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1.
Muscle Mass Changes After Daily Consumption of Protein Mix Supplemented With Vitamin D in Adults Over 50 Years of Age: Subgroup Analysis According to the Serum 25(OH)D Levels of a Randomized Controlled Trial.
Kang, Y, Kim, N, Lee, Y, An, X, Chung, YS, Park, YK
Clinical nutrition research. 2023;12(3):184-198
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Sarcopenia is an age-related decrease in muscle mass and strength and increases the risk of falls and death. Protein intake and vitamin D are important for the maintenance of muscle mass, and the amino acid leucine plays a role in the regulation of muscle protein turnover. The aim of this 12-week double-blind, randomised, placebo-controlled trial was to evaluate the efficacy of a supplement containing protein, vitamin D, leucine and calcium for maintaining muscle mass, strength and physical functioning in healthy Koreans aged 50-80 years. Increases in muscle mass were seen in those with low vitamin D levels (< 30 ng/ml) but not in those with higher vitamin D levels. No differences were observed in muscle strength and physical functioning. The authors concluded that a supplement containing protein, including high levels of leucine, vitamin D and calcium may be of benefit for muscle mass to middle-aged and older adults with low vitamin D levels.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Consider supplementing protein in combination with leucine, vitamin D and calcium in middle-aged or older adults with insufficient vitamin D levels for prevention of sarcopenia.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
- Sarcopenia increases the risk of falls and death
- Protein and vitamin D are important for maintaining muscle mass whilst leucine is involved in regulating muscle protein turnover
- The aim of this study was to evaluate the effects of a supplement containing protein, vitamin D, leucine and calcium on muscle mass, physical functioning, muscle strength, and physical ability in middle-aged and older adults.
Methods
- Double-blind, randomised, placebo-controlled trial, with a duration of 12 weeks. Included 120 healthy Koreans aged 50-80 years
- Participants were assigned to “insufficient” subgroup if vitamin D levels were <30ng/ml and to the “sufficient” subgroup if vitamin D was 30ng/ml or higher
- Intervention: 2.5g powder (containing 20g protein (90% milk/10% soya, incl. 3g leucine), 800 IU vitamin D, 300 mg calcium) mixed into beverage of choice twice a day. Control: isocaloric placebo powder
- Primary outcome: Muscle mass determined by dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA)
- Secondary outcomes: Muscle strength (femoral muscle and grip strength); physical functioning (short physical performance battery (SPPB), International Physical Activity Questionnaire (IPAQ)).
Results
- At baseline, age of participants in the “sufficient” intervention subgroup was higher than that of the “sufficient” control subgroup (p=0.02)
- Increase in vitamin D levels in intervention group relative to control group, in both sufficient and insufficient subgroups (difference in changes between groups 11.5 ng/ml and 13.9 ng/ml, respectively, both p=0.00)
- No difference in change in muscle index as measured by DXA between groups
- In the “insufficient” subgroup, BIA increases in muscle mass were seen when normalised by height (p=0.037) and weight (p=0.05)
- No differences in changes in physical functioning or muscle strength between groups.
Conclusion
- The authors conclude that a supplement containing protein, with high levels of leucine, vitamin D and calcium may be of benefit for muscle mass to middle-aged and older adults with insufficient vitamin D levels.
Clinical practice applications:
- Middle-aged and older adults with insufficient vitamin D levels may gain muscle mass through supplementation of protein, leucine, vitamin D and calcium
- Middle-age and older adults with sufficient vitamin D levels do not appear to benefit from the same intervention.
Considerations for future research:
- Longer-term studies may help identify whether increases in muscle mass lead to improved physical functioning over time
- A study combining supplementation and exercise may help identify additive or synergistic effects.
Abstract
UNLABELLED Early prevention of sarcopenia can be an important strategy for muscle maintenance, but most studies target subjects at slightly pre-sarcopenic state. Our previous paper describes the effect of protein supplements rich in leucine and vitamin D on muscle condition, and in this paper, we performed a sub-analysis to evaluate who benefitted the most in terms of improvement in muscle health. A 12-week randomized clinical trial of 120 healthy adults (aged 50 to 80) assigned to an intervention group (n = 60) or control group (n = 60) were analyzed. Subjects in the intervention group received, twice per day, a protein supplement containing (per serving) 800 IU of vitamin D, 20 g of protein (3 g of total leucine), 300 mg of calcium, 1.1 g of fat, and 2.5 g of carbohydrate. The subjects were classified into 'insufficient' and 'sufficient' groups at 25-hydroxyvitamin D (25[OH]D) value of 30 ng/mL. The skeletal muscle mass index normalized to the square of the skeletal muscle mass (SMM) height (kg/m2) increased significantly in the 'insufficient group' difference value of change between weeks 0 and 12 (Δ1.07 ± 2.20; p = 0.037). The SMM normalized by body weight (kg/kg, %) was higher, but not significantly, in the insufficient group (Δ0.38 ± 0.69; p = 0.050). For people with insufficient (serum 25[OH]D), supplemental intake of protein and vitamin D, calcium, and leucine and adequate energy intake increases muscle mass in middle-aged and older adults and would be likely to exert a beneficial effect on muscle health. TRIAL REGISTRATION Clinical Research Information Service Identifier: KCT0005111.
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2.
Effect of Vitamin D3 Supplementation on Acute Fracture Healing: A Phase II Screening Randomized Double-Blind Controlled Trial.
Slobogean, GP, Bzovsky, S, O'Hara, NN, Marchand, LS, Hannan, ZD, Demyanovich, HK, Connelly, DW, Adachi, JD, Thabane, L, Sprague, S
JBMR plus. 2023;7(1):e10705
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Almost half of all adult patients with fractures are vitamin D deficient. The aim of this double-blind, randomised, placebo-controlled trial was to evaluate the efficacy of different vitamin D regimens on the healing of acute tibia and femur fractures. 102 18-50-year-old patients were enrolled in the study and randomised to receive a) two high doses (150,000 IU) at time of injury and after 6 weeks, b) 4000 IU daily, c) 600 IU daily or d) placebo for 3 months. After 3 months, there were no statistically significant differences between the 3 intervention groups with respect to clinical or radiographic outcomes of fracture healing. The authors report a significantly better clinical, but not radiographic, outcome for 4000 IU per day versus placebo with a p-value of 0.15 (note: generally, to be considered statistically significant, p should be < 0.05). Similar results were observed after 12 months. There was no significant correlation between vitamin D levels and fracture healing. The authors concluded that high dose vitamin D may confer a modest benefit for fracture healing but that this requires confirmation from a larger clinical trial.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The evidence base for the use of vitamin D supplements in isolation to support fracture healing is weak.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
- Low levels of vitamin D can have negative effects on bone metabolism and healing of fractures
- Almost half of all adult fracture patients are vitamin D deficient
- The aim of this study was to evaluate the effectiveness of supplementing vitamin D3 (VD3) to improve tibia and femur fracture healing.
Methods
- Four-arm, double-blind, randomised, phase II screening, placebo-controlled trial
- 102 adult patients (aged 18-50 years) with a non-osteoporotic tibial or femoral shaft fracture were randomised into 1 of 4 treatment groups
- Just over half (56%) of participants were vitamin D3 deficient at baseline
- Intervention groups: 1) 150,000 IU VD3 loading dose at injury and at 6 weeks (high loading) plus daily placebo; 2) placebo loading doses plus 4000 IU VD3 daily (high dose); 3) placebo loading doses plus 600 IU VD3 daily (low dose); 4) placebo loading dose plus placebo daily
- Duration: 3 months intervention, further 9 months follow-up. Vitamin D levels were assessed at 6 weeks and 3 months.
