Yuwei Liu

Biology of Ageing and Role of Dietary Antioxidants

Interest in relationship between diet and ageing is growing. Research has shown that dietary calorie restriction and some antioxidants extend lifespan in various ageing models. On the one hand, oxygen is essential to aerobic organisms because it is a final electron acceptor in mitochondria. On the other hand, oxygen is harmful because it can continuously generate reactive oxygen species (ROS), which are believed to be the factors causing ageing of an organism. To remove these ROS in cells, aerobic organisms possess an antioxidant defense system which consists of a series of enzymes, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). In addition, dietary antioxidants including ascorbic acid, vitamin A, vitamin C, α-tocopherol, and plant flavonoids are also able to scavenge ROS in cells and therefore theoretically can extend the lifespan of organisms. In this connection, various antioxidants including tea catechins, theaflavins, apple polyphenols, black rice anthocyanins, and blueberry polyphenols have been shown to be capable of extending the lifespan of fruit flies. The purpose of this review is to brief the literature on modern biological theories of ageing and role of dietary antioxidants in ageing as well as underlying mechanisms by which antioxidants can prolong the lifespan with focus on fruit flies as an model.

Cholesterol-lowering activity of sesamin is associated with down-regulation on genes of sterol transporters involved in cholesterol absorption.

Sesame seed is rich in sesamin. The present study was to (i) investigate the plasma cholesterol-lowering activity of dietary sesamin and (ii) examine the interaction of dietary sesamin with the gene expression of sterol transporters, enzymes, receptors, and proteins involved in cholesterol metabolism. Thirty hamsters were divided into three groups fed the control diet (CON) or one of two experimental diets containing 0.2% (SL) and 0.5% (SH) sesamin, respectively, for 6 weeks. Plasma total cholesterol (TC) levels in hamsters given the CON, SL, and SH diets were 6.62 ± 0.40, 5.32 ± 0.40, and 5.00 ± 0.44 mmol/L, respectively, indicating dietary sesamin could reduce plasma TC in a dose-dependent manner. Similarly, the excretion of total fecal neutral sterols was dose-dependently increased with the amounts of sesamin in diets (CON, 2.65 ± 0.57; SL, 4.30 ± 0.65; and SH, 5.84 ± 1.27 μmol/day). Addition of sesamin into diets was associated with down-regulation of mRNA of intestinal Niemann-Pick C1 like 1 protein (NPC1L1), acyl-CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP-binding cassette transporters subfamily G members 5 and 8 (ABCG5 and ABCG8). Results also showed that dietary sesamin could up-regulate hepatic cholesterol-7α-hydroxylase (CYP7A1), whereas it down-regulated hepatic 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase and liver X receptor alpha (LXRα). It was concluded that the cholesterol-lowering activity of sesamin was mediated by promoting the fecal excretion of sterols and modulating the genes involved in cholesterol absorption and metabolism.

Plasma Cholesterol-Lowering Activity of Gingerol- and Shogaol-Enriched Extract Is Mediated by Increasing Sterol Excretion

The present study investigated the cholesterol-lowering activity of gingerol- and shogaol-enriched ginger extract (GSE). Thirty hamsters were divided into three groups and fed the control diet or one of the two experimental diets containing 0.5 and 1.0% GSE. Plasma total cholesterol, liver cholesterol, and aorta atherosclerotic plaque were dose-dependently decreased with increasing amounts of GSE added into diets. The fecal sterol analysis showed dietary GSE increased the excretion of both neutral and acidic sterols in a dose-dependent manner. GSE down-regulated the mRNA levels of intestinal Niemann-Pick C1-like 1 protein (NPC1L1), acyl CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter 5 (ABCG5), whereas it up-regulated hepatic cholesterol-7α-hydroxylase (CYP7A1). It was concluded that beneficial modification of the lipoprotein profile by dietary GSE was mediated by enhancing excretion of fecal cholesterol and bile acids via up-regulation of hepatic CYP7A1 and down-regulation of mRNA of intestinal NPC1L1, ACAT2, and MTP.

Cranberry anthocyanin extract prolongs lifespan of fruit flies.

