Gayle Perrone

Safety and Tolerability of Esterified Phytosterols Administered in Reduced-Fat Spread and Salad Dressing to Healthy Adult Men and Women

Objective/Design: The safety and tolerability of three levels of plant sterol-esters administered in reduced-fat spread and salad dressing vs. control products were evaluated in this randomized, double-blind, four-arm parallel study. Methods: Eighty-four free-living men and women consumed reduced-fat spread and salad dressing providing 0.0 g/day (n = 21), 3.0 g/day (n = 21), 6.0 g/day (n = 19) or 9.0 g/day (n = 23) of phytosterols as esters for an eight-week treatment period. Results: Side effects did not differ among the groups during the study, and there were no study product-related serious adverse events. There were no changes in clinical laboratory values in response to phytosterol intake. Blood concentrations of all fat-soluble vitamins remained within normal reference ranges, and there were no differences in serum vitamin responses among the four groups. Alpha- and trans-β-carotene levels were reduced in the 9.0 g/day group vs. control (p < 0.05), but all carotenoid values remained within normal ranges throughout the study. All groups receiving phytosterols had significant increases in serum campesterol vs. control (p < 0.001), but β-sitosterol responses did not differ from control. Total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol responses did not differ significantly among the groups. The total:HDL cholesterol response in the 9.0 g/day group was significantly different from the control group response (−9.6% vs. 2.6%, p < 0.05). A median increase of 7.8% in serum triglycerides was observed in the control group, which differed significantly from the response in the 3.0 g/day arm (−13.3%, p < 0.05). Discussion: The results of this study indicate that phytosterol esters are well tolerated and show no evidence of adverse effects at a daily intake of up to 9.0 g of phytosterols for eight weeks.

Dietary calorie restriction in the Emory mouse: effects on lifespan, eye lens cataract prevalence and progression, levels of ascorbate, glutathione, glucose, and glycohemoglobin, tail collagen breaktime, DNA and RNA oxidation, skin integrity, fecundity, and cancer

The Emory mouse is the best model for age-related cataract. In this work we compare the effects of feeding a control diet (C) with a diet restricted (R) by 40% relative to C animals. In the R animals, median lifespan was extended by 40%. The proportion of R mice with advanced cataract was lower than C mice as early as 5 months of age. The mean grade of cataract was lower in R animals, beginning at 11 months and continuing until the end of the study. Ascorbate levels in R plasma and liver were 41-56% of C animals. There was no difference between diet groups with respect to lens ascorbate. Aging was associated with a decrease in ascorbate in lenses and kidneys in C and R mice. By 22 months, R animals had 48% higher liver glutathione levels than C mice. Liver glutathione levels were maximal at 12 months. Plasma glucose levels were > 27% lower in R animals at 6.5 and 22 months, and there was a 14% increase in glucose levels upon aging for both diet groups. In R mice, glycohemoglobin levels were 51% lower and tail collagen breaktime was decreased by 40%, even in younger animals. Collagen breaktime increased > 360% upon aging for both diet groups. Rates of production of urinary oxo8dG and oxo8G were higher in R animals compared with C animals, and increased upon aging. C animals exhibited more cancer and dermatological lesions, but less tail tip necrosis and inflamed genitals than R mice. These data allow evaluation of several theories of aging.

The effects of a multivitamin/mineral supplement on micronutrient status, antioxidant capacity and cytokine production in healthy older adults consuming a fortified diet.

Background: Inadequate micronutrient intake among older adults is common despite the increased prevalence of fortified/enriched foods in the American diet. Although many older adults take multivitamin supplements in an effort to compensate, studies examining the benefits of this behavior are absent. Objective: To determine whether a daily multivitamin/mineral supplement can improve micronutrient status, plasma antioxidant capacity and cytokine production in healthy, free-living older adults already consuming a fortified diet. Methods: An eight-week double-blind, placebo-controlled clinical trial among 80 adults aged 50 to 87 years (mean=66.5±8.6 years). Results: Multivitamin treatment significantly increased (p<0.01, compared to placebo) plasma concentrations of vitamins D (77 to 100 nmol/L), E (27 to 32 μmol/L), pyridoxal phosphate (55.1 to 75.2 nmol/L), folate (23 to 33 nmol/L), B12 (286 to 326 pmol/L)), C (55 to 71 μmol/L), and improved the riboflavin activity coefficient (1.23 to 1.15), but not vitamins A and thiamin. The multivitamin reduced the prevalence of suboptimal plasma levels of vitamins E (p=0.003), B12 (p=0.004), and C (p=0.08). Neither glutathione peroxidase activity nor antioxidant capacity (ORAC) were affected. No changes were observed in interleukin−2, −6 or −10 and prostaglandin E2, proxy measures of immune responses. Conclusions: Supplementation with a multivitamin formulated at about 100% Daily Value can decrease the prevalence of suboptimal vitamin status in older adults and improve their micronutrient status to levels associated with reduced risk for several chronic diseases.

