Harumi Okuyama

Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review

Objective It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue. Setting, participants and outcome measures We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60u2005years from the general population. Results We identified 19 cohort studies including 30 cohorts with a total of 68u2005094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found. Conclusions High LDL-C is inversely associated with mortality in most people over 60u2005years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.

Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms

In contrast to the current belief that cholesterol reduction with statins decreases atherosclerosis, we present a perspective that statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 and ‘heme A’, and thereby ATP generation. Statins inhibit the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification. Statins inhibit the biosynthesis of selenium containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative stress. An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, reminiscent of the dilated cardiomyopathies seen with selenium deficiency. Thus, the epidemic of heart failure and atherosclerosis that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs. We propose that current statin treatment guidelines be critically reevaluated.

Dietary Lipids Impacts on Healthy Ageing

Healthy ageing is gaining attention in the lipid nutrition field. As in vivo biomarkers of healthy ageing, we have evaluated the survival, learning/memory performance, and physical potencies in rodents fed a diet supplemented with high-linoleic acid (LNA, ω6) safflower oil or high-α-linolenic acid (ALA, ω3) perilla oil for long periods. The results suggested that perilla oil with a low ω6/ω3 ratio is beneficial for healthy ageing. In order to address this issue further, we determined the survival of stroke-prone SHR (SHRSP) rats fed a conventional rodent diet supplemented with 10% fat or oil. Survival was longer with ω3-rich oils compared with ω6-rich oils. However, some kinds of vegetable oils and hydrogenated oils shortened the survival of SHRSP rats to an unusual degree (ca. 40% compared with that of ω6-rich oil) that could not be accounted for by the fatty acid and phytosterol composition of the oils. The observed decrease in platelet counts was associated with pathological changes in the kidney and other organs. Dihydro-vitamin K1 is proposed as a likely candidate as a stroke-stimulating factor in hydrogenated oils. Thus, factors other than fatty acids (ω6/ω3 balance) and phytosterols must be taken into account when fats and oils are evaluated in relation to healthy ageing.

Regional differences of the mouse brain in response to an α-linolenic acid-restricted diet: neurotrophin content and protein kinase activity.

AIMSnThe purpose of this study was to determine a relatively short-term effect of feeding an α-linolenic acid (ALA, n-3)-restricted, linoleic acid (LA, n-6)-adequate diet on neurotrophin contents and protein kinase activities in brain regions of the mouse.nnnMAIN METHODSnAfter feeding mice a safflower oil (SAF) diet (ALA-restricted, LA-adequate) or perilla oil (PER) diet (containing adequate amounts of ALA and LA) for 4 weeks from weaning, the fatty acid compositions of brain regions were analyzed by capillary column gas-liquid chromatography, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) contents were measured using enzyme-linked immunosorbent assay.nnnKEY FINDINGSnThe striatum and hippocampus, but not the cerebral cortex, from the SAF group, contained a smaller amount of docosahexaenoic acid (DHA, 22:6n-3) than those from the PER group. The NGF contents in these brain regions were not different between the two dietary groups. However, the striatal BDNF content of the SAF group was significantly lower than that of the PER group. Protein kinase A, protein kinase C, and p44/42 mitogen-activated protein kinase (p44/42 MAPK) activities in brain regions showed no significant difference between the two dietary groups. However, the striatal p38 MAPK activity was significantly lower in the SAF group than in the PER group. No such differences were observed in the hippocampus or the cerebral cortex.nnnSIGNIFICANCEnA relatively short-term feeding of an α-linolenic acid-restricted, linoleic acid-adequate diet was found to lower the DHA content, BDNF content and p38 MAPK activity in the mouse striatum.

The Questionable Benefits of Exchanging Saturated Fat With Polyunsaturated Fat

ormanyyearswehavebeentoldthattoprevent cardiovascular disease (CVD), wemust lower our intake of saturated fattyacids (SFAs) and instead eat more carbohydratesand polyunsaturated fatty acids(PUFAs).Backedup by the National Cholesterol Education Pro-gram, the National Institutes of Health, and theAmerican Heart Association, the medical profes-sionhaspromotedthisideaeagerly,althoughthenumber of contradictory scientificreportsisalmost endless. There is in fact much evidencethat doing the opposite is more relevant.The ContradictionsThe main argumentforusingthis diethasbeenthatitlowerstheconcentrationofcholesterolinthe blood and thus prevents CVD. This ideawas proposed for the first time by Keys,

