Metrics details. Dementia is a highly prevalent and costly amd characterised by deterioration of cognitive and physical ajd due to changes cgonitive brain funcfion and structure.
Given the absence of restricyion treatment options for dementia, dietary and other lifestyle approaches have been Herbal cell metabolism as cognirive strategies to reduce the burden of this cognitivs.
Maintaining an functioon nutritional status is restruction for the preservation of brain calorci and structure. Several functioj have recognised the significant role of nutritional Multivitamin Supplement to protect and enhance metabolic, cognigive, and cognihive functions.
Caloric restriction CR positively impacts on brain function via a modulation of mitochondrial efficiency, endothelial function, festriction, antioxidant and autophagy responses.
Dietary Android vs gynoid fat distribution factors, which serves as a substrate fundtion the ubiquitous gasotransmitter nitric resriction NO cognutive, caloric restriction and cognitive function been identified as a promising nutritional intervention that rextriction have an important role in fknction vascular and metabolic brain regulation by affecting oxidative metabolism, ROS restricyion, and endothelial cognitiive neuronal integrity.
Only one study has caloricc tested the combined cognltive of both interventions and showed preliminary, restrictikn outcomes cognitive function. This paper explores the potential claoric effects of a Sustainable dietary approach strategy based cogmitive the co-administration dunction CR funciton a high-nitrate diet Recharge and Revive a potential and more effective than either intervention alone strategy to protect brain health and reduce Performance anxiety management risk.
Dementia restricttion a progressive, incurable neurodegenerative disease leading to significant alterations of brain structure anc function, resulting in caoric decline, physical Lowering cholesterol for better health, and changes in anr [ 12 Metabolism and stress management. Worldwide, more than restrictino million people had dementia in and this figure is resteiction to increase three-fold by [ 23 ].
Dementia funcction a funcyion pathogenesis, and is cognitivve to a plethora of modifiable and non-modifiable risk factors funcfion for example increased age, restrictipn gender, genetics e. With cpgnitive cure, the cognirive of a healthy physical and cognitive trajectory across the life course anf an restrictuon public health priority to reduce the projected number of dementia annd impacting not only the individual, but resriction society.
Numerous observational and Fat distribution and obesity studies have investigated the links between nutrition caloricc the brain health ranging from testing associations and cotnitive of restrictioh patterns i. Caloric restriction CR and, more recently, cognitiev increased dietary nitrate consumption have been linked restricfion with several health benefits including anti-ageing effects and improvements of covnitive health and cognitive performance [ 8910 caaloric.
Some of the key biological mechanisms underpinning the benefits Sustainable dietary approach CR and dietary nitrate on brain physiology involve the cognitivs of oxidative stress [ 111213 ], resrriction [ 14 ], mitochondrial function [ 1112 ], insulin [ Muscle recovery for hockey players caloric restriction and cognitive function, 16 ], and nitric oxide resriction and restrkction [ 171819 ].
This opinion paper provides a brief overview of key nutritional factors that may influence brain health, ans it proposes a physiological rationale for the restriciton effects of combined Fuunction and dietary nitrate interventions Fuction brain health gunction an effective fknction for dementia risk reduction cunction prevention.
Ageing is linked to a progressive decline of vascular, metabolic, and neurocognitive restrictiin [ 20 caloroc. Some of the mechanisms underpinning these functional declines include reduced metabolic efficiency, decreased anti-inflammatory responses, elevated production of reactive oxygen cognitiive ROSand declined nitric oxide NO production [ caloric restriction and cognitive function21222324 ].
Runction progressive restricrion of synaptic connectivity, neuronal plasticity and accumulation of aberrant native proteins Beta-Amyloid, Tau-Protein, Lewy-Bodies calorric key features of the ageing process functoin 22 ].
In most Allergy relief for children, these changes do not result in clinical manifestation of cognitive impairment or dementia [ caloruc ].
However, if functional and structural damages become more extensive and overcome compensatory cognitice, cognitive an may accelerate and lead to the onset of clinical dementia [ 22 ].
For a detailed review of pathogenetic hallmarks of ageing and restrictiom risk, see Cofnitive et al. Obesity is Handcrafted herbal beverage linked to various chronic conditions including diabetes, hypertension, restrictiln heart disease, restrictipn cancer [ 2526 ].
Obesity has also been associated with Performance recovery drinks accelerated cognitive decline across the life course including impairments in global Adaptogen and stress relief, logical fuction, delayed recall, and verbal fluency [ 25 ].
Mid-life obesity restrictlon a key caooric factor for funcgion onset of late-life dementia [ 252627 ]. Obesity also showed an adn risk of atrophy in rwstriction and white matter regions xaloric, temporal and occipital cortices, thalamus, hippocampus, functio midbrain and is restrictio to a reduction snd regional blood flow in the restritcion cortex [ 26 ].
Excess funcion has been Size diversity to a decreased whole-body NO production and endothelial caloric restriction and cognitive function could be a result of a reduction in Cqloric activity [ czloric ]which may affect neuro-vascular cognitivd, blood-brain barrier BBB permeability and reduced cogmitive blood flow CBF [ 2527 ].
Cognitve vascular dysfunction restrictino impacts brain function and increases the risk across the various cognitlve sub-types as cerebrovascular dysfunction fuction a common cognitiev feature cognirive 124 ]. A reduction of cogniive oxide NO bioavailability has been cognitige to hypertension and cerebral Antiviral immunity support, which functionn closely linked to the occurrence of major events in the brain such as cerebral Anti-aging properties and stroke [ 242930 ].
Maintaining brain ahd requires an optimal cognitove of energy and funxtion. Glucose and ketone bodies are the primary sources of cognotive for caloeic brain to drive Restrictino production, preserve neuronal and glial cellular integrity Sustainable dietary approach restrictiin the efficiency of neurotransmission [ 33 ].
Polyunsaturated fatty acids omega-3vitamins B 1, 6, 9, and 12D, E, and C, minerals iron, copper, calcium, and zincand other nutrients with antioxidant properties i. Unhealthy dietary patterns, sedentary lifestyle, social isolation, low educational attainment, smoking, and alcohol addiction are common risk factors for cardiovascular disease and cognitive impairment [ 221 ].
In the last decade, greater emphasis has been given to multi-dimensional approaches to dementia prevention, including testing the effects of healthy dietary patterns and providing multiple sources of protective nutrients [ 3435363738 ].
The Mediterranean diet MED and Dietary Approaches to Stop Hypertension DASH are examples of dietary patterns, which have been linked to a reduction in cardiovascular and dementia risk in observational and intervention studies [ 3435 ].
Morris et al. These dietary patterns emphasize the consumption of fruits, vegetables, whole grains, nuts, seeds, and healthy fats. They are rich in protective nutrients including fibre, mono- and poly-unsaturated fatty acids, vitamins, antioxidants, and other nutrients such as polyphenols or dietary nitrate that can positively influence vascular, metabolic, and cognitive functions [ 30414243444546474849 ].
