Life Extension Magazine®

Issue: Oct 2016

CoQ10 and Selenium, Diabetes/cardiovascular disease Conferences, Tocotrienols, and blood sugar

CoQ10 and Selenium, Diabetes/cardiovascular disease Conferences, Tocotrienols, and blood sugar

CoQ10 and Selenium

Reduced Cardiovascular Mortality 10 Years after Supplementation with Selenium and Coenzyme Q10 for Four Years: Follow-Up Results of a Prospective Randomized Double-Blind Placebo-Controlled Trial in Elderly Citizens.

BACKGROUND: Selenium and coenzyme Q10 are important antioxidants in the body. As the intake of selenium is low in Europe, and the endogenous production of coenzyme Q10 decreases as age increases, an intervention trial using selenium and coenzyme Q10 for four years was performed. As previously reported, the intervention was accompanied by reduced cardiovascular mortality. The objective of the present study was to analyze cardiovascular mortality for up to 10 years after intervention, to evaluate if mortality differed in subgroups differentiated by gender, diabetes, ischemic heart disease (IHD), and functional class. METHODS: Four-hundred forty-three healthy elderly individuals were included from a rural municipality in Sweden. All cardiovascular mortality was registered, and no participant was lost to the follow-up. Based on death certificates and autopsy results mortality was registered. FINDINGS: Significantly reduced cardiovascular mortality could be seen in those on selenium and coenzyme Q10 intervention. A multivariate Cox regression analysis demonstrated a reduced cardiovascular mortality risk in the active treatment group (HR: 0.51; 95%CI 0.36–0.74; P = 0.0003). The reduced mortality could be seen to persist during the 10-year period. Subgroup analysis showed positive effects in both genders. An equally positive risk reduction could be seen in those with ischemic heart disease (HR: 0.51; 95% CI 0.27–0.97; P = 0.04), but also in the different functional classes. CONCLUSIONS: In a 10-year follow-up of a group of healthy elderly participants given four years of intervention with selenium and coenzyme Q10, significantly reduced cardiovascular mortality was observed. The protective action was not confined to the intervention period, but persisted during the follow-up period. The mechanism explaining the persistency remains to be elucidated. Since this was a small study, the observations should be regarded as hypothesis-generating.

PLoS One. 2015 12/01

Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens.

BACKGROUND: Selenium and coenzyme Q10 are essential for the cell. Low cardiac contents of selenium and coenzyme Q10 have been shown in patients with cardiomyopathy, but inconsistent results are published on the effect of supplementation of the two components separately. A vital relationship exists between the two substances to obtain optimal function of the cell. However, reports on combined supplements are lacking. METHODS: A 5-year prospective randomized double-blind placebo-controlled trial among Swedish citizens aged 70 to 88 was performed in 443 participants given combined supplementation of selenium and coenzyme Q10 or a placebo. Clinical examinations, echocardiography and biomarker measurements were performed. Participants were monitored every 6th month throughout the intervention. The cardiac biomarker N-terminal proBNP (NT-proBNP) and echocardiographic changes were monitored and mortalities were registered. End-points of mortality were evaluated by Kaplan-Meier plots and Cox proportional hazard ratios were adjusted for potential confounding factors. Intention-to-treat and per-protocol analyses were applied. RESULTS: During a follow up time of 5.2 years a significant reduction of cardiovascular mortality was found in the active treatment group vs. the placebo group (5.9% vs. 12.6%; P=0.015). NT-proBNP levels were significantly lower in the active group compared with the placebo group (mean values: 214 ng/L vs. 302 ng/L at 48 months; P=0.014). In echocardiography a significant better cardiac function score was found in the active supplementation compared to the placebo group (P=0.03). CONCLUSION: Long-term supplementation of selenium/coenzyme Q10 reduces cardiovascular mortality. The positive effects could also be seen in NT-proBNP levels and on echocardiography.

Int J Cardiol. 2013 Sep 1; 167(5): 1860-1866.

Oral coenzyme Q10 supplementation improves clinical symptoms and recovers pathologic alterations in blood mononuclear cells in a fibromyalgia patient.

Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology. Recent studies have shown evidence demonstrating that mitochondrial dysfunction and oxidative stress may have a role in the pathophysiology of FM. Coenzyme Q10 (CoQ10) is an essential electron carrier in the mitochondrial respiratory chain and a strong antioxidant. Low CoQ10 levels have been detected in patients with FM, and a significant decrease of clinical symptoms has been reported after oral CoQ10 supplementation. In this report, we show the effect of CoQ10 treatment on clinical symptoms, blood mononuclear cells, and mitochondrial and oxidative stress markers from a woman with FM. After CoQ10 treatment, the patient reported a significant improvement of clinical symptoms. At the cellular level, CoQ10 treatment restored mitochondrial dysfunction and the mtDNA copy number, decreased oxidative stress, and increased mitochondrial biogenesis. Our results suggest that CoQ10 could be an alternative therapeutic approach for FM.

Nutrition. 2012 Nov-Dec; 28(11-12): 1200-1203.

Increased bioavailability of ubiquinol compared to that of ubiquinone is due to more efficient micellarization during digestion and greater GSH-dependent uptake and basolateral secretion by Caco-2 cells.

The oral bioavailability of ubiquinol recently has been reported to be greater than that of ubiquinone in healthy adults. The basis for this influence of redox state of coenzyme Q (CoQ) on bioavailability has been investigated using the coupled in vitro digestion/Caco-2 cell model. Solubilized ubiquinol and ubiquinone were added to yogurt and subjected to simulated gastric and small intestinal digestion. Partitioning of CoQ in mixed micelles during small intestinal digestion was significantly greater during digestion of yogurt enriched with ubiquinol. Similarly, apical uptake from mixed micelles and transepithelial transport of CoQ by Caco-2 cells were significantly greater after digestion of the ubiquinol-rich yogurt compared to digested ubiquinone-rich yogurt. Reduction of cellular GSH significantly decreased cell uptake and basolateral secretion of both ubiquinol and ubiquinone, although the adverse impact was much greater for ubiquinol. These data suggest that the enhanced bioaccessibility and bioavailability of ubiquinol compared to ubiquinone results from reduced coenzyme being more efficiently incorporated into mixed micelles during digestion and its greater uptake and basolateral secretion in a glutathione-dependent mechanism.