Different effects of 26-week dietary intake of rapeseed oil and soybean oil on plasma lipid levels, glucose-6-phosphate dehydrogenase activity and cyclooxygenase-2 expression in spontaneously hypertensive rats

We intended to determine whether or not dietary canola oil (CO) elevates plasma lipids and oxidative stress, since both of these are, possibly, related to the CO-induced life shortening through exacerbation of hypertension-associated vascular lesions found in stroke-prone spontaneously hypertensive rats (SHRSP). Spontaneously hypertensive rats (SHR) were used in this study to avoid a potential bias in the results due to the irregular death by stroke seen in SHRSP. SHR were fed for 26 weeks on a chow containing either, 10 wt/wt% of CO or soybean oil (SO), i.e., the control. Elevated plasma lipids and glucose-6-phosphate dehydrogenase (G6PD) activation in the liver and erythrocyte were found in SHR fed CO compared to that fed SO, while anti-oxidative enzymes other than G6PD were not activated. The CO diet brought about significant vascular lesions in the kidney, in which abundant cyclooxygenase-2 (COX-2) positive foci were immunochemically located in the juxtaglomerular apparatus. These results suggest that dietary CO induces a hyperlipidemic condition, in which G6PD may serve as an NADPH provider, and aggravates genetic diseases in SHR (also, probably, in SHRSP). The increased COX-2 expression indicates a role of renin-angiotensin-aldosterone system activation in the increased vascular lesions, whereas the effects of oxidative stress remain unclear.

Three Dissimilar High Fat Diets Differentially Regulate Lipid and Glucose Metabolism in Obesity-Resistant Slc:Wistar/ST Rats

Epidemiologic and ecologic studies suggest that dietary fat plays an important role in the development of obesity. Certain Wistar rat strains do not become obese when fed high-fat diets unlike others. In a preliminary study, we confirmed that Slc:Wistar/ST rats did not become obese when fed high-fat diets. The mechanisms governing the response of hepatic lipid-metabolizing enzymes to large quantities of dietary lipids consumed by obesity-resistant animals are unknown. The aim of the present study is to examine how obesity-resistant animals metabolize various types of high-fat diets and why they do not become obese. For this purpose, male Slc:Wistar/ST rats were fed a control low-fat diet (LS) or a high-fat diet containing fish oil (HF), soybean oil (HS), or lard (HL) for 4xa0weeks. We observed their phenotypes and determined lipid profiles in plasma and liver as well as mRNA expression levels in liver of genes related to lipid and glucose metabolism using DNA microarray and quantitative reverse transcriptase polymerase chain analyses. The body weights of all dietary groups were similar due to isocaloric intakes, whereas the weight of white adipose tissues in the LS group was significantly lower. The HF diet lowered plasma lipid levels by accelerated lipolysis in the peroxisomes and suppressed levels of very-low-density lipoprotein (VLDL) secretion. The HS diet promoted hepatic lipid accumulation by suppressed lipolysis in the peroxisomes and normal levels of VLDL secretion. The lipid profiles of rats fed the LS or HL diet were similar. The HL diet accelerated lipid and glucose metabolism.

Similar changes in clinical and pathological parameters in Wistar Kyoto rats after a 13-week dietary intake of canola oil or a fatty acid composition-based interesterified canola oil mimic.

Canola oil (CO) given as a dietary fat deteriorates hypertension-related condition and shortens the life of stroke-prone spontaneously hypertensive rats (SHRSP). Although substances other than fatty acids have been presumed as causatives, CO mimics consisting of oils other than CO also shorten the life. In this study we intended to examine whether or not fatty acid composition unique to CO participates in the adverse effect. CO or an interesterified CO mimic (ICOM) consisting of safflower oil, flaxseed oil and erucic acid was fed as a dietary fat for 13 weeks to Wistar Kyoto (WKY) rats, and clinical and pathological signs were compared. WKY rats were used to avoid the difficulty in evaluating the results in SHRSP due to irregular deterioration in conditions by stroke. Compared to a standard diet, both diets containing CO or ICOM similarly elevated blood pressure, increased plasma lipids, activated hepatic glucose-6-phosphate dehydrogenase, decreased platelets, shortened blood coagulation times and induced abnormalities in the kidney. Thus, CO-specific fatty acid composition appeared to affect the pathophysiology of the rat and produce consequent aggravation of pathological status, especially in SHRSP. However, the existence of causative factors other than fatty acids was suggested by increased neutrophil count exclusively induced by CO.

