Resveratrol-Induced Suppression of C-type Natriuretic Peptide Associates With Increased Vertebral Bone Density in Postmenopausal Women.

C-type natriuretic peptide (CNP) is a paracrine growth factor essential in driving endochondral bone growth in mammals including humans. Despite evidence from animal experiments and tissues that CNP signaling stimulates osteoblast proliferation and osteoclast activity, whether CNP participates in bone remodeling in the mature skeleton is unknown. Using stored plasma samples from a previous randomized controlled clinical trial (RESHAW) of resveratrol supplementation in postmenopausal women exhibiting mild osteopenia, we have studied changes in plasma aminoterminal proCNP (NTproCNP) and concurrent change in bone turnover markers of formation (osteocalcin [OC] and alkaline phosphatase [ALP]) and resorption (C-terminal telopeptide type 1 collagen [CTX]) with bone mineral density (BMD) over a 2-year period of study in 125 subjects. In year one, subjects received placebo or resveratrol, switching to resveratrol or placebo, respectively, in year two. Across all time points, there were no significant associations of NTproCNP with CTX, ALP, or OC. During year one, plasma NTproCNP declined significantly in both groups. In the crossover comparison, analysis of change within individuals showed that, compared with placebo, NTproCNP declined after resveratrol (p = 0.011) and ALP increased (p = 0.008), whereas CTX and OC were unchanged. Inverse association of NTproCNP (r = -0.31; p = 0.025) and positive association of OC (r = 0.32, p = 0.022) with BMD at the lumbar spine were identified after resveratrol but not found after placebo. Decline in NTproCNP was independently associated with resveratrol treatment. This is the first evidence that CNP is modulated during a period of increasing BMD in postmenopausal women. Further study of NTproCNP and associations with drivers of bone formation or resorption can be expected to clarify CNP's role during other interventions directed to bone health in adults. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A Randomised, Double-Blind, Placebo-Controlled Crossover Trial of Resveratrol Supplementation for Prophylaxis of Hormonal Migraine.

Resveratrol, a vasoactive phytoestrogen, has beneficial effects on cerebrovascular function. Previous research has shown that hormonal migraineurs have poorer cerebrovascular function than non-migraineur women. We aimed to investigate if resveratrol supplementation for three months could reduce the hormonal migraine burden index (HMBI: the number of days with menstrual migraine per month), reduce migraine-related disability and improve migraine-related quality of life. A randomised, double-blind, placebo-controlled, crossover, intervention trial was conducted in 62 hormonal migraineurs (mean age: 37.5 ± 0.8 years). Participants consumed 75 mg of resveratrol or matching placebo capsules twice daily for three months before crossing over to the other treatment arm. Participants completed a daily diary and the Headache Impact Test-6™, Migraine Disability Assessment and Migraine-Specific Quality of Life questionnaires at months 0, 3 and 6. The HMBI was the primary outcome and was calculated using data extracted from the participant's diary. No differences in the HMBI (p = 0.895), the Headache Impact Test-6™, the Migraine Disability Assessment and Migraine-Specific Quality of Life were found between the resveratrol and placebo treatments. Resveratrol supplementation for three months did not affect the HMBI, the migraine-related disability or quality of life measures in our cohort of hormonal migraineurs.

Long-term effects of resveratrol on cognition, cerebrovascular function and cardio-metabolic markers in postmenopausal women: A 24-month randomised, double-blind, placebo-controlled, crossover study.

Ageing and menopause contribute to endothelial dysfunction, causing impaired cerebral perfusion, which is in turn associated with accelerated cognitive decline. In a 14-week pilot study, we showed that supplementation with low-dose resveratrol, a phytoestrogen that can enhance endothelial function, improved cerebrovascular and cognitive functions in postmenopausal women. We sought to confirm these benefits in a larger, longer-term trial. A 24-month randomized, placebo-controlled crossover trial was undertaken in 125 postmenopausal women, aged 45-85 years, who took 75 mg trans-resveratrol or placebo twice-daily for 12 months and then crossover to the alternative treatment for another 12 months. We evaluated within individual differences between each treatment period in measures of cognition (primary outcome), cerebrovascular function in the middle cerebral artery (cerebral blood flow velocity: CBFV, cerebrovascular responsiveness: CVR) and cardio-metabolic markers as secondary outcomes. Subgroup analyses examined effects of resveratrol by life stages. Compared to placebo, resveratrol supplementation resulted a significant 33% improvement in overall cognitive performance (Cohen's d = 0.170, P = 0.005). Women ≥65 years of age showed a relative improvement in verbal memory with resveratrol compared to those younger than 65 years. Furthermore, resveratrol improved secondary outcomes including resting mean CBFV (d = 0.275, P = 0.001), CVR to hypercapnia (d = 0.307, P = 0.027), CVR to cognitive stimuli (d = 0.259, P = 0.032), fasting insulin (d = 0.174, P = 0.025) and insulin resistance index (d = 0.102, P = 0.034). Regular supplementation with low-dose resveratrol can enhance cognition, cerebrovascular function and insulin sensitivity in postmenopausal women. This may translate into a slowing of the accelerated cognitive decline due to ageing and menopause, especially in late-life women. Further studies are warranted to observe whether these cognitive benefits of resveratrol can reduce the risk of dementia.