Primary outcome measures at 3 months:
- Clinical assessment using the Function IndeX for Trauma (FIX-IT)
- Radiographic assessment using the Radiographic Union Score for Tibial fractures (RUST).
Secondary outcomes: as above at 6, 9 and 12 months.
Results at 3 months:
- No statistically significant difference between high loading and high dose, high and low dose or low dose and placebo for either clinical or radiological assessment (all p-values ≥0.4)
- Post-hoc analysis of any dose vs placebo showed no significant difference with either clinical or radiological assessment (all p-values ≥0.25)
- Post-hoc analysis of high dose vs placebo showed no significant difference for radiological assessment (p=0.76) whilst it was reported as statistically significant for clinical assessment with p=0.16, with a benefit of VD3 supplementation.
- Similar results were seen at 12 months with reported benefit of high dose VD3 for fracture healing with p=0.18
- Vitamin D levels improved in all 3 VD3 groups from baseline to 6 weeks
- There was no statistically significant correlation between fracture healing and vitamin D level.
Conclusion
The authors conclude that VD3 supplementation may be of modest benefit for fracture healing, but further, larger trials are needed to confirm this.
Clinical practice applications:
- When working with clients who present with a fracture, it should be noted that the evidence for benefit of vitamin D supplementation alone for fracture healing is weak.
Considerations for future research:
- Larger studies to increase the statistical power to detect smaller benefits are required
- Larger studies may also identify differences in potential benefits between patient populations with different baseline levels of vitamin D.
Abstract
Nearly half of adult fracture patients are vitamin D deficient (serum 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Many surgeons advocate prescribing vitamin D supplements to improve fracture healing outcomes; however, data supporting the effectiveness of vitamin D3 supplements to improve acute fracture healing are lacking. We tested the effectiveness of vitamin D3 supplementation for improving tibia and femur fracture healing. We conducted a single-center, double-blinded phase II screening randomized controlled trial with a 12-month follow-up. Patients aged 18-50 years receiving an intramedullary nail for a tibia or femoral shaft fracture were randomized 1:1:1:1 to receive (i) 150,000 IU loading dose vitamin D3 at injury and 6 weeks (n = 27); (ii) 4000 IU vitamin D3 daily (n = 24); (iii) 600 IU vitamin D3 daily (n = 24); or (iv) placebo (n = 27). Primary outcomes were clinical fracture healing (Function IndeX for Trauma [FIX-IT]) and radiographic fracture healing (Radiographic Union Score for Tibial fractures [RUST]) at 3 months. One hundred two patients with a mean age of 29 years (standard deviation 8) were randomized. The majority were male (69%), and 56% were vitamin D3 deficient at baseline. Ninety-nine patients completed the 3-month follow-up. In our prespecified comparisons, no clinically important or statistically significant differences were detected in RUST or FIX-IT scores between groups when measured at 3 months and over 12 months. However, in a post hoc comparison, high doses of vitamin D3 were associated with improved clinical fracture healing relative to placebo at 3 months (mean difference [MD] 0.90, 80% confidence interval [CI], 0.08 to 1.79; p = 0.16) and within 12 months (MD 0.89, 80% CI, 0.05 to 1.74; p = 0.18). The study was designed to identify potential evidence to support the effectiveness of vitamin D3 supplementation in improving acute fracture healing. Vitamin D3 supplementation, particularly high doses, might modestly improve acute tibia or femoral shaft fracture healing in healthy adults, but confirmatory studies are required. The Vita-Shock trial was awarded the Orthopaedic Trauma Association's (OTA) Bovill Award in 2020. This award is presented annually to the authors of the most outstanding OTA Annual Meeting scientific paper. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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3.
Effects of whey and soy protein supplementation on inflammatory cytokines in older adults: a systematic review and meta-analysis.
Prokopidis, K, Mazidi, M, Sankaranarayanan, R, Tajik, B, McArdle, A, Isanejad, M
The British journal of nutrition. 2023;129(5):759-770
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Reduced muscle mass and reduction in physical activity may lead to sarcopenia in older people. Age-related sarcopenia is associated with increased systemic low-grade inflammation and obesity. Protein supplementation is found to be beneficial in reducing circulating pro-inflammatory cytokines in old people. Previous research has shown that supplementation with isolated whey and soy protein reduces the levels of inflammatory cytokines in older adults. However, there is limited research on intact whey and soy protein supplementation in reducing age-related inflammation. This systematic review and meta-analysis investigated the effect of intact whey and soy protein on serum inflammatory markers such as C-reactive protein (CRP), Interleukin-6 (IL6) and TNF-α in older adults. The results of this meta-analysis show a significant reduction in circulating IL-6 and TNF-α levels after the supplementation with whey and soy protein. The addition of soy isoflavones resulted in a further decline in serum CRP levels. Subgroup analysis showed that the whey protein supplementation significantly improved sarcopenia and pre-frailty. Healthcare professionals can use the result of this systematic review and meta-analysis to understand the anti-inflammatory properties of intact whey and soy protein and soy isoflavones. However, further robust studies are required to assess the anti-inflammatory properties of whey and soy protein due to the high heterogeneity of included studies in this review.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Nutritional strategies such as whey and soy protein supplementation may be regarded as safe and effective to attenuate adverse changes in muscle mass with ageing, however need to be considered alongside individual dietary intake and health status.
- Consider optimising protein intake and quality of protein through diet as an alternative or first line strategy.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
- A decline in muscle mass and physical capacity, known as sarcopenia, may start in the fourth decade with accumulation of adiposity, resulting in elevated circulating proinflammatory cytokines.
- Systematic and local elevation of oxidative stress and reactive oxygen species accumulation may accelerate age-related muscle wasting, however may be mitigated with antioxidant nutrients.
- This SR and MA evaluated whey and soy proteins effects on interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) in older adults.
Methods
SR followed PRISMA guidelines, was registered on PROSPERO and included 31 RCT studies published in English between 2004-21. Intervention group received soy/whey supplements and comparator group received a placebo; circulating levels of CRP, IL-6 and/or TNF-α were assessed. MA used random-effects to calculate the pooled effects. Overall quality of evidence was rated as moderate.
Results
Males and females with a mean age 50 - 80 years were included.
Whey protein:
- IL-6 levels were reduced significantly (Number of studies (k) = 12, Mean Difference (MD): −0·79, 95 % Confidence Interval (CI): −1·15, −0·42, p< 0.01), however, high heterogeneity was observed (I2 = 96 %).
- Treatment duration ≤ 8 weeks showed a significant reduction in serum CRP (k = 4, MD: –0·30, 95 % CI: –0·39, –0·21, I2 = 0 %) compared with > 8 weeks (k = 6, MD: 0·13, 95 % CI: –0·13, 0·40, I2 = 9 %), whereas TNF-α and IL-6 remained unaltered.
- Individuals with sarcopenia and pre-frailty displayed a significant reduction of IL-6 (k = 3, MD: –0·98, 95 % CI: –1·56, –0·39, I2 = 0 %) but no benefits were observed for CRP or TNF.
Soy protein:
- There was a significant reduction in TNF-α (k = 6, MD: −0·16, 95 % CI: −0·26, p<0·05).
- The addition of isoflavones demonstrated a significant decrease in TNF-α (k = 5, MD: –0·20, 95 % CI: –0·31, –0·08, I2 = 34 %) but an increase in CRP (k = 7, MD: 0·53, 95 % CI: 0·12, 0·94), however high heterogeneity was observed in the latter (I2 = 91 %).
Conclusion
- The study found a significant reduction in IL-6 following whey protein with effects augmented in those with frailty and sarcopenia and a significant reduction in TNF-α following soy protein with effects augmented by additional soy isoflavones, possibly due to antioxidant effects.