B Complex Vitamin Patterns in Geriatric and Young Adult Inpatients with Major Depression

This study compared the B complex vitamin status at time of admission of 20 geriatric and 16 young adult non‐alcoholic inpatients with major depression. Twenty‐eight percent of all subjects were deficient in B2 (riboflavin), B6 (pyridoxine), and/or B12 (cobalamin), but none in B1 (thiamine) or folate. The geriatric sample had significantly higher serum folate levels. Psychotic depressives had lower B12 than did non‐psychotic depressives. Poorer blood vitamin status was not associated with higher scores on the Hamilton Depression Rating Scale or lower scores on the Mini‐Mental State Examination in either age group. The data support the hypothesis that poorer status in certain B vitamins is present in major depression, but blood measures may not reflect central nervous system vitamin function or severity of affective syndromes as measured by the assays and scales in the present study.

Ascorbic acid and plasma lipids.

We examined the association between plasma lipids and total ascorbic acid in 256 men and 221 women age 20–65 years. Among men, we observed that high-density lipoprotein (HDL) cholesterol was 2.1 mg per dl higher, total:HDL cholesterol was 5.4% lower, total cholesterol was 4.8 mg per dl lower, low-density lipoprotein (LDL) cholesterol was 5.6 mg per dl lower, and triglyceride was 5.2% lower for each 0.5 mg per dl increment in ascorbic acid. The association between ascorbic acid and total:HDL cholesterol ratio in men was modified by glucose concentration. Among women, we observed that HDL cholesterol was 14.9 mg per dl higher for women with ascorbic acid levels ≤1.05 mg per dl and 0.9 mg per dl lower for women with ascorbic acid levels >1.05mg per dl for each 0.5 mg per dl increment in ascorbic acid. Total:HDL cholesterol ratio was 10.9% lower for women with ascorbic acid concentrations ≤1.45 mg per dl and 0.6% higher for women with ascorbic acid concentrations >1.45 mg per dl for each 0.5 mg per dl increment. The associations among ascorbic acid concentration, total and LDL cholesterol, and triglyceride concentrations were weak or absent among women. These results are consistent with earlier observations relating ascorbic acid and HDL cholesterol and indicate that ascorbic acid might also be related to total and LDL cholesterol concentrations in men.

Vitamin C prevents hyperbaric oxygen-induced growth retardation and lipid peroxidation and attenuates the oxidation-induced up-regulation of glutathione in guinea pigs

Hyperbaric oxygen therapy is used to treat various clinical conditions, but it also causes oxidative damage. The objectives of this study are to determine if increased vitamin C intake can prevent hyperbaric oxygen-induced damage and to determine interactions among vitamin C, glutathione and vitamin E in response to oxidative stress. The growth rates of unexposed guinea pigs fed 1.25 mg vitamin C/day were indistinguishable from that of guinea pigs fed 50 mg vitamin C/day. In contrast, hyperbaric oxygen exposure resulted in growth retardation in guinea pigs fed 1.25 mg vitamin C/day, but it had little effect on the growth rates of guinea pigs fed 50 mg vitamin C/day. Increased vitamin C intake also prevented hyperbaric oxygen-induced lipid peroxidation in the liver. In guinea pigs not exposed to hyperbaric oxygen, levels of vitamin C in tissues were closely related to vitamin C intake, but tissue levels of glutathione and vitamin E were not related to vitamin C intake. However, interactions between vitamin C and glutathione were observed upon chronic hyperbaric oxygen exposure. Chronic hyperbaric oxygen exposure resulted in >2-fold increases in the levels of glutathione in liver and lung of guinea pigs fed 1.25 mg vitamin C/day. In comparison, the oxidation-induced increases in glutathione were significantly attenuated in guinea pigs fed 50 mg vitamin C/day. These data show that increased intake of vitamin C can prevent or alleviate the hyperbaric oxygen-induced damage. The interactions between vitamin C and glutathione upon hyperbaric oxygen exposure indicate that there is a homeostatic regulation of antioxidant capacity in guinea pig tissues.