Evaluation of Cognitive Performance following Fish-Oil and Curcumin Supplementation in Middle-Aged and Older Adults with Overweight or Obesity.

BACKGROUND: Obesity accelerates age-related cognitive decline, which is partly mediated by vascular dysfunction. OBJECTIVE: The aim was to test the hypothesis that supplementation with fish oil and curcumin can enhance cognitive performance by improving cerebral circulatory function in overweight or obese middle-aged to older adults. METHODS: In a 16-wk double-blind, placebo-controlled intervention trial, adults [50-80 y; BMI (kg/m2): 25-40] were randomly assigned to either fish oil (2000 mg/d DHA + 400 mg/d EPA), curcumin (160 mg/d), or a combination. Effects on cerebrovascular function (primary outcome) and cardiovascular risk factors were reported previously. Effects on cognitive performance and cerebrovascular responsiveness (CVR) to cognitive stimuli are reported herein. One-factor ANOVA with post hoc analyses was conducted between groups in the whole cohort and in males and females separately. Two-factor ANOVA was conducted to assess independent effects of fish oil and curcumin and a potential interaction. Correlations between outcomes (those obtained herein and previously reported) were also examined. RESULTS: Compared with placebo, fish oil improved CVR to a processing speed test (4.4% ± 1.9% vs. -2.2% ± 2.1%; P = 0.023) and processing speed in males only (Z-score: 0.6 ± 0.2 vs. 0.1 ± 0.2; P = 0.043). Changes in processing speed correlated inversely with changes in blood pressure (R = -0.243, P = 0.006) and C-reactive protein (R = -0.183, P = 0.046). Curcumin improved CVR in a working memory test (3.6% ± 1.2% vs. -0.2% ± 0.2%, P = 0.026) and, in males only, performance of a verbal memory test compared with placebo (Z-score: 0.2 ± 0.1 vs. -0.5 ± 0.2, P = 0.039). Combining fish oil with curcumin did not produce additional benefits. CONCLUSIONS: Improvements in processing speed following fish-oil supplementation in middle-aged to older males might be mediated by improvements in circulatory function. Mechanisms underlying the cognitive benefit seen with curcumin are unknown. As cognitive benefits were found in males only, further evaluation of sex differences in responsiveness to supplementation is warranted. This trial was registered at the Australian and New Zealand Clinical Trial Register at https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370788 as ACTRN12616000732482p.

An Exploratory Analysis of Changes in Mental Wellbeing Following Curcumin and Fish Oil Supplementation in Middle-Aged and Older Adults.

Curcumin has previously been shown to enhance mood in non-depressed older adults. However, observed benefits were limited to short-term supplementation (4 weeks). In a 16 week randomized, double-blind, placebo-controlled, 2 × 2 factorial design trial, we supplemented overweight or obese non-depressed adults (50-80 years) with curcumin (160 mg/day), fish oil (2000 mg docosahexaenoic acid +400 mg eicosapentaenoic acid/day), or a combination of both. Secondary outcomes included mental wellbeing measures (mood states and subjective memory complaints (SMCs)) and quality of life (QoL). Furthermore, plasma apolipoprotein E4 (APOE4) was measured to determine whether APOE4 status influences responses to fish oil. Curcumin improved vigour (p = 0.044) compared to placebo and reduced SMCs compared to no curcumin treatment (p = 0.038). Fish oil did not affect any mood states, SMCs or QoL; however, responses to fish oil were affected by APOE4 status. In APOE4 non-carriers, fish oil increased vigour (p = 0.030) and reduced total mood disturbances (p = 0.048) compared to placebo. Improvements in mental wellbeing were correlated with increased QoL. Combining curcumin with fish oil did not result in additive effects. This exploratory analysis indicates that regular supplementation with either curcumin or fish oil (limited to APOE4 non-carriers) has the potential to improve some aspects of mental wellbeing in association with better QoL.