Clinical practice applications:
- Consider whey and/or soy protein supplementation in older adults particularly those reported with pre-frailty and sarcopenia as an effective and safe strategy to attenuate low-grade inflammation and associated risks.
- Soy isoflavones may have additional antioxidant benefits for older adults although further research is needed to confirm this due to high heterogeneity found.
Considerations for future research:
Future research could:
- Evaluate other factors which influence the inflammatory profile such as nutrient density, vitamins and minerals supplementation and exercise.
- Include those with co-morbidities and healthy populations with placebo comparator groups.
- Evaluate dose and type of soy isoflavones on circulating inflammatory markers and the effect of combined whey and soy protein.
Abstract
BACKGROUND AND AIMS Low-grade inflammation is a mediator of muscle proteostasis. This study aimed to investigate the effects of isolated whey and soy proteins on inflammatory markers. METHODS We conducted a systematic literature search of randomised controlled trials (RCT) through MEDLINE, Web of Science, Scopus and Cochrane Library databases from inception until September 2021. To determine the effectiveness of isolated proteins on circulating levels of C-reactive protein (CRP), IL-6 and TNF-α, a meta-analysis using a random-effects model was used to calculate the pooled effects (CRD42021252603). RESULTS Thirty-one RCT met the inclusion criteria and were included in the systematic review and meta-analysis. A significant reduction of circulating IL-6 levels following whey protein [Mean Difference (MD): -0·79, 95 % CI: -1·15, -0·42, I2 = 96 %] and TNF-α levels following soy protein supplementation (MD: -0·16, 95 % CI: -0·26, -0·05, I2 = 68 %) was observed. The addition of soy isoflavones exerted a further decline in circulating TNF-α levels (MD: -0·20, 95 % CI: -0·31, -0·08, I2 = 34 %). According to subgroup analysis, whey protein led to a statistically significant decrease in circulating IL-6 levels in individuals with sarcopenia and pre-frailty (MD: -0·98, 95 % CI: -1·56, -0·39, I2 = 0 %). These findings may be dependent on participant characteristics and treatment duration. CONCLUSIONS These data support that whey and soy protein supplementation elicit anti-inflammatory effects by reducing circulating IL-6 and TNF-α levels, respectively. This effect may be enhanced by soy isoflavones and may be more prominent in individuals with sarcopenia.
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4.
Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial.
Katayoshi, T, Uehata, S, Nakashima, N, Nakajo, T, Kitajima, N, Kageyama, M, Tsuji-Naito, K
Scientific reports. 2023;13(1):2786
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Plain language summary
Nicotinamide adenine dinucleotide (NAD+) is a coenzyme that plays a crucial role in energy metabolism and different biological processes. Sirtuins (SIRT1) are NAD+-dependent deacetylases, an enzyme that plays a key role in enhancing metabolic efficiency. Nicotinamide mononucleotide (NMN) is a precursor to NAD+. NMN supplementation may help to reduce the risk of developing metabolic diseases and cardiovascular diseases. This randomised, double-blinded, and placebo-controlled, parallel trial investigated the effects of 12 weeks of 125 mg NMN supplementation on metabolic health parameters, including CVD risk factors, blood NAD+ metabolites level, and SIRT1 expression in middle-aged men and women. Serum nicotinamide was significantly higher and arterial stiffness was lower in the NMN test group of middle-aged men and women after 12 weeks of NMN supplementation. The results of the study indicate that the administration of 250mg of nicotinamide mononucleotide (NMN) daily for an extended period is considered safe and well-tolerated. Healthcare professionals can use this finding to understand the significant implications of the use of NMN as a potential therapeutic agent in individuals seeking to improve their metabolic and cardiovascular health. Further robust studies are required to evaluate the effects of NMN supplementation due to the limitations and high baseline variability between the participants of this study.
Expert Review
Conflicts of interest:
None
Take Home Message:
- As we age, NAM levels decline, which could have a negative effect on cardiovascular health.
- Middle-aged adults may like to consider NMN supplementation to improve NAM metabolism and arterial stiffness.
- However, without data on CVD events, it is difficult to determine actual risk reductions.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
- Nicotinamide adenine dinucleotide (NAD+) is a coenzyme involved in metabolism. When we age, NAD+ levels decline resulting in poorer metabolism and age-related disease such as cardiovascular disease (CVD). Nicotinamide mononucleotide (NMN) is a precursor in the biosynthesis of NAD+.
- This double-blind, randomised control trial aimed to determine the effect of supplementing NMN on NAD+ levels, CVD risk factors and sirtuin 1 (SIRT1) expression, which relies on NAD+ for adequate functioning.
Methods
- 36 healthy male and female individuals aged between 40-65 years of age were assigned to either NMN (125mg/day) or placebo for 12 weeks.
- One capsule was taken twice per day after meals.
- Serum nicotinamide (NAM), NAD+, NMN, advanced glycation end products (AGES), 8-hydroxydeoxyguanosine (8-OHdG) and SIRT1 mRNA expression were measured.
- The condition of blood vessels (arterial stiffness) was also assessed using the ankle brachial index (ABI).
- In a sub-analysis, individuals with hypertension, above average body mass index (BMI), or blood glucose level were also assessed for blood vessel condition using the ABI.
Results
- The results showed that from baseline serum NAM decreased in the placebo group (P=0.014), whereas it increased in the NMN group (P=0.006). This resulted in an increase in the NMN group compared to placebo (P=0.037).
- Interestingly serum NAM was lower in the NMN group compared to placebo at baseline (P=0.001).
- There was no statistically significant difference in ABI with NMN supplementation.
- Amongst those with hypertension there was also no change in ABI. However, those with high BMI or blood glucose, there was an improvement in vascular condition compared to placebo (P=<0.007 and P=0.019 respectively).
- 8-OHdG, SIRT1 mRNA and AGEs remained unchanged by NMN supplementation
Conclusion
- NMN supplementation enhanced NAD+ metabolism in middle-aged adults.
- It also relieved arterial stiffness and reduced CVD risk factors.
Clinical practice applications:
- Apparently healthy middle-aged adults who would like to activate NAD metabolism and decrease their risk for CVD, should consider 12-week supplementation with NMN (125mg/day).
- ABI should be monitored to ensure desired effects.
- It is unclear as to the effects of NMN supplementation after 12-weeks.
Considerations for future research:
- Future research should consider longer supplementation duration and/or adding in a follow-up period to determine duration of effect.
- Different supplemental doses should also be researched to determine an optimal dose.
Abstract
Many animal studies have shown that oral administration of the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) prevents the reduction of NAD+ levels in organs and tissues, helping alleviate aging-related diseases. However, there are very few clinical reports of NMN supplementation in humans. Thus, this study aimed to investigate the influence of a 12-week NMN oral supplementation on biochemical and metabolic health parameters. A 12-week randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD+ metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events. NMN safely and effectively elevated NAD+ metabolism in healthy middle-aged adults. Additionally, NMN supplementation showed potential in alleviating arterial stiffness.
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5.
Effect of Intermittent Fasting Diet on Glucose and Lipid Metabolism and Insulin Resistance in Patients with Impaired Glucose and Lipid Metabolism: A Systematic Review and Meta-Analysis.