J Agric Food Chem. 2014 Jul 23; 62(29): 7174-7182.

Ubiquinol-10 ameliorates mitochondrial encephalopathy associated with CoQ deficiency.

Coenzyme Q10 (CoQ10) deficiency (MIM 607426) causes a mitochondrial syndrome with variability in the clinical presentations. Patients with CoQ10 deficiency show inconsistent responses to oral ubiquinone-10 supplementation, with the highest percentage of unsuccessful results in patients with neurological symptoms (encephalopathy, cerebellar ataxia or multisystemic disease). Failure in the ubiquinone-10 treatment may be the result of its poor absorption and bioavailability, which may be improved by using different pharmacological formulations. In a mouse model (Coq9(X/X)) of mitochondrial encephalopathy due to CoQ deficiency, we have evaluated oral supplementation with water-soluble formulations of reduced (ubiquinol-10) and oxidized (ubiquinone-10) forms of CoQ10. Our results show that CoQ10 was increased in all tissues after supplementation with ubiquinone-10 or ubiquinol-10, with the tissue levels of CoQ10 with ubiquinol-10 being higher than with ubiquinone-10. Moreover, only ubiquinol-10 was able to increase the levels of CoQ10 in mitochondria from cerebrum of Coq9(X/X) mice. Consequently, ubiquinol-10 was more efficient than ubiquinone-10 in increasing the animal body weight and CoQ-dependent respiratory chain complex activities, and reducing the vacuolization, astrogliosis and oxidative damage in diencephalon, septum-striatum and, to a lesser extent, in brainstem. These results suggest that water-soluble formulations of ubiquinol-10 may improve the efficacy of CoQ10 therapy in primary and secondary CoQ10 deficiencies, other mitochondrial diseases and neurodegenerative diseases.

Biochim Biophys Acta. 2014 Jul; 1842(7): 893-901.

Redox Roles of Reactive Oxygen Species in Cardiovascular Diseases.

Cardiovascular disease (CVD), a major cause of mortality in the world, has been extensively studied over the past decade. However, the exact mechanism underlying its pathogenesis has not been fully elucidated. Reactive oxygen species (ROS) play a pivotal role in the progression of CVD. Particularly, ROS are commonly engaged in developing typical characteristics of atherosclerosis, one of the dominant CVDs. This review will discuss the involvement of ROS in atherosclerosis, specifically their effect on inflammation, disturbed blood flow and arterial wall remodeling. Pharmacological interventions target ROS in order to alleviate oxidative stress and CVD symptoms, yet results are varied due to the paradoxical role of ROS in CVD. Lack of effectiveness in clinical trials suggests that understanding the exact role of ROS in the pathophysiology of CVD and developing novel treatments, such as antioxidant gene therapy and nanotechnology-related antioxidant delivery, could provide a therapeutic advance in treating CVDs. While genetic therapies focusing on specific antioxidant expression seem promising in CVD treatments, multiple technological challenges exist precluding its immediate clinical applications.

Int J Mol Sci. 2015 16(11): 27770-27780.

Effect of selenium and Q10 on the cardiac biomarker NT-proBNP.

OBJECTIVE: To investigate whether the effect of 48-month usage of coenzyme Q10 and selenium on cardiac function was different for participants with different levels of cardiac wall tension as measured by plasma levels of N-terminal natriuretic peptide (NT-proBNP) at baseline. METHODS: A 48-month randomized double-blind controlled trial in a cohort of community-dwelling elderly (mean age 78 years) was carried out. A total of 443 participants were given coenzyme Q10 combined with selenium, or a placebo. NT-proBNP measured at baseline and 48 months was used to evaluate the cardiac wall tension. RESULTS: After 48 months, supplementation of coenzyme Q10 and selenium had varying impacts depending on the severity of impairment of cardiac function. Analyses of the responses in the different quintiles of baseline NT-proBNP showed that those with active supplementation, and a plasma level of NT-proBNP in the second to fourth quintiles demonstrated significantly reduced NT-proBNP levels (p = 0.022) as well as cardiovascular mortality after 48 months (p = 0.006). CONCLUSION: Long-term supplementation of coenzyme Q10/selenium reduces NT-proBNP levels and cardiovascular mortality in those with baseline NT-proBNP in the second to fourth quintiles indicating those who gain from supplementation are patients with mild to moderate impaired cardiac function.

Scand Cardiovasc J. 2013 Oct; 47(5): 281-288.

Improved Health-Related Quality of Life, and More Days out of Hospital with Supplementation with Selenium and Coenzyme Q10 Combined. Results from a Double Blind, Placebo-Controlled Prospective Study.

BACKGROUND: The impact of supplementation with selenium and coenzyme Q10 (CoQ10) on health-care usage and health-related quality of life (Hr-QoL) in community-dwelling elderly people has, to our knowledge, not previously been investigated. AIM: To investigate the effect of 48 months supplementation with CoQ10 and selenium on community-dwelling elderly as regards: (I) the number of days out of hospital, and (II) the effect on Hr-QoL. METHODS: A 48-month double-blind randomized placebo-controlled trial was carried out. A total of 443 participants were given CoQ10 and organic selenium yeast combined, or a placebo. All admissions to the Department of Internal Medicine or Cardiology were evaluated. Hr-QoL were measured with the Short Form-36 (SF-36), the Cardiac Health Profile (CHP) and one item overall-quality of life (overall-QoL). RESULTS: A total of 206 participants were evaluated after 48 months. No changes were found in the number of days out of hospital or Hr-QoL. A sub-analysis of participants matched for age, gender and baseline cardiac wall tension as measured by NT-proBNP was performed. The mean number of days out of hospital was 1,779 for those taking the active substance compared to 1,533 for those taking the placebo (p=0.03). Those with active substance declined significantly less in the HR-QoL domains of physical role performance (p=0.001), vitality (p=0.001), physical component score (p=0.001), overall QoL (p=0.001), somatic dimension (p=0.001), conative dimension (p=0.001) and global function (p=0.001). CONCLUSION: In a match-group analysis selenium and CoQ10 increased the number of days out of hospital and slowed the deterioration in Hr-QoL.