Fish oil supplementation reduces osteoarthritis-specific pain in older adults with overweight/obesity.

OBJECTIVES: OA is a leading cause of chronic pain and disability. Next to inflammation, vascular pathology has been hypothesized to play a role in its aetiology and progression. Owing to side effects and the low efficacy of pharmacological treatments, dietary supplements are popular as alternative treatments, but evidence of efficacy is limited. We tested whether fish oil and curcumin supplementation can reduce chronic pain and OA burden in older adults. METHODS: A 16-week randomized, double-blind, placebo-controlled, 2 × 2 factorial design supplementation trial with fish oil (2000 mg/day docosahexaenoic acid + 400 mg/day eicosapentaenoic acid), curcumin (160 mg/day) or a combination of both was undertaken in sedentary overweight/obese older adults. Secondary outcomes included treatment-induced changes in self-reported chronic pain and OA burden and whether changes were related to changes in small artery elasticity (surrogate marker for microvascular function), CRP (inflammatory marker) and well-being. RESULTS: The majority of participants (131 of 152) reported chronic pain, which was predominantly OA specific. Fish oil significantly reduced OA-specific pain (P = 0.002, Cohen's d = 0.56) and burden (P = 0.015, Cohen's d = 0.45) compared with no fish oil treatment; reductions were correlated with improvements in microvascular function and well-being. Curcumin, alone or in combination with fish oil, did not reduce pain measures. CONCLUSION: Our findings indicate potential for fish oil to alleviate OA pain and burden in overweight/obese older adults. Further investigations should be undertaken in patients with clinically diagnosed OA to evaluate fish oil alone and as an adjunct to conventional pharmacotherapy and to investigate underlying mechanisms. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370788, ACTRN12616000732482p.

Long-term resveratrol supplementation improves pain perception, menopausal symptoms, and overall well-being in postmenopausal women: findings from a 24-month randomized, controlled, crossover trial.

OBJECTIVE: Following concerns about hormone therapy, postmenopausal women need alternative options to manage menopause-related symptoms and improve their well-being. A 14-week pilot study has shown that supplementation with resveratrol, a phytoestrogen with circulatory benefits, can improve aspects of well-being including chronic pain, which is a common complaint in postmenopausal women. We aimed to confirm these benefits in a larger, long-term study. METHODS: The Resveratrol for Healthy Ageing in Women study, a 24-month randomized, double-blind, placebo-controlled, two-period crossover intervention trial of resveratrol supplementation (75 mg BID) was conducted in 125 healthy postmenopausal women to evaluate effects on cognitive performance (results published elsewhere). Aspects of well-being including pain perception, mood and depressive symptoms, menopausal symptoms, sleep quality, and quality of life were assessed with questionnaires as secondary outcomes of the study. Cerebrovascular responsiveness to hypercapnia was measured as a surrogate marker of cerebrovascular function. RESULTS: Resveratrol supplementation reduced composite pain score (P < 0.001), especially in overweight individuals; this was associated with improvements in cerebrovascular responsiveness to hypercapnia (R = -0.329, P = 0.014). Somatic menopausal symptoms (P = 0.024) and general well-being (P = 0.010) were also improved after resveratrol supplementation. CONCLUSIONS: These results confirm the pilot study finding that resveratrol supplementation can reduce chronic pain in age-related osteoarthritis and improve menopause-related quality of life in postmenopausal women. These improvements are sustained by supplementation for at least 12 months and are associated with enhancement of circulatory function. CLINICAL TRIAL REGISTRATION: ACTRN12616000679482p.

Video Summary:http://links.lww.com/MENO/A638.

Regular Supplementation With Resveratrol Improves Bone Mineral Density in Postmenopausal Women: A Randomized, Placebo-Controlled Trial.