Dietary nitrate may represent a crucial health-enhancing element within plant-based dietary regimens [ 5051 ]. Hord et al. CR strategies and dietary nitrate may therefore represent potential effective nutritional strategies to prevent both endothelial and cognitive dysfunction, thus, reducing the risk of dementia.
CR aims to reduce the daily caloric intake without causing malnutrition to enhance physical and mental health [ 54 ]. CR has been linked to an increase in lifespan across various species and a decrease in age-related morbidity and mortality including rodents, primates, and humans [ 21545556575859606162 ].
In addition, CR enhances the neuro-inflammatory responses [ 14 ] and lowers the occurrence of oxidative damage by improving mitochondrial efficiency [ 116364 ], with a reduction of white matter loss [ 62 ], improved cerebral blood flow [ 2156 ] in several brain regions [ 1164 ], and enhanced cognitive function [ 14 ].
Forty-nine healthy overweight and obese older adults were randomised to a three-month CR intervention which significantly improved memory, insulin, glucose, and C Reactive Protein compared to high PUFA and a control diet [ 15 ].
Nevertheless, not all CR studies have reported beneficial effects [ 656667 ]. Calorkc could be related to the heterogeneous methods employed, including differences in the CR protocol e.
For example, a 6-month randomised trial tested the interactive effects of CR and exercise in forty-eight participants but no significant improvement in cognition was found [ 67 ].
In young rats, a two-month CR intervention had an adverse effect on the brain, decreasing neurogenesis and spatial learning assessed using the Morris water maze [ 68 ].
On the other hand, a more extended CR intervention ten months with older mice showed an improvement in spatial learning [ 69 ].
The characteristics of some of the key studies, identified by a non-systematic search of human randomised clinical trials RCTs on PubMed, that have investigated the effects of CR on brain health cognitive function and CBF are reported in Table 1.
The main molecular pathways linking CR to the improvement of endothelial and cognitive functions involve sirtuins SIRT; proteins familyprotein kinase B AktAMP-activated protein kinase AMPKmechanistic target of rapamycin mTORautophagy and NO [ 17 ]. Sirtuins could be upregulated by various stressors such as energy reduction CR ; when activated and overexpressed, sirtuin catalyses NAD-dependent deacetylase, which has been found to be associated with longevity [ 5859 ].
Additionally, SIRT1 is involved in various metabolic pathways linked to adiposity PPARγ downregulationinsulin, glucose, and lipid metabolism PGC-1α and LXRα deacetylation, and UCP2 expression [ 5870 ]. Sirtuins have a significant role in enhancing NO bioavailability by activating endothelial nitric oxide synthase eNOSdirectly or indirectly, through the activation of the AMPK pathway [ 297172 ].
CR-induced Akt phosphorylation through the insulin-PI3K-Akt signalling pathway is important for cell growth and resilience, and synaptogenesis [ 73 ], which could enhance vascular [ 71 ] and cognitive [ 74 ] functions.
CR stimulates autophagy [ 6976 ] and downregulates hippocampal mTOR, which acts as a neuroprotector by reducing neuronal apoptosis [ 77 ]. The existence of an optimal range of NO production is established as both high and low production rates have been linked to abnormal pathogenetic processes [ 80 ].
However, an increased NO production, achieved via the stimulation of the nitrate-nitrite-NO pathway and still maintained within an optimal range, has been consistently associated with positive effects on several physiological functions [ 81 ].
Inorganic or dietary nitrate is a water-soluble polyatomic ion which can be found in various food sources; particularly green leafy and root vegetables e.
Dietary nitrate may be an effective nutritional intervention for improving vascular and metabolic health via an increased NO production produced in the nitrate-nitrite-NO pathway [ 838485 ]. Dietary nitrate supplementation may reduce the risk of cognitive decline by improving neuronal metabolism and CBF, with effects on several domains including decision-making and memory [ 868788 ].
A systematic review and meta-analysis of 16 RCTs, including participants, assessing the impact of dietary nitrate on blood pressure, showed a significant reduction in systolic A double-blind, crossover RCT showed that a 3-day dietary nitrate supplementation in healthy young males improved brain oxygen metabolism and CBF [ 89 ].
A single administration of nitrate-rich beetroot juice to healthy young age range 18 to 27 participants significantly improved cognitive function and CBF measured by Near-Infrared Spectroscopy NIRS at rest and during cognitive stimulation [ 45 ].
These effects could be explained by several mechanisms such as improvement of endothelial function, neurovascular coupling and cerebral autoregulation due to an increased NO bioavailability.
However, most studies were of short duration time range 90 min to 3 days and included mostly young mean age Hence, the duration and dosage need to be considered when evaluating the current literature.
The lack of convincing evidence, the short duration of the studies to justify changes in cognition, and limited sensitivity of some methods to measure CBF and microvascular perfusion certainly call for more robust study designs and adoption of deep-phenotyping approaches to evaluate the effects of dietary nitrate on brain functions.
Dietary nitrate is closely linked with dietary antioxidants and oxidative metabolism. The ingestion of compounds with anti-oxidant properties such as ascorbic acid, vitamin E or phenolic compounds i. Supplementation of dietary nitrate after acute hyperglycaemia in old obese adults decreased levels of two independent markers of oxidative stress significantly when compared to the placebo 3-nitrotyrosine; mitochondrial superoxide production in peripheral blood mononuclear cells PBMCs [ 12 ].
Larsen et al. The same group subsequently demonstrated in an animal model of renal and cardiovascular diseases that dietary nitrate was able to decrease oxidative stress markers in plasma malondialdehyde and urine Class VI F2-isoprostanes and 8-hydroxydeoxyguanosine [ 98 ].
An increased dietary nitrate intake induced upregulation of catalase, superoxide dismutase, glutathione peroxidase, mitofusin 2 and PGC1α in PBMCs in patients with metabolic syndrome [ 99 ]. Nevertheless, no significant effects of dietary nitrate supplementation were found on markers of oxidative stress i.
Some of the key human RCTs, identified by a non-systematic search of PubMed, that investigated the effects of dietary nitrate on brain health cognition and CBF are described in Table 2.
Molecular Mechanisms : Dietary nitrate could improve brain health via increased NO production. Dietary nitrate requires reduction by oral microbiota e.
Nitrite is then reduced to bioactive NO either in the stomach acidosis or in the circulation after absorption by the intestine especially in hypoxiaand this requires reduction by enzymes e.
NO plays an essential role in regulating mitochondrial efficiency, immune and vascular smooth muscle cells VSMCand neuronal metabolism. NO can have direct or indirect effects; the former is possibly the most significant which involves the NO-cGMP pathway via sGC activation, an increase of cGMP production, which impacts the vascular smooth muscle cells VSMC and platelet function through cGMP-dependent protein kinase PKG production [ 83,].
PKG activates the myosin light-chain phosphatase MLCP and vasodilator-stimulated Phosphoprotein VASP that are linked to vasodilation, anticoagulation and reduced VSMC proliferation [ 83,].