Yuan, X, Wang, J, Yang, S, Gao, M, Cao, L, Li, X, Hong, D, Tian, S, Sun, C
International journal of endocrinology. 2022;2022:6999907
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The prevalence of obesity and metabolic syndrome may increase the risk of cardiovascular disease (CVD), diabetes, and neurological conditions. The imbalance in glucose and lipid metabolism and hypertension characterises the development of these chronic diseases. Intermittent fasting (IF) has been considered an effective dietary strategy for reducing the risk of obesity, insulin resistance, dyslipidaemia, diabetes, and CVD. This systematic review and meta-analysis include ten randomised controlled trials to evaluate the effects of IF intervention on glucose and lipid metabolism in people with metabolic syndrome. IF intervention regulated glucose metabolism by improving fasting blood glucose, glycosylated haemoglobin, insulin, and insulin resistance. IF intervention also positively impacted the body mass index and waist circumference. The total cholesterol, low-density lipoprotein levels, and triglyceride levels also improved, followed by the IF, showing the impact on lipid metabolism. Further robust studies are required due to heterogeneity between the included studies in type of IF, duration, the health status of participants, ethnicity, and outcome measurements. However, healthcare professionals can use the results of this systematic review and meta-analysis to understand the therapeutic effect of IF intervention on glycolipid metabolism in people with metabolic syndrome.
Expert Review
Conflicts of interest:
None
Take Home Message:
- IF does not require calorie restriction which may result in greater compliance
- IF does not restrict macronutrients such as CHO and fats, so may avoid the exclusion of key nutrients e.g. healthy fats and wholegrains.
- IF may have fewer adverse effects on daily routines and quality of life, which may mean adherence is easier.
- Improved glucose and lipid metabolism may prevent the development of chronic health conditions such as T2D, CVD and cancer.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Management of glucose and lipid metabolism can be achieved through weight reduction using dietary interventions such as very low calorie or CHO diets, which may be effective but difficult to sustain long term. An alternative approach for weight management, improved insulin resistance and subsequent prevention of comorbitities e.g. Type 2 Diabetes (T2D), Cardiovascular Disease (CVD) and cancer, is Intermittent Fasting (IF). such as time restricted or periodic fasting.
This study summarises the effects of IF dietary interventions lasting less than three months in overweight and obese women with Metabolic Syndrome, defined as the presence of any metabolic dysfunction including obesity, hyperglycaemia, dyslipidaemia or hypertension.
The meta-anlaysis was carried out following PRISMA guidelines. A literature search in PubMed and Medline using the keywords obesity/overweight, IF diet, metabolic syndrome, RCT’s and humans resulted in 10 studies with 12 types of intervention for analysis. The following outcomes were evaluated: glucose and lipid metabolism, insulin resistance, weight loss and blood pressure.
Results were analysed in R software using mean differences and 95% confidence intervals, and either random or fixed effects depending on the Cochrane’s Q and I(2) statistics. Funnel plots were inspected for potential bias and Egger’s regression tests for publication bias.
There were significant differences before and after the interventions for all glucose and lipid metabolism markers as well as body weight and systolic blood pressure :
Glucose metabolism:
- Fasting glucose reduced by 0.15mmol/L
- Insulin plasma reduced by 13.25uUI
- HbA1c reduced by 0.08%
- HOMA-IR (insulin resistance index) reduced by 0.31 on average
Lipid metabolism:
- Total cholesterol reduced by 0.32mmol/L
- LDL reduced by 0.22mmol/L
- Triglyceride reduced by 0.04mmol/L
Weight loss:
- Body weight reduced by 1.87kg
- BMI reduced by 0.8kg/m2
- Waist circumference reduced by 2.08cm
Blood pressure:
- Systolic reduced by 2.58mmHg
- Diastolic reduced by 3.12mmHg
Despite limitations of the meta-analysis, this study demonstrates IF has therapeutic effects on those with disordered lipid and glucose metabolism, and may prove to be an effective and sustainable approach.
Clinical practice applications:
- IF may be an effective alternative to restricted calorie or CHO diets for weight management with the associated benefits of glucose and lipid metabolism.
- IF has been shown to have therapeutic effects on individuals with impaired glucose and lipid metabolism.
- IF may be considered as a sustainable lifestyle choice rather than a ‘weight loss’ programme such as a very low calorie diet, which can result in poor quality of life and subsequent reduced adherence.
- Since it may take time for impaired glucose and lipid metabolism to progress to more serious disease states, establishing IF as an early intervention, may be considered as a prudent form of preventative medicine.
- IF has shown to have other health benefits such as reduced blood pressure and may be considered as adjuvant therapy.
Considerations for future research:
- Compares the effects of IF on different ethnicities, sex and age categories
- Evaluates the effect of IF on other disease states e.g. cancer, auto-immune conditions
- Assesses the response of other biomarkers e.g. inflammatory cytokines
- Compares different types and durations of IF on health biomarkers (eg periodic, time restricted)
Abstract
The question of whether or not intermittent fasting diets improve the clinical indicators of glycolipid metabolism remains unclear. This study systematically reviewed the relevant clinical trials to evaluate the effects of intermittent fasting diet on glucose and lipid metabolism and insulin sensitivity in patients with metabolic syndrome. To evaluate the effect of intermittent fasting diet intervention on patients with disorders of glucose and lipid metabolism, random-effect or fixed-effect meta-analysis models were used to calculate the average difference before and after intermittent fasting diet intervention and the corresponding 95% confidence intervals (CIs). After intermittent fasting diet intervention, in terms of glucose metabolism, fasting blood glucose reduced by 0.15 mmol/L (95% CI: -0.23; -0.06), glycosylated hemoglobin reduced by 0.08 (95% CIs: -0.25; -0.10), insulin plasma levels reduced by 13.25 uUI (95% CIs: -16.69; -9.82), and HOMA-IR decreased by 0.31 on an average (95% CIs: -0.44; -0.19). In addition, BMI decreased by 0.8 kg/m2 (95% CIs: -1.32; -0.28), body weight reduced by 1.87 kg (95% CIs: -2.67; -1.07), and the waist circumference decreased by 2.08 cm (95% CIs: -3.06; -1.10). Analysis of lipid metabolism showed that intermittent fasting diet intervention effectively reduced the total cholesterol level by 0.32 mmol/L (95% CIs: -0.60; -0.05), low-density lipoprotein level by 0.22 mmol/L (95% CIs: -0.37; -0.07), and triglyceride level by 0.04 mmol/L (95% CIs: -0.15; -0.07). Intermittent fasting diets have certain therapeutic effects on blood glucose and lipids in patients with metabolic syndrome and significantly improve insulin resistance. It may be considered as an auxiliary treatment to prevent the occurrence and development of chronic diseases.
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6.
Effects of Oat Beta-Glucan Intake on Lipid Profiles in Hypercholesterolemic Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Yu, J, Xia, J, Yang, C, Pan, D, Xu, D, Sun, G, Xia, H
Nutrients. 2022;14(10)
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Dyslipidaemia is one of the risk factors associated with cardiovascular disease. Beta-glucan is a viscous soluble fibre found in microalgae, fungi and grains like oats, barley, sorghum etc. This systematic review and meta-analysis included thirteen randomised controlled trials to evaluate the effectiveness of oat beta-glucans on the lipid profiles of patients with hypercholesterolemia. This research showed a significant reduction in total cholesterol and low-density lipoprotein levels in hypercholesterolemic adults after beta-glucan intake. However, beta-glucans did not impact triglyceride and high-density lipoprotein cholesterol. Beta-glucan's effect on lipid profiles depended on the severity of hypercholesterolemia, the duration of the intervention, the source of beta-glucan, and the dosage of beta-glucan. Healthcare professionals can use the results of this study to understand the lipid profile-improving effects of beta-glucans in adults with moderate hypercholesterolemia. However, further robust studies are required to evaluate the effects of beta-glucan on lipid profiles and how the effect is affected by gender differences.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Consumption of oat beta glucans may be beneficial for improving total cholesterol and LDL-c in people with mild and moderate hypercholesterolemia
- The U.S Food and Drug Administration (FDA) recommends 3g or more of oat beta glucans per day to reap the benefits. This could be from 90g of oats (3 x 30g portions) or 1 30g portion of oats, 3 oatcakes and 1-2 tbsp of oat bran.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Authors highlight that Hypercholesterolemia is a risk factor for cardiovascular disease and a symptom of Metabolic Syndrome. Hypercholesterolemia commonly includes; elevated levels of total cholesterol and low-density lipoprotein cholesterol (LDL-c) and lower levels of high-density lipoprotein cholesterol (HDL-c).
