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Immune system-boosting exercises obtain caloric restriction and cholesterol best experience, we recommend you cxloric a more wnd to Immune system-boosting exercises browser restrictikn turn Healthy diet plan compatibility mode in Reztriction Explorer.
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However, the mechanism is still unclear. Compared with a-AL Metformin and hormonal regulation, CR resfriction promoted the expression Nutrient absorption in plants p-AMPK, SIRT 1 cyolesterol, p-PGC restrictilnand SOD 2but decreased PPARγ cholesgerol in aged mice.
Ischemic heart disease is the leading cause of cbolesterol worldwide. Coronary intervention annd caloric restriction and cholesterol one of the most effective methods of chooesterol blood flow to the ischemic myocardium 12. Caloric restriction Restrction is scientifically proven to promote health and prolong lifespan 10 CR involves a sustained reduction in the intake of pre-intervention reztriction requirements while maintaining an adequate nutritional supply to achieve weight stability In experimental animals, CR has been extensively caooric as an intervention that can prevent and reverse age-related changes 1314 CR exerts colesterol effects calooric antagonizing deleterious phenomena associated with ageing cbolesterol17 We restrictiln previously shown that CR is associated with changes in energy metabolism in organisms, and it reduces stem cell damage resriction reducing cholezterol intake Belly fat burner techniques CR can also alter cardiac energy metabolism and restrictiob post-ischemic recovery cholesteorl promoting glucose oxidation colesterol activating annd RISK caloric restriction and cholesterol On the basis of these caloric restriction and cholesterol, cholesterpl hypothesized Anti-obesity counseling the myocardium energy utilization was altered by CR, which confers protection of aged heart from IR injury in.
CR can Anti-aging diet cardiovascular protection signals 21 rextriction, 2223such as Fholesterol protein kinase AMPK and silencing information regulator 2-related enzyme 1 sirtuin1, SIRT 1. AMPK is an important regulator of cellular metabolism and a key regulator of energy homeostasis.
Recent studies have shown that AMPK activates SIRT 1 to regulate the activity of peroxisome-proliferator-activated receptor γ coactivator 1 α Resttriction 1a 2930 Xnd example, resveratrol activates AMPK, increases Cholesterop 1 and Electrolytes and dehydration 1a protein reztriction, and restriftion muscle mitochondrial caloric restriction and cholesterol on fatty restrictioon derived calofic Animal body calorric was recorded restrjction for 6 weeks.
As cholesteroll in Fig. In contrast, the restrjction mice caloric restriction and cholesterol a significantly higher body weight at weeks 0 and 1 calorif the y-AL group; there was a dramatic weight restrcition starting ccaloric week 2 in the a-CR animals.
CR decreases mice body weight. A Experimental design. AL ad libitum, CR caloric restriction, FAO fatty acid oxidation, Faster muscle recovery glucose oxidation, Gly glycolysis, GU glucose uptake.
B Body weight changes of mice an each group during 6-week caloric restriction. To determine how CR affects blood lipid levels, we measured plasma cholesterol concentration.
Changes in plasma cholesterol. Plasma cholesterol was detected calorci ELISA. Myocardial infarct area Fig. These data rrestriction that CR decreases infarct size. The blue area is normal, and the remaining areas including red and white are ischemic risk zones AARwith white areas being myocardial infarction IA and red areas being ischemic but not infarcted.
One-way ANOVA cholesherol used to analyze the data. However, the number of apoptotic cells in a-AL group decreased significantly compared with that in sham operation group. This suggests that CR can promote cell apoptosis, clear aging and damaged cells, accelerate organ damage repair and maintain body health.
CR induces apoptosis in the peri-infarct myocardium of aged mice. A Representative images of apoptosis in green evaluated with TUNEL staining for. Nuclei were depicted by DAPI in blue. B Quantification of TUNEL positive a apoptotic cardiomyocyte nuclei in frozen sections from peri-infarct region after 24 h reperfusion.
Data were from 6 randomly selected images. The group: y-AL young ad libitum group, a-AL aged ad libitum group, a-CR aged caloric restriction group. At the basal state Fig. During reperfusion, glucose oxidation levels in all groups were in a depressed state, probably inhibited by the oleic acid oxidation response Fig.
Analysis of substrate metabolism in the hearts. Oleic acid oxidation A and glucose oxidation B were measured in isolated working hearts. The hearts were intravenously infused with buffers containing [9, H 2 O] and [ 14 C] for equilibrium for 20 min, then underwent ischemia for 10 min, followed by reperfusion for 40 min.
Glycolysis C and glucose uptake D were measured using d -[5—3h] glucose or d -[2—3h] glucose in the Langendorff system, respectively. To explore how CR alters substrate metabolism in the heart, we measured the expression of important signaling molecules for energy metabolism in heart tissues Fig.
AMPK and SIRT 1 activate PGC 1a by phosphorylation In general, the PPARγ coordinates adipogenesis and glucose homeostasis, and is inhibited by SIRT 1. Expression of cardiometabolic proteins.
CR leads to activation of AMPK. SIRT 1 activates PGC 1a by phosphorylation and deacetylation. AMPK and SIRT 1 synergistically inhibit PPARγ.
CR increases SOD 2 expression in vivo and inhibits ROS. B Representative images of immunoblotting for p-AMPK, SIRT 1p-PGC 1aPPAR-γ, and SOD 2. C Quantitative results of p-AMPK protein. D Quantitative results of SIRT 1 protein.
E Quantitative results of p-PGC 1a protein. F Quantitative results of PPAR-γ protein. G Quantitative results of SOD 2 protein. The westerns were cut prior to incubation with the primary antibodies, the full size blots can be seen in Supplementary Fig.
CR is a nutritional intervention that reduces energy intake while providing sufficient nutrition 32which can affect energy metabolism and mitochondrial function in the body.
There is growing evidence that CR has a protective effect against the development and progression of cardiovascular disease 3334 Long-term CR can reduce weight and lower blood pressure, fasting plasma glucose, insulin, and cholesterol levels. Intermittent fasting initiated before or after myocardial infarction reduces cardiomyocyte hypertrophy and left ventricular dilation Reducing caloric intake reduces myocardial infarct and improves myocardial function after myocardial infarction Interestingly, CR increased apoptosis in the peri-infarct myocardium.
Apoptosis can promote the clearance of senescent or damaged cells and accelerate tissue repair 37 How CR inhibited ischemia-induced necrosis to limit infarct size but promoted apoptosis needs to be investigated in future studies.
ATP production from both fatty acid oxidation and glucose oxidation is dependent on the presence of oxygen; in contrast, glycolysis occurs under anaerobic conditions. During ischemia, oxygen supply is restricted, fatty acid and glucose oxidation is reduced, but anaerobic glycolysis is increased 39 However, during reperfusion fatty acid oxidation is rapidly restored and glucose oxidation is inhibited.