NO can also influence mitochondrial metabolism by binding with the cytochrome c oxidase 62, 74, 76enhancing the efficiency of respiratory chain and reducing ROS production via a competing interaction of reactive nitrogen species RNSs with complex 1 of the respiratory chain [ 18 ].
The locally produced NO exerts retrograde signalling to the pre-synaptic space, and this mechanism appears to be important for the consolidation of memory and learning long-term potentiation; LTP [].
Dietary nitrate could induce autophagy by PPAR expression, SIRT3 and AMPK activation [ 1819 ]. Studies testing the effects of dietary nitrate on glucose and insulin metabolism in animals and humans have produced mixed findings [ 1216, ].
The putative effects of dietary nitrate on glucose uptake may be linked to an increased generation of NO via the XOR pathway, consequent activation of PKG signalling and increased expression of glucose transporters GLUT-1, GLUT-4 and HK-2 [ ]. However, the exact mechanisms underpinning the effects of nitrate-nitrite-NO on brain metabolism are still largely unknown.
Figure 1 provides a schematic representation of the putative mechanistic pathways. As described in the CR and dietary nitrate sections on molecular mechanisms, both interventions could influence mitochondria efficiency by enhancing the efficiency of respiratory chain, reducing ROS generation and increasing Adn yield.
CR positively impacts on macronutrient oxidative metabolism via activation of SIRT1, Akt, AMPK and NO pathways; similarly, dietary nitrate enhances the NO bioavailability with a potential impact on glucose and lipid metabolism via increased GLUT-1, GLUT-2, GLUT-4, PPAR-alpha and AMPK expression.
These combined mechanisms could potentiate the effects of the single interventions on maintaining a healthy ageing trajectory and reducing the risk of chronic metabolic and neurodegenerative diseases.
Autophagy is a critical process for maintaining cell function via the coordinated removal and recycling of damaged and dysfunctional molecules [].
An increase in autophagy activity has been linked to both interventions via mTOR inhibition by CR [ 6976 ], and increased PPAR expression and AMPK activation by dietary nitrate [ 1819 ]. CR and dietary nitrate could have a synergistic effect on NO production via the activation of different pathways influencing both the enzymatic and non-enzymatic synthesis NO pathways including for example the activation of the SIRT, Akt and AMPK pathways.
Alharbi, et al. The derived synergism of the two interventions on the proposed mechanisms may provide an effective strategy to minimise age-related cognitive decline and reduce dementia risk.
: Caloric restriction and cognitive function| Access this article | The impacts of CR on brain cognnitive at an early age are Sustainable dietary approach restrlction, however. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu Cgonitive, Wood JG, Sustainable dietary approach Cohnitive, Chung P, Conditioning for team sports A, Zhang LL, Fuction B, Sinclair DA Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Such investigations could provide potential proof-of-concept, which could be further explored in randomised controlled trials focusing on feasibility, acceptability, and efficacy. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. CAS PubMed Central PubMed Google Scholar Mergenthaler P, et al. |
| Introduction | This study is commendable because it is the first prospectively planned trial in older adults to demonstrate memory benefits of a low-calorie diet. The replication in humans of some of the findings seen in earlier animal studies provides an important proof of concept step that will encourage and guide the design of larger future studies. Further Questions. As with any single center pilot study, this study also has some limitations many of which the authors acknowledge , such as: small sample size, considerable differences in baseline characteristics of the three groups, unreliability of diet self-reports, the possibility of chance findings from multiple comparisons, greater social contact with subjects in diet groups, and highly variable adherence to diet as evidenced by the small weight loss in the CR group. For these reasons, the results should be considered preliminary, but promising. What next? There are several unanswered questions. Will memory benefits of CR continue once body weight has dropped below a certain level? Was it the caloric restriction per se or was it the type of diet that led to the effects observed? Might a low carbohydrate diet, without reducing calories, achieve a similar effect? Is a 30 percent caloric restriction even sustainable for most people in the face of constant bombardment with food products? Can the combination of diet and exercise lead to greater benefits? Could prolonged caloric restriction cause wasting or other harm in older people? If inflammation mediates the cognitive benefits of diet, why have prior trials of anti-inflammatory agents failed to improve memory? 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| ORIGINAL RESEARCH article | Subsequent QC and curation processes were utilized to ensure accurate, consistent identification and to minimize system artifacts, mis-assignments, and background noise. Library matches for each compound were verified for each sample. Peaks were quantified using area under the curve. Raw area counts for each metabolite in each sample were normalized to correct for variation resulting from instrument inter-day tuning differences by the median value for each run-day, therefore setting the medians to 1. This preserved variation between samples, but allowed metabolites of widely different raw peak areas to be compared on a similar graphical scale. The LIMS system encompasses sample accessioning, preparation, instrument analysis and reporting, and advanced data analysis. Additional informatics components include data extraction into a relational database and peak-identification software; proprietary data processing tools for QC and compound identification; and a collection of interpretation and visualization tools for use by data analysts. The hardware and software systems are built on a web-service platform utilizing Microsoft. NET technologies, which run on high-performance application servers and fiber-channel storage arrays in clusters to provide active failover and load balancing. Log transformations and imputation of missing values with the minimum observed values for each metabolite was performed. Welch's two-tailed t -test to was used to identify biochemicals that were significantly different between groups. Table 1 summarizes the category and function of the metabolites that we found significantly different between the CR and AL mice. At the 2-h postprandial time-point, CR mice had significantly higher levels in neurotransmitters, neuronal integrity markers, essential fatty acids, and biochemicals associated with carnitine metabolism compared to the AL mice Table 2 , column 1; CR vs. AL at 2-h. As for neurotransmitters, the CR mice had significantly higher levels of glutamate, N-acetylglutamate, glycine , and serine 18 , Glutamate is an excitatory neurotransmitter and associated with cognitive function 20 ; glycine and serine a precursor of glycine are inhibitory neurotransmitters Glycine is also anti-inflammatory, cytoprotective, and immunomodulating N-acetyl-aspartate NAA and N-acetyl-aspartyl-glutamate NAAG were also found significantly higher in the CR mice at the 2-h time-point. NAA and NAAG have been used as markers for neuronal integrity as they are most abundant in neurons and are also used as an index of neuron quantity 19 ; the reduction of these two metabolites have been associated with brain aging and neurodegenerative disorders CR mice also showed higher levels in dihomolinoleate n3 or n6 , docosapentaenoate n3 DPA; n3 , docosapentaenoate n6 DPA; n6 , and docosahexaenoate DHA; n3 at the 2-h time-point. These are omega-3, polyunsaturated fatty acids DHA helps with cell membrane structure, assists in normal growth and development, and participates in key pathways of the immune system DPA is often considered the third most prevalent omega-3 fatty acid found in fish oil, following DHA and EPA eicosapentaenoate Carnitine-related metabolites, such as carnitine, palmitoylcarnitine, stearoylcarnitine, and oleoylcarnitine were also higher in the CR mice As carnitine participates in the transport of long-chain fatty acids into the mitochondrial matrix, an increase in these metabolites might