Conventional medical treatment for hypercholesterolemia is statins, however, statins can have a number of adverse side effects. For this reason, dietary interventions have been investigated including the use of oat beta-glucans for their potential lipid lowering effects.
The aim of this systematic review and meta-analysis was to synthesise and evaluate the evidence for the effects of oat beta-glucans on serum cholesterol and triglyceride (TG) levels in adults with hypercholesterolemia.
Thirteen randomised controlled trials (RCTs) published between 1999 – 2021 met the study inclusion criteria. These studies included a total population of 927 people aged between 38-76 years and from 7 different countries worldwide. The majority of participants were diagnosed with mild hypercholesterolemia.
Participants were randomised into an intervention group receiving dietary sources of oat beta-glucans or food with added oat beta-glucans or a placebo control group consisting of diets without beta-glucans.
Study lengths ranged from 3 to 8 weeks with doses of oat beta-glucans between 1.5g to 6g. The studies were also broken down into sub-groups for high and low doses of oat beta-glucan and mild and moderate hypercholesterolemia.
Baseline and endpoint cholesterol (total cholesterol C, HD-c & LDL-c) and triglycerides were used to assess the effectiveness of the interventions and a weighted mean difference (WMD) calculated with a 95% confidence interval (CI).
Key Findings:
- a reduction in total cholesterol (WMD = -0.24mmol/L; 95% CI)
- a reduction in LDL-c (WMD = -0.27mmol/L; 95% CI )
- Sub-groups found that oat beta-glucans reduced serum TG levels in patients with moderate hypercholesterolemia (WMD = -0.11 mmol/L; 95% CI) but not in cases of mild hypercholesterolemia. (WMD = -0.01 mmol/L; 95% CI)
- Higher daily doses of oat beta glucans had more positive effects on TG levels, however the results were not statistically significant in this meta-analysis
- <3g WMD -0.11 mmol/L; 95% CI: -0.13 to -0.08 mmol/L
- >3g WMD -0.00 mmol/L; 95% CI: -0.16 to -0.16 mmol/L
- Greater reductions in HDL -c were found in patients with moderate hypercholesterolemia (WMD-0.06 mmol/L; 95% CI; -0.07 to -0.05 mmol/L) compared to mild cases (WMD-0.01 mmol/L; 95% CI; -0.08 to -0.10 mmol/L).
Conclusion
Dietary intake of oat beta-glucans may support the reduction of total cholesterol and low density lipoprotein cholesterol, however, no significant changes were found for high density lipoprotein cholesterol or serum triglycerides. Due to the heterogeneity between studies and inconsistencies in results, more trials are needed with larger sample sizes and longer durations.
Notes: The authors reported no conflicts of interest.
Clinical practice applications:
Based on the pooled results of this meta-analysis:
- 1.5g -6g of dietary intake of oat beta-glucans could support a reduction of TC and LDL-c in cases of mild and moderate hypercholesterolemia
- Intake of oat beta glucans >3g may reduce TG levels
- HDl -c may be improved with oat beta glucan intake of between 1.5g to 6g for clients with moderate hypercholesterolemia.
Considerations for future research:
The findings of 8 of the 13 RCTs indicated that when compared to the control group, LDL-c could be lowered by oat beta-glucans whilst the other 5 trials did not. However, the cumulative results of this meta analysis found a reduction in LDL-c.
There were also several limitations to this study:
- Heterogeneity between studies and inconsistent results
- Short study duration
- Small populations and limited sample size
- The results varied for different levels of hypercholesterolemia
- Results may also differ by sex and source of oat beta glucans
Larger and longer trials are therefore needed to confirm the results.
Abstract
(1) Background: hyperlipidemia is one of the cardiovascular diseases which becomes a great threat to the health of people worldwide. Oat beta-glucan is reported to have a beneficial effect on lowering blood lipids. To probe the effect of oat beta-glucan consumption on serum lipid profiles (total cholesterol, total triglyceride, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol), we carried out a systematic search on randomized controlled trials of oat beta-glucan intervention on hypercholesterolemic individuals. (2) Methods: the pieces of literature were obtained from PubMed, Scopus, Cochrane Library, Web of Science, and the Embase from inception to 28 February 2022. The results were presented with the weighted mean difference (WMD) with a 95% CI. The random-effects or fixed-effects model was applied according to the heterogeneity. The subgroup analysis and meta-regression were used to identify the source of heterogeneity. (3) Results: thirteen trials with 927 participants were included in our meta-analysis. Overall, oat beta-glucan supplementation significantly reduced levels of TC (pooled WMD = -0.24 mmol/L; 95%CI: -0.28 to -0.20 mmol/L), LDL-c (pooled WMD = -0.27 mmol/L; 95%CI: -0.35 to -0.20 mmol/L). Furthermore, beta-glucan consumption did not show significant effects on TG (pooled WMD = -0.04 mmol/L; 95%CI: -0.13 to 0.05 mmol/L), HDL-c (pooled WMD = 0.00 mmol/L; 95%CI: -0.05 to 0.05 mmol/L). Subgroup analysis indicated that critical factors, such as disease severity of participants, the daily intervention of oat beta-glucan, source of oat beta-glucan, and duration of intervention had impacts on outcomes. (4) Conclusions: oat beta-glucan intake may significantly decrease the level of TC and LDL-c while no significant changes in TG and HDL-c were observed. This meta-analysis supports the health benefits of oat beta-glucan, especially for its cholesterol-lowering features, although it has some inevitable limitations.
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A Randomized Controlled Trial of Fasting and Lifestyle Modification in Patients with Metabolic Syndrome: Effects on Patient-Reported Outcomes.
Jeitler, M, Lauche, R, Hohmann, C, Choi, KA, Schneider, N, Steckhan, N, Rathjens, F, Anheyer, D, Paul, A, von Scheidt, C, et al
Nutrients. 2022;14(17)
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The metabolic syndrome (MetS) is a condition characterized by the presence of at least three cardiovascular risk factors, such as abdominal obesity, hypertension, insulin resistance, and dyslipidaemia. The aim of this study was to assess effects of fasting followed by the Mind-Body Medicine in Integrative and Complementary Medicine (MICOM) lifestyle modification intervention in patients with MetS on patient-reported outcomes, compared to a lifestyle modification intervention only. This study is a single-blind, bicentre, randomized controlled study. Patients (n=145) were randomly assigned in a 1:1 ratio into one of the 2 groups: fasting and lifestyle modification or the lifestyle modification. They started with 2 vegan days (max. 1200 kcal/day), followed by 5 days of fasting (max. 350 kcal/day), and a stepwise reintroduction of food. Then they participated in the 10-week MICOM comprehensive multimodal lifestyle modification intervention with weekly 6-h sessions. Results show that after the multimodal lifestyle modification intervention, there were improvements for all outcome measures, namely quality of life, anxiety, depression, stress, mood as well as self-efficacy, mindfulness, and self-compassion, which persisted at the follow-up after 24 weeks. Authors conclude that their findings show beneficial and clinically relevant effects of fasting and intensified lifestyle modification on quality of life and psychological parameters.
Expert Review
Conflicts of interest:
None
Take Home Message:
For clients with Metabolic syndrome a 5-day fast consisting of max. 350 kcal/day, in conjunction with therapies that focus on improved emotional, mental, social, spiritual, and behavioural factors may directly affect health and support improved mood.
Therapies include mindfulness and specific group training rooted in psycho-neuroendocrinology, and the use of formal meditation and gentle yoga exercises. As well as nutritional education included lectures, cooking workshops, as well as group support.