Cranberry is an excellent source of dietary antioxidants. The present study investigated the effect of cranberry anthocyanin (CrA) extract on the lifespan of fruit flies with focus on its interaction with aging-related genes including superoxide dismutase (SOD), catalase (CAT), methuselah (MTH), insulin receptor (InR), target of rapamycin (TOR), hemipterus (Hep), and phosphoenolpyruvate carboxykinase (PEPCK). Results showed that diet containing 20mg/mL CrA could significantly prolong the mean lifespan of fruit flies by 10% compared with the control diet. This was accompanied by up-regulation of SOD1 and down-regulation of MTH, InR, TOR and PEPCK. The stress resistance test demonstrated that CrA could reduce the mortality rate induced by H2O2 but not by paraquat. It was therefore concluded that the lifespan-prolonging activity of CrA was most likely mediated by modulating the genes of SOD1, MTH, InR, TOR and PEPCK.

Capsaicinoids but Not Their Analogue Capsinoids Lower Plasma Cholesterol and Possess Beneficial Vascular Activity

Capsaicinoids exist in chili peppers, whereas capsinoids are present in some sweet peppers. The present study investigated the effects of capsaicinoids and capsinoids on plasma lipids, relaxation of the aorta, atherosclerotic plaque development, and fecal sterol excretion in hamsters fed a high-cholesterol diet. Five groups of male hamsters were given the control diet or one of the four experimental diets containing 1.3 mmol of capsaicinoids (NL), 2.6 mmol of capsaicinoids (NH), 1.3 mmol of capsinoids (OL), or 2.6 mmol of capsinoids (OH), respectively. Results showed capsaicinoids but not capsinoids could decrease plasma total cholesterol (TC), reduce the formation of atherosclerotic plaque, and relax the aortic artery. This was accompanied by a 28-175% increase in fecal excretion of acidic sterols in hamsters fed the diets containing capsaicinoids. Similarly, capsaicinoids but not capsinoids could decrease the pad weights of epididymal and prerenal adipose tissues. It was concluded that capsaicinoids but not capsinoids could favorably modulate plasma lipids and possess beneficial vascular activity.

Plasma cholesterol-lowering activity of dietary dihydrocholesterol in hypercholesterolemia hamsters

OBJECTIVE Cholesterol analogs have been used to treat hypercholesterolemia. The present study was to examine the effect of dihydrocholesterol (DC) on plasma total cholesterol (TC) compared with that of β-sitosterol (SI) in hamsters fed a high cholesterol diet. METHODS AND RESULTS Forty-five male hamsters were randomly divided into 6 groups, fed either a non-cholesterol diet (NCD) or one of five high-cholesterol diets without addition of DC and SI (HCD) or with addition of 0.2% DC (DA), 0.3% DC (DB), 0.2% SI (SA), and 0.3% SI (SB), respectively, for 6 weeks. Results showed that DC added into diet at a dose of 0.2% could reduce plasma TC by 21%, comparable to that of SI (19%). At a higher dose of 0.3%, DC reduced plasma TC by 15%, less effective than SI (32%). Both DC and SI could increase the excretion of fecal sterols, however, DC was more effective in increasing the excretion of neutral sterols but it was less effective in increasing the excretion of acidic sterols compared with SI. Results on the incorporation of sterols in micellar solutions clearly demonstrated both DC and SI could displace the cholesterol from micelles with the former being more effective than the latter. CONCLUSION DC was equally effective in reducing plasma cholesterol as SI at a low dose. Plasma TC-lowering activity of DC was mediated by inhibiting the cholesterol absorption and increasing the fecal sterol excretion.

Plasma cholesterol-raising potency of dietary free cholesterol versus cholesteryl ester and effect of β-sitosterol.

The present study (i) compared plasma cholesterol-raising activity of free cholesterol (FC) with that of cholesteryl palmitate (CP) and (ii) examined plasma cholesterol-reducing activity of β-sitosterol in FC-induced and CP-induced hypercholesterolemia. Male hamsters were divided into five groups and fed one of the five diets containing no cholesterol (NC), 2.6mmol cholesterol (C), 2.6mmol cholesterol plus 2.6mmol β-sitosterol (C+S), 2.6mmol cholesteryl palmitate (CP), and 2.6mmol CP plus 2.6mmol β-sitosterol (CP+S), respectively, for 8weeks. Hamsters fed diet C had plasma TC of 317.5mg/dl whereas hamsters fed diet CP has plasma TC of 281.3mg/dl. β-Sitosterol reduced plasma TC by 17.4% and 11.6%, respectively, in FC-induced and CP-induced hypercholesterolemia (not significant). It was concluded that plasma cholesterol-raising activity of dietary cholesterol was a function of its chemical forms in diet, and β-sitosterol could similarly suppress the hypercholesterolemia induced by both dietary FC and CP.