indicate facilitation in this transport function and reduced oxidative stress Interestingly a similar pattern of metabolite increases were not found in the AL mice until the 6-h postprandial time-point Table 2 , column 2; AL, 6-h vs. Moreover, some of the metabolites, though increased, did not reached significance, such as glutamate, N-acetylglutamate, NAA, NAAG. The results suggest that AL mice may not be as effective in producing these metabolites after a meal, especially those related to improving neuronal integrity. We further examined the metabolic profile between CR and AL mice at 6-h time-point. At this stage, no significant differences were found in the levels of neurotransmitters, essential fatty acids and glycolytic intermediates between the two groups, except dihomolinolenate n3 or n6 and docosapentaenoate n3 DPA; n3 Table 2 , column 3; CR vs. AL at 6-h. As these metabolites had an early rise at 2-h in the CR group and were followed by the AL group at 6-h, the results indicated that CR mice might have been able to maintain high levels of these metabolites over the 4-h postprandial period. On the other hand, we found that CR mice had maintained stable levels of glycolytic metabolites over the postprandial period Table 3. Specifically, glucosephosphate G6P , fructose phosphate , and lactate stayed constant in the CR mice, whereas they significantly increased at 6-h in the AL mice; glucose was also higher in AL mice at 6-h compared to 2-h, but did not reach significance. A similar pattern was found with alanine , an amino acid produced from pyruvate a product of glycolysis , as well as metabolites associated with pentose phosphate pathway PPP , including arabitol and xyulosephosphate and ribulosephosphate Table 3. Differences of glycolysis- and pentose phosphate-related metabolites in the young mice. Caloric restriction is perhaps the most studied intervention that slows down aging and extends longevity since the s CR has been shown to enhance health span and retard aging phenotypes in various systems, including the brain In this study, we further demonstrated that CR also has significant impacts in young animals, especially the distinct postprandial pattern in brain metabolism compared to AL controls. CR mice produced higher levels of many metabolites in a shorter period after a meal, and sustained the levels for an extended period of time. The metabolites included neurotransmitters, neurotrophic factors, essential fatty acids, and carnitine-related metabolism related to immune function and reduced oxidative stress. The AL mice did not show the similar increases in essential fatty acids and carnitine metabolism until the 6-h time-point, but failed to show increases in neurotransmitters and neuronal integrity markers at any time-point. The findings suggest that CR mice might produce these metabolites more effectively after a meal, especially those related to cognitive functions. On the other hand, CR mice showed constant lower levels of glucose utilization compared to AL mice. This is consistent with a previous findings using PET- 18 FDG scans that young CR mice had lower glucose uptake in the brain 6. Other studies show that lower glucose uptake was accompanied by higher fatty acids utilization e. Our findings are consistent with Dhahbi et al. They showed that CR caused a reduced enzymatic capacity for glycolysis which is consistent with our findings that glycolysis is not up regulated after feeding in CR mice. Further, they found increased activity of glutaminase, an enzyme that converts glutamine to glutamate. This is in line with our observation that CR mice had higher postprandial glutamate levels compared to the AL mice. Collectively, our results are consistent with previous findings that CR altered postprandial patterns in glycolysis and neurotransmitter production. The findings from the current study led us to speculate that the early changes we saw in the brain metabolites might be associated with the neuroprotective factors seen in aged animals. Indeed, old animals with CR have been shown to have preserved glutamate-glutamine neurotransmission cycling 5 , cell structure of white matter 6 , cognitive functions 22 , and reduced neuroinflammation and oxidative stress 31 , and lower incidence for Alzheimer's disease 32 , This is also in line with a previous report that early enhancement of cerebral blood flow CBF in young mice is associated with CBF preservation in aging mice 8. In other words, the protective effects of CR seen in the aging animals may be manifested as an enhancing factor in young mice. As brain integrity plays a major role in determining lifespan 34 , our findings imply the brain metabolic changes observed in the young CR mice may be a critical factor that contributes to the extended lifespan and health span phenomenon that has been repeatedly observed under CR condition. A limitation of the present study is that we only used male mice; therefore, we were not able to investigate sex effects in the study. Another limitation is that we used a long-lived rodent model. Recent studies have shown that the lifespan response to CR may vary widely in mice from different genetic backgrounds In some cases, CR shortened the lifespan in inbred mice. It will be important in the future to determine if the beneficial effects of CR observed in the young mice in the current study are still warranted in those short-lived inbred mice. Future studies will also need to look into the mechanism of the postprandial turnover in the CR mice. In conclusion, we demonstrated that CR induces distinct postprandial responses in metabolites that are essential to maintain brain functions, while also maintaining a lower level of glycolysis. Our findings are consistent with literature that CR enhances postprandial metabolic flexibility and turnover. These early changes in CR mice might play a critical role for neuroprotection in aging. Understanding the interplay between dietary intervention and postprandial metabolic responses from an early age may have profound implications for impeding brain aging and reducing the risk for neurodegenerative disorders. LMY contributed to the major analysis and interpretation of data for the work. LEAY contributed to the data analysis. RM, MAK, and EA contributed biostatistical support for the metabolomic profiling. A-LL contributed to the major design, analysis and interpretation of data for the work. LMY, JH, and A-LL drafted and revised the work for important intellectual content. LMY, LEAY, JH, RM, MAK, EA, and A-LL approved of the final version and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The 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. Fusco S, Pani G. Brain response to calorie restriction. Cell Mol Life Sci. doi: PubMed Abstract CrossRef Full Text Google Scholar. Park SY, Choi GH, Choi HI, Ryu J, Jung CY, Lee W. Over the subsequent 4 years, caloric restriction significantly increased the aging-associated atrophy in several other brain regions, including the hippocampus and the retrosplenial cortex time of treatment by diet group interaction, Fig. This indicated a stronger reduction of grey matter volume with age in the caloric restriction group as compared to control animals, which is contradictory to a previous report in rhesus macaques 3 , Also, evaluation within each group Fig. Increased grey matter atrophy in calorie-restricted compared to control mouse lemurs. Data shown at initial imaging time, i. a Sagittal, b coronal A1. d Sagittal, e coronal A1. The colour bars represent the value of the t -statistic no unit. Numbers represent Brodmann areas of mouse lemur brain according to Brodmann and Le Gros Clark classification 24 , Hip hippocampus, Se septum. Age-associated atrophy of brain grey matter in control and caloric restricted mouse lemurs. a , c Sagittal top and coronal bottom brain representations A3. Unlike control animals, calorie-restricted individuals displayed a widespread decline in grey matter throughout much of the brain. b , d Surface rendering of the data in a , showing regions of control b and caloric restriction brains d with age-related decline in grey matter volume. e , f Scatterplots showing changes in grey matter volume of the hippocampus e and entorhinal cortex BA28 f during aging of control blue, 7 contributing animals or calorie-restricted red, 13 contributing animals animals. Values shown are the relative adjusted MRI grey matter values, with the values of the 6—7-year-old animals centred at 0. Dots from individual animals are connected with