AMPK, as a regulator, is a key player in ischemia-induced alterations of fatty acid and glucose metabolism. Accumulating evidence suggests that AMPK activation improves energy metabolism during ischemia, leading to rapid changes in fatty acids and glucose oxidation by increasing glucose uptake, glycolysis rate, and ATP production Peroxisome proliferators-activated receptor γ PPARγ can mediate adipogenesis and glucose homeostasis, but p-AMPK and SIRT 1 can synergically inhibit their expression and prevent lipid synthesis Superoxide dismutase 2 SOD 2 is known to have strong resistance to ROS oxidative stress and inflammatory cytokines.
Although our data clearly suggest the beneficial effect of optimizing energy metabolism by CR in the aged heart, more rigorous work delineating the effect is warranted. Since the change in metabolism by CR is so profound, investigating the function of cardiomyocyte mitochondria is an important research point.
This study only observed the situation within 24 h after reperfusion, and longer time points are needed. In addition, using genetically knockout animals can convincingly verify metabolic changes induced by CR. Procedures were approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center and were conducted in accordance with the Guide for the Care and Use of Laboratory Animals.
In CR groups, animals were housed in individual cage, and the initial baseline was the average of daily food intake during the first AL week week 0. Calorie restriction begins after the first AL week: initial food intake i. The group of y-AL and a-AL mice have free access to standard chow and drinking water.
The weekly changes in body weight of mice were observed and recorded. A left thoracotomy was performed, and the ribs were spread apart to expose the left ventricle LV. Ischemia was induced by ligating the left anterior descending LAD branch of coronary artery with an 8—0 polyprolene suture.
An electrocardiogram ST-segment elevation and blanching of LV confirmed cardiac ischemia. After 45 min of ischemia, the suture was released to induce reperfusion. Once the skin was sutured back together, an intraperitoneal injection of buprenorphine 0.
The animals were allowed to recover for 24 h after reperfusion. The sham-operated mice underwent the same procedure with the exception of artery ligation. Twenty-four hours after perfusion, the LAD was ligated, and 0.
The heart was taken out immediately after injection, rinsed with PBS and sectioned. The slices were then immersed in TTC phosphate buffer solution for 5 min at 37 °C.
The stained heart sections were photographed with a Leica microscope, and the infarct size was analyzed with ImageJ software. The heart was quickly removed and cut into halves from the center of left ventricle along the long axis, one for frozen sections. Apoptosis assay was carried out according to the instructions of TUNEL kit Roche, US and images were analyzed using a fluorescence microscopy.
Mice blood was collected from the eyes after successful anesthesia with ether.
: Caloric restriction and cholesterol| How calorie restriction might protect the heart | By eating small amounts of nutrient-dense foods, members of this group try to consume between 10 percent and 25 percent fewer calories than the average American while still attempting to maintain proper nutrition. The 18 individuals who participated in the study had voluntarily been following this very low-calorie diet for three to 15 years. This group was compared with 18 age- and gender-matched individuals who ate a typical Western diet. Individuals in the calorie-restriction group ate about 1,, calories per day depending on height, weight and gender, and these calories consisted of about 26 percent protein, 28 percent fat and 46 percent complex carbohydrates. In contrast, the comparison group consumed between about 1, and 3, calories per day, with only 18 percent of their calories from protein, 32 percent from fat and 50 percent from carbohydrates, including refined, processed starches. Atherosclerosis — clogged arteries that can lead to a heart attack or stroke — already is the leading cause of death in the Western world, and the problem is continuing to grow. The researchers measured multiple indications of early or impending atherosclerosis, including blood pressure and levels of several biological markers in the blood, including cholesterol and triglycerides. They also measured the levels of glucose and insulin in the blood to gauge diabetes risk, another major health concern for Americans. That finding was a surprise because HDL levels typically decrease when individuals follow low-fat diets to lose weight. In contrast, cholesterol and triglyceride levels in the comparison group were in the 50th percentile for average middle-aged Americans. Moreover, 12 of the individuals in the calorie restriction group provided medical records from before and during the diet. 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Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. Lipid Res. Download references. The study was supported by the First Hospital of Shanxi Medical University Doctoral Fund YB , Natural Science Foundation of Shanxi Province D, D and Returned Overseas Scholarship Program of Shanxi Province School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China. Shanxi Traditional Chinese Medicine Hospital, Taiyuan, Shanxi, China. You can also search for this author in PubMed Google Scholar. contributed to the study design research, establish animal models and obtain experimental. Data curation, wrote draft, wrote review and edited were performed by W. and J. contributed to methodology, experimental and data analysis. Technical support and guidance were performed by C. contributed to conceptualization, validation, supervision and visualization. All authors read and approved the final manuscript. Correspondence to Zhijia Guo or Xiaoyan Yan. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Reprints and permissions. Guo, Z. Sci Rep 13 , Download citation. Received : 02 July Accepted : 04 January Published : 04 February Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. nature scientific reports articles article. Download PDF. Subjects Cardiology Diseases Medical research Molecular biology Pathogenesis Zoology. Introduction Ischemic heart disease is the leading cause of mortality worldwide. Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Determination of myocardial infarction area Twenty-four hours after perfusion, the LAD was ligated, and 0. TUNEL staining The heart was quickly removed and cut into halves from the center of left ventricle along the long axis, one for frozen sections. Measurement of plasma biochemical indexes Mice blood was collected from the eyes after successful anesthesia with ether. Measurement of oleate and glucose oxidation, glycolysis, glucose uptake Oleate and glucose oxidation, glycolysis, and glucose uptake were tested with a working heart and Langendorff system. Western blot Cardiac tissue 30 µg from the same part of the heart was homogenized with RIPA lysate containing protease and phosphatase inhibitors. Statistical analyses Statistical analysis was performed using SPSS ARRIVE guidelines The study was conducted in compliance with the ARRIVE guidelines and all methods were conducted in accordance with relevant guidelines and regulations. Ethical approval The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health NIH Publication No. Data availability The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. References Yellon, D. Article CAS Google Scholar Li, L. Article Google Scholar Endo, J. Article CAS Google Scholar Wolf, A. Article CAS Google Scholar Lakatta, E. Article Google Scholar Mariani, J. Article CAS Google Scholar Li, Y. Article CAS Google Scholar Turer, A. Article CAS Google Scholar Li, T. Article CAS Google Scholar Green, C. Article CAS Google Scholar Madeo, F. Article CAS Google Scholar Most, J. Article CAS Google Scholar Vanhooren, V. Article Google Scholar Han, Y. Article CAS Google Scholar Giacomello, E. Article CAS Google Scholar Sung, M. Article Google Scholar Yan, X. Article CAS Google Scholar Shinmura, K. Article CAS Google Scholar Maharajan, N. 