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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:1832-1835, July 2004

Nutrition and Aging

Hyperhomocysteinemia in Healthy Young Men and Elderly Men with Normal Serum Folate Concentration Is Not Associated with Poor Vascular Reactivity or Oxidative Stress1

Sandra Hirsch2, Ana María Ronco, Marcela Vasquez, María Pía de la Maza, Argelia Garrido, Gladys Barrera, Vivien Gattas, Andrea Glasinovic*, Laura Leiva and Daniel Bunout

Institute of Nutrition and Food Technology (INTA), University of Chile and * Clínica Santa María, Santiago, Chile

2To whom correspondence should be addressed. E-mail: shirsch{at}inta.cl.


   ABSTRACT
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 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
The mechanism by which homocysteine (Hcy) causes endothelial dysfunction is probably mediated by oxidative stress. The aim of this study was to evaluate the effect of oxidative stress on endothelial function in young and elderly hyperhomocysteinemic (HHcy) men. A total of 35 HHcy (Hcy > 15 µmol/L), young (n = 15; 20–40 y) and elderly men (n = 20; > 65 y) and 33 normohomocysteinemic (NHcy; controls) young (n = 14) and elderly (n = 19) men (Hcy < 13 µmol/L), without classic cardiovascular risk factors were recruited. Serum Hcy, folate, and vitamin B-12, whole-blood glutathione, plasma total antioxidants status, TBARS, and 8-F2{alpha} isoprostanes were determined. Noninvasive ultrasound measurements of endothelium-dependent (EDVR) and -independent dilatation (EIVR) were performed. EDVR, EIVR, and markers of oxidative stress did not differ among the groups. Folate concentrations were higher in elderly than in young men (P < 0.001), independent of Hcy concentrations. Vitamin B-12 concentrations were lower in HHcy than in NHcy elderly men (P < 0.045). EDVR was correlated with folate concentrations in young men (r = 0.40, P = 0.04) and negatively with BMI in elderly men (r = –0.52, P = 0.002). In the present study, HHcy with normal serum folate concentrations was not associated with poor EDVR or oxidative stress in healthy young and elderly men.

KEY WORDS: • homocysteine • vascular function • folate

Hyperhomocysteinemia (HHcy)3 can be considered to be an age-related risk factor for cardiovascular disease that might be related to several physiologic changes associated with the aging process. In a previous study, we observed that healthy elderly men with HHcy had lower endothelium-dependent dilatation (EDVR) than normohomocysteinemic (NHcy) elderly and both NHcy and HHcy young healthy men (1).

The mechanism by which homocysteine (Hcy) causes endothelial dysfunction in elderly people is likely mediated by oxidative stress (2,3). Bellamy et al. (4) showed a reduction in total plasma Hcy after 6 wk of supplementation with 5 mg folate and an improvement in EDVR associated with a reduction in oxidative stress. Chambers (5) observed that oral ascorbic acid, acting as a potent antioxidant, prevented endothelial dysfunction associated with increased Hcy concentration after a methionine load.

Increased oxidative stress has been hypothesized to play an important role in the aging process (6). A role for oxidative damage in normal aging is supported by studies in experimental animals (7,8), but there is limited evidence in humans. Mutlu-Turkoglu et al. (9) observed in healthy elderly subjects that plasma malondialdehyde (MDA), oxidative protein damage indicated by carbonyl content protein, and DNA damage in lymphocytes were correlated with aging. Others have described age-related changes in erythrocyte antioxidant enzyme activities (10) or an increase in lipid peroxidation (11,12). Other authors did not detect alterations in oxidative stress with healthy aging, measuring 8-F2{alpha} isoprostanes (8-isoPGF2{alpha}) and MDA plasma concentrations, as markers of in vivo lipid peroxidation (13,14).

We hypothesized that age-induced oxidative stress could be involved in endothelial dysfunction in elderly HHcy men. In this work, we examined the effect of hyperhomocysteinemia on vascular response and oxidative stress markers in young and elderly men.


   SUBJECTS AND METHODS
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 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Subjects. This study was carried out in 14 NHcy [total Hcy (tHcy) < 13 µmol/L] and 15 HHcy (tHcy > 15 µmol/L) men between 18 and 40 y old and 19 NHcy and 20 HHcy elderly men > 65 y old, recruited from a periodic health examination. Exclusion criteria included smoking, intake of vitamin supplements, personal history of hypothyroidism or hyperthyroidism, cardiovascular or renal disease, hypertension, diabetes, BMI > 30 kg/m2, blood pressure > 140/90 mm/Hg, LDL cholesterol > 4.65 mmol/L, triacylglycerol > 2.29 mmol/L, fasting glucose > 6.1 mmol/L, creatinine > 130 µmol/L, or thyroid-stimulating hormone > 6 mU/L. All subjects gave informed, written consent. The study was approved by the local ethics committee.