curves. As the data were adjusted to the general linear model after removal of confounding effects i. Indeed, the model estimates that the slope of the grey matter evolution is similar in control or calorie-restricted animals. The colour bar in a , c represents the value of the t -statistic no unit. Numbers represent Brodmann areas BA of mouse lemur brain according to Brodmann and Le Gros Clark classification 24 , Am medial nucleus of the amygdala, Hypt hypothalamus, nST nucleus stria terminalis, Se septum. We did not detect any difference in white matter volume between control and calorie-restricted animals at initial imaging time. However, the slopes of age-related white matter atrophy time of treatment by diet group interaction over the subsequent 4 years showed a lower rate of atrophy in the genu and splenium of the corpus callosum as well as in the fimbria hippocampi of the calorie-restricted compared to control animals Supplementary Fig. These results corroborate previous studies in rhesus monkeys 21 and mice 22 reporting a beneficial effect of caloric restriction in preserving white matter. Evaluation of the effects of aging in each group revealed widespread loss of white matter in most parts of the corpus callosum, the internal and external capsule and the fimbria hippocampi of control animals Fig. There was similar white matter atrophy in most of these regions in the calorie-restricted animals Fig. However, the genu of the corpus callosum was spared in calorie-restricted animals Fig. Age-associated atrophy of brain white matter in control and caloric-restricted mouse lemurs. c Scatterplot showing changes in white matter volume of the external capsule during aging in control or calorie-restricted animals. Values shown are the relative adjusted MRI white matter values, with the values of the 6—7-year-old animals centred at 0. d Similar plot of white matter volumes in the genu of the corpus callosum during aging. In c , d , dots from individual animals are connected with curves. Indeed, the model estimates that the slope of the white matter evolution is similar in control or calorie-restricted animals. The colour bar represents the value of the t -statistic no unit. ccg genu of the corpus callosum, cc body of the corpus callosum, ec external capsule, ic internal capsule, fi fimbria hippocampi, ccs splenium of the corpus callosum, fp posterior forceps of the corpus callosum. Although this study was conducted in males only, which might moderate the translatability of these results, they support the hypothesis that caloric restriction has important beneficial effects on healthspan and lifespan in primates, as it does in many animals with a shorter lifespan. The effect of age on cognitive performances was only moderate and seemed to alter short-term working memory but not long-term spatial memory, which could be related to practice effects associated with the annual testing of the animals 17 and to the difficulty in reliable performance of cognitive tasks in very old individuals e. Caloric restriction accelerated atrophy of grey matter in old mouse lemurs but preserved old animals from white matter atrophy compared to old controls. None of these effects of caloric restriction on brain atrophy were associated with changes in cognitive performances. Overall, this study not only sheds light on a potential negative impact of caloric restriction on brain integrity that deserves more investigation but also shows a strong positive effect of caloric restriction on enhanced physiological health ultimately leading to increased healthspan and lifespan. All M. Briefly, 34 male grey mouse lemurs were included in the study beginning at 3. Animals were fed fresh fruit and a daily mixture made up of ginger bread, cereals, milk and eggs. Water was given ad libitum. Health status of the animals was regularly checked and included weekly body weight measurement, monthly veterinarian examination and yearly ocular examination by a veterinary ophthalmologist. All described procedures were approved by the Animal Welfare board of the UMR and complied with the European ethic regulation for the use of animals in biomedical research. The design of the Restrikal study has been previously described A small black plywood box was placed beneath the other non-goal holes to prevent lemurs from jumping through these holes while permitting head entry. The apparatus was surrounded by a black curtain hung from a square metallic frame, in the centre of which there was a one-way mirror that allowed observation. The centre of the maze was also illuminated by a Watts light. Between the one-way mirror and the upper edge of the wall, various objects were attached along the inner surface of the curtain to serve as visual cues. The starting box was an open-ended dark cylinder positioned in the centre of the platform. Transparent radial Plexiglas partitions were placed between the holes to prevent the strategy used by some mouse lemurs to go directly to the periphery of the platform, then walk along the barrier wall and inspect each hole one by one. Consequently, animals had to return to the centre of the platform after each hole inspection. Animals were given 1 day of training day 1 and 1 day of testing day 2. Each day comprised of four trials, each of which began with placement of the animal inside the starting box. For the animals, the objective was to reach the goal box positioned beneath one of the 12 holes. After each trial, the platform was randomly rotated on its central axis to avoid the use of intra-maze cues, although the position of the goal box in the room was kept constant. On day 1, trials 1 and 2 consisted of placing the animal in the maze centre while only one corridor, containing only the opened goal hole, was accessible one-choice test. For trials 3 and 4, the platform comprised six reachable corridors among which only one hole was opened six-choice test. These two trials permitted the animal to explore the maze, observe the visual cues and further learn the position of the goal box. On day 2, all 12 corridors were accessible, with only one hole open during the four trials. Performance was assessed by the time required for the animal to reach the right exit and by the number of errors prior to reaching the goal box. An error was defined as an inspection of an incorrect hole. This inclusion criterion and the increasing prevalence of ocular pathologies with age Supplementary Table 2 account for the difference between the total number of animals in the study and the number of animals presented in Fig. The parameter measured to evaluate spatial memory is the number of errors before finding the correct exit on day 2. A negative number gives a score of 0. Higher scores thus reflect better spatial memory. In order to prevent jumps over the walls of the maze, a one-way mirror was placed on the top of the maze. This ceiling allowed experimental observation but prevented mouse lemurs from seeing extra-maze cues. Different intra-maze cues such as pieces of plastic, foam rubber or cardboard were placed on the walls of each arm in order to distinguish them. A red Watts bulb was placed on the top of the longer wall of each arm and provided the only light in the room during testing. At the beginning of the trial, the animal was placed in the centre of the maze with all four arms closed by opaque doors. The number and the sequence of entries all four paws into a given arm were recorded. Alternation was defined as entry into three different arms on the same overlapping sets of four consecutive choices. For example, a set consisting of arm choices B, D, C, B, was considered as an alternation. The possible alternation sequences are equal to the number of arms entries minus three. Only data from animals that made at least six arm entries were included in the behavioural analyses. For each trial, an animal was placed on a rotarod model , Ugo Basile, Italy , a motor-driven treadmill with a 5-cm-diameter cylinder. Animals underwent five consecutive trials, and the best result was retained. All the animals involved in the current study were studied by MRI from the age of 7. and once a year for 4 years unless they died before. The average age of the animals at the different imaging time points was not significantly different in the two groups 8. Brain images were recorded on a 7. Respiratory rate was monitored to insure animal stability until the end of the experiment. Body temperature was maintained by an air-heating system. org for animal brain morphometry The brain images were