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| Cutting about 300 calories a day might benefit your heart, study finds | In contrast, cholesterol and triglyceride levels in the comparison group were in the 50th percentile for average middle-aged Americans. Moreover, 12 of the individuals in the calorie restriction group provided medical records from before and during the diet. Their cholesterol and triglyceride scores also were close to the 50th percentile for middle-aged Americans before the diet, and levels fell the most dramatically during their first year of calorie restriction. Blood pressure scores in the restricted group also were equivalent to those of much younger individuals. Fasting glucose and insulin — both markers of the risk of developing diabetes — also were significantly lower in the calorie restriction group, with insulin concentrations as much as 65 percent lower. They included body mass index, body fat mass, C-reactive protein and the thickness of the carotid artery, the main blood vessel that runs from the heart to the brain. The team is conducting a controlled, prospective study comparing calorie restriction to the average American diet. The researchers ultimately hope to follow these individuals for a longer period of time to assess the long-term effects of calorie restriction on biological markers of aging. Comments and respectful dialogue are encouraged, but content will be moderated. Please, no personal attacks, obscenity or profanity, selling of commercial products, or endorsements of political candidates or positions. We reserve the right to remove any inappropriate comments. We also cannot address individual medical concerns or provide medical advice in this forum. CSD research informs Senate proposal. However, calorie restriction is not practical for most people and it is difficult to maintain long-term, despite the significant morbidity and likely mortality benefits. This does not, however, mean the study of CR is without merit or does not have broader applicability. This line of research has provided significant insights into dietary effects on human metabolism and overall impacts on health, illness, aging, and possibly lifespan. Home Knowledge Center Article Calorie Restriction CR — What is it and what does the research tell us? In Brief. Table Comparison of heart rate and hr HRV between long-term CR and WD individuals 4. Percentage change in cardiometabolic parameters, adapted from reference. More Like This Mind Your Manual and Eat Your Vegetables. Read More about Mind Your Manual and Eat Your Vegetables. Jeffrey P. Research and White Papers. Obesity: A Silent Pandemic. Read More about Obesity: A Silent Pandemic. The Expanding Diabetes Classification Matrix: Types 1, 2 And More …. Read More about The Expanding Diabetes Classification Matrix: Types 1, 2 And More …. Global Medical Researcher, Strategic Research. References Weiss, E. Caloric restriction: powerful protection for the aging heart and vasculature. American Journal of Physiology Oct; 4 : HH et al Calorie restriction in humans: an update. Ageing Research Reviews Oct; Available from: Calorie restriction in humans: An update - PubMed nih. Can calorie restriction extend your lifespan? Harvard University. Available from: Can Calorie Restriction Extend Your Lifespan? Caloric restriction may reverse age-related autonomic decline in humans. Aging Cell. Available from: Caloric restriction may reverse age-related autonomic decline in humans - PubMed nih. The heart was quickly removed and cut into halves from the center of left ventricle along the long axis, one for frozen sections. Apoptosis assay was carried out according to the instructions of TUNEL kit Roche, US and images were analyzed using a fluorescence microscopy. Mice blood was collected from the eyes after successful anesthesia with ether. The blood was immediately placed in centrifuge tubes pre-treated with sodium heparin and centrifuged at 4 °C, rpm for 15 min to collect the plasma. Plasma cholesterol content was determined by ELISA kit. Oleate and glucose oxidation, glycolysis, and glucose uptake were tested with a working heart and Langendorff system. Perfusate was recycled and collected every 5 min to test the radioactivity, and 3 H and 14 C signals were detected to discriminate metabolic products from fatty acid and glucose, respectively. The fatty acid level was determined by the production of [9, 10]- 3 H 2 O from oleate by filtering through anion-exchange 1-X2 resin Bio-Rad, Hercules, CA, US. Meanwhile, glucose oxidation was measured by both the 14 CO 2 gaseous dissolved in sodium hydroxide and 14 CO 2 separated from 14 C-glucose by sulfuric acid. For glucose uptake and glycolysis measurements, perfused radio buffer was recycled only through aorta and collected every 5 min to test the radioactivity. The rate of glucose uptake and glycolysis was calculated by the amount of 3 H 2 O production. Scintillation fluid 10 mL was added to each vial and mixed well to measure radioactive signal on a liquid scintillation counter. Cardiac tissue 30 µg from the same part of the heart was homogenized with RIPA lysate containing protease and phosphatase inhibitors. Protein concentration was determined using a BCA protein assay kit Beyotime Institute of Biotechnology, China. Rabbit antibodies P-AMPKα thr, , AMPKα s , PPAPγ s , and SOD 2 , were purchased from Cell Signaling Technology UK rabbit anti-P-PGC 1a ser, AF , and PGC 1a NFP from Novus Biologics, and SIRT 1 monoclonal antibody ab from Abcam USA. The target signals were detected using ECL luminescence reagents and an electrophoretic gel imaging and analysis system. Statistical analysis was performed using SPSS The significance of differences was determined by the use of a two-tailed Student's t test and analysis of variance ANOVA. The study was conducted in compliance with the ARRIVE guidelines and all methods were conducted in accordance with relevant guidelines and regulations. The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health NIH Publication No. The University of Mississippi adheres to the principles for biomedical research involving animals developed by the Council for International Organizations of Medical Sciences and complies with the US Council on Animal Care guidelines. All animal procedures were approved by the UMMC Health Sciences Animal Welfare Committee. The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Yellon, D. Myocardial reperfusion injury. Article CAS Google Scholar. Li, L. et al. Ginsenoside Rg1 ameliorates rat myocardial ischemia—reperfusion injury by modulating energy metabolism pathways. Article Google Scholar. Endo, J. Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. Wolf, A. Astaxanthin protects mitochondrial redox state and functional integrity against oxidative stress. Lakatta, E. Perspectives on mammalian cardiovascular aging: Humans to molecules. Part A Mol. Mariani, J. Tolerance to ischemia and hypoxia is reduced in aged human myocardium. Li, Y. Theranostics 10 12 , — Turer, A. Circulation 13 , — Li, T. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia—reperfusion injury. Cell Metab. Green, C. Molecular mechanisms of dietary restriction promoting health and longevity. Cell Biol. Madeo, F. Caloric restriction mimetics against age-associated disease: Targets, mechanisms, and therapeutic potential. Most, J. Impact of calorie restriction on energy metabolism in humans. Vanhooren, V. The mouse as a model organism in aging research: Usefulness, pitfalls and possibilities. Ageing Res. Han, Y. β-Hydroxybutyrate prevents vascular senescence through hnRNP A1-mediated upregulation of Oct4. Cell 71 6 , — e5 Giacomello, E. The potential of calorie restriction and calorie restriction mimetics in delaying aging: Focus on experimental models. Nutrients 13 7 , Sung, M. Age-related cardiovascular disease and the beneficial effects of calorie restriction. Heart Fail. Yan, X. The effect of caloric restriction on the increase in senescence-associated T cells and metabolic disorders in aged mice. PLoS One 16 6 , e Shinmura, K. Impact of long-term caloric restriction on cardiac senescence: Caloric restriction ameliorates cardiac diastolic dysfunction associated with aging. Maharajan, N. Caloric restriction maintains stem cells through niche and regulates stem cell aging. Improved cardiac metabolism and activation of the RISK pathway contributes to improved post-ischemic recovery in calorie restricted mice. North, B. The intersection between aging and cardiovascular disease. Effects of caloric restriction on cardiac oxidative stress and mitochondrial bioenergetics: Potential role of cardiac sirtuins. Song, Y. Metformin alleviates hepatosteatosis by restoring SIRT 1 -mediated autophagy induction via an AMP-activated protein kinase-independent pathway. Autophagy 11 1 , 46—59 Xin, C. Qi, D. AMPK: Energy sensor and survival mechanism in the ischemic heart. Trends Endocrinol. Zhang, Y. Pineal Res. Meng, X. Becatti, M. SIRT 1 modulates MAPK pathways in ischemic-reperfused cardiomyocytes. Life Sci. CMLS 69 13 , — Timmers, S. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Thirupathi, A. Multi-regulatory network of ROS: The interconnection of ROS, PGC-1 alpha, and AMPK—SIRT 1 during exercise. Tian, L. Calorie restriction in humans: An update. Spindler, S. Caloric restriction: From soup to nuts. Article ADS CAS Google Scholar. Kirkham, A. The effect of caloric restriction on blood pressure and cardiovascular function: A systematic review and meta-analysis of randomized controlled trials. Edinburgh, Scotland 40 3 , — Okoshi, K. Influence of intermittent fasting on myocardial infarction-induced cardiac remodeling. BMC Cardiovasc. van den Brom, C. Reducing caloric intake prevents ischemic injury and myocardial dysfunction and affects anesthetic cardioprotection in type 2 diabetic rats. Diabetes Res. Google Scholar. Nakaya, M. Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. Chang, J. |
| Targeting Cardiovascular Risk Factors Through Dietary Adaptations and Caloric Restriction Mimetics | Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. You can also search for this author in PubMed Google Scholar. University of Western Ontario, London, Ontario, Canada. George W. Reprints and permissions. Effects of Caloric Restriction on Cholesterol Metabolism in Hyperlipemic Obese Subjects. In: Manning, G. eds Atherosclerosis. Advances in Experimental Medicine and Biology, vol Springer, Boston, MA. Publisher Name : Springer, Boston, MA. Print ISBN : Online ISBN : eBook Packages : Springer Book Archive. Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Policies and ethics. Skip to main content. Abstract It has been known for some time that cholesterol synthesis is decreased on caloric restriction and is increased in obesity 1,2. Keywords Bile Acid Caloric Restriction Cholesterol Synthesis Dietary Cholesterol Fecal Excretion These keywords were added by machine and not by the authors. Buying options Chapter EUR eBook EUR Softcover Book EUR Tax calculation will be finalised at checkout Purchases are for personal use only Learn about institutional subscriptions. Preview Unable to display preview. References Tomkins, G. PubMed CAS Google Scholar Nestel, P. Article PubMed CAS Google Scholar Schreibman, P. The Mediterranean diet is characterized by high fruit and vegetable intake combined with plenty of fish and unsaturated fatty acids derived mainly from extra-virgin olive oil, with minimal or no consumption of low saturated fat and processed food. Many epidemiological studies and randomized clinical trials report that the traditional Mediterranean diet is associated with lower risk for all-cause and cardiovascular disease mortality, coronary heart disease, metabolic syndrome, and diabetes mellitus type 2 37 , In a sub-study derived from the PREDIMED principal trial, the Mediterranean diet was found to improve high-density lipoprotein HDL atheroprotective functions Remarkably, similar effects on HDL function were reported in individuals suffering from metabolic syndrome, which were subjected to the Mediterranean diet coupled to exercise for 12 weeks only Increased polyphenol intake from Mediterranean diet is associated with improved levels of LDL-cholesterol, HDL-cholesterol, and systolic and diastolic blood pressures in older participants at high risk for cardiovascular disease. Furthermore, elevated polyphenol consumption reduces circulating inflammatory biomarkers, such as vascular cell adhesion protein-1, interleukin-6, tumor necrosis factor-α, which are linked to atherosclerosis Another sub-study of the PREDIMED trial reported reduced expression of genes involved in vascular inflammation, foam cell formation and thrombosis in a high cardiovascular disease risk population Growing evidence suggests that the markedly reduced risk for cardiovascular disease by the Mediterranean diet is attributed to its plant-rich nutrient composition with seafood as the predominant source of animal protein. For example, the Women's Health Initiative Observational Study demonstrated that increased consumption of baked or boiled fish, but not fried fish, inversely correlates with heart failure risk in postmenopausal women In agreement with these findings, a year follow-up study suggested that increased intake of long-chain omega-3 polyunsaturated fatty acids PUFAs and non-fried fish in early adulthood protects against the development of metabolic syndrome Similarly, the Mediterranean diet enriched with extra-virgin olive oil, but without reduced caloric intake, reduces the risk for diabetes mellitus type 2 in individuals with high cardiovascular risk In sum, the Mediterranean diet is a promising and feasible diet with manifold cardiometabolic benefits. However, since the PREDIMED trial has had its limitations 40 , additional randomized clinical studies are warranted to corroborate the efficacy of this most extensively studied dietary regimen. Caloric restriction is defined as a chronic reduction of overall calorie consumption without malnutrition. In patients with metabolic syndrome, caloric restriction reduces body weight and exerts beneficial effects on insulin levels, fasting glucose levels, lipoprotein composition and pro-inflammatory cytokines within 6 months of intervention In addition to weight loss in obese or overweight women, caloric restriction reduces leptin, total C-reactive protein CRP , LDL-cholesterol, triglycerides, blood pressure, fasting insulin and insulin resistance In another study, improved body weight and reduced epicardial fat accumulation were also observed in patients with diabetes mellitus type 2 subjected to caloric restriction. These effects were further augmented by physical activity, while cardiometabolic profiles were apparently unchanged Caloric restriction was shown to be a safe and well-tolerable intervention in healthy, non-obese individuals 41 , leading to body weight loss 19 , 20 , 42 , reduced fat mass and waist circumference 20 , 21 , 42 , and improved general health A long-term clinical trial reported increased energy expenditure without negatively affecting the quality of life in non-obese to moderately overweight cohorts A week long intervention with caloric restriction also potently improved peak oxygen consumption in older and obese patients with heart failure with preserved ejection fraction Caloric restriction exerts cardiac-specific effects that ameliorate aging-related decline in diastolic function These salutary effects on heart function might be mediated by the effect of caloric restriction on blood pressure, systemic inflammation, and cardiac fibrosis Mechanistically, the beneficial effects of caloric restriction are closely linked to autophagy, a cellular recycling process essential for cardiovascular homeostasis 44 , Caloric restriction mediates positive effects on the heart also via increased activity of SIRT1 and peroxisome proliferator-activated receptor gamma coactivator 1-α PGC1α , leading to reduced amount of reactive oxygen species ROS , and less fibrosis and inflammation Furthermore, caloric restriction lowers oxidative stress in the heart and vasculature by increasing the expression of endothelial nitric oxide synthase eNOS , and activating superoxide dismutase SOD and NADPH oxidase Importantly, non-cell autonomous mechanisms also contribute to the cardiovascular health benefits of prolonged caloric restriction. In fact, fasting