J Nutr Health Aging. 2015 Nov; 19(9): 870-877.

Comparison study of plasma coenzyme Q10 levels in healthy subjects supplemented with ubiquinol versus ubiquinone.

The bioavailability of the reduced form of coenzyme Q10 (ubiquinol) was compared to oxidized coenzyme Q10 (ubiquinone) with identical soft gel capsule excipients by measuring steady state plasma coenzyme Q10 (CoQ10 ) levels in 12 healthy volunteers. After baseline levels of ubiquinol, ubiquinone, total CoQ10 , alpha-tocopherol, and total cholesterol were obtained, follow-up lab work was performed after 4 weeks of 200 mg/day of ubiquinone, after 4 weeks washout, and after 4 weeks of 200 mg/day of ubiquinol. Plasma total CoQ10 increased from 0.9 to 2.5 microg/mL (P < 0.001) after 4 weeks of ubiquinone and increased from 0.9 to 4.3 microg/mL (P < 0.001) after 4 weeks of ubiquinol. Total CoQ10 /cholesterol ratio increased from 0.2 to 0.7 micromol/mmol after 4 weeks of ubiquinone and increased from 0.2 to 1.2 micromol/mmol after 4 weeks of ubiquinol. Both the increase in plasma CoQ10 and the increase in CoQ10 /cholesterol ratio were significantly better after ubiquinol (P < 0.005 and P < 0.001, respectively) than after ubiquinone indicating superior bioavailability. Plasma ubiquinol/total CoQ10 ratio increased from baseline during ubiquinol supplementation (P < 0.005) and remained unchanged after ubiquinone supplementation. No side effects were noted in this study.

Clin Pharmacol Drug Dev. 2014 Jan; 3(1): 13-17.

Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease.

OBJECTIVE: The purpose of this study was to investigate the effect of coenzyme Q10 supplementation on oxidative stress and antioxidant enzyme activity in patients with coronary artery disease (CAD). METHODS: This was an intervention study. Patients who were identified by cardiac catheterization as having at least 50% stenosis of one major coronary artery or receiving percutaneous transluminal coronary angioplasty (n = 51) were randomly assigned to the placebo group (n = 14) or one of the two coenzyme Q10-supplemented groups (60 mg/d, n = 19 [Q10-60 group]; 150 mg/d, n = 18 [Q10-150 group]). Intervention was administered for 12 wk. Patients’ blood samples were analyzed every 4 wk for plasma coenzyme Q10 concentrations, malondialdehyde (MDA), and antioxidant enzyme (catalase [CAT], superoxide dismutase [SOD], glutathione peroxidase) activity. RESULTS: Forty-three subjects with CAD completed intervention study. Plasma coenzyme Q10 concentration increased significantly after coenzyme the Q10-150 intervention (P < 0.01). The MDA levels were significantly lower than baseline in the Q10-150 group at week 4 (P = 0.03). The Q10-150 group had significantly lower MDA levels than the placebo group at week 8 (P = 0.03). With respect to antioxidant enzyme activity, subjects in the Q10-150 group had significantly higher CAT (P = 0.03) and SOD (P = 0.03) activity than the placebo group at week 12. The plasma coenzyme Q10 concentration was significantly correlated with MDA levels (r = -0.35, P = 0.02) and CAT (r = 0.43, P = 0.01) and SOD activity (r = 0.39, P = 0.01). The ratio of plasma coenzyme Q10 to total cholesterol was significantly correlated with SOD activity (r = 0.39, P = 0.02). The ratio of plasma coenzyme Q10 to low-density lipoprotein was significantly correlated with CAT (r = 0.35, P = 0.04) and SOD (r = 0.45, P = 0.01) activity. However, there was no relation between coenzyme Q10 concentration and glutathione peroxidase activity. CONCLUSION: Coenzyme Q10 supplements at a dose of 150 mg can decrease oxidative stress and increase antioxidant enzyme activity in patients with CAD. A higher dose of coenzyme Q10 supplements (>150 mg/d) might promote rapid and sustainable antioxidation in patients with CAD.

Nutrition. 2012 Mar; 28(3): 250-255.

Diabetes/Cardiovascular Disease Conferences

Current understanding of metformin effect on the control of hyperglycemia in diabetes.

Metformin is a first-line oral anti-diabetic agent that has been used clinically to treat patients with type 2 diabetes for over 60 years. Due to its efficacy in therapy and affordable price, metformin is taken by more than 150 million people each year. Metformin improves hyperglycemia mainly through the suppression of hepatic gluconeogenesis along with the improvement of insulin signaling. However, its mechanism of action remains partially understood and controversial, especially in regard to the role of AMPK in metformin’s action and the mechanism of AMPK activation. In this review, we discuss recent advances in the understanding of metformin’s suppression of hepatic glucose production and the mechanism related to the improvement of insulin signaling.

J Endocrinol. 2016 Mar; 228(3): R97-106.

Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.