Resveratrol, a naturally occurring polyphenol in red grapes and berries, can act as a phytoestrogen. It has been shown to improve both systemic and cerebral circulatory functions, possibly through activation of endothelial estrogen receptors. in vitro and in vivo studies in rodent models also indicate a bone-protective role for resveratrol, particularly in ovariectomized rat models that mimic postmenopausal osteoporosis caused by estrogen deficiency. Hypothesizing a circulatory benefit of resveratrol in bone tissue, we investigated whether resveratrol supplementation could improve bone health in postmenopausal women. The Resveratrol for Healthy Aging in Women (RESHAW) trial was a 24-month randomized, double-blind, placebo-controlled, two-period crossover intervention conducted to evaluate the effects of resveratrol (75 mg twice daily) on cognition, cerebrovascular function, bone health, cardiometabolic markers, and well-being in postmenopausal women. After 12 months of supplementation with resveratrol versus placebo, there were positive effects on bone density in the lumbar spine (+0.016 ± 0.003 g/cm2 ) and neck of femur (+0.005 ± 0.002 g/cm2 ), which were accompanied by a 7.24% reduction in C-terminal telopeptide type-1 collagen levels, a bone resorption marker, compared with placebo. The increase in bone mineral density in the femoral neck resulted in an improvement in T-score (+0.070 ± 0.018) and a reduction in the 10-year probability of major and hip fracture risk. The magnitude of improvement was higher in women with poor bone health biomarker status. Importantly, the improvement in femoral neck T-score with resveratrol correlated with improvement in perfusion. Our subanalysis also revealed that the bone-protective benefit of resveratrol was greater in participants who supplemented with vitamin D plus calcium. Regular supplementation with 75 mg of resveratrol twice daily has the potential to slow bone loss in the lumbar spine and femoral neck, common fracture sites in postmenopausal women without overt osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Effects of fish oil and curcumin supplementation on cerebrovascular function in older adults: A randomized controlled trial.

BACKGROUND AND AIMS: Chronic conditions such as obesity, which contribute to endothelial dysfunction in older adults, can cause impairments in cerebrovascular perfusion, which is associated with accelerated cognitive decline. Supplementing the diet with bioactive nutrients that can enhance endothelial function, such as fish oil or curcumin, may help to counteract cerebrovascular dysfunction. METHODS AND RESULTS: A 16-week double-blind, randomized placebo-controlled trial was undertaken in 152 older sedentary overweight/obese adults (50-80 years, body mass index: 25-40 kg/m2) to investigate effects of fish oil (2000 mg docosahexaenoic acid + 400 mg eicosapentaenoic acid/day), curcumin (160 mg/day) or a combination of both on cerebrovascular function (measured by Transcranial Doppler ultrasound), systemic vascular function (blood pressure, heart rate and arterial compliance) and cardiometabolic (fasting glucose and blood lipids) and inflammatory (C-reactive protein) biomarkers. The primary outcome, cerebrovascular responsiveness to hypercapnia, was not affected by the interventions. However, cerebral artery stiffness was significantly reduced in males following fish oil supplementation (P = 0.007). Furthermore, fish oil reduced heart rate (P = 0.038) and serum triglycerides (P = 0.006) and increased HDL cholesterol (P = 0.002). Curcumin did not significantly affect these outcomes either alone or in combination with fish oil. CONCLUSION: Regular supplementation with fish oil but not curcumin improved biomarkers of cardiovascular and cerebrovascular function. The combined supplementation did not result in additional benefits. Further studies are warranted to identify an efficacious curcumin dose and to characterize (in terms of sex, BMI, cardiovascular and metabolic risk factors) populations whose cerebrovascular and cognitive functions might benefit from either intervention. CLINICAL TRIAL REGISTRATION: ACTRN12616000732482p.

Postmenopausal health interventions: Time to move on from the Women's Health Initiative?

Menopause is a critical period during which, without timely interventions, increased risks of cardiovascular and metabolic diseases, osteoporosis, sexual dysfunction and premature cognitive decline will contribute to diminished quality-of-life in women. Hormone therapy (HT) used to be the standard of care for managing vasomotor symptoms and prevention of chronic diseases until publication of the Women's Health Initiative (WHI) in 2002. Concerned about risks highlighted in WHI publications, many symptomatic women promptly ceased HT which resulted in increased vasomotor symptoms, osteoporosis-related-fractures and insomnia. Data from post-hoc WHI analyses and newer clinical trials consistently show reductions in coronary heart disease and mortality when estrogen therapy is initiated soon after menopause, whereas administration in later years and/or in combination with progesterone carries increased risks. However, no validated primary preventive strategies are available for younger postmenopausal women (<60 years), highlighting the need to re-evaluate the use of estrogen alone for which the risk-benefit balance appears positive. In contrast, in older women (>60 years), risks associated with oral HT exceed benefits; however transdermal estrogen may offer a safer alternative and should be further evaluated. Alternative therapies such as phytoestrogens and non-hormonal prescriptions may be beneficial for older women or those who are unsuitable for HT. Long-term head-to-head comparisons of HT with alternative interventions are warranted to confirm their efficacy for chronic disease prevention.