Cholesteryl Ester Species Differently Elevate Plasma Cholesterol in Hamsters

This study was to examine the effect of free cholesterol (C) and individual cholesteryl ester (CE) species, namely cholesteryl palmitate (CP), cholesteryl stearate (CS), cholesteryl oleate (CO), and cholesteryl linoleate (CL) on plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triacylglycerols (TG) in hamsters. Results showed that addition of dietary CE species into diet at 0.1% differently raised plasma TC concentrations, with CO elevating plasma TC to 331 mg/dL, while CS raised plasma TC only to 220 mg/dL. It was found that CS was a poor substrate of pancreatic cholesterol esterase, while CO was a good substrate. The fecal analysis showed CS-fed hamsters had the highest fecal cholesterol concentration, while RT-PCR analysis found CS feeding was associated with down-regulations of intestinal Niemann-Pick C1 like 1 (NPC1L1) and acyl-CoA: cholesterol acyltransferase 2 (ACAT2) as well as microsomal triacylglycerol transport protein (MTP). It was therefore concluded that the plasma cholesterol-raising activity of CE species was partially governed by their hydrolysis rates in the intestine, and the relative low raising activity associated with CS was mediated by down-regulation of intestinal NPC1L1, ACAT2, and MTP.

Purple sweet potato anthocyanin attenuates fat-induced mortality in Drosophila melanogaster

A high fat diet induces the accumulation of lipid hydroperoxides (LPO), accelerates the ageing process and causes a greater mortality in Drosophila melanogaster. Purple sweet potato is rich in antioxidant anthocyanin. The purpose of the present study was to examine if supplementation of purple sweet potato anthocyanin (PSPA) could reduce the mortality of fruit flies fed a high-fat diet. Results showed that the mean lifespan of fruit flies was shortened from 56 to 35days in a dose-dependent manner when lard in the diet increased from 0% to 20%. PSPA supplementation partially attenuated the lard-induced mortality. The maximum lifespan and 50% survival time were 49 and 27days, respectively, for the 10% lard control flies, in contrast, these parameters increased to 57 and 30days in the PSPA-supplemented fruit flies. Similarly, addition of lard into diet increased the total body LPO, while addition of PSPA partially attenuated its increase. Real-time PCR analysis indicated that PSPA-supplemented diet significantly up-regulated the mRNA of superoxide dismutase (SOD), catalase (CAT) and Rpn11, compared with the control lard diet. The western blot analysis also demonstrated that PSPA supplementation was associated with up-regulation protein mass of SOD1, SOD2, and CAT. In addition, PSPA supplementation could restore the climbing ability of fruit flies fed a 10% lard diet. We could conclude that the lifespan-prolonging activity of PSPA was potentially mediated by modulating the genes of SOD, CAT and Rpn11.

CHAPTER 31:Interaction of Dietary Calcium with Genes of Transporters, Receptors and Enzymes Involved in Cholesterol Metabolism

Dietary calcium has been shown to decrease plasma total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, particularly in postmenopausal women who have regularly taken calcium supplement for prevention of osteoporosis. Two possible mechanisms are associated with cholesterol-lowering activity of calcium supplement. First, calcium increases the bile-acid excretion due to its binding interaction with bile acids in the intestine. This is companied by upregulation of cholesterol-7α-hydroxylase (CYP7A1), a key enzyme in converting cholesterol to bile acids in the liver. Secondly, calcium supplement increases the cholesterol excretion, possibly mediated by downregulation of intestinal Niemann-Pick C1 like 1 (NPC1L1) and acyl coenzyme A: cholesterol acyltransferase 2 (ACAT-2), both of which are responsible for cholesterol absorption.