induces the conversion of hepatic fatty acids into ketone bodies e. Notably, severe caloric restriction ~ kcal per day induces changes of gut microbiome composition during weight loss 50 , However, the consequences of gut microbiome composition alteration for health and disease in response to stringent caloric restriction are only beginning to unveil. A very recent clinical trial, with 80 post-menopausal women who were overweight or obese, revealed that severe calorie restriction imparts a reversible shift in the gut microbiome associated with improved glucose regulation and decreased adiposity, indicating improved metabolic health in dieters Collectively, caloric restriction exerts clear cardiometabolic benefits in both obese and non-obese individuals. However, caloric restriction might also cause adverse side effects on immunity, fertility and bone density. Hence, further research is warranted to develop more suitable dietary patterns or pharmacological alternatives to reproduce the health benefits of caloric restriction. In an effort to circumvent the complexity of counting calories and avoid the side effects associated with caloric restriction, other forms of dietary restriction with food intake limited to a daily time window, such as intermittent fasting and alternate-day fasting, have been proposed. Longer fasting periods of 24 h followed by ad-libitum food intake for 24 h are also practiced and known as alternate-day fasting. Although intermittent fasting and alternate-day fasting are not as well-studied as caloric restriction, emerging evidence suggests that they are more tolerable and their side effects are less prominent than in caloric restriction and, thus, both dietary interventions could represent promising and more feasible strategies to curtail the hypercaloric pandemic in the Western societies To this end, a study comparing the efficacy of caloric restriction and intermittent fasting restricted to 2 days a week in obese diabetic patients at risk of cardiovascular disease showed that both regimens reduce body weight and HbA1c levels, a measure of long-term blood glucose control Consistently, another small observational study on obese subjects with diabetes mellitus type 2 and receiving metformin reported that short-term intermittent fasting effectively reduces body weight and improves morning glucose levels. Interestingly, 6 out of 10 participants in this study described that intermittent fasting is highly tolerable, and reported readiness to follow intermittent fasting after study completion Of note, intermittent fasting was capable to improve health parameters in healthy, male athletes. Specifically, intermittent fasting reduced body fat mass without worsening body fat-free mass, muscle area and strength. These effects were associated with lower concentrations of insulin-like growth factor-1 IGF-1 and higher adiponectin levels, while leptin was not found reduced after adjusting for body fat mass By contrast, a recent meta-analysis concluded that the evidence supporting a positive effect of intermittent fasting on glucose remains uncertain, despite the robust body weight-lowering effect Interestingly, the analysis suggested that both intermittent fasting and caloric restriction equally improve cardiometabolic risk factors. Irrespectively, larger studies with long-term follow-up are necessary to clearly determine the effect of either regimen on hard cardiovascular end-points, such as myocardial infarction, heart failure as well as cardiac and all-cause mortality. With regard to alternate-day fasting, a short-term trial conducted in obese adults, which showed high adherence to alternate-day fasting at least for 8 weeks, revealed manifold cardiometabolic benefits, including reduced body weight, body fat percentage, total and LDL-cholesterol, triglycerides as well as systolic blood pressure Interestingly, short-term alternate-day fasting effectively reduces body weight, body fat mass and waist circumference despite high-fat dietary intake on non-fasting days. However, although alternate-day fasting improves plasma levels of LDL-cholesterol and triacylglycerol in obese individuals, HDL-cholesterol, blood pressure and heart rate are not altered At variance with short-term studies, a long-term trial reported low adherence to the prescribed amount of energy intake and, accordingly, a high dropout of obese, otherwise metabolically healthy adults subjected to alternate-day fasting within the 1-year follow-up This study also included a caloric restriction group, which exhibited higher compliance rates than the alternate-day fasting group. Although reduction in body weight was evident upon both alternate-day fasting and caloric restriction, none of the fasting regimens improved blood pressure, plasma lipid profile, or markers of glucose control and inflammation. In addition, HDL-cholesterol levels that were higher at 6 months of alternate-day fasting, were not improved after 12 months Further studies with larger cohorts and longer duration are warranted to examine the fasting-specific effects of alternate-day fasting and intermittent fasting, and directly compare their effects to diets that only reduce daily net calories. Along similar lines, initial short-term studies in non-obese individuals highlighted the positive impact of alternate-day fasting on body weight loss in absence of clear metabolic changes, but increased fat oxidation. Notably, participants reported difficulty to adhere to alternate-day fasting due to severe hunger on the fasting days By contrast, the InterFast trial showed that alternate-day fasting is capable of improving cardiometabolic markers in healthy non-obese subjects, including reduced body weight, fat-to-lean ratio, and LDL-cholesterol Furthermore, alternate-day fasting increases ketone bodies on fasting and non-fasting days , and reduces the inflammatory marker sICAM-1, suggesting that alternate-day fasting is a viable dietary adaptation also for non-obese individuals. Importantly, this 4-week long intervention trial reported no adverse effects on immunity or bone density. In sum, growing body of evidence indicates potential cardiovascular benefits of intermittent and alternate-day fasting However, it is still not clear whether these nutritional regimens, wherein food intake is limited to a consistent time-restricted interval without changes in nutritional quality or quantity, confer a significantly better adherence than caloric restriction. Also, it remains elusive whether the cardiometabolic benefits of these regimens can be applied to the general healthy population or specific groups with disorders, such as obese individuals with metabolic disease. Hence, larger studies, preferably with long-term follow-up, will be required to address these open issues. Recent years have seen an increasing interest in fasting-mimicking diets and caloric restriction, which might offer a more feasible alternative to stringent forms of fasting. For example, a randomized clinical trial was designed to investigate the effects of fasting mimicking diets, which are low in carbohydrates and protein and high in unsaturated fats, on cardiovascular disease and risk factors, including aging and diabetes mellitus type 2 The authors observed that practicing low calorie fasting mimicking diet for only 5 consecutive days per month results in a reduction of body mass index BMI , arterial blood pressure, fasting glucose, and IGF-1 levels. Generally, subjects who are at greater risk for disease, exhibit a larger benefit than individuals who have no other risk factors, confirming the relevance of fasting mimicking diet for disease prevention. Similarly, caloric restriction mimetics—natural and pharmaceutical compounds with intrinsic pro-autophagic action—might offer superior compliance, and are under intensive investigation as they have been shown to improve cardiovascular health and they might be used for the treatment of cardiovascular disease Therefore, in the following section commonly used and well-studied caloric restriction mimetics will be discussed. Further, we will briefly describe their mode of actions and summarize the current evidence for the cardiovascular and metabolic effects of