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Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.
Stekovic, S, Hofer, SJ, Tripolt, N, Aon, MA, Royer, P, Pein, L, Stadler, JT, Pendl, T, Prietl, B, Url, J, et al
Cell metabolism. 2019;30(3):462-476.e6
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Plain language summary
Intermittent fasting and calorie restriction are believed to reduce cardiometabolic risk factors and increase longevity. Fasting alternate days (ADF) involves fasting for 36 hours and eating ad libitum for 12 hours. Thirty healthy participants were randomly assigned to a long-term ADF intervention group for ≥6 months against sixty participants in the control group. After completing the cross-sectional study arm, sixty healthy participants in the control group were randomly assigned to either a four-week short-term ADF intervention group or a control group with an ad libitum diet. Study participants adhered well to the fasting regimen. Both short-term and long-term ADF intervention groups showed a significant reduction in calorie intake, improvements in anthropometric and cardiovascular parameters including reduced BMI, substantial reduction in trunk fat, lower heart rate, increased serum β-hydroxybutyrate which is cardioprotective and anti-ageing, reduced circulating triiodothyronine (fT3) levels which indicate longevity. Short-term ADF reduced systolic and diastolic pressure, mean arterial pressure, pulse pressure, and pulse wave velocity. Long-term ADF intervention reduced circulating total cholesterol, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and triglycerides, the age-related biomarker sICAM-1 for disease and inflammation, and improved lipid and amino acid metabolites. ADF did not affect insulin sensitivity. Although red blood cells and iron levels were altered, ADF interventions were not associated with iron deficiency. Healthcare professionals can use the results of this study to understand the cardioprotective and anti-ageing properties of ADF. However, further long-term robust studies are required to evaluate the effect of long-term ADF on bone health.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Short duration (<4 weeks) alternate day fasting may be an effective way to implement caloric restriction, improve body composition and reduce cardiovascular disease risk in healthy non-overweight adults.
- >6 months alternate fasting does not appear to be associated with reduced bone mass, bone mineral density of the lumbar spine region, white blood cell counts, ferritin and transferrin when compared to healthy controls.
- Both short term and long term alternate day fasting may reduce triiodothyronine in healthy adults. Low levels of fT3 without thyroid gland dysfunction has been associated with longevity in humans.
- Alternate day fasting should be performed alongside a trained clinician to reduce the risk of adverse effects due to critical medical conditions.
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
Animal models have consistently demonstrated the healthspan and lifespan benefits of caloric restriction. However, chronic caloric restriction in humans has proven difficult to maintain.
Intermittent fasting may serve as a more manageable alternative to continuous caloric restriction. This randomised controlled trial and cross sectional analysis aimed to investigate the effects of alternate day fasting (ADF) on heart rate, blood pressure, cholesterol levels, CVD risk, body composition, and the metabolome and proteome of healthy, non-overweight adults (cohort median age between 48 and 52 years).
Methods
Prior to the enrollment of the study a cross sectional analysis was conducted on healthy adults engaged in long term (>6 months) alternate day fasting (n=30) and a control group (n=60).
The 60 participants from the cross sectional analysis control group were then randomised to either a 4 week ADF group or a control group. In both the >6 months and 4 weeks of ADF groups, participants were instructed to eat every second-day ad libitum, but to completely exclude solid and liquid foods and caloric beverages on fasting days.
Results
The cross sectional analysis identified that the alternate day fasting group:
- Consumed fewer calories vs the control group (−28.56%, p=0.0002).
- Had lower levels of circulating total cholesterol (p=0.004), LDL (p=0.011), VLDL (p=0.009), triglycerides (p=0.010) and a lower heart rate (p=0.040) vs the control group.
- Lower levels of soluble intercellular adhesion molecule-1 (sICAM-1) (p value 0.048), an age-associated inflammatory marker.
- Reduced circulating triiodothyronine (p<0.001) compared to the control group.
- In the metabolome, 54 out of 113 detected significantly modified metabolites (p value < 0.05) were at least 20% higher after 36 h of fasting, of which the majority (>95%) were lipids or free fatty acids, including polyunsaturated free fatty acids (PUFAs), α-tocopherol, and a type of vitamin E. 49 metabolites were at least 20% lower, consisting mainly (44.9%) of amino acids or related metabolites. Low levels of circulating amino acids have been found to increase lifespan in model organisms. The authors concluded that the elevation in fatty acids may be due to increased lipolysis from adipose tissue while the reduction in amino acids may be the result of increased gluconeogenesis.