    Laboratory procedures. After an overnight fast, 40 mL of venous blood was drawn to measure serum total proteins, creatinine, total cholesterol, LDL cholesterol (LDL-C), HDL-C, triacylglycerol, Hcy, folic acid, and vitamin B-12 levels, total blood glutathione (GSH), plasma total antioxidant status (TAS), plasma TBARS, and plasma 8-isoPGF2{alpha}. The blood samples were immediately centrifuged (760 x g for 15 min) and frozen at –70°C until assayed.

Glucose, creatinine, total cholesterol, HDL-C, and triacylglycerol were measured by routine laboratory automated methods, using the following Roche Kits for the Hitachi 917 autoanalyzer: enzymatic for glucose, Kinetic colorimetric Jaffe method for creatinine, enzymatic colorimetric for cholesterol, HDL-C plus second generation, and triacylglycerol.

Folic acid and vitamin B-12 were measured by an ion capture technique using Abbott kits (IMX system folate and B-12, Abbott Laboratories, Diagnostic division). Serum Hcy was also measured using Abbott Kits (Abbott IMx homocysteine). This procedure is based on the fluorescence polarization immunoassay technology.

GSH was analyzed by a colorimetric method using 5,5'-dithio-bis(2-nitrobenzoic acid) as previously described (15,16). TBARS were determined according to the method described by Wasowicz et al. (17) and modified by Lapenna et al. (18).

TAS was measured as previously reported (19). The assay relies on the ability of antioxidants in the plasma to inhibit the oxidation of ABTS (2,2'-azino-di-[3-ethylbenz-thiazoline sulfonate] to ABTS·+ by metmyoglobin (a peroxidase).

Total plasma 8-isoPGF2{alpha} were determined by an EIA kit (Cayman Chemicals) in a previously purified and concentrated sample. For purification and concentration of 8-iso PGF2{alpha}, an affinity sorbent that contains mouse anti-8-isoprostane covalently bound to Sepharose 4B, was used.

    Arterial reactivity studies. Endothelium-dependent and independent arterial dilatation was measured by an ultrasound method (1,20). Brachial arterial diameter was measured using a 7.0-MHz linear array transducer in a standard Advanced Technology Laboratories 3000 system. Each study was performed after 3 h of fasting and 15 min of supine rest. A pneumatic cuff was placed around the forearm, 2 cm distal of the middle arm, and inflated to a pressure of 300 mm Hg for 5 min, followed by deflation. Arterial end diastolic internal diameter was measured at basal, 60, and 90 s after cuff deflation. The brachial artery was scanned again after a 15-min rest and 3 min after 0.6 mg sublingual nitroglycerin, to evaluate endothelium-independent dilatation (EIVR). The maximum increase in end diastolic brachial artery diameter from baseline was used as the measure of dilatation. All of the ultrasound procedures were recorded on videotape, for later measurement. The vessel diameter was measured by 2 independent observers who were unaware of the individual’s clinical and laboratory details.

    Statistical analysis. Statistical analysis was done using Statistica for Windows version 4.5 (StatSoft). Descriptive data are expressed as means ± SD. Comparisons between study groups were done using 2-way ANOVA. The Scheffé post-hoc test was used when the interaction was significant. The Kruskal-Wallis ANOVA median test was performed to compare the effect of HHcy on vascular reactivity between groups. Simple correlations between variables were calculated using Pearson’s correlation coefficient. Differences were considered significant at P < 0.05. The sample size was based on the significant differences in the EDVR measurements obtained in our previous study (1).


   RESULTS
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
Clinical and biochemical characteristics of the 4 groups are summarized in Table 1. All subjects had normal blood pressure, fasting blood glucose, and lipid profile. Serum vitamin B-12 concentrations were lower in elderly men with high serum Hcy concentrations (P < 0.004) than in those with low Hcy concentrations. Serum folate concentrations were higher in both elderly groups (P < 0.0001) compared with young HHcy or NHcy men.


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  		TABLE 1 Demographic variables and clinical biochemistry of young and elderly hyperhomocysteinemic men and their controls1

 
Biochemical indicators of antioxidant status and vascular reactivity did not differ due to age or Hcy concentration (Table 2). Hcy was correlated negatively with serum vitamin B-12 concentrations (r = –0.36, P = 0.002). No correlations were found among Hcy, serum folate concentrations, and markers of oxidative stress.


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  		TABLE 2 Oxidative status and vascular function of young and elderly hyperhomocysteinemic men and their controls1, 2

 
In young men, EDVR was positively correlated with serum folate concentrations (r = 0.40, P = 0.04) and negatively correlated with age (r = –0.41, P = 0.04). In elderly men, BMI was inversely correlated with EDVR (r = –0.52, P = 0.002). EDVR and folate concentrations were not correlated in this age group.