selected caloric restriction mimetics Figure 2. Figure 2. Cardiovascular and metabolic health-promoting effects of caloric restriction mimetics in animal models with cardiovascular risk factors. Spermidine is a natural polyamine and autophagy inducer that exerts pleiotropic cardioprotective effects by lowering high blood pressure in salt-sensitive Dahl rats, while reducing maladaptive hypertrophy and attenuating the decline of diastolic function 59 , 60 , and arterial elastance in aged mice In addition to its direct cardioprotective effects, accumulating evidence demonstrated the anti-obesity impact of spermidine supplementation in rodents consuming a high-fat diet HFD. In particular, spermidine counteracts HFD-induced body weight gain and obesity-associated alterations by increasing lipolysis in visceral fat and improving blood glucose control in obese mice 62 , 63 , and diabetic rats Interestingly, spermidine treatment appears to provide no additional metabolic benefit in young and old mice consuming normal chow 59 , 63 , suggesting that salutary metabolic effects of spermidine might be limited to hypercaloric and pro-diabetic dietary regimens. Beside the regulation of lipid metabolism, spermidine attenuates inflammatory response in the adipose tissue by decreasing inflammatory cytokine and chemokines expression Spermidine is also capable of reducing circulating TNFα levels during aging, thereby counteracting chronic low-grade inflammation in old mice The cardiovascular health-promoting effects of spermidine supplementation are predominantly attributed to its cytoprotective autophagy-inducing properties. For example, cardiomyocyte-specific Atg5-deficient mice exhibit no cardiac benefits upon spermidine supplementation 59 , while the aortic rings of spermidine-fed mice display no functional advantages over their non-treated controls upon incubation with the autophagy inhibitor chloroquine Autophagy-inducing capacity of spermidine relies on the inhibition of several acetyltransferases, including EP, one of the major negative regulators of autophagy These autophagy-stimulatory properties are mediated via hypoacetylation of histones 67 , and autophagy-related genes, such as Atg5, Atg7 , and Atg8 In addition, spermidine has been proven to inhibit the mammalian target of rapamycin complex 1 mTORC1 66 , a key regulator of cell growth and metabolism, and to activate AMP-dependent protein kinase AMPK More recently, spermidine was reported to stimulate autophagy through the hypusination of eukaryotic translation initiation factor 5A-1 eIF5A , which in turn controls the expression of transcription factor EB TFEB , a master regulator of lysosome biogenesis and autophagy By contrast, age-related decline of spermidine levels and subsequent down-regulation of TFEB may cause reduced autophagic activity in the adaptive immune system, as well as in other tissues. However, although many protective effects of spermidine are autophagy-dependent and associated also with increased mitophagy, a selective form of autophagy that degrades dysfunctional mitochondria 59 , 71 , a recent study showed that enhanced lipolysis by spermidine was independent of autophagy in adipose tissue Indeed, spermidine effectively stimulated lipolysis in HFD-fed mice with adipose-specific autophagy deficiency. In humans, circulating spermidine levels decline with age 72 , and reduced endogenous concentrations of spermidine appear to be associated with age-related deterioration of cellular homeostasis attributed to decreased autophagy The upregulation of endogenous spermidine levels extends lifespan across multiple species, including mice. Spermidine is abundantly found in wheat germ, soybeans, and nuts 73 , and reportedly enriched also in the Mediterranean diet While the optimal concentration of spermidine in humans to maintain optimal autophagy levels for healthy aging still needs to be determined, self-reported dietary spermidine intake has been shown to inversely correlate with arterial blood pressure, risk of both fatal and overt heart failure as also other cardiovascular disease 59 , and overall mortality Taken together preclinical evidence supports the translational potential of spermidine to ameliorate cardiovascular risk factors, including hypertension and HFD-induced obesity. Dietary spermidine supplementation has been proven safe with no adverse effects reported and well-tolerated in healthy volunteers 74 , 76 , and older adults at risk for dementia Further larger and long-term clinical investigations are needed to elucidate whether cardiovascular risk factors may be counteracted by ingesting polyamine-rich food items, polyamine-enriched plant extracts, synthetic spermidine, or by stimulating polyamine synthesis in the gut microbiome through supplementation of prebiotics or probiotics. The polyphenol resveratrol, which is abundantly found in the skin of grapes and red wine, is one of the most extensively studied natural and bona fide caloric restriction mimetics. Interest in the cardiovascular health-promoting properties of resveratrol has been greatly influenced by experimental studies, demonstrating that resveratrol protects against metabolic disturbances induced by HFD and, thus, prevent early mortality in obese mice The favorable effects of resveratrol on the cardiovascular system could be, at least in part, explained by its capability to promote vasodilation 79 , 80 , suppress atherosclerosis 81 , improve glucose tolerance and insulin sensitivity 78 , 82 , 83 , inhibit LDL oxidation 84 , 85 , and decrease plasma triglycerides and cholesterol accumulation In addition to reported protection from the negative consequences of an obesogenic diet, such as insulin resistance 87 , resveratrol has been demonstrated to exhibit anti-inflammatory effects 88 , The anti-inflammatory properties of resveratrol include down-regulation of genes involved in inflammatory pathways 90 , as well as systemically inhibited expression of TNFα, IL-6 90 , 91 , IL-1β, ICAM-1, and iNOS Evidence has accumulated indicating that resveratrol, both in vivo and at nutritionally relevant concentrations in vitro , can activate several interrelated signaling pathways in the cardiovascular system. Many of the beneficial cardiovascular effects of resveratrol are mediated by pathways that require SIRT1 in cardiomyocytes and endothelial cells 93 , Although both SIRT1 and AMPK are necessary for resveratrol-induced health promotion 87 , 95 , there are likely other molecular targets of resveratrol that contribute to its cardioprotective effects. Studies reported that resveratrol inhibits the nuclear factor kappa-light-chain-enhancer of activated B-cells NF-kB pathway 96 , attenuates vascular oxidative stress 97 , 98 , and upregulates eNOS 99 , , which is known to improve endothelium-dependent vasodilation through increased nitric oxide bioavailability. Importantly, SIRT1-mediated activation of autophagy is a key process in mediating many beneficial effects of resveratrol — Very recently, resveratrol was found to promote lysosomal function via endoplasmic reticulum calcium-dependent TFEB activation, which is associated with reduced intracellular lipid accumulation Importantly, inhibition of mTORC1 activity and presence of Unclike kinase 1 ULK1 were shown to be required for autophagy induction by resveratrol However, although resveratrol attenuates the activation of mTORC1, low dose resveratrol reportedly induces the expression of Rictor, a component of mTORC2 pathway Overall, despite the large number of molecular targets that have been identified responsible for the promiscuous effects of resveratrol, more research effort is needed before definitive mechanisms can be assigned to its multifaceted cardioprotective benefits. On the basis of available evidence, it can be endorsed that resveratrol-induced cardiovascular protection is controlled by many of the pathways e. Encouraging results from preclinical research have greatly increased the interest in resveratrol supplementation to mitigate cardiovascular risk factors in humans. A recent meta-analysis of 17 randomized clinical trials validated the blood pressure lowering effect of resveratrol Of note, lower systolic blood pressure