- 13 out of 2,089 significantly (p value < 0.05) modulated protein hits within the PBMC proteome showed an increase of ≥15%, while the remaining proteins were downregulated after 36 h of fasting. Gene set enrichment analysis (GSEA) performed on the PBMC proteome unveiled changes in pathways related to lipid metabolism, pathways related to energy metabolism and stress response.
Following the 4 week intervention the alternate day fasting group demonstrated:
- Reduced caloric intake from baseline vs. the control group (−37.40% vs. −8.22%, p=0.0012).
- Greater reductions in body weight (−3.5kg vs −0.2kg, p<0.0001), BMI (−1.23kg/m2 vs −0.02kg/m2, p<0.0001) and improvements in their fat to lean mass ratio (−6.3% ± 5.0 percentage points, p value < 0.0001).
- Reduced systolic (−4.5mmHg, p=0.006) and diastolic (−2.5mmHg, p=0.03) blood pressure, heart rate (-4.5 b/min, p=0.0019), arterial (−3mmHg, p=0.0087) and pulse pressure (−2.5mmHg, p=0.0088) as well as pulse wave velocity (−1.538%, p=0.0362). Pulse wave velocity measures the rate at which pressure moves down the vessel wall and is a measure of arterial stiffness.
- Reduced circulating triiodothyronine (p<0.001) from baseline values.
Clinical practice applications:
The cross sectional analysis did not identify any differences in the long-term (>6 months) alternate day fasting group and control group in bone mass, bone mineral density of the lumbar spine region, white blood cell counts, ferritin and transferrin when compared to healthy controls. RBC counts and iron metabolism markers in the blood plasma (hematocrit, haemoglobin, iron, and transferrin saturation), were lower in the >6 months of ADF group but stayed within the reference range.
The randomised controlled trial demonstrated that alternate day fasting may be an effective intervention to reduce caloric intake, improve body composition and reduce cardiovascular disease risk in healthy non-overweight adults within 4 weeks.
Compliance rate was high with only 1 drop out in the alternate day fasting group of the randomised controlled trial.
Both the 4 week intervention and long-term (>6 month) analysis identified a reduction in triiodothyronine amongst the ADF groups. Low levels of triiodothyronine in absence of thyroid gland dysfunction has been associated with longevity in humans.
Considerations for future research:
- Future larger studies in non-healthy and/or overweight/obese populations would be useful to determine safety and efficacy of alternate day fasting within that population group.
- Further studies comparing alternate day fasting with continuous caloric restriction would be useful to identify which intervention is most beneficial for body composition and cardioprotection.
- Subgroup analysis of diet composition and diet quality may help to identify the most appropriate/inappropriate diet to compliment alternate day fasting.
- Longer duration randomised controlled trials are needed to identify any health risks or deficiencies which may develop with long term caloric restriction and alternate day fasting.
Abstract
Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.
2.
Effect of 12-Week Daily Intake of the High-Lycopene Tomato (Solanum Lycopersicum), A Variety Named "PR-7", on Lipid Metabolism: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study.
Nishimura, M, Tominaga, N, Ishikawa-Takano, Y, Maeda-Yamamoto, M, Nishihira, J
Nutrients. 2019;11(5)
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Plain language summary
Tomatoes are a rich source of lycopene, a compound believed to have many health benefits. Researchers in Japan conducted a randomised, double-blind, placebo-controlled trial to investigate the effects of eating a type of tomato bred to be high in lycopene on 74 healthy volunteers with raised cholesterol levels. Participants were given 50g per day of either semi-dried high-lycopene tomato or lycopene-free tomato. Those eating the high-lycopene tomatoes significantly reduced their levels of LDL cholesterol over 12 weeks. The researchers concluded that their findings support the health benefits of eating tomatoes rich in lycopene.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Lycopene, a carotenoid, has antioxidant effects and exhibits the highest physical quenching rate constant for singlet oxygen.
- Lycopene has also been reported to inhibit the production of serum lipid peroxide and oxidize low-density lipoprotein (LDL)
- This study reported that the intake of 50g of high-lycopene (lycopene, 22.0-27.8mg) for 12 weeks significantly decreased LDL-C in subjects with LDL-C ranging from 120–139 mg/dL.
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 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group study was conducted to investigate the effects of the regular and continuous intake of high-lycopene tomato, a variety named PR-7, for 12 weeks on 74 healthy Japanese subjects with low-density lipoprotein cholesterol (LDL-C) levels > 120 to <160mg/dL.