Effects of Long Chain Omega-3 Polyunsaturated Fatty Acids on Brain Function in Mildly Hypertensive Older Adults.

Purported benefits of long chain omega-3 polyunsaturated fatty acid (LCn-3PUFA) for brain function may be attributable, at least in part, to improved cerebral perfusion. A pilot randomised controlled trial was undertaken to investigate effects of taking a DHA-rich fish oil supplement for 20 weeks on cerebrovascular function, mood and cognitive performance. Borderline hypertensives aged 40⁻85 years with low habitual LCn-3PUFA intake took four capsules/day of EPAX (1600 mg DHA + 400 mg EPA) or placebo (corn oil). Cerebrovascular function was assessed at baseline and after 20 weeks in 38 completers (19 on each supplement) using transcranial Doppler ultrasound of blood flow in the middle cerebral artery at rest and whilst performing a battery of cognitive tasks (neurovascular coupling). The primary outcome, cerebrovascular responsiveness (CVR) to hypercapnia, increased 26% (p = 0.024) in women; there was no change in men. In contrast, neurovascular coupling increased significantly (p = 0.01 for the overall response) in men only; the latter correlated with an increase of EPA in erythrocytes (r = 0.616, p = 0.002). There was no associated improvement of mood or cognition in either men or women. These preliminary observations indicate that LCn-3PUFA supplementation has the potential to enhance blood flow in the brain in response to both hypercapnic and cognitive stimuli. Future studies should examine differential effects of EPA and DHA and take account of the gender differences in responsiveness to supplementation.

Can Curcumin Counteract Cognitive Decline? Clinical Trial Evidence and Rationale for Combining ω-3 Fatty Acids with Curcumin.

The rate of cognitive decline in the elderly is highly variable. One potential factor contributing to accelerated cognitive decline is chronic systemic inflammation, because it has been linked to cognitive impairment and increased dementia risk. Certain lifestyle factors, such as excess body weight and sedentary behavior, can exacerbate a proinflammatory state in older adults, resulting in chronic low-grade inflammation. Supplementing the diet with curcumin, an anti-inflammatory polyphenolic compound from the curry spice turmeric, is a potential approach to prevent accelerated cognitive decline by counteracting chronic inflammatory processes. Although the anti-inflammatory effects of curcumin are well established, the potential cognitive benefits of curcumin were discovered more recently. Several animal and epidemiologic studies on the effect of curcumin supplementation on cognition showed promising results; however, randomized controlled trials in humans are limited. In this review, we identified 5 randomized controlled trials, of which only 2 observed a beneficial effect of curcumin supplementation on cognition by improving working memory. By critically examining the methodologies of those studies, we identified some limitations, one of which is that none of the studies explored the possibility that anti-inflammatory mechanisms were mediating cognitive benefits (i.e., no study tested participants with low-grade inflammation or measured inflammatory biomarkers). Other factors influencing the likelihood of conclusive outcomes include choice of study population (cognitively unimpaired compared with impaired), study duration, curcumin dose and its bioavailability, and neurocognitive test battery. On the basis of these findings, we offer recommendations for future studies to examine the potential cognitive benefits of curcumin in humans, which include evaluating its effects on cerebral endothelial vasodilator function and boosting its cognitive effects by combining it with long-chain omega-3 (n-3) fatty acids.

Long Chain Omega-3 Polyunsaturated Fatty Acid Supplementation Protects Against Adriamycin and Cyclophosphamide Chemotherapy-Induced Bone Marrow Damage in Female Rats.