BACKGROUND: The benefits of blood pressure lowering treatment for prevention of cardiovascular disease are well established. However, the extent to which these effects differ by baseline blood pressure, presence of comorbidities, or drug class is less clear. We therefore performed a systematic review and meta-analysis to clarify these differences. METHOD: For this systematic review and meta-analysis, we searched MEDLINE for large-scale blood pressure lowering trials, published between Jan 1, 1966, and July 7, 2015, and we searched the medical literature to identify trials up to Nov 9, 2015. All randomised controlled trials of blood pressure lowering treatment were eligible for inclusion if they included a minimum of 1,000 patient-years of follow-up in each study arm. No trials were excluded because of presence of baseline comorbidities, and trials of antihypertensive drugs for indications other than hypertension were eligible. We extracted summary-level data about study characteristics and the outcomes of major cardiovascular disease events, coronary heart disease, stroke, heart failure, renal failure, and all-cause mortality. We used inverse variance weighted fixed-effects meta-analyses to pool the estimates. RESULTS: We identified 123 studies with 613,815 participants for the tabular meta-analysis. Meta-regression analyses showed relative risk reductions proportional to the magnitude of the blood pressure reductions achieved. Every 10 mm Hg reduction in systolic blood pressure significantly reduced the risk of major cardiovascular disease events (relative risk [RR] 0.80, 95% CI 0.77-0.83), coronary heart disease (0.83, 0.78-0.88), stroke (0.73, 0.68-0.77), and heart failure (0.72, 0.67-0.78), which, in the populations studied, led to a significant 13% reduction in all-cause mortality (0.87, 0.84-0.91). However, the effect on renal failure was not significant (0.95, 0.84-1.07). Similar proportional risk reductions (per 10 mm Hg lower systolic blood pressure) were noted in trials with higher mean baseline systolic blood pressure and trials with lower mean baseline systolic blood pressure (all ptrend>0.05). There was no clear evidence that proportional risk reductions in major cardiovascular disease differed by baseline disease history, except for diabetes and chronic kidney disease, for which smaller, but significant, risk reductions were detected. beta blockers were inferior to other drugs for the prevention of major cardiovascular disease events, stroke, and renal failure. Calcium channel blockers were superior to other drugs for the prevention of stroke. For the prevention of heart failure, calcium channel blockers were inferior and diuretics were superior to other drug classes. Risk of bias was judged to be low for 113 trials and unclear for 10 trials. Heterogeneity for outcomes was low to moderate; the I(2) statistic for heterogeneity for major cardiovascular disease events was 41%, for coronary heart disease 25%, for stroke 26%, for heart failure 37%, for renal failure 28%, and for all-cause mortality 35%. INTERPRETATION: Blood pressure lowering significantly reduces vascular risk across various baseline blood pressure levels and comorbidities. Our results provide strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg and providing blood pressure lowering treatment to individuals with a history of cardiovascular disease, coronary heart disease, stroke, diabetes, heart failure, and chronic kidney disease. FUNDING: National Institute for Health Research and Oxford Martin School.

Lancet. 2016 Mar 5; 387(10022): 957-967.

Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality.

Obesity and type 2 diabetes are becoming increasingly prevalent worldwide, and both are associated with an increased incidence and mortality from many cancers. The metabolic abnormalities associated with type 2 diabetes develop many years before the onset of diabetes and, therefore, may be contributing to cancer risk before individuals are aware that they are at risk. Multiple factors potentially contribute to the progression of cancer in obesity and type 2 diabetes, including hyperinsulinemia and insulin-like growth factor I, hyperglycemia, dyslipidemia, adipokines and cytokines, and the gut microbiome. These metabolic changes may contribute directly or indirectly to cancer progression. Intentional weight loss may protect against cancer development, and therapies for diabetes may prove to be effective adjuvant agents in reducing cancer progression. In this review we discuss the current epidemiology, basic science, and clinical data that link obesity, diabetes, and cancer and how treating obesity and type 2 diabetes could also reduce cancer risk and improve outcomes.

Physiol Rev. 2015 Jul; 95(3): 727-748.

Premature myocardial infarction is strongly associated with increased levels of remnant cholesterol.

BACKGROUND: Remnant cholesterol has been defined as the cholesterol present in triglyceride-rich remnant lipoproteins. Elevated levels of remnant cholesterol have been associated with increased cardiovascular risk. Acute myocardial infarction (AMI) in very young individuals (</=40 years) represents a rare disease with a typical risk factor profile and a lipid phenotype that is characterized by a predominance of elevated triglyceride-rich lipoproteins. OBJECTIVE: The aim of this study was to investigate the role of remnant cholesterol in premature AMI. METHODS: We prospectively enrolled 302 patients into our multicenter case-control study comprising 102 consecutive myocardial infarction survivors (</=40 years) and 200 hospital controls. Myocardial infarction patients were frequency matched for age, gender, and center. Remnant cholesterol was calculated from standard lipid parameters. RESULTS: Remnant cholesterol was 1.7-fold higher in premature AMI patients compared with controls (61.1 +/- 36.8 vs 35.8 +/- 16.8 mg/dL; P < .001). Remnant cholesterol was the lipid fraction most strongly associated with premature myocardial infarction (odds ratio 3.87; 95% confidence interval 2.26-6.64; P < .001) for an increase of 1-standard deviation. This observation was independent from clinical risk factors and plasma lipid levels. CONCLUSIONS: Remnant cholesterol is strongly associated with premature myocardial infarction, can be easily calculated, and might serve as a new potent risk marker in this young patient population.

J Clin Lipidol. 2015 Nov-Dec; 9(6): 801-806.e801.

Aspects of Hyperglycemia Contribution to Arterial Stiffness and Cardiovascular Complications in Patients With Type 1 Diabetes.