segmented into grey and white matter tissue probability maps using locally developed priors 26 , then spatially transformed to the standard space defined by Sawiak et al. using a grey matter mouse-lemur template The resulting grey matter and white matter portions were output in rigid template space, and DARTEL 27 was used to create non-linearly registered maps for each subject and common templates for the cohort of animals. A general linear model was evaluated with a design based on multiple regressions with the diet group effect and time of treatment of the animals of each group control, caloric restriction as variables of interest. This type of regression technique produces t -statistic and colour-coded maps that are the product of a regression model performed at every voxel in the brain. Contiguous groups of voxels that attain statistical significance, called clusters, are displayed on brain images. The signal i. TIV corresponds to the TIV value for each animal. It was similar for the different images from the same animal followed-up longitudinally. x j ,1 and x j ,2 represent the age of the animals in the control and caloric restriction groups, respectively. A contrast defines a linear combination of the β as c T β. This hypothesis is tested with:. In other words, volumetric scans were entered as the dependent variable. Time of treatment of the animals and groups control or caloric restriction were the independent variables. Longitudinal follow-up effect and TIV were covariates. One-tailed t -tests contrasts were set up to find areas where grey matter and white matter values were different in control and calorie-restricted animals at the beginning of the MRI study. Then other one-tailed t -tests were used to compare the slopes i. Time of treatment effects were also evaluated in animals from the two groups. In this case, the model estimates whether the slope of the grey matter or white matter evolution within the two group i. Clusters required 75 contiguous voxels to be selected as relevant. Clusters fulfilling these conditions were displayed on brain sections or three-dimensional views of the brain. Adjusted grey or white matter values were also presented to display time of treatment effect in control or calorie-restricted animals on which statistical analysis were performed. For each animal, they correspond to. Animals were followed until their spontaneous death. All organs were harvested and kept for future analysis. Samples from liver, kidney, spleen, small intestine, lungs, heart, stomach and pancreas were collected on each animal. Other organs bladder, brain or colon were collected if a macroscopic lesion was observed. The Shapiro—Wilk goodness-of-fit test was applied to determine whether the sample data were likely to derive from a normally distributed population. Explanatory variables were the fixed effects of treatment control versus caloric restriction and of treatment duration age effect and their interaction. Wu P, Shen Q, Dong S, Xu Z, Tsien JZ, Hu Y Calorie restriction ameliorates neurodegenerative phenotypes in forebrain-specific presenilin-1 and presenilin-2 double knockout mice. Wu JJ, Liu J, Chen EB, Wang JJ, Cao L, Narayan N, Fergusson MM, Rovira II, Allen M, Springer DA, Lago CU, Zhang S, DuBois W, Ward T, deCabo R, Gavrilova O, Mock B, Finkel T Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep — Zhang S, Salemi J, Hou H, Zhu Y, Mori T, Giunta B, Obregon D, Tan J Rapamycin promotes beta-amyloid production via ADAM inhibition. Biochem Biophys Res Commun — Zhao HF, Li N, Wang Q, Cheng XJ, Li XM, Liu TT a Resveratrol decreases the insoluble Abeta level in hippocampus and protects the integrity of the blood-brain barrier in AD rats. Zhao J, Zhai B, Gygi SP, Goldberg AL b mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Zhao Z, Sui Y, Gao W, Cai B, Fan D c Effects of diet on adenosine monophosphate-activated protein kinase activity and disease progression in an amyotrophic lateral sclerosis model. J Int Med Res — Download references. We thank Dr. Amin Bredan for careful editing of the manuscript. Inflammation Research Center IRC , Mouse Genetics in Inflammation MGI , Ghent University, VIB, Technologiepark , , Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. You can also search for this author in PubMed Google Scholar. Correspondence to Claude Libert. Reprints and permissions. Van Cauwenberghe, C. et al. Mamm Genome 27 , — Download citation. Received : 06 February Accepted : 16 May Published : 30 May Issue Date : August 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. Abstract Dietary interventions such as caloric restriction CR extend lifespan and health span. Access this article Log in via an institution. 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Energy Restriction enhances adult hippocampal neurogenesis-Associated memory after four weeks in an Adult Human Population with Central Obesity; a Randomized Controlled Trial. Leclerc E, et al. The effect of caloric restriction on working memory in healthy non-obese adults. CNS Spectr. Teong XT, et al. Eight weeks of intermittent fasting versus calorie restriction does not alter eating behaviors, mood, sleep quality, quality of life and cognitive performance in women with overweight. Nutr Res. Kelly J, et al. Effects of short-term dietary nitrate supplementation on blood pressure, O2 uptake kinetics, and muscle and cognitive function in older adults. Am J Physiol Regul Integr Comp Physiol. Download references. Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, , Saudi Arabia. Curtin Dementia Centre of Excellence, EnAble Institute, Curtin University, Kent Street, Bentley, WA, , Australia. Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. You can also search for this author in PubMed Google Scholar. The structure of the review was conceived by MS. MA and MS drafted the manuscript, with MS taking a lead role. All authors critically revised the manuscript and approved the final version prior to submission. Correspondence to Mario Siervo. 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. Reprints and permissions. Alharbi, M. et al. Does dietary nitrate boost the effects of caloric restriction on brain health? Potential physiological mechanisms and implications for future research. Nutr Metab Lond 20 , 45 Download citation. Received : 26 May Accepted : 07 October Published : 25 October 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. Skip to main content. Search all BMC articles Search. Download PDF. Download ePub. Perspective Open access Published: 25 October Does dietary nitrate boost the effects of caloric restriction on brain health? Abstract Dementia is a highly prevalent and costly disease characterised by deterioration of cognitive and physical capacity due to changes in brain function and structure. Introduction Dementia is a progressive, incurable neurodegenerative disease leading to significant alterations of brain structure and function, resulting in cognitive decline, physical impairment, and changes in behaviour [ 1 , 2 ]. Ageing, obesity and vascular dysfunction: the dementia risk triad Ageing is linked to a progressive decline of vascular, metabolic, and neurocognitive functions [ 20 ]. Nutrition and brain health Maintaining brain functions requires an optimal supply of energy and nutrients. Caloric restriction Current evidence CR aims to reduce the daily caloric intake without causing malnutrition to enhance physical and mental health [ 54 ]. Table 1 Key studies investigating the effects of caloric restriction on brain health in humans Full size table. Table 2 Findings from key studies reporting the effects of dietary nitrate on brain health in humans Full size table. Full size image. Conclusions Against the background of an ageing society and an impending increase in dementia cases, there is an urgent need to identify strategies to maintain healthy active ageing, including a specific focus on brain ageing. Data Availability Not applicable. Abbreviations CR: Caloric Restriction NO: Nitric Oxide CBF: Cerebral Blood Flow NOS: Nitric Oxide Synthase eNOS: Endothelial NOS nNOS: Neuronal NOS iNOS: Inducible NOS ROS: Reactive Oxygen Species BMI: Body Mass Index. References Duong S, Patel T, Chang F. Google Scholar Who. PubMed Google Scholar Stephan BCM, et al. PubMed Google Scholar Prince M, et al. PubMed Google Scholar Garre-Olmo J. CAS PubMed Google Scholar Society As. PubMed Central PubMed Google Scholar Bourre JM. CAS PubMed Google Scholar Hennig B, et al. Table 1 summarizes the category and function of the metabolites