The subjects were randomly assigned to either the high-lycopene tomato or placebo (lycopene-free tomato) group. Each subject in the high-lycopene group ingested 50g of semi-dried PR-7 (lycopene, 22.0-27.8mg) per day. Medical interviews were conducted, vital signs were monitored, and blood and saliva samples were taken at 0 (baseline) and at 4, 8 and 12 weeks.
Primary clinical outcomes were:
- The intake of high-lycopene tomato improved LDL-C at week 12 when compared to the placebo group (Week 12: placebo, 4,1 +- 15.7mg/dL; high-lycopene tomato, -3.7 +- 13.8.mg/dL; p=0.027).
- Based on a subgroup analysis, the ingestion of high-lycopene tomato significantly decreased LDL-C in subjects with LDL-C ranging from 120–139 mg/dL at week 12 (Week 12: placebo, 4.3 15.1 mg/dL; high-lycopene tomato, +- 5.1 9.5 mg/dL; p = 0.030).
Secondary clinical outcomes were:
- There were no significant differences between the high-lycopene tomato and placebo groups in terms of lipid profiles comprising of total cholesterol (TC), HDL-C, triglycerides (TG), LDL-C/HDL-C ratio, and non-HDL, and adiponectin.
- The intake of high-lycopene tomato increased lycopene levels compared to the placebo group (Week 12: placebo,
+-24.2 49.3 g/dL; high-lycopene tomato, 22.7 47.9 g/dL; p < 0.001).
- In addition, beta-carotene levels increased in the high-lycopene tomato group compared to those in the placebo group at week 12 (Week 12: placebo, 0.9 13.6 g/dL; high-lycopene tomato, 12.0 24.5 g/dL; p = 0.009).
Clinical practice applications:
- A previous meta-analysis demonstrated that LDL-C decreases when more than 25 mg per day of lycopene is ingested. The biological mechanism was associated with a reduction in 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity in the liver, activation of LDL-receptors, and increased expression of the ABCA1 transporter gene, the key component of HDL-C production.
- This study also suggests that there is a decrease in LDL-C at 12 weeks in subjects with LDL-C ranging from 120–139 mg/dL.
- Based on these findings, a practitioner could therefore consider recommending 25mg of lycopene to help reduce LDL-C in patients with an LDL-C range of 120–139 mg/dL for at least 12 weeks.
Considerations for future research:
- Lycopene has been reported to possess the strongest singlet oxygen scavenging ability among the eight carotenoids, as measured by the singlet oxygen absorption capacity method, and some researchers have found that lycopene and tomato display antioxidant effects. However, other reports suggest that ingesting lycopene does not affect oxidative markers. These findings suggest that further investigation is needed to evaluate the effect of lycopene on oxidative markers.
- The LOX index is a biomarker for the early risk of arteriosclerosis, cerebral infarction, and myocardial infarction. Lycopene might be ineffective against LOX-1 which is a product of the peroxidation reaction. Additional studies with a longer intake period are required to investigate the effect of lycopene on the risk of arteriosclerosis.
- The subjects in this study were asked to avoid cooking the test food (semi-dried tomato). It is, therefore, necessary to investigate the differences in the effect of the high-lycopene tomato based on various cooking methods.
Abstract
Tomato (Solanum lycopersicum) is a rich source of lycopene, a carotenoid that confers various positive biological effects such as improved lipid metabolism. Here, we conducted a randomized, double-blind, placebo-controlled, parallel-group comparative study to investigate the effects of regular and continuous intake of a new high-lycopene tomato, a variety named PR-7, for 12 weeks, based on 74 healthy Japanese subjects with low-density lipoprotein cholesterol (LDL-C) levels ≥120 to <160 mg/dL. The subjects were randomly assigned to either the high-lycopene tomato or placebo (lycopene-free tomato) group. Each subject in the high-lycopene group ingested 50 g of semidried PR-7 (lycopene, 22.0-27.8 mg/day) each day for 12 weeks, while subjects in the placebo group ingested placebo semidried tomato. Medical interviews were conducted, vital signs were monitored, body composition was determined, and blood and saliva samples were taken at weeks 0 (baseline), 4, 8, and 12. The primary outcome assessed was LDL-C. The intake of high-lycopene tomato increased lycopene levels in this group compared to levels in the placebo group (p < 0.001). In addition, high-lycopene tomato intake improved LDL-C (p = 0.027). The intake of high-lycopene tomato, PR-7, reduced LDL-C and was confirmed to be safe.