Controlling the blood glucose level is of outmost importance for the prevention of the micro- and macrovascular diabetic complications observed in patients with type 1 diabetes (T1D). Although the pathogenesis behind the complex cascade of complications is far from solved, one possible mechanism could be a negative effect of glucose on the arteries resulting in a stiffening of the arteries and ultimately in vascular complications. Intriguingly, patients with T1D have been shown to suffer from premature arterial aging compared to nondiabetic subjects-an association that is even more evident in the presence of diabetic complications such as diabetic nephropathy. Arterial stiffness has in several patient populations been shown to independently predict cardiovascular disease. However, interventional studies aimed at attenuating arterial stiffness to reduce cardiovascular disease in T1D are yet to come. Moreover, most of the data on pharmacological treatments of arterial stiffening are directed toward pathophysiological pathways other than hyperglycemia. Interestingly, the sodium-glucose transport-2 (SGLT2) inhibitor empagliflozin was recently shown to reduce both blood pressure and arterial stiffness in patients with type 2 diabetes. Whether, these effects can also be replicated in patients with T1D is an intriguing question. Tight metabolic and antihypertensive control are still of central importance for the prevention and the treatment of diabetic complications. However, the need for a noninvasive intermediate marker to identify at risk patients for aggressive treatment is evident. One such tool might be arterial stiffness linking diabetes to increased cardiovascular risk. Future research efforts exploring large-scale databases will play a key role in the identification of other clinically useful markers.

J Diabetes Sci Technol. 2016 Mar 7.

Active workstation allows office workers to work efficiently while sitting and exercising moderately.

OBJECTIVE: To determine the effects of a moderate-intensity active workstation on time and error during simulated office work. METHODS: The aim of the study was to analyse simultaneous work and exercise for non-sedentary office workers. We monitored oxygen uptake, heart rate, sweating stains area, self-perceived effort, typing test time with typing error count and cognitive performance during 30 min of exercise with no cycling or cycling at 40 and 80 W. RESULTS: Compared baseline, we found increased physiological responses at 40 and 80 W, which corresponds to moderate physical activity (PA). Typing time significantly increased by 7.3% (p = 0.002) in C40W and also by 8.9% (p = 0.011) in C80W. Typing error count and cognitive performance were unchanged. CONCLUSIONS: Although moderate intensity exercise performed on cycling workstation during simulated office tasks increases working task execution time with, it has moderate effect size; however, it does not increase the error rate. Participants confirmed that such a working design is suitable for achieving the minimum standards for daily PA during work hours.

Appl Ergon. 2016 May; 54: 83-89.

A systematic review of standing and treadmill desks in the workplace.

OBJECTIVES: Standing and treadmill desks are intended to reduce the amount of time spent sitting in today’s otherwise sedentary office. Proponents of these desks suggest that health benefits may be acquired as standing desk use discourages long periods of sitting, which has been identified as an independent health risk factor. Our objectives were thus to analyze the evidence for standing and treadmill desk use in relation to physiological (chronic disease prevention and management) and psychological (worker productivity, well-being) outcomes. METHODS: A computer-assisted systematic search of Medline, PubMed, PsycINFO, SPORTDiscus, CINAHL, CENTRAL, and EMBASE databases was employed to identify all relevant articles related to standing and treadmill desk use. RESULTS: Treadmill desks led to the greatest improvement in physiological outcomes including postprandial glucose, HDL cholesterol, and anthropometrics, while standing desk use was associated with few physiological changes. Standing and treadmill desks both showed mixed results for improving psychological well-being with little impact on work performance. DISCUSSION: Standing and treadmill desks show some utility for breaking up sitting time and potentially improving select components of health. At present; however, there exist substantial evidence gaps to comprehensively evaluate the utility of each type of desk to enhance health benefits by reducing sedentary time.

Prev Med. 2015 Jan; 70: 50-58.

Associations of sitting behaviours with all-cause mortality over a 16-year follow-up: the Whitehall II study.

BACKGROUND: Sitting behaviours have been linked with increased risk of all-cause mortality independent of moderate to vigorous physical activity (MVPA). Previous studies have tended to examine single indicators of sitting or all sitting behaviours combined. This study aims to enhance the evidence base by examining the type-specific prospective associations of four different sitting behaviours as well as total sitting with the risk of all-cause mortality. METHODS: Participants (3,720 men and 1,412 women) from the Whitehall II cohort study who were free from cardiovascular disease provided information on weekly sitting time (at work, during leisure time, while watching TV, during leisure time excluding TV, and at work and during leisure time combined) and covariates in 1997-99. Cox proportional hazards models were used to investigate prospective associations between sitting time (h/week) and mortality risk. Follow-up was from date of measurement until (the earliest of) death, date of censor or July 31, 2014. RESULTS: Over 81 373 person-years of follow-up (mean follow-up time 15.7 +/- 2.2 years) a total of 450 deaths were recorded. No associations were observed between any of the five sitting indicators and mortality risk, either in unadjusted models or models adjusted for covariates including MVPA. CONCLUSIONS: Sitting time was not associated with all-cause mortality risk. The results of this study suggest that policy makers and clinicians should be cautious about placing emphasis on sitting behaviour as a risk factor for mortality that is distinct from the effect of physical activity.

Int J Epidemiol. 2015 Dec; 44(6): 1909-1916.

A perspective on vegetarian dietary patterns and risk of metabolic syndrome.

The vegetarian dietary pattern is traditionally a plant-based diet that includes fruits, vegetables, cereals, legumes, nuts, vegetable oils, soya, and possibly dairy products and/or eggs. Vegetarians and other populations who follow a plant-based dietary pattern enjoy longevity. Specifically, vegetarian dietary patterns have been associated with a lower risk for developing IHD, type 2 diabetes, hypertension, specific cancers, lower all-cause mortality and reduction in cause-specific mortality. The prevalence of the metabolic syndrome (MetS) in the USA is approximately 20% and is currently increasing in developing countries in line with the obesity epidemic. The health care costs associated with the MetS are on a magnitude of 1.6 overall compared with healthy individuals, which makes it an important public health problem. Current evidence from several cross-sectional and case-control studies shows an association between consumption of a vegetarian dietary pattern and a reduced prevalence or risk of developing the MetS. There is a need for further research to be conducted, particularly prospective cohort studies to evaluate the effect of vegetarian dietary patterns on reducing the incidence of the MetS and, clinical trials should be designed to explore vegetarian dietary patterns for the reversal of the MetS in high-risk populations. This research could contribute to reduce the societal and economic burdens associated with the disorder.