Although bone marrow and bone toxicities have been reported in breast cancer survivors, preventative strategies are yet to be developed. Clinical studies suggest consumption of long chain omega-3 polyunsaturated fatty acids (LCn3PUFA) can attenuate age-related bone loss, and recent animal studies also revealed benefits of LCn3PUFA in alleviating bone marrow and bone toxicities associated with methotrexate chemotherapy. Using a female rat model for one of the most commonly used anthracycline-containing breast cancer chemotherapy regimens (adriamycin + cyclophosphamide) (AC) chemotherapy, this study investigated potential effects of daily LCn3PUFA consumption in preserving bone marrow and bone microenvironment during chemotherapy. AC treatment for four cycles significantly reduced bone marrow cellularity and increased marrow adipocyte contents. It increased trabecular bone separation but no obvious changes in bone volume or bone cell densities. LCn3PUFA supplementation (375 mg/100 g/day) attenuated AC-induced bone marrow cell depletion and marrow adiposity. It also partially attenuated AC-induced increases in trabecular bone separation and the cell sizes and nuclear numbers of osteoclasts formed ex vivo from bone marrow cells isolated from AC-treated rats. This study suggests that LCn3PUFA supplementation may have beneficial effects in preventing bone marrow damage and partially protecting the bone during AC cancer chemotherapy.

Does phytoestrogen supplementation improve cognition in humans? A systematic review.

Recent evidence indicates that resveratrol, a phytoestrogen, can improve cognitive function in postmenopausal women by enhancing cerebral vasodilator responsiveness. We examine the effects of phytoestrogen supplementation on cognition and compare resveratrol with other phytoestrogens. Databases were searched for reports of randomized controlled trials (RCTs) containing terms describing phytoestrogens together with terms relating to cognition. Effect sizes were determined for changes in cognition. We identified 23 RCTs, 15 with isoflavone and eight with resveratrol or grape formulations. Six soy isoflavone studies showed positive cognitive effects of medium size. Greater benefits were seen in women who were <10 years postmenopausal and supplemented for <6 months. Small-to-medium effect-size cognitive benefits of resveratrol were seen in four studies of older adults of mixed gender and in postmenopausal women who took 150-200 mg resveratrol daily for at least 14 weeks. No benefits were seen in three studies using red clover or grape formulations. Supplementation with either soy isoflavone or resveratrol improved executive function and memory domains of cognitively normal older adults in half of the included studies, mostly with medium effect sizes. The cognitive benefit of resveratrol was related to improved cerebral perfusion.

Childhood cancer chemotherapy-induced bone damage: pathobiology and protective effects of resveratrol and other nutraceuticals.

Intensive cancer chemotherapy causes significant bone loss, for which the mechanisms remain unclear and effective treatments are lacking. This is a significant issue particularly for childhood cancers, as the most common ones have a >75% cure rate following chemotherapy; there is an increasing population of survivors who live with chronic bone defects. Studies suggest that these defects are the result of reduced bone from increased marrow fat formation and increased bone resorption following chemotherapy. These changes probably result from altered expression/activation of regulatory molecules or pathways regulating skeletal cell formation and activity. Treatment with methotrexate, an antimetabolite commonly used in childhood oncology, has been shown to increase levels of proinflammatory/pro-osteoclastogenic cytokines (e.g., enhanced NF-κB activation), leading to increased osteoclast formation and bone resorption, as well as to attenuate Wnt signaling, leading to both decreased bone and increased marrow fat formation. In recent years, understanding the mechanisms of action and potential health benefits of selected nutraceuticals, including resveratrol, genistein, icariin, and inflammatory fatty acids, has led to preclinical studies that, in some cases, indicate efficacy in reducing chemotherapy-induced bone defects. We summarize the supporting evidence.

Effects of Long-Chain Omega-3 Polyunsaturated Fatty Acids on Endothelial Vasodilator Function and Cognition-Are They Interrelated?

Long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFA) may improve brain functions by acting on endothelial cells in the cerebrovasculature to facilitate vasodilatation and perfusion. The aim of this review is to explore this hypothesis by analyzing the effect of LCn-3 PUFA supplementation on systemic vasodilator and cognitive function and finding evidence to link LCn-3 PUFA intake, vasodilator function and cognition. Forty randomized controlled trials examining the effect of LCn-3 PUFA supplementation in humans on either endothelial vasodilator function or cognition were identified and pooled effects measured with a weighted analysis. Compared to placebo, LCn-3 PUFA tended to increase flow-mediated dilatation and significantly improved cognitive function. Emerging evidence links vasodilator dysfunction to cognitive impairment, but evidence that LCn-3 PUFA can improve cognition through enhancements of vasodilator function is still lacking. Further research is needed to determine: (1) whether LCn-3 PUFA can enhance dilatation of cerebral vessels; (2) if improvements in cerebrovascular responsiveness by LCn-3 PUFA are accompanied by cognitive benefits; and (3) the target population groups.