is associated with metabolic changes In this small randomized control trial, 30 days of resveratrol supplementation decreased intrahepatic lipid content, circulating levels of glucose and triglycerides, and inflammation markers, while it stimulated adipose tissue lipolysis in obese men. By contrast, a recent study failed to demonstrate the efficacy of resveratrol against metabolic syndrome In fact, although resveratrol has been shown to modify risk factors in experimental models of obesity and cardiovascular diseases by phenocopying most of the transcriptional aspects and molecular mechanisms of caloric restriction, including the suppression of inflammatory response 91 , , it is important to note that clinical trials mostly failed to reproduce cardiometabolic improvements likely due to low in vivo bioavailability of resveratrol This is particularly relevant because in vivo evidence has been viewed increasingly important in endeavors to understand how resveratrol elicits its effects in humans and to ascertain the optimum doses and routes for mitigating cardiovascular risk factors. To this end, other small-molecule activators of SIRT1 have been developed. For instance, SRT has been demonstrated to extend lifespan and improve metabolic syndrome, insulin sensitivity, and endothelial dysfunction in mice, while a related compound, SRT, has undergone clinical phase I and II trials, revealing only minor adverse effects Interestingly, rapid metabolism of resveratrol and the composition of the gut microbiome were proposed to control the production of resveratrol metabolites, which are detected at higher levels in humans after intake than their parent compound, with similar biological effects Owing to its capability in modulating the composition of the gut microbiota, resveratrol may affect central energy metabolism and modify concentrations of satiety hormones to produce anti-obesity effects. Similar to resveratrol and spermidine, fasting also induces changes to the gut microbiome and improves immune homeostasis with a sustained beneficial effect on body weight and blood pressure in hypertensive patients with metabolic syndrome , suggesting that caloric restriction mimetics and dietary interventions promote cardiovascular health at least in part by regulating the abundance of certain microbes in the gut Along similar lines, nicotinamide NAM, also known as vitamin B3 was found to improve glucose homeostasis associated with positive effects on liver metabolism in absence of obesity-lowering effects in aged mice fed HFD Recently, we have also demonstrated that orally administered NAM to male and female ZSF1 obese rats with cardiometabolic syndrome evidently reduces hyperphagia-induced obesity This effect could be partially attributed to increased energy expenditure and improved metabolic flexibility. In addition, NAM moderately lowers high arterial blood pressure, while it improves diastolic dysfunction in ZSF1 obese rats, Dahl salt-sensitive rats and aged mice In another study, oral NMN supplementation late in life to aged mice was also found to elicit anti-aging effects on the vasculature by improving aortic stiffness in association with increased arterial SIRT1 activation and reduced vascular oxidative stress, suggesting that NMN delays arterial aging and its pathological sequelae Moreover, NR supplementation was shown to activate SIRT1 and SIRT3, improve mitochondrial function and protect against HFD-induced obesity in mice In fact, health-promoting effects of NAM coincide with reduced inflammation, oxidative stress and adipose tissue infiltration with leukocytes , The impact of niacin on lipid control and cardiovascular risk in humans was recently re-examined in a meta-analysis based on a systematic review of clinical trials that included 35, patients Collectively, this analysis revealed a marginal benefit of niacin as a monotherapy to elevate HDL-cholesterol levels, but raised doubts about the safety profile of niacin, especially in combination with statins. Despite its poor tolerability, niacin remains in use as an alternative lipid-lowering agent in statin-intolerant patients at cardiovascular risk. Amongst these, NR and NMN are the main precursors in ongoing or lately completed clinical trials In fact, a recent study in postmenopausal, overweight women with prediabetes, demonstrated that 10 weeks of NMN supplementation increases skeletal muscle insulin signaling, insulin sensitivity, and muscle remodeling These beneficial metabolic effects of NMN supplementation differ from the observations reported from NR trials conducted in obese middle-age and older men and women — , suggesting different biological functions of NMN and NR. Another clinical investigation showed that NR may have the potential for reducing blood pressure and aortic stiffness in healthy middle-aged and older individuals Additionally, NR has been shown to exert anti-inflammatory effects not only in aged healthy individuals, but also in hospitalized patients with heart failure , Of note, high doses of oral NAM are safe and have also been shown to reduce non-melanoma skin cancers as well as markers of cardiorenal injury , opening a new perspective on the previously understudied therapeutic potential of NAM. In this regard, a diet enriched in NAM and NA is associated with lower blood pressure and a reduced risk of overall and cardiac-specific mortality in humans Taken together, several challenges need to be overcome before experimental findings on rodent models of cardiovascular risk factors can be translated into clinics. Future clinical trials need to be of longer duration and include a follow-up assessment, involve large numbers of patients, and consider more appropriate conversion of drug doses from rodent studies to human trials The biguanide metformin, which originates from the French lilac, is the first-line drug used for the treatment of diabetes mellitus type 2 Although best known for its glucose-lowering effects, a growing body of evidence indicates that metformin extends lifespan and healthspan by mitigating age-associated conditions , , such as cancer, cognitive decline and cardiovascular diseases across various species , , Metformin exhibits a plethora of direct effects on the cardiovascular system. For example, it potently protects against hypertrophy in a pressure overload rat model, likely via increased AMPK and eNOS phosphorylation and higher nitric oxide production , leading to improved endothelial function and vasodilation Metformin effectively reduces atherosclerotic plaque size in high-cholesterol diet fed rabbits by decreasing high-sensitivity C-reactive protein and inhibiting the NF-kB pathway in the vascular wall In addition, metformin is capable of stabilizing atherosclerotic plaques by activating AMPK in ApoE -knock-out mice , resulting in better cardiovascular outcomes as calcification of plaques is associated with their instability and serves as a negative predictor of mortality , Metformin attenuates inflammatory response in rabbits fed an atherogenic diet by reducing infiltration of macrophages , which is known to result in their differentiation to foam cells and atherosclerotic plaque formation Furthermore, metformin suppresses the NLRP3 inflammasome and upregulates autophagy in mice with diabetic cardiomyopathy through the activation of AMPK and inhibition of mTORC , , both of which regulate aging-related pathways, leading to prolonged lifespan Furthermore, metformin increases the expression and activity of SIRT1, while it attenuates the activation of PGC1α, a central energy metabolism regulator As most of the research endeavors focused on the glucose-lowering effect of metformin, it is not surprising that the majority of clinical trials were designed to investigate the beneficial role of metformin on diabetes mellitus type 2. However, several human studies assessed the impact of metformin monotherapy on other age-associated comorbidities as well. For example, metformin reduces pro-inflammatory cytokine levels in older diabetic patients, suggesting that metformin has the potential to attenuate age-related low-grade chronic inflammation, reduce the predisposition toward inflammation-related comorbidities, and