Bottom line: The use of complimentary therapies such as mindfulness, yoga and medication in conjunction with nutritional advice and may be effective to support improved mood in clients with Metabolic syndrome.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Metabolic syndrome (MetS) is a condition characterised by the presence of at least three cardiovascular risk factors such as abdominal obesity, hypertension, insulin resistance, and dyslipidemia.
The authors refer to epidemiological studies that have identified the role of psychological risk factors such as psychosocial stress, depression and anxiety in patients with MetS and cardiovascular disease.
This single-blind, bi-centre RCT assessed the effects of fasting followed by a comprehensive lifestyle modification program MICOM (Mind-Body Medicine in Integrative and Complementary Medicine) in 145 participants with Metabolic Syndrome (MetS) (62.8% women; 59.7 ± 9.3 years) randomised to:
1. 5-day fasting followed by 10 weeks of lifestyle modification (F + LM; modified DASH diet, exercise, mindfulness; n = 73) or
2. 10 weeks of lifestyle modification only (LM; n = 72)
The study duration was 24 weeks occurring from April 2014 to December 2014, with the last follow-up assessment in December 2015. 73 Participants were randomised into an F + LM group and 72 participants into an LM group between the ages of 59 and 60.
Outcomes were assessed at weeks 0, 1, 12, and 24, for quality of life (Short-Form 36 Health Survey Questionnaire, SF-36), anxiety/depression (Hospital Anxiety and Depression Scale, HADS), stress (Cohen Perceived Stress Scale, CPSS), mood (Profile of Mood States, POMS), self-efficacy (General Self-Efficacy Scale, GSE), mindfulness (Mindfulness Attention Awareness Scale, MAAS), and self-compassion (Self-Compassion Scale, SCS).
At week 1, POMS depression and fatigue scores were significantly lower in F + LM compared to LM. At week 12, most self-report outcomes improved in both groups—only POMS vigour was significantly higher in F + LM than in LM. Most of the beneficial effects within the groups persisted at week 24.
Clinical practice applications:
This randomised controlled trial highlights fasting-induced mood-modulating effects in the short term (<24 months).
LM induced several positive effects on quality of life and psychological parameters in participants with MetS.
The compliance rate for this study was good and there were no adverse effects reported suggesting a potentially effective lifestyle modification intervention for adults with metabolic syndrome.
The authors did note the extent to which participants adhered to the program by using stress reduction techniques at home was not assessed.
Considerations for future research:
MBM lifestyle modification intervention led to an improvement of self-efficacy, mindfulness, and self-compassion.
Further studies to explore explanatory models for the effects of MBM are needed.
Mediating variables on mindfulness, self-efficacy, and compassion, and the effects on physical and psychological parameters, need to be examined more closely.
Future studies could use condition-specific questionnaires in addition to generic ones, which have previously been used to facilitate the comparison of the study results with those in the population.
Abstract
Lifestyle interventions can have a positive impact on quality of life and psychological parameters in patients with metabolic syndrome (MetS). In this randomized controlled trial, 145 participants with MetS (62.8% women; 59.7 ± 9.3 years) were randomized to (1) 5-day fasting followed by 10 weeks of lifestyle modification (F + LM; modified DASH diet, exercise, mindfulness; n = 73) or (2) 10 weeks of lifestyle modification only (LM; n = 72). Outcomes were assessed at weeks 0, 1, 12, and 24, and included quality of life (Short-Form 36 Health Survey Questionnaire, SF-36), anxiety/depression (Hospital Anxiety and Depression Scale, HADS), stress (Cohen Perceived Stress Scale, CPSS), mood (Profile of Mood States, POMS), self-efficacy (General Self-Efficacy Scale, GSE), mindfulness (Mindfulness Attention Awareness Scale, MAAS), and self-compassion (Self-Compassion Scale, SCS). At week 1, POMS depression and fatigue scores were significantly lower in F + LM compared to LM. At week 12, most self-report outcomes improved in both groups-only POMS vigor was significantly higher in F + LM than in LM. Most of the beneficial effects within the groups persisted at week 24. Fasting can induce mood-modulating effects in the short term. LM induced several positive effects on quality of life and psychological parameters in patients with MetS.
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The effect of high-polyphenol Mediterranean diet on visceral adiposity: the DIRECT PLUS randomized controlled trial.
Zelicha, H, Kloting, N, Kaplan, A, Yaskolka Meir, A, Rinott, E, Tsaban, G, Chassidim, Y, Bluher, M, Ceglarek, U, Isermann, B, et al
BMC medicine. 2022;20(1):327
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Visceral adipose tissue (VAT) accumulation is one of the main key factors that differentiate between metabolic healthy and unhealthy obese individuals. VAT is closely related to the development of multiple cardiovascular risk factors. The Mediterranean (MED) diet, high in polyphenol content and rich in plant food sources, was shown to have an enhanced effect on VAT reduction in combination with physical activity (PA), regardless of weight loss The aim of this study was to assess the effect of the MED diet, further enriched with polyphenols, and lower in red and processed meat (“green-MED diet”) on visceral adiposity in the 18-month Dietary Intervention Randomized Controlled Trial-Polyphenols, Unprocessed trial. This study is a randomised controlled trial. Participants were randomly assigned to one of three intervention groups (1:1:1 ratio): healthy dietary guidelines, MED diet, or green-MED diet, all included PA recommendations, with a free gym membership and educational sessions promoting moderate-intensity PA. Results show that participants following the green-MED diet achieved more than twice the degree of VAT reduction compared to those following the MED diet, despite similar weight loss. In fact, VAT loss was specifically related to lower red meat intake and increased walnuts, green tea, Wolfa globosa, and dietary fibre (this was reflected by higher plasma polyphenol and serum folate levels). Authors conclude that a green-MED diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the MED diet for targeted VAT reduction.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The positive health effects of the traditional MED diet, moderately high in PUFAs and MUFAs and low in red meat, are well-established
- Higher levels of total plasma polyphenol and serum folate may reflect higher consumption of “green” dietary components, which were significantly associated with greater VAT loss
- The green-MED diet, richer in dietary polyphenols and green plant-based proteins and lower in red meat, might be a more effective strategy for VAT loss than the traditional healthy MED diet, achieving more than twice the degree of VAT reduction, despite similar weight loss.
- VAT loss was specifically related to lower red meat intake and increased walnuts, green tea, Wolffia globosa, and dietary fibre and was reflected by higher plasma polyphenol and serum folate levels.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
A mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. Visceral adipose tissue (VAT) accumulation is one of the main factors that differentiate between metabolic healthy and unhealthy obese individuals.
In this Dietary Intervention Randomised Controlled Trial PoLyphenols UnproceSsed (DIRECT‐ PLUS) weight‐loss trial, 294 participants were randomised to: (A) healthy dietary guidelines (HDG), (B) MED, or (C) green‐MED diets, all combined with physical activity. The study duration was 18‐months.
This study explored the effect of the green‐MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT) and used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues.
Both isocaloric (with the same calorific value) MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green‐MED group further consumed green tea (3–4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake.
The mean weight loss (HDG: −0.4% (5.0), MED: −2.7% (5.6), green-MED: −3.9% (6.5)) and WC loss (HDG: −3.6% (5.1), MED: −4.7% (5.0), green-MED: −5.7%(5.7)) after 18 months were similar between the two MED diets (p > 0.05 for all) and higher as compared to the HDG (weight: HDG vs. MED: p = 0.02; HDG vs. green+MED: p < 0.001; WC: HDG vs. MED: p = 0.33, HDG vs. green+MED: p = 0.02).
