Hyperhomocysteinemia (high serum total homocysteine) remains a problem for seniors even in this era of highly folate-fortified food in the United States. This paradox is explained because many seniors continue to have undiagnosed and untreated vitamin B 12 deficiency as shown by elevated serum methylmalonic acid concentrations. Hyperhomocysteinemia due to vitamin deficiency or renal failure may cause elevations of S-adenosylhomocysteine with a low S-adenosylmethionine/S-adenosylhomocysteine ratio, which may impair crucial methylations of brain neurotransmitters, phospholipids and myelin. A new stable isotope dilution liquid chromatography/mass spectrometry method will be used to explore the relationships between homocysteine and S-adenosylmethionine, S-adenosylhomocysteine and ratio in human seniors and rats with vitamin deficiency and renal failure. The pattern of the serum and urine metabolites will be studied after high dose oral vitamin B 12 and folic acid treatment in seniors who have vitamin B 12 deficiency and/or elevated serum S-adenosylhomocysteine concentrations. The baseline and post treatment S-adenosylmethionine and S-adenosylhomocysteine and ratio will be correlated with depression and neurologic symptoms. Enzymes of methionine metabolism such as cystathionine beta-synthase, gamma-cystathionase, methionine adenosyltransferase and S-adenosylhomocysteine hydrolase will be studied in tissues from B 12 deficient rats and in cell culture models. The long term goals of these studies are to determine whether vitamin B 12 deficiency impairs the balance of S-adenosylmethionine and S-adenosylhomocysteine. It will be determined whether the pattern of urine and serum metabolites in renal insufficiency could be differentiated from vitamin B 12 deficiency since treatment and complications might be different. New understanding of the control of regulation of methionine metabolism will be obtained in the setting of vitamin B 12 deficiency and renal insufficiency, conditions which continue to be important clinically and for which treatment with vitamins or S-adenosylmethionine supplements will be safe and widely available.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG009834-12
Application #
6756523
Study Section
Nutrition Study Section (NTN)
Program Officer
Nayfield, Susan G
Project Start
1997-09-01
Project End
2008-06-30
Budget Start
2004-07-15
Budget End
2005-06-30
Support Year
12
Fiscal Year
2004
Total Cost
$267,961
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Stabler, Sally P; Sekhar, Jeevan; Allen, Robert H et al. (2009) Alpha-lipoic acid induces elevated S-adenosylhomocysteine and depletes S-adenosylmethionine. Free Radic Biol Med 47:1147-53
Kraus, Jan P; Hasek, Jindrich; Kozich, Viktor et al. (2009) Cystathionine gamma-lyase: Clinical, metabolic, genetic, and structural studies. Mol Genet Metab 97:250-9
Matteini, A M; Walston, J D; Fallin, M D et al. (2008) Markers of B-vitamin deficiency and frailty in older women. J Nutr Health Aging 12:303-8
Barbosa, P R; Stabler, S P; Machado, A L K et al. (2008) Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women. Eur J Clin Nutr 62:1010-21
Allen, Robert H; Stabler, Sally P (2008) Identification and quantitation of cobalamin and cobalamin analogues in human feces. Am J Clin Nutr 87:1324-35
Sekhar, Jeevan; Stabler, Sally P (2007) Life-threatening megaloblastic pancytopenia with normal mean cell volume: Case series. Eur J Intern Med 18:548-50

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