Br J Nutr. 2015 Apr; 113 Suppl 2: S136-143.


Cellular Senescence as the Causal Nexus of Aging.

In this paper we present cellular senescence as the ultimate driver of the aging process, as a “causal nexus” that bridges microscopic subcellular damage with the phenotypic, macroscopic effect of aging. It is important to understand how the various types of subcellular damage correlated with the aging process lead to the larger, visible effects of anatomical aging. While it has always been assumed that subcellular damage (cause) results in macroscopic aging (effect), the bridging link between the two has been hard to define. Here, we propose that this bridge, which we term the “causal nexus”, is in fact cellular senescence. The subcellular damage itself does not directly cause the visible signs of aging, but rather, as the damage accumulates and reaches a critical mass, cells cease to proliferate and acquire the deleterious “senescence-associated secretory phenotype” (SASP) which then leads to the macroscopic consequences of tissue breakdown to create the physiologically aged phenotype. Thus senescence is a precondition for anatomical aging, and this explains why aging is a gradual process that remains largely invisible during most of its progression. The subcellular damage includes shortening of telomeres, damage to mitochondria, aneuploidy, and DNA double-strand breaks triggered by various genetic, epigenetic, and environmental factors. Damage pathways acting in isolation or in concert converge at the causal nexus of cellular senescence. In each species some types of damage can be more causative than in others and operate at a variable pace; for example, telomere erosion appears to be a primary cause in human cells, whereas activation of tumor suppressor genes is more causative in rodents. Such species-specific mechanisms indicate that despite different initial causes, most of aging is traced to a single convergent causal nexus: senescence. The exception is in some invertebrate species that escape senescence, and in non-dividing cells such as neurons, where senescence still occurs, but results in the SASP rather than loss of proliferation plus SASP. Aging currently remains an inevitable endpoint for most biological organisms, but the field of cellular senescence is primed for a renaissance and as our understanding of aging is refined, strategies capable of decelerating the aging process will emerge.

Frontiers in Genetics. 2016 02/12

Specific roles of tocopherols and tocotrienols in seed longevity and germination tolerance to abiotic stress in transgenic rice.

Tocopherols and tocotrienols are lipophilic antioxidants that are abundant in plant seeds. Although their roles have been extensively studied, our understanding of their functions in rice seeds is still limited. In this study, on the basis of available RNAi rice plants constitutively silenced for homogentisate phytyltransferase (HPT) and tocopherol cyclase (TC), we developed transgenic plants that silenced homogentisate geranylgeranyl transferase (HGGT). All the RNAi plants showed significantly reduced germination percentages and a higher proportion of abnormal seedlings than the control plants, with HGGT transgenics showing the most severe phenotype. The accelerated aging phenotype corresponded well with the amount of H2O2 accumulated in the embryo, glucose level, and ion leakage, but not with the amount of O(2-) accumulated in the embryo and lipid hydroperoxides levels in these genotypes. Under abiotic stress conditions, HPT and TC transgenics showed lower germination percentage and seedling growth than HGGT transgenics, while HGGT transgenics showed almost the same status as the wild type. Therefore, we proposed that tocopherols in the germ may protect the embryo from reactive oxygen species under both accelerated aging and stress conditions, whereas tocotrienols in the pericarp may exclusively help in reducing the metabolic activity of the seed during accelerated aging.

Plant Sci. 2016 Mar; 244: 31-39.

Tocotrienol and cancer metastasis.

Tumor metastasis involves some of the most complex and dynamic processes in cancer, often leading to poor quality of life and inevitable death. The search for therapeutic compounds and treatment strategies to prevent and/or manage metastasis is the ultimate challenge to fight cancer. In the past two decades, research focus on vitamin E has had a shift from saturated tocopherols to unsaturated tocotrienols (T3). Despite sharing structural similarities with tocopherols, T3 strive to gain scientific prominence due to their anti-cancer effects. Recent studies have shed some light on the anti-metastatic properties of T3. In this review, the roles of T3 in each step of the metastatic process are discussed. During the invasion process, signaling pathways that regulate the extracellular matrix and tumor cell motility have been reported to be modulated by T3. Although studies on T3 and tumor cell migration are fairly limited, they were shown to play a vital role in the suppression of angiogenesis. Furthermore, the anti-inflammatory effect of T3 could be highly promising in the regulation of tumor microenvironment, which is crucial in supporting tumor growth in distant organs. (c) 2016 BioFactors, 42(2):149-162, 2016.

Biofactors. 2016 Mar-Apr; 42(2): 149-162.

Tocotrienol improves learning and memory deficit of aged rats.

To define whether tocotrienol (T-3) improves cognitive deficit during aging, effect of T-3 on learning and memory functions of aged rats was assessed. It was found that T-3 markedly counteracts the decline in learning and memory function in aged rats. Quantitative analysis of T-3 content in the rat brain showed that the aged rats fed T-3 mixture-supplemented diet revealed the transport of alpha- and gamma-T-3 to the brain. In contrast, normal young rats fed the same diet did not exhibit brain localization. Furthermore, the T-3 inhibited age-related decreases in the expression of certain blood brain barrier (BBB) proteins, including caludin-5, occludin and junctional adhesion molecule (JAM). It was found that the activation of the cellular proto-oncogene c-Src and extracellular signal-regulated protein kinase (ERK), in the mitogen-activated protein kinase (MAPK) cell signaling pathway for neuronal cell death, was markedly inhibited by T-3. These results may reveal that aging induces partial BBB disruption caused by oxidative stress, thereby enabling the transport of T-3 through the BBB to the central nervous system, whereupon neuronal protection may be mediated by inhibition of c-Src and/or ERK activation, resulting in an improvement in age-related cognitive deficits.

J Clin Biochem Nutr. 2016 Mar; 58(2): 114-121.

The Tocotrienol-Rich Fraction Is Superior to Tocopherol in Promoting Myogenic Differentiation in the Prevention of Replicative Senescence of Myoblasts.