The effect of high-dose ascorbate supplementation on plasma lipoprotein(a) levels in patients with premature coronary heart disease.

Study Objective. To determine the efficacy of high‐dose ascorbate supplementation in lowering lipoprotein(a) [Lp(a)] levels in patients with premature coronary heart disease (CHD).

The effects of aging and calorie restriction on plasma nutrient levels in male and female Emory mice

We examined the effect of diet, age (4.5, 13 and 23 months), and sex on plasma levels of retinol, tocopherol, ascorbate, cholesterol, glucose and glycohemoglobin in male and female Emory mice which were fed control (C) and 50% calorie restricted (R) diets. Results showed that C fed animals tended to have higher levels of plasma ascorbate (50-71%), cholesterol (23-71%), glucose (38-81%) and glycohemoglobin (50%). However, these diet differences varied with the age and sex of the animals. Plasma retinol levels were lower only in R males vs. C males (50%). Novel sex-related differences in levels of plasma retinol (2-fold higher in C male mice than in C or R female mice) are described. Aging was associated with trends towards lower levels of plasma ascorbate (14-25%), glucose (34-36%) and glycohemoglobin (47-57%) from 4.5 to 23 months of age. However, these age differences depended upon the diet and sex of the animals. These data suggest that lower plasma levels of glucose, glycosylated hemoglobin and cholesterol may be causally related to the life extension noted in R animals since elevated levels of these moieties have been related to aging. Since oxidative stress is thought to be causally related to aging it appears unlikely that retinol, tocopherol and ascorbate are causally related to R-induced life-extension.

Low thyroxine levels in female psychiatric inpatients with riboflavin deficiency: implications for folate-dependent methylation.

Intermediates in the folate‐dependent methylation pathways may play a role in the etiology and treatment of such mental disorders as major depression. These pathways include a step dependent on a riboflavin (B2)‐derived coenzyme, flavin adenine dinucleotide (FAD), which is reportedly sensitive to thyroid status and to phenothiazine and tricyclic drug exposure. In a sample of 52 male and female acute psychiatric inpatients, 17% (n= 9) showed B2 deficiency (i.e., insufficient FAD activity) on a functional red blood cell enzyme assay, but only one B2‐deficient individual showed deficiency in another B‐complex vitamin (folate). All patients with B2 deficiency were women, who were also significantly younger than the rest of the sample. The B2‐deficient women had significantly lower thyroxine levels, even when controlling for sex and covarying for age. B2‐deficient patients exhibited a nonsignificant trend toward more unipolar depression (44%vs 14%), but not toward bipolar or schizophrenic disorders. As in a previous study, drug exposure did not show a relationship to riboflavin deficiency in this sample. The findings suggest that B2 (FAD) activity may serve as a sensitive marker of thyroxine status in certain female psychiatric inpatients and that B2 deficiency may play an etiological role in defects of the methylation pathways in a subset of mentally ill individuals.

High dose ascorbate supplementation fails to affect plasma homocyst(e)ine levels in patients with coronary heart disease

Pharmacologic doses of folate, in the absence of clinical folate deficiency, can reduce plasma levels of the putatively atherothrombotic amino acid, homocysteine (H(e)). Data suggesting that H(e) may accumulate in experimental scurvy prompted us to explore the efficacy of high dose ascorbate supplementation as a H(e)-lowering treatment, in the absence of clinical ascorbate deficiency. A randomized, placebo-controlled trial of 12 weeks of high dose (4.5 g/day) ascorbate supplementation was completed by 44 patients with established coronary heart disease. No significant change in mean fasting total plasma H(e) levels was demonstrable despite a marked increase in mean fasting plasma ascorbate levels amongst those patients randomized to active treatment. Ascorbate supplementation to prevent the development of fasting hyperhomocysteinemia may only be relevant at scorbutic levels of plasma ascorbate.