All three abdominal fat depots decreased over 18 months of intervention (p < 0.05 vs. baseline for all). The green-MED group achieved a greater reduction in VAT than the other intervention groups (HDG: −4.2% (22.5), MED: −6.0%(31.3), green-MED: −14.1%(27.7); p < 0.05 green-MED vs. MED or vs. HDG groups). These differences in VAT loss across the groups remained significant after adjusting for age, sex, and 18-month WC change (green-MED vs. MED p = 0.023; green-MED vs. HDG p = 0.002) (Fig. 1)
Limitations of the study included a low proportion of women, and different VAT proportions at baseline across groups limit the generalisability of findings to women.
The authors of the study did not identify the exact components responsible for the dietary effects when they compared dietary regimens and not specific nutrients.
Adherence was by a validated, self-reported dietary intake assessment tool, which the authors acknowledge is subject to error
Strengths of the study included the relatively large sample size, high retention rate, and use of 3-T MRI measurements (considered one of the gold standards tools for the quantification of specific fat depots
Clinical practice applications:
- This trial shows that, when combined with a Mediterranean diet, higher dietary consumption of green tea, walnuts, and dietary fibre and reduced red meat consumption were significantly associated with greater %VAT loss
- The authors observed a significant synergistic interaction effect between decreased red meat consumption and increased serum folate on VAT loss
- A reduction in VAT accumulation, known as a key risk factor in CVD development, may reduce metabolic complications, improve the lipid profile, and decrease cardiometabolic risk.
Considerations for future research:
- Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity.
- Future studies could explore whether the results are replicable in both male and female participants, as this sample was largely male.
Abstract
BACKGROUND Mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. We explored the effect of the green-MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT). METHODS In the 18-month Dietary Intervention Randomized Controlled Trial PoLyphenols UnproceSsed (DIRECT-PLUS) weight-loss trial, 294 participants were randomized to (A) healthy dietary guidelines (HDG), (B) MED, or (C) green-MED diets, all combined with physical activity. Both isocaloric MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green-MED group further consumed green tea (3-4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake. We used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues. RESULTS Participants (age = 51 years; 88% men; body mass index = 31.2 kg/m2; 29% VAT) had an 89.8% retention rate and 79.3% completed eligible MRIs. While both MED diets reached similar moderate weight (MED: - 2.7%, green-MED: - 3.9%) and waist circumference (MED: - 4.7%, green-MED: - 5.7%) loss, the green-MED dieters doubled the VAT loss (HDG: - 4.2%, MED: - 6.0%, green-MED: - 14.1%; p < 0.05, independent of age, sex, waist circumference, or weight loss). Higher dietary consumption of green tea, walnuts, and Wolffia globosa; lower red meat intake; higher total plasma polyphenols (mainly hippuric acid), and elevated urine urolithin A polyphenol were significantly related to greater VAT loss (p < 0.05, multivariate models). CONCLUSIONS A green-MED diet, enriched with plant-based polyphenols and lower in red/processed meat, may be a potent intervention to promote visceral adiposity regression. TRIAL REGISTRATION ClinicalTrials.gov , NCT03020186.
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9.
Effect of mitochondrial-targeted antioxidants on glycaemic control, cardiovascular health, and oxidative stress in humans: A systematic review and meta-analysis of randomized controlled trials.
Mason, SA, Wadley, GD, Keske, MA, Parker, L
Diabetes, obesity & metabolism. 2022;24(6):1047-1060
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Reactive oxygen species (ROS) are free radical oxygen molecules produced by mitochondria, which cause molecular damage known as oxidative stress. Chronic diseases such as diabetes, heart disease, cancer, and Parkinson's disease are more likely to develop when ROS levels are elevated. Mitochondrial‐targeted antioxidants (mitoAOX) may be effective in treating chronic diseases by targeting mitochondrial ROS. In this systematic review and meta-analysis, 19 randomised controlled trials were included to evaluate the effects of mitoAOXs on glycaemic control, cardiovascular health, and oxidative stress in humans. The evidence is limited, but there were improvements in endothelial function, blood pressure, oxidative stress, and functional capacity. The mitoAOX agents, dosage, and participant characteristics varied between the studies, making it difficult to draw conclusions. Due to the heterogeneity of studies included in this study, there is a need for larger, longer-term robust studies to investigate mitoAOXs' effects on mitochondrial ROS and markers of oxidative stress in different clinical populations. As a result of this study, healthcare professionals can gain a better understanding of mitoAOX's potential in tackling oxidative stress. However, caution must be exercised before implementing it as a therapeutic strategy due to concerns over possible adverse effects and a low evidence certainty.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Mitochondria are a major producer of reactive oxygen species (ROS) in cells. Excess mitochondrial ROS has been implicated in the pathophysiology of various chronic diseases including Parkinson’s disease, cardiovascular disease (CVD), Type 2 diabetes and cancer.
- This review reported that there is limited evidence to support the use of mitoAOXs in the management of glycaemic control and cardiovascular health. However, there are promising findings on the effect of mitoAOXs on endothelial function that warrant consideration and further investigation in target clinical population groups.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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X
B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Background
A systematic review and meta-analysis was conducted to evaluate the current evidence from randomised control trials (RCTs) in humans on the effects of mitochondrial-targeted antioxidant (mitoAOXs) on glycaemic control, cardiovascular health, and oxidative stress.
Methodology
19 Randomised control trials (n= 884 participants) using mitoAOXs (including Elamipretide, MitoQ and MitoTEMPO) were included from MEDLINE-PubMed, Scopus, EMBASE and Cochrane Library databases. A Cochrane Collaboration’s tool was used to assess risk bias and to grade the quality of the trials and their certainty of the evidence.
Results
Primary clinical outcomes were:
- A quantitative analysis on glycaemic control found no significant effect for fasting glucose in response to MitoQ supplementation.
- A quantitative analysis on cardiovascular health related outcomes found a significant lowering effect of mitoAOXs brachial flow-mediated dilation (FMD) (standardized mean difference: 1.19, 95% CI: 0.28, 2.16; I2: 67%) and an improved blood pressure (standardized mean difference: -0.32, 95% CI:-0.95, 0.30; I2: 0%) in patients with atherosclerosis-related impairment of renal blood flow.
- A quantitative analysis on oxidative stress-related outcomes found no significant effect of mitoAOX on malondialdehyde or F2-Isoprostanes.
Clinical practice applications:
- The findings from this review suggest limited evidence to support the use of mitoAOX in the management of glycaemic control or cardiovascular health.
- However, there are some potential promising findings which included improved endothelial function (particularly brachial FMD) and improved blood pressure in patients with atherosclerosis-related impairment of renal blood flow.
- Based on this review, practitioners may consider recommending the use of mitoAOXs only in quite specific circumstances, namely to improve endothelial function in patients with a risk of brachial FMD or high blood pressure associated with atherosclerosis-related impairment of renal blood flow.
Considerations for future research:
- The studies included in this review were mostly one to three months in duration therefore, there is a need for long-term, follow-up studies to be conducted to better investigate these outcomes.
- Given the pathogenic factors of elevated mitochondrial ROS and oxidative stress in chronic diseases such as CVD and Type2 diabetes, further investigation is needed into the effects of mitoAOXs on mitochondrial ROS and oxidative stress markers in target clinical population groups.
- It appears that mitoAOXs may improve endothelial function, therefore further research is needed to focus on the effect of mitoAOXs on endothelial function in target clinical populations.
- Additionally, further reviews are required to provide a more comprehensive review of the safety and adverse effects of mitoAOXs.
- Furthermore, only antioxidants specific to microconidia were included in this review. It is possible that other more general acting antioxidants may have redox-related effects in mitochondria. Therefore, a more comprehensive review is needed to include all possible antioxidant compounds that have mitochondrial effect.