improve survival of diabetic patients In another clinical investigation, the use of metformin was assessed in the context of cardiovascular outcome in patients with diabetes mellitus type 2 and chronic kidney disease The authors that analyzed data from the TREAT trial demonstrated that metformin reduces the incidence of cardiovascular events as well as cardiovascular death and all-cause mortality. Importantly, metformin was found to be safe for patients with chronic kidney disease, which is in contrast with the previous assertion that metformin commonly induces lactic acidosis In pubertal children with diabetes mellitus type 2 and metabolic syndrome, metformin improves various health parameters, including BMI, leptin levels, fat mass and liver fat Interestingly, some of these beneficial effects were maintained after completing the 24 months of metformin treatment, suggesting that metformin is well-tolerated and has a potential long-term benefit in adolescents at risk. In the REMOVAL trial, patients with diabetes mellitus type 1 displayed lower LDL-cholesterol levels after 3 years of metformin treatment Recently, a meta-analysis that included 16 studies and nearly 2 million participants revealed that metformin reduces overall cardiovascular risk, including mortality and incidence, in patients with diabetes mellitus type 2 Another comprehensive meta-analysis of studies described a general drop in all-cause mortality and occurrence of cardiovascular disease in diabetic patients upon metformin treatment as compared to diabetic patients receiving other medication and, interestingly, even non-diabetic subjects These observations highlight that metformin could extend lifespan and healthspan by acting as a geroprotective drug. However, studies in healthy or non-diabetic populations are rare and showed conflicting results. For example, the CAMERA study failed to produce the beneficial effects of metformin on cardiovascular disease prevention in non-diabetic patients with high cardiovascular risk By contrast, 6 weeks of metformin treatment reduced body weight, improved insulin secretion, lowered LDL and triglyceride levels in an elderly population exhibiting impaired glucose tolerance but no previous history of diabetes Of note, the 6-year Targeting Aging with MEtformin TAME clinical trial 3 , which started in as a large randomized controlled and multicenter study, including over 3, participants between the ages of 65—79 without diabetes but who are at high risk for the development of chronic diseases of aging, is expected to generate highly valuable new knowledge about the impact of metformin on the primary outcome of death and major age-related chronic disease development, such as cardiovascular disease, cancer, and dementia Recent years have seen a growing interest in understanding how dietary interventions shape and interact with the most common cardiovascular risk factors, including hypertension, obesity, metabolic syndrome, and diabetes mellitus type 2. Substantial cardiometabolic improvements have been reported with fasting interventions such as reduction in blood pressure, body weight and fat mass, lower blood glucose, and improvement in insulin sensitivity, both in experimental and clinical studies. Although caloric restriction consistently improves several aspects of health, its application has been hampered by poor compliance and adverse side effects on bone health and immune response, especially in the elderly. To overcome these major hurdles, clinical trials on alternate-day or intermittent fasting, with higher statistical power and follow-up, are strongly needed before they can be implemented as a treatment strategy. Individuals practicing alternate-day or intermittent fasting should consider to include regular physical activity to maintain their energy expenditure. Emerging evidence indicates that the optimal cardioprotective diet is constructed around the traditional Mediterranean eating pattern. Another interesting aspect that warrants further attention is the effect of caloric restriction mimetics or dietary interventions aimed at weight loss on the gut microbiome changes in obese patients with diabetes mellitus type 2 or metabolic syndrome. Although these interventions propose beneficial clinical outcomes, their effect on the gut microbiome is only beginning to unfold. Interestingly, a combination therapy of resveratrol and spermidine synergistically induces autophagy at doses, which do not trigger effects of the same magnitude if administered alone. At present, however, it remains elusive what is the optimal dose for any of the caloric restriction mimetics that could provide health benefits or protect humans at risk of cardiovascular disease. Unlike the current drug development approaches that focus on individual diseases in isolation and consider specificity as a desirable outcome in disease prevention and treatment, both caloric restriction mimetics and caloric restriction exhibit a spurious mode of action, intercepting with multiple different targets Such pleiotropic mode of action appears advantageous in targeting the complex process of aging as the greatest risk factor for cardiovascular diseases and associated comorbid conditions. Thus, dietary interventions should aim to maintain optimum health and prevent cardiovascular diseases by attenuating the molecular causes of biological aging directly. Non-cell autonomous effects of caloric restriction mimetics and caloric restriction itself, such as the anti-inflammatory or immune modulatory functions, are increasingly viewed as relevant as cell autonomous mechanisms. Taking this into account, more research is needed to ascertain how different forms of fasting and caloric restriction mimetics can be the most favorable to further improve cardiometabolic markers in healthy adults and patients living with or at risk of developing cardiovascular disease. Based on the currently available data, harnessing caloric restriction mimetics or dietary interventions, such as intermittent fasting or the Mediterranean diet represent a promising preventive venue, which might reduce cardiovascular risk and the burden of cardiovascular disease. SS conceptualized the manuscript. JV, MA, and SS contributed to the research for writing the manuscript. JV and SL-H designed the figures and table. All authors contributed to the discussion, writing, and review of the manuscript. This work was supported by the Austrian Science Fund—FWF I and the European Research Area Network on Cardiovascular disease ERA-CVD, MINOTAUR to SS. MA acknowledges funding received from the European Society of Cardiology, the Austrian Society of Cardiology Präsidentenstipendium der ÖKG , and the Medical University of Graz START Fund. SL-H reports funding by the Austrian Science Fund - FWF V and BioTechMed-Graz Young Researcher Groups [YRG]. MA and SS are involved in a patent application related to the cardiometabolic effects of caloric restriction mimetics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. 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| Introduction | Apo B and apo A-I reduced, respectively, from 1. AL ad libitum, CR caloric restriction, FAO fatty acid oxidation, GO glucose oxidation, Gly glycolysis, GU glucose uptake. Aging Cell. CAS PubMed Google Scholar Young JB, Landsberg L. Article CAS PubMed Google Scholar Ahmed T, Das SK, Golden JK, Saltzman E, Roberts SB, Meydani SN. |
| Calorie Restriction (CR) – What is it and what does the research tell us? | RGA | Article CAS Calloric Scholar Zhang, Y. More on this caloric restriction and cholesterol Genes rdstriction dyslipoproteinaemias. Caloric restriction and cholesterol DH, Kim Immune system-boosting exercises, Yu BP, Chung HY. Copyright © Oxford University Press Cookie caloriv Cookie policy Privacy policy Legal notice. CR causes alterations which protect against age-related diseases and reduces inflammation, delaying or preventing age-related senescence. The study was conducted in compliance with the ARRIVE guidelines and all methods were conducted in accordance with relevant guidelines and regulations. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
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