Aging results in a loss of muscle mass and strength. Myoblasts play an important role in maintaining muscle mass through regenerative processes, which are impaired during aging. Vitamin E potentially ameliorates age-related phenotypes. Hence, this study aimed to determine the effects of the tocotrienol-rich fraction (TRF) and alpha-tocopherol (ATF) in protecting myoblasts from replicative senescence and promoting myogenic differentiation. Primary human myoblasts were cultured into young and senescent stages and were then treated with TRF or ATF for 24 h, followed by an analysis of cell proliferation, senescence biomarkers, cellular morphology and differentiation. Our data showed that replicative senescence impaired the normal regenerative processes of myoblasts, resulting in changes in cellular morphology, cell proliferation, senescence-associated beta-galactosidase (SA-beta-gal) expression, myogenic differentiation and myogenic regulatory factors (MRFs) expression. Treatment with both TRF and ATF was beneficial to senescent myoblasts in reclaiming the morphology of young cells, improved cell viability and decreased SA-beta-gal expression. However, only TRF treatment increased BrdU incorporation in senescent myoblasts, as well as promoted myogenic differentiation through the modulation of MRFs at the mRNA and protein levels. MYOD1 and MYOG gene expression and myogenin protein expression were modulated in the early phases of myogenic differentiation. In conclusion, the tocotrienol-rich fraction is superior to alpha-tocopherol in ameliorating replicative senescence-related aberration and promoting differentiation via modulation of MRFs expression, indicating vitamin E potential in modulating replicative senescence of myoblasts.

PLoS One. 2016 11(2): e0149265.

Pleiotropic Effects of Tocotrienols and Quercetin on Cellular Senescence: Introducing the Perspective of Senolytic Effects of Phytochemicals.

The possibility to target cellular senescence with natural bioactive substances open interesting therapeutic perspective in cancer and aging. Engaging senescence response is suggested as a key component for therapeutic intervention in the eradication of cancer. At the same time, delaying senescence or even promote death of accumulating apoptosis-resistant senescent cells is proposed as a strategy to prevent age related diseases. Although these two desired outcome present an intrinsic dichotomy, there are examples of promising natural compounds that appear to satisfy all the requirements to develop senescence- targeted health promoting nutraceuticals. Tocotrienols (T3s) and quercetin (QUE), albeit belonging to different phytochemical classes, display similar and promising effects “in vitro” when tested in normal and cancer cells. Both compounds have been shown to induce senescence and promote apoptosis in a multitude of cancer lines. Conversely, they display senescence delaying activity in primary cells and rejuvenating effects in senescent cells. More recently, QUE has been shown to display senolytic effects in some primary senescent cells, likely as a consequence of its inhibitory effects on specific anti-apoptotic genes (i.e. PI3K and other kinases). Senolytic activity has not been tested for T3s but part of metabolic and apoptotic pathways affected by these compounds in cancer cells overlap with those of QUE. This suggests that the rejuvenating effects of T3s and QUE on pre-senescent and senescent primary cells might be the net results of a senolytic activity on senescent cells and a selective survival of a sub-population of non-senescent cells in the culture. The meaning of this hypothesis in the context of adjuvant therapy of cancer and preventive anti-aging strategies with QUE or T3s is discussed.

Curr Drug Targets. 2016 17(4): 447-459.

Estrogen receptor-mediated effect of delta-tocotrienol prevents neurotoxicity and motor deficit in the MPTP mouse model of Parkinson’s disease.

Neuroprotection following signal transduction has been investigated recently as a strategy for Parkinson’s disease (PD) therapy. While oxidative stress is important in the pathogenesis of PD, neuroprotection using antioxidants such as alpha-tocopherol have not been successful. delta-tocotrienol (deltaT3), a member of the vitamin E family, has received attention because of activities other than its antioxidative effects. In the present study, we examined the estrogen receptor-beta (ERbeta)-mediated neuroprotective effects of deltaT3 in a mouse model of PD. ERbeta is expressed in neuronal cells, including dopaminergic neurons in the substantia nigra. Daily forced oral administration of deltaT3 inhibited the loss of dopaminergic neurons in the substantia nigra. In addition, the ER inhibitor tamoxifen canceled the neuroprotective effects of deltaT3. Moreover, deltaT3 administration improved the performance of the PD mice in the wheel running activity, while tamoxifen inhibited this improved performance. These results suggest that the oral administration of deltaT3 may be useful in the treatment of PD patients, and ERbeta may be a candidate target for the neuroprotection activity of deltaT3.

Neurosci Lett. 2016 Jan 1; 610: 117-122.

Vitamin E therapy beyond cancer: Tocopherol versus tocotrienol.

The discovery of vitamin E (alpha-tocopherol) began in 1922 as a vital component required in reproduction. Today, there are eight naturally occurring vitamin E isoforms, namely alpha-, beta-, gamma- and delta-tocopherol and alpha-, beta, gamma- and delta-tocotrienol. Vitamin E is potent antioxidants, capable of neutralizing free radicals directly by donating hydrogen from its chromanol ring. alpha-Tocopherol is regarded the dominant form in vitamin E as the alpha-tocopherol transfer protein in the liver binds mainly alpha-tocopherol, thus preventing its degradation. That contributed to the oversight of tocotrienols and resulted in less than 3% of all vitamin E publications studying tocotrienols. Nevertheless, tocotrienols have been shown to possess superior antioxidant and anti-inflammatory properties over alpha-tocopherol. In particular, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase to lower cholesterol, attenuating inflammation via downregulation of transcription factor NF-kappaB activation, and potent radioprotectant against radiation damage are some properties unique to tocotrienols, not tocopherols. Aside from cancer, vitamin E has also been shown protective in bone, cardiovascular, eye, nephrological and neurological diseases. In light of the different pharmacological properties of tocopherols and tocotrienols, it becomes critical to specify which vitamin E isoform(s) are being studied in any future vitamin E publications. This review provides an update on vitamin E therapeutic potentials, protective effects and modes of action beyond cancer, with comparison of tocopherols against tocotrienols. With the concerted efforts in synthesizing novel vitamin E analogs and clinical pharmacology of vitamin E, it is likely that certain vitamin E isoform(s) will be therapeutic agents against human diseases besides cancer.