Abstract
AIM: To investigate the effects of mitochondrial-targeted antioxidants (mitoAOXs) on glycaemic control, cardiovascular health, and oxidative stress outcomes in humans. MATERIALS AND METHODS Randomized controlled trials investigating mitoAOX interventions in humans were searched for in databases (MEDLINE-PubMed, Scopus, EMBASE and Cochrane Library) and clinical trial registries up to 10 June 2021. The Cochrane Collaboration's tool for assessing risk of bias and Grading of Recommendations, Assessment, Development and Evaluations were used to assess trial quality and evidence certainty, respectively. RESULTS Nineteen studies (n = 884 participants) using mitoAOXs (including Elamipretide, MitoQ and MitoTEMPO) were included in the systematic review. There were limited studies investigating the effects of mitoAOXs on glycaemic control; and outcomes and population groups in studies focusing on cardiovascular health were diverse. MitoAOXs significantly improved brachial flow-mediated dilation (n = 3 trials; standardized mean difference: 1.19, 95% CI: 0.28, 2.16; I2 : 67%) with very low evidence certainty. No significant effects were found for any other glycaemic, cardiovascular or oxidative stress-related outcomes with mitoAOXs in quantitative analyses, with evidence certainty rated mostly as low. There was a lack of serious treatment-emergent adverse events with mitoAOXs, although subcutaneous injection of Elamipretide increased mild-moderate injection site-related events. CONCLUSION While short-term studies indicate that mitoAOXs are generally well tolerated, there is currently limited evidence to support the use of mitoAOXs in the management of glycaemic control and cardiovascular health. Review findings suggest that future research should focus on the effects of mitoAOXs on glycaemic control and endothelial function in target clinical population groups.
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10.
Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults.
Singh, A, D'Amico, D, Andreux, PA, Fouassier, AM, Blanco-Bose, W, Evans, M, Aebischer, P, Auwerx, J, Rinsch, C
Cell reports. Medicine. 2022;3(5):100633
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A gradual decline in muscle mass and strength with aging is natural, however, environmental factors such as diet and exercise dictate the trajectory of the decline. Exercise and healthy nutrition are the primary interventions to prevent and manage age-associated decline in muscle health and metabolic diseases. This study was designed as a proof-of-concept investigation of the efficacy of long-term oral supplementation with urolithin A (UA) on physiological endpoints in middle-aged adults. This study is a randomised, double-blind, placebo-controlled study. An overweight middle-aged population with a high body mass index and average physical endurance was selected for the study. Results showed improved lower-body muscle strength in the hamstring skeletal muscle at both doses of UA. Furthermore, it positively impacted aerobic endurance and physical-performance measures such as walking distance. Authors conclude that supplementation with UA is safe and increases circulating levels of UA.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Mitochondrial dysfunction is associated with ageing and linked to deterioration of skeletal muscle and sarcopenia. Improving mitochondrial health may therefore help to improve muscle health as we age.
- Previous studies have demonstrated improvements in muscle endurance with long term UA intake in older adults (1) and the study by Singh et al. supports these findings in middle-aged adults.
- For middle-aged clients who are noticing a decline in muscle strength, exercise performance, or a general increase in fatigue, taking 500-1,000 mg UA daily for two to four months could lead to noticeable improvements in symptoms.
- The compounds from which UA is derived are also found in polyphenol-rich plant foods including pomegranates, berries and walnuts, therefore consuming these foods may be useful dietary additions for the same purpose.
- These findings are likely to be relevant for younger populations too, as mitophagy, which is part of the action of UA, contributes to the removal and recycling of dysfunctional mitochondria, allowing healthier intact mitochondria to take their place.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
- Urolithin A (UA) is a microbiome metabolite – known as a postbiotic - of elligitannins and polyphenolic compounds found in some plant foods including pomegratate, berries and walnuts.
- In animal models, UA has previously been shown to have a range of potential health benefits involving induction of mitophagy and on mitochondrial function, as well as on disease states including osteoarthritis, inflammatory bowel disease, cardiovascular disease, and neurodegenerative disorders.
- The current study sought to establish proof-of-concept of the efficacy and safety of long-term UA supplementation on physiological endpoints in middle-aged adults.
- The primary outcome was peak power output and secondary outcomes included a range of clinical and physiological parameters linked to muscle strength, exercise tolerance and physical performance.
- The study tested UA in 500mg and 1000 mg doses against placebo in a 3-arm randomized-controlled trial in n= 88 subjects aged 40-64y who were healthy, overweight (BMI 25.0-34.9 kg/m2), sedentary, and who had a low VO2max at study inclusion. 79 subjects completed the study.
- Subjects were assessed at baseline, midpoint (2 months) and endpoint (4 months). In addition to the UA intervention, subjects were asked to maintain low physical activity status for the duration of the trial, and avoid pomegranates and supplements known to influence muscle performance (high protein, CoQ10m vitamin B3 or L-carnitine).
- Though a difference in peak power output (primary outcome) was not observed, muscle strength improved by up to c. 12% with 500 mg daily UA (p=0.027). With 1000 mg UA daily, aerobic endurance improved by up to 15% (p=0.03), gait speed increased by 7% (p=0.004), and in the 6-minute walk test subjects improved by 7% (p=0.008) and walked on average more than 30 additional meters, indicating a clinically meaningful difference in mobility.
- In addition, subjects in the UA groups had improved biomarkers of cellular health. With 1000 mg UA daily, inflammation was reduced (CRP, p<0.05; IFN-γ and TNF-α, both p<0.05). In addition, biomarkers of mitochondrial efficiency were also improved with 500 mg UA daily, Iing increased protein levels related to improved mitophagy, and expression of genes belonging to mitochondria.
- UA was deemed as safe and well tolerated at both 500 mg and 1000 mg doses for 4 months’ administration.
- A strength of the study was that the groups were balanced for all physiological parameters at baseline. However, the ratio of females was 2:1, and ethnicity was mainly western European. This may limit interpretation of the findings.
- All authors except one are either employees, board members or members of the scientific advisory board of Amazentis SA, who both manufacture Mitopure, the UA supplement used, and who funded this trial.
Clinical practice applications:
- Mitophagy is an important step in improving mitochondrial health. This study demonstrates the potential of UA to activate this pathway.
- In healthy middle-aged adults who are overweight or obese, sedentary and with low physical performance, oral UA supplementation at a sufficient dose and duration may:
- increase muscle strength
- increase mitophagy proteins in human skeletal muscle, as well as various other mitochondrial markers
- increase exercise performance and aerobic exercise
- be a valuable intervention to consider in clients who are suffering from mitochondrial dysfunction
Considerations for future research:
- This study was exploratory and the sample size for some of the outcomes was very small and inadequate to demonstrate true statistical significance. Future studies of similar design are needed to confirm the findings
- Nevertheless, the study was well-structured with carefully elaborated markers. It could be used as a template for future studies.
Abstract
Targeting mitophagy to activate the recycling of faulty mitochondria during aging is a strategy to mitigate muscle decline. We present results from a randomized, placebo-controlled trial in middle-aged adults where we administer a postbiotic compound Urolithin A (Mitopure), a known mitophagy activator, at two doses for 4 months (NCT03464500). The data show significant improvements in muscle strength (∼12%) with intake of Urolithin A. We observe clinically meaningful improvements with Urolithin A on aerobic endurance (peak oxygen oxygen consumption [VO2]) and physical performance (6 min walk test) but do not notice a significant improvement on peak power output (primary endpoint). Levels of plasma acylcarnitines and C-reactive proteins are significantly lower with Urolithin A, indicating higher mitochondrial efficiency and reduced inflammation. We also examine expression of proteins linked to mitophagy and mitochondrial metabolism in skeletal muscle and find a significant increase with Urolithin A administration. This study highlights the benefit of Urolithin A to improve muscle performance.