioxidant capacity and because they are consumed in relatively large
amounts. For example, a normal diet contains >200 mg polyphenols
compared with 3–5 mg beta-carotene. More attention should be paid
to these food components than in the past. Also, it is important to
study these other bioactive components, because aging persons might be
more prone to supplement themselves with these substances in large
amounts to "stave off" the aging process.
To better define drug/nutrient interactions, of which now we know very little.
The focus should be on drugs that are commonly taken by older persons.
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSpecific problem nutrientsResearch agenda for elderly...REFERENCES |
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1. Arora S., Kassarjian Z., Krasinski S., Kaplan M., Russell R. M. Effects of age on tests of intestinal and hepatic function in normal healthy elderly humans. Gastroenterology 1989;96:1560-1565[Medline]
2. Barragry J. M., France M. W., Corless D., Gupta S. P., Switala S., Boucher B. J., Cohen R. D. Intestinal cholecalciferol absorption in the elderly and in younger adults. Clin. Sci. Mol. Med. 1978;55:213-220[Medline]
3. Camilo E., Zimmerman J., Mason J. B., Golner B., Russell R. M., Selhub J., Rosenberg I. H. Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology 1996;110:991-998[Medline]
4. Choudhurry M. R., Williams J. Iron absorption and gastric operations. Clin. Sci. 1959;18:527[Medline]
5. Ebeling P. R., Sandgren M. E., DiMagno E. P., Lane A. W., DeLuca H. F., Riggs B. L. Evidence of an age-related decrease in intestinal responsiveness to vitamin D: relationship between serum 1,26 dihydroxyvitamin D3 and intestinal vitamin D receptor concentrations in normal women. J. Clin. Endocrinol. Metab. 1992;75:176-182[Abstract]
6. Feldman M., Cryer B., McArthur K. E., Huet B. A., Lee E. Effects of aging and gastritis on gastric acid and pepsin secretion in humans: a prospective study. Gastroenterology 1996;110:1043-1052[Medline]
7. Herrmann W., Quast S., Ullrich M., Schultze H., Bodis M., Geisel J. Hyperhomocysteinemia in high-aged subjects: relation to B-vitamins, folic acid, renal function and the methylenetetrahydrofolate reductase mutation. Atherosclerosis 1999;144:91-101[Medline]
8. Hollander D., Dadufalza V.D. Aging: its influence on the intestinal unstirred water layer thickness, surface area, and resistance in the unanesthetized rat. Can. J. Physiol. Pharm. 1983;61:1501-15080[Medline]
9. Holick M. F., Matsuoka L. Y., Wortsman J. Age, vitamin D, and solar ultraviolet. Lancet 1989;2:1104-1105[Medline]
10.
Hurwitz A., Brady D. A., Schaal S., Samloff I. M., Dedon J., Ruhl C. E. J. Am. Med. Assoc. 1997;278:659-662
11. Ireland P., Dordtran J. S. Effect of dietary calcium and age on jejunal calcium absorption in humans studied by intestinal perfusion. J. Clin. Invest. 1973;52:2672-2681
12. King C. D., Leibach J., Toskes P.P. Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12. Dig. Dis.Sci. 1979;24:397-402
13. Krasinski S. D., Russell R. M., Dallal G. E. Aging changes vitamin A absorption characteristics. Gastroenterology 1985;88:1715
14. Krasinski S. D., Russell R. M., Samloff I. M., Jacob R. A., Dallal G. E., McGandy R. B., Hartz S. C. Fundic atrophic gastritis in an elderly population. J. Am. Geriatr. Soc. 1986;34:800-806[Medline]
15. Ribaya-Mercado J. D., Otradovec C. L., Russell R. M., Samloff I. M. Atrophic gastritis does not impair vitamin B6 status of the elderly. Gastroenterology 1987;93:222[Medline]
16. Ribaya-Mercado J. D., Russell R. M., Sahyoun N., Morrow F. D., Gershoff S.N.L Vitamin B6 requirements of elderly men and women. J. Nutr. 1991;121:1062-1074
17. Russell R. M. Implications of gastric atrophy for vitamin and mineral nutriture. Hutchinson M. L. Munro H. M. eds. Nutrition and Aging 1986:59-67 Academic Press San Diego, CA.
18. Russell R. M., Dhar G. J., Dutta S. K., Rosenberg I. H. Influence of intraluminal pH on folate absorption: studies in control subjects and in patients with pancreatic insufficiency. J. Lab. Clin. Med. 1979;93:428-436[Medline]
19. Russell R. M., Krasinski S. D., Samloff I. M., Jacob R. A., Hartz S. C., Brovender S. R. Folic acid malabsorption in atrophic gastritis: compensation by bacterial folate synthesis. Gastroenterology 1986;91:1476-1482[Medline]
20.
Sokoll L. J., Russell R. M., Sadowski J. A., Morrow F. D. Establishment of creatinine clearance reference values for older women. Clin. Chem. 1994;40:2276-2281
21. Suter P. M., Golner B. B., Goldin B. R., Morrow F. D., Russell R. M. Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. Gastroenterology 1991;101:1039-1045[Medline]
22.
Tang G. W., Serfaty-Lacrosniere C., Camilo M. E., Russell R. M. Gastric acidity influences the blood response to a beta-carotene dose in humans. Am. J.Clin. Nutr. 1996;64:622-626
23. Tsai K. S., Heath H., III, Kumar R., Riggs B. L. Impaired vitamin D metabolism with aging in women: possible role in pathogenesis of senile osteoporosis. J. Clin. Invest. 1984;73:1668-1672
24. Werner I., Hambraeus L. The digestive capacity of elderly people. Carlson L. A. eds. Nutrition in Old Age 1972:55-60 Almqvist and Wiksell Uppsala, Sweden.
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