Effects of Resveratrol Supplementation on Methotrexate Chemotherapy-Induced Bone Loss.

Intensive cancer chemotherapy is known to cause bone defects, which currently lack treatments. This study investigated the effects of polyphenol resveratrol (RES) in preventing bone defects in rats caused by methotrexate (MTX), a commonly used antimetabolite in childhood oncology. Young rats received five daily MTX injections at 0.75 mg/kg/day. RES was orally gavaged daily for seven days prior to, and during, five-day MTX administration. MTX reduced growth plate thickness, primary spongiosa height, trabecular bone volume, increased marrow adipocyte density, and increased mRNA expression of the osteogenic, adipogenic, and osteoclastogenic factors in the tibial bone. RES at 10 mg/kg was found not to affect bone health in normal rats, but to aggravate the bone damage in MTX-treated rats. However, RES supplementation at 1 mg/kg preserved the growth plate, primary spongiosa, bone volume, and lowered the adipocyte density. It maintained expression of genes involved in osteogenesis and decreased expression of adipogenic and osteoclastogenic factors. RES suppressed osteoclast formation ex vivo of bone marrow cells from the treated rats. These data suggest that MTX can enhance osteoclast and adipocyte formation and cause bone loss, and that RES supplementation at 1 mg/kg may potentially prevent these bone defects.

Resveratrol supplementation reduces pain experience by postmenopausal women.

OBJECTIVE: Pain is a common complaint among postmenopausal women. It has been postulated that vascular dysfunction caused by estrogen decline at menopause plays a key role in the initiation and progression of degradative joint disease, namely age-related osteoarthritis. We evaluated whether supplementation with resveratrol, a phytoestrogen, could improve aspects of well-being such as chronic pain that is commonly experienced by postmenopausal women. METHODS: A 14-week randomized, double-blind, placebo-controlled intervention with trans-resveratrol (75 mg, twice daily) was conducted in 80 healthy postmenopausal women. Aspects of well-being, including pain, menopausal symptoms, sleep quality, depressive symptoms, mood states, and quality of life were assessed by Short form-36 at baseline and at the end of treatment. Rating scales were averaged to provide a composite score representing overall well-being. Cerebral vasodilator responsiveness to hypercapnia was also assessed as a surrogate marker for cerebrovascular function. RESULTS: Compared with placebo treatment, there was a significant reduction in pain and an improvement in total well-being after resveratrol supplementation. Both benefits, including measures of quality of life, correlated with improvements in cerebrovascular function. CONCLUSIONS: Our preliminary findings indicate potential for resveratrol treatment to reduce chronic pain in age-related osteoarthritis. Resveratrol consumption may also boost perceptions of well-being in postmenopausal women. Further investigation to elucidate underlying mechanisms is warranted.

Effects of Resveratrol on Cognitive Performance, Mood and Cerebrovascular Function in Post-Menopausal Women; A 14-Week Randomised Placebo-Controlled Intervention Trial.

We tested whether chronic supplementation with resveratrol (a phytoestrogen) could improve cerebrovascular function, cognition and mood in post-menopausal women. Eighty post-menopausal women aged 45-85 years were randomised to take trans-resveratrol or placebo for 14 weeks and the effects on cognitive performance, cerebral blood flow velocity and pulsatility index (a measure of arterial stiffness) in the middle cerebral artery (using transcranial Doppler ultrasound), and cerebrovascular responsiveness (CVR) to both cognitive testing and hypercapnia were assessed. Mood questionnaires were also administered. Compared to placebo, resveratrol elicited 17% increases in CVR to both hypercapnic (p = 0.010) and cognitive stimuli (p = 0.002). Significant improvements were observed in the performance of cognitive tasks in the domain of verbal memory (p = 0.041) and in overall cognitive performance (p = 0.020), which correlated with the increase in CVR (r = 0.327; p = 0.048). Mood tended to improve in multiple measures, although not significantly. These results indicate that regular consumption of a modest dose of resveratrol can enhance both cerebrovascular function and cognition in post-menopausal women, potentially reducing their heightened risk of accelerated cognitive decline and offering a promising therapeutic treatment for menopause-related cognitive decline.