Dietary n-3/long-chain n-3 polyunsaturated fatty acids for prevention of sporadic colorectal tumors: A randomized controlled trial in polypectomized participants

To address preventive effects of n-3 PUFAs/LC n-3 PUFAs on CRTs, a randomized controlled trial was conducted. One-hundred four experimental group participants were advised to increase intake of n-3 PUFAs, including fish/shell fish, fish oil supplements and perilla oils, and to decrease consumption of n-6 PUFAs and fats/oils as a whole for 24 months. One-hundred one control group participants were only cautioned to reduce consumption of fats/oils as a whole. Random allocation was satisfactorily attained, and participants sufficiently complied with our regimen. Intakes, plasma concentrations, and compositions of the RBC and sigmoid colon membranes of n-3 PUFAs, LC n-3 PUFAs, EPA and DHA increased, and the ratios of n-6 PUFAs/n-3 PUFAs and AA/LC n-3 PUFAs decreased without any adverse response. Twenty-four months after the intervention, the multivariate-adjusted hazard ratio (95% confidence intervals) was estimated to be 0.805 (0.536-1.209) with a signal towards the reduced CRT incidence.

No scientific support for linking dietary saturated fat to CHD.

Pedersen et al. express concern that recently published research had downplayed the importance of SFA consumption as a risk factor for CHD. Their main argument is that prospective cohort studies are unreliable. There are of course uncertainties in such studies, but it is difficult to ignore that more than thirty cohort studies have shown that patients with CVD did not eat more SFA than had hearthealthy people; in six of them, stroke patients had actually eaten less. To make their case, Pedersen et al. presented a small and biased subset of ecological studies apparently linking reduced consumption of SFA to a low incidence of CHD. However, they neglected to mention the many ecological studies that have documented findings from groups with a high consumption of SFA, but with low rates of CHD, including Masai people, French, Italian-Americans and Polynesians. They also claim that the association between the decline of CHD mortality in Finland and the lowered intake of SFA was causal. However, the decline began in North Karelia 3 years before the start of the cholesterol campaign, and it occurred also in the districts where no advice was given. Pedersen et al. asserted that SFA with twelve to sixteen carbon atoms are the most potent LDLand total cholesterolraising fatty acids. However, other researchers reported that the serum content of these fatty acids is inversely associated with serum cholesterol, and in seven studies, the content of twelve to sixteen carbon fatty acids in the blood or the fat cells was similar or lower in patients with acute CHD than in healthy people. The content of certain SFA in the serum reflects the intake of dairy fat, and such intake is inversely associated with BMI, waist circumference, ratio of LDL:HDL and fasting glucose concentration, and positively associated with HDL and apoA-I. In accordance, a meta-analysis of twenty-five cohort studies showed that the lowest total mortality, cardiovascular incidence and mortality, and incidence of diabetes were seen among those with the highest intake of dairy fat. Pedersen et al. endorse the many reports emphasising the importance of increasing the intake of PUFA. This advice is not based on randomised, controlled dietary trials, because no such trial has ever succeeded in lowering cardiovascular or total mortality by exchanging SFA with PUFA. Rather, the advice is based on statistical calculations using data from unreliable cohort studies. Pedersen et al. refer to a meta-analysis of such trials, the authors of which claimed benefit, but they had excluded two trials, where CHD mortality had increased in the treatment groups, and included a trial where a decreased risk was seen only in the participants who increased their intake of fish, and also the Finnish Mental Hospital Study, a trial which does not satisfy the quality criteria for a correctly performed randomised controlled trial. A reduction of SFA was part of the intervention in three multifactorial trials, but these trials were unsuccessful as well; in one of these, total mortality was twice as high in the treatment group. Numerous studies on laboratory animals and human subjects have also shown that an increased intake of PUFA, in particular of the n-6 type, is associated with many adverse health effects such as allergy, asthma, immunosuppression, decreased fertility, pre-eclampsia, encephalopathy and cancer. In accordance with this, Israeli Jews have a high intake of the ‘recommended’ n-6 type of PUFA (from grains and soyabean oil), and they exhibit a high incidence of cancer and CHD mortality compared with other Western countries. In conclusion, Pedersen et al. do not provide sufficient evidence to implicate SFA in CHD risk. There is increasingly strong evidence that SFA are not involved.