   DISCUSSION
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
In this study, we did not detect an age-associated increase in oxidative stress, nor a relation between markers of oxidative injury and EDVR. Hcy concentrations were not associated with changes in endothelium-dependent vascular reactivity or oxidative stress in healthy elderly men with high serum folate concentrations, even in those with low vitamin B-12 concentrations. In young men, folate concentrations and age were predictors of endothelium-dependent vascular reactivity, whereas in elderly men, BMI was the only significant predictor detected. Earlier studies described a relation between Hcy and age with lipid peroxidation in humans, measured by changes in plasma TBARS or MDA, 8-isoprostanes, and total GHS. However, these studies did not exclude individuals with hypercholesterolemia, diabetes, or smokers (21,22). In the present work, we excluded young and elderly men with classical cardiovascular risk factors, diabetes, vascular, renal, liver or respiratory disease, to avoid the possible confounding effect of such factors on lipid peroxidation. It is noteworthy that extreme longevity is associated with a low degree of oxidative stress (23,24). It is possible that the healthy elderly men that we studied represent a subset of individuals with successful aging, in whom oxidative stress is counteracted more efficiently.

Diet-induced HHcy is associated with altered vasomotor function in animals and humans (25). However, other authors have not demonstrated that HHcy is able to modify endothelial function in the absence of additional risk factors (26,27). Consequently, it is not possible to determine whether impaired vascular function is caused by HHcy or by the vitamin deficiencies that cause it. In most studies that demonstrated an association between vascular function and HHcy, folate but not vitamin B-12 depletion is also present (28). For example, Lentz et al. (29) observed that monkeys with diet-induced HHcy, had decreased folate plasma levels. Folic acid supplementation improves endothelial function in patients with cardiovascular disease, independently of baseline Hcy or its reduction (30,31). In addition, folic acid supplementation significantly improved endothelial function in otherwise healthy NHcy cigarette smokers, and in hypercholesterolemic subjects (32,33). In children with type 1 diabetes, folate status was associated with endothelial function independently of Hcy levels (34). In a previous study, we found lower serum folate levels in patients with peripheral vascular disease and coronary disease without differences in Hcy concentrations compared with control subjects (35). These results suggest a direct action of folic acid on vascular function.

It was postulated that the acute modifications in vascular function induced by folic acid are unrelated to changes in Hcy concentrations. In endothelial cells, 5-methyltetrahydrofolate, the active form of folic acid, has intrinsic antioxidant actions, such as a reduction in superoxide production. It also increases nitric oxide synthase–induced nitric oxide production under conditions of reduced cofactor tetrahydrobiopterin bioavailability (36,37). In vivo, oral folic acid prolongs the lag time of LDL oxidation in children with chronic renal failure (38).

In healthy subjects, supplementation with folic acid (10 mg) prevents nitric oxide synthase dysfunction induced by continuous nitroglycerin infusion (which induces tolerance to the vasodilator effects of nitrate) (39). Therefore, the correlation between endothelium-dependent vascular reactivity and folate concentrations that we observed in young adults, independent of Hcy, could be related to nitric oxide availability. The lack of correlation observed in elderly subjects could be due to a ceiling effect because that group had higher serum folate concentrations. It is tempting to speculate that the age-related deterioration of the nitric oxide pathway and availability could be overcome by exceptionally high folate concentrations.

The high concentrations of folate found in this study are explained by flour fortification (220 µg of synthetic folic acid per 100 g of wheat flour), a program initiated in Chile in January, 2000. This program was instituted initially to reduce the risk of neural tube defects (40).

The negative association between EDVR and BMI in elderly subjects is not surprising. Body fat content increases with age (41). Al Suwaidi et al. (42), measuring coronary vascular reactivity using an infusion of adenosine, acetylcholine, and nitroglycerin, demonstrated that obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries.

In summary, this study demonstrated that HHcy with normal serum folate concentrations in healthy young and elderly men is not associated with poor EDVR function or oxidative stress. The influence of serum folate concentrations and BMI on EDVR requires further research.


   FOOTNOTES
 
1 Supported by the Fondo Nacional de Ciencia y Tecnología, Fondecyt grant #1010571. Back

3 Abbreviations used: EDVR, endothelium-dependent dilatation; EIVR, endothelium-independent dilatation; GSH, glutathione; Hcy, homocysteine; HHcy: hyperhomocysteinemic subjects; 8-isoPGF2{alpha}, 8-F2{alpha} isoprostanes; MDA, malondialdehyde; NHcy, normohomocysteinemic subjects; TAS, plasma total antioxidant status; tHcy, total Hcy. Back

Manuscript received 20 January 2004. Initial review completed 1 March 2004. Revision accepted 29 April 2004.


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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
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