that we found significantly different between the CR and AL mice. At the 2-h postprandial time-point, CR mice had significantly higher levels in neurotransmitters, neuronal integrity markers, essential fatty acids, and biochemicals associated with carnitine metabolism compared to the AL mice Table 2 , column 1; CR vs. AL at 2-h. As for neurotransmitters, the CR mice had significantly higher levels of glutamate, N-acetylglutamate, glycine , and serine 18 , Glutamate is an excitatory neurotransmitter and associated with cognitive function 20 ; glycine and serine a precursor of glycine are inhibitory neurotransmitters Glycine is also anti-inflammatory, cytoprotective, and immunomodulating N-acetyl-aspartate NAA and N-acetyl-aspartyl-glutamate NAAG were also found significantly higher in the CR mice at the 2-h time-point. NAA and NAAG have been used as markers for neuronal integrity as they are most abundant in neurons and are also used as an index of neuron quantity 19 ; the reduction of these two metabolites have been associated with brain aging and neurodegenerative disorders CR mice also showed higher levels in dihomolinoleate n3 or n6 , docosapentaenoate n3 DPA; n3 , docosapentaenoate n6 DPA; n6 , and docosahexaenoate DHA; n3 at the 2-h time-point. These are omega-3, polyunsaturated fatty acids DHA helps with cell membrane structure, assists in normal growth and development, and participates in key pathways of the immune system DPA is often considered the third most prevalent omega-3 fatty acid found in fish oil, following DHA and EPA eicosapentaenoate Carnitine-related metabolites, such as carnitine, palmitoylcarnitine, stearoylcarnitine, and oleoylcarnitine were also higher in the CR mice As carnitine participates in the transport of long-chain fatty acids into the mitochondrial matrix, an increase in these metabolites might indicate facilitation in this transport function and reduced oxidative stress Interestingly a similar pattern of metabolite increases were not found in the AL mice until the 6-h postprandial time-point Table 2 , column 2; AL, 6-h vs. Moreover, some of the metabolites, though increased, did not reached significance, such as glutamate, N-acetylglutamate, NAA, NAAG. The results suggest that AL mice may not be as effective in producing these metabolites after a meal, especially those related to improving neuronal integrity. We further examined the metabolic profile between CR and AL mice at 6-h time-point. At this stage, no significant differences were found in the levels of neurotransmitters, essential fatty acids and glycolytic intermediates between the two groups, except dihomolinolenate n3 or n6 and docosapentaenoate n3 DPA; n3 Table 2 , column 3; CR vs. AL at 6-h. As these metabolites had an early rise at 2-h in the CR group and were followed by the AL group at 6-h, the results indicated that CR mice might have been able to maintain high levels of these metabolites over the 4-h postprandial period. On the other hand, we found that CR mice had maintained stable levels of glycolytic metabolites over the postprandial period Table 3. Specifically, glucosephosphate G6P , fructose phosphate , and lactate stayed constant in the CR mice, whereas they significantly increased at 6-h in the AL mice; glucose was also higher in AL mice at 6-h compared to 2-h, but did not reach significance. A similar pattern was found with alanine , an amino acid produced from pyruvate a product of glycolysis , as well as metabolites associated with pentose phosphate pathway PPP , including arabitol and xyulosephosphate and ribulosephosphate Table 3. Differences of glycolysis- and pentose phosphate-related metabolites in the young mice. Caloric restriction is perhaps the most studied intervention that slows down aging and extends longevity since the s CR has been shown to enhance health span and retard aging phenotypes in various systems, including the brain In this study, we further demonstrated that CR also has significant impacts in young animals, especially the distinct postprandial pattern in brain metabolism compared to AL controls. CR mice produced higher levels of many metabolites in a shorter period after a meal, and sustained the levels for an extended period of time. The metabolites included neurotransmitters, neurotrophic factors, essential fatty acids, and carnitine-related metabolism related to immune function and reduced oxidative stress. The AL mice did not show the similar increases in essential fatty acids and carnitine metabolism until the 6-h time-point, but failed to show increases in neurotransmitters and neuronal integrity markers at any time-point. The findings suggest that CR mice might produce these metabolites more effectively after a meal, especially those related to cognitive functions. On the other hand, CR mice showed constant lower levels of glucose utilization compared to AL mice. This is consistent with a previous findings using PET- 18 FDG scans that young CR mice had lower glucose uptake in the brain 6. Other studies show that lower glucose uptake was accompanied by higher fatty acids utilization e. Our findings are consistent with Dhahbi et al. They showed that CR caused a reduced enzymatic capacity for glycolysis which is consistent with our findings that glycolysis is not up regulated after feeding in CR mice. Further, they found increased activity of glutaminase, an enzyme that converts glutamine to glutamate. This is in line with our observation that CR mice had higher postprandial glutamate levels compared to the AL mice. Collectively, our results are consistent with previous findings that CR altered postprandial patterns in glycolysis and neurotransmitter production. The findings from the current study led us to speculate that the early changes we saw in the brain metabolites might be associated with the neuroprotective factors seen in aged animals. Indeed, old animals with CR have been shown to have preserved glutamate-glutamine neurotransmission cycling 5 , cell structure of white matter 6 , cognitive functions 22 , and reduced neuroinflammation and oxidative stress 31 , and lower incidence for Alzheimer's disease 32 , This is also in line with a previous report that early enhancement of cerebral blood flow CBF in young mice is associated with CBF preservation in aging mice 8. In other words, the protective effects of CR seen in the aging animals may be manifested as an enhancing factor in young mice. As brain integrity plays a major role in determining lifespan 34 , our findings imply the brain metabolic changes observed in the young CR mice may be a critical factor that contributes to the extended lifespan and health span phenomenon that has been repeatedly observed under CR condition. A limitation of the present study is that we only used male mice; therefore, we were not able to investigate sex effects in the study. Another limitation is that we used a long-lived rodent model. Recent studies have shown that the lifespan response to CR may vary widely in mice from different genetic backgrounds In some cases, CR shortened the lifespan in inbred mice. It will be important in the future to determine if the beneficial effects of CR observed in the young mice in the current study are still warranted in those short-lived inbred mice. Future studies will also need to look into the mechanism of the postprandial turnover in the CR mice. In conclusion, we demonstrated that CR induces distinct postprandial responses in metabolites that are essential to maintain brain functions, while also maintaining a lower level of glycolysis. Our findings are consistent with literature that CR enhances postprandial metabolic flexibility and turnover. These early changes in CR mice might play a critical role for neuroprotection in aging. Understanding the interplay between dietary intervention and postprandial metabolic responses from an early age may have profound implications for impeding brain aging and reducing the risk for neurodegenerative disorders. LMY contributed to the major analysis and interpretation of data for the work. LEAY contributed to the data analysis. RM, MAK, and EA contributed biostatistical support for the metabolomic profiling. A-LL contributed to the major design, analysis and interpretation of data for the work. LMY, JH, and A-LL drafted and revised the work for important intellectual content. LMY, LEAY, JH, RM, MAK, EA, and A-LL approved of the final version and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The 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. Fusco S, Pani G. Brain response to calorie restriction. Cell Mol Life Sci. doi: PubMed Abstract CrossRef Full Text Google Scholar. Park SY, Choi GH, Choi HI, Ryu J, Jung CY, Lee W. Calorie restriction improves whole-body glucose disposal and insulin resistance in association with the increased adipocyte-specific GLUT4 expression in Otsuka Long-Evans Tokushima fatty rats. Arch Biochem Biophys. Duan W, Ross CA. Potential therapeutic targets for neurodegenerative diseases: lessons learned from calorie restriction. Curr Drug Targets. Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, et al. Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging. Lin AL, Coman D, Jiang L, Rothman DL, Hyder F. Caloric restriction impedes age-related decline of mitochondrial function and neuronal activity. J Cereb Blood Flow Metab. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today. A recent study on caloric restriction and memory led by the neurologist Agnes Floel and her colleagues at the University of Munster took the first step in examining this issue. They recruited 50 older ages 50 to 80 years adults with a normal memory. Subjects on average were slightly overweight. The researchers assigned the volunteers to three groups, based on their age, gender and weight. Group 1 got a diet with 30 percent reduced daily calories and normal levels of other essential nutrients; the minimal level was set at 1, calories daily to prevent malnourishment. The control was Group 3 —who had a diet as usual. None of the participants were advised to change their exercise habits. The researchers gave subjects in the first two groups individualized dietary plans and monitored their diet via self-reports. All subjects underwent memory and blood tests before and after the three months in the trial. At the end of three months, the reduced-calorie diet group showed a small reduction in body weight by 2. Their memory improvement tended to be correlated with reductions in blood insulin and markers of inflammation C-reactive protein and TNF-alpha. Memory did not change in the other two diet groups. This study is commendable because it is the first prospectively planned trial in older adults to demonstrate memory benefits of a low-calorie diet. The replication in humans of some of the findings seen in earlier animal studies provides an important proof of concept step that will encourage and guide the design of larger future studies. |
| Does Eating Fewer Calories Improve the Brain? | Without one, the deposition of byproducts disrupts the normal microenvironment and causes brain damage. The starting box was an open-ended dark cylinder positioned in the centre of the platform. Article PubMed Google Scholar Bendlin, B. Yang, C. Forte M et al. Joseph JA, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale B Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging. |
Caloric restriction and cognitive function -
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J Hypertens. Venturelli M, et al. Front Physiol. Paul V, Ekambaram P. Indian J Med Res. Clifford T, et al. Effects of inorganic nitrate and nitrite consumption on cognitive function and cerebral blood flow: a systematic review and meta-analysis of randomized clinical trials.
Aamand R, et al. A NO way to BOLD? Dietary nitrate alters the hemodynamic response to visual stimulation. Fan JL, et al. Dietary nitrate supplementation enhances cerebrovascular CO 2 reactivity in a sex-specific manner. J Appl Physiol Dietary nitrate reduces blood pressure and cerebral artery velocity fluctuations and improves cerebral autoregulation in transient ischemic Attack patients.
Babateen AM et al. Incremental doses of Nitrate-Rich Beetroot Juice do not modify cognitive function and cerebral blood Flow in overweight and obese older adults: a Week pilot randomised clinical trial.
Moderate doses of dietary nitrate elicit greater effects on blood pressure and endothelial function than a high dose: a week pilot study. Nutr Metab Cardiovasc Dis; Baião DDS, Silva D, Paschoalin VMF.
Beetroot, a remarkable vegetable: its nitrate and phytochemical contents can be adjusted in Novel formulations to Benefit Health and Support Cardiovascular Disease therapies.
Volume 9. Antioxidants Basel ; Georgiev VG, et al. Antioxidant activity and phenolic content of Betalain extracts from intact plants and hairy Root cultures of the Red Beetroot Beta vulgaris cv.
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Am J Physiol Regul Integr Comp Physiol. Download references. Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, , Saudi Arabia. Curtin Dementia Centre of Excellence, EnAble Institute, Curtin University, Kent Street, Bentley, WA, , Australia.
Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. You can also search for this author in PubMed Google Scholar. The structure of the review was conceived by MS.
MA and MS drafted the manuscript, with MS taking a lead role. All authors critically revised the manuscript and approved the final version prior to submission. Correspondence to Mario Siervo. 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. Reprints and permissions. Alharbi, M. et al. Does dietary nitrate boost the effects of caloric restriction on brain health? Potential physiological mechanisms and implications for future research.
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Abstract Dementia is a highly prevalent and costly disease characterised by deterioration of cognitive and physical capacity due to changes in brain function and structure. Introduction Dementia is a progressive, incurable neurodegenerative disease leading to significant alterations of brain structure and function, resulting in cognitive decline, physical impairment, and changes in behaviour [ 1 , 2 ].
Ageing, obesity and vascular dysfunction: the dementia risk triad Ageing is linked to a progressive decline of vascular, metabolic, and neurocognitive functions [ 20 ]. Nutrition and brain health Maintaining brain functions requires an optimal supply of energy and nutrients.
Caloric restriction Current evidence CR aims to reduce the daily caloric intake without causing malnutrition to enhance physical and mental health [ 54 ]. Table 1 Key studies investigating the effects of caloric restriction on brain health in humans Full size table. Table 2 Findings from key studies reporting the effects of dietary nitrate on brain health in humans Full size table.
Full size image. Conclusions Against the background of an ageing society and an impending increase in dementia cases, there is an urgent need to identify strategies to maintain healthy active ageing, including a specific focus on brain ageing. Data Availability Not applicable.
Abbreviations CR: Caloric Restriction NO: Nitric Oxide CBF: Cerebral Blood Flow NOS: Nitric Oxide Synthase eNOS: Endothelial NOS nNOS: Neuronal NOS iNOS: Inducible NOS ROS: Reactive Oxygen Species BMI: Body Mass Index.
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We thank Dr. Amin Bredan for careful editing of the manuscript. Inflammation Research Center IRC , Mouse Genetics in Inflammation MGI , Ghent University, VIB, Technologiepark , , Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. You can also search for this author in PubMed Google Scholar. Correspondence to Claude Libert. Reprints and permissions. Van Cauwenberghe, C. et al. Mamm Genome 27 , — Download citation.
Received : 06 February Accepted : 16 May Published : 30 May Issue Date : August 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. Abstract Dietary interventions such as caloric restriction CR extend lifespan and health span.
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Aging Blood pressure medication neurodegenerative cognltive are frequently associated with the disruption of daloric extracellular microenvironment, which resfriction caloric restriction and cognitive function and body fluid components. Caloric restriction An has been caloric restriction and cognitive function restiction a lifestyle intervention that can improve long-term health. In addition to preventing metabolic disorders, CR has been shown to improve brain health owing to its enhancing effect on cognitive functions or retarding effect on the progression of neurodegenerative diseases. This article summarizes current findings regarding the neuroprotective effects of CR, which include the modulation of metabolism, autophagy, oxidative stress, and neuroinflammation. This review may offer future perspectives for brain aging interventions.
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