Pharmacol Ther. 2016 Jun; 162: 152-169.

Blood Sugar

Fasting blood glucose and long-term prognosis of non-metastatic breast cancer: a cohort study.

High circulating glucose has been associated with increased risk of breast cancer (BC). There may also be a link between serum glucose and prognosis in women treated for BC. We assessed the effect of peridiagnostic fasting blood glucose and body mass index (BMI) on long-term BC prognosis. We retrospectively investigated 1,261 women diagnosed and treated for stage I-III BC at the National Cancer Institute, Milan, in 1996, 1999 and 2000. Data on blood tests and follow-up were obtained by linking electronic archives, with follow-up to end of 2009. Multivariate Cox modelling estimated hazard ratios (HR) with 95% confidence intervals (CI) for distant metastasis, recurrence and death (all causes) in relation to categorized peridiagnostic fasting blood glucose and BMI. Mediation analysis investigated whether blood glucose mediated the BMI-breast cancer prognosis association. The risks of distant metastasis were significantly higher for all other quintiles compared to the lowest glucose quintile (reference <87 mg/dL) (respective HRs: 1.99 95% CI 1.23-3.24, 1.85 95% CI 1.14-3.0, 1.73 95% CI 1.07-2.8, and 1.91 95% CI 1.15-3.17). The risk of recurrence was significantly higher for all other glucose quintiles compared to the first. The risk of death was significantly higher than reference in the second, fourth and fifth quintiles. Women with BMI >/= 25 kg/m(2) had significantly greater risks of recurrence and distant metastasis than those with BMI < 25 kg/m(2), irrespective of blood glucose. The increased risks remained invariant over a median follow-up of 9.5 years. Mediation analysis indicated that glucose and BMI had independent effects on BC prognosis. Peridiagnostic high fasting glucose and obesity predict worsened short- and long-term outcomes in BC patients. Maintaining healthy blood glucose levels and normal weight may improve prognosis.

Breast Cancer Res Treat. 2013 Apr; 138(3): 951-959.

Pleiotropic effects of thiazolidinediones: implications for the treatment of patients with type 2 diabetes mellitus.

Thiazolidinediones (TZDs) are insulin-sensitizing antidiabetes agents that act through the peroxisome proliferator-activated receptor-gamma to cause a durable improvement in glycemic control in patients with type 2 diabetes mellitus. Although less well recognized, TZDs also exert a protective effect on beta-cell function. In addition to their beneficial effects on glucose homeostasis, TZDs-especially pioglitazone-exert a number of other pleiotropic effects that make them ideal agents as monotherapy or in combination with other oral agents, glucagon-like peptide-1 analogs, or insulin. Pioglitazone improves endothelial dysfunction, reduces blood pressure, corrects diabetic dyslipidemia, and reduces circulating levels of inflammatory cytokines and prothrombotic factors. Pioglitazone also redistributes fat and toxic lipid metabolites in muscle, liver, beta cells, and arteries, and deposits the fat in subcutaneous adipocytes where it cannot exert its lipotoxic effects. Consistent with these antiatherogenic effects, pioglitazone reduced major adverse cardiac event endpoints (ie, mortality, myocardial infarction, and stroke) in the Prospective Pioglitazone Clinical Trial in Macrovascular Events and in a meta-analysis of all other published pioglitazone trials. Pioglitazone also mobilizes fat out of the liver, improving liver function and histologic abnormalities in patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Pioglitazone also reduces proteinuria, all-cause mortality, and cardiovascular events in patients with type 2 diabetes mellitus with a reduced glomerular filtration rate. These benefits must be weighed against the side effects of the drug, including weight gain, fluid retention, atypical fractures, and, possibly, bladder cancer. When low doses of pioglitazone are used (eg, 7.5-30 mg/d) with gradual titration, and physician recognition of the potential side effects are applied, the risk-to-benefit ratio is very favorable. Despite having similar effects on glycemic control, pioglitazone and rosiglitazone appear to have different effects on cardiovascular outcomes. Rosiglitazone has been associated with an increased risk of myocardial infarction, and its use in the United States is restricted because of cardiovascular safety concerns.

Hosp Pract (1995). 2013 Apr; 41(2): 132-147.

Comparison of inhibitory activities and mechanisms of five mulberry plant bioactive components against alpha-glucosidase.

The alpha-glucosidase inhibitory effects of five bioactive components, namely 1-deoxynojirimycin, cyanidin-3-glucoside, cyanidin-3-rutinoside, resveratrol and oxyresveratrol contained in mulberry (Morus, Moraceae) plants have been compared. Spectroscopy methods were employed to compare their alpha-glucosidase inhibitory mechanisms. The results revealed that 1-deoxynojirimycin (competitive), resveratrol and oxyresveratrol (noncompetitive) were stronger inhibitors than acarbose, while cyanidin-3-glucoside and cyanidin-3-rutinoside (mix competitive and noncompetitive) showed modest activities. 1-Deoxynojirimycin, resveratrol and oxyresveratrol could quench the fluorescence spectra statically by forming stable complexes, while the quenching of cyanidin-3-rutinoside and cyanidin-3-glucoside belonged to dynamic quenching by the collision of molecules. The interactions between ligands and alpha-glucosidase were mainly driven by hydrophobic force, or hydrogen bonding consequently induced conformational changes and reduced surface hydrophobicity. Docking results suggested that they could bind to alpha-glucosidase at different sites. This work provides useful information for the understanding of the ligands-alpha-glucosidase interactions and identifies oxyresveratrol as a potent alpha-glucosidase inhibitor.

J Agric Food Chem. 2013 Aug 28; 61(34): 8110-8119.

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