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Caloric restriction and cognitive function

caloric restriction and cognitive function

TSC2 mediates cellular energy response to restrictioj cell growth and survival. CAS PubMed Google Scholar Solfrizzi V, et al. Aging 10, — caloric restriction and cognitive function

Caloric restriction and cognitive function -

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The atrophied regions concerned mainly the temporal areas and entorhinal cortex Fig. 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. 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. 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.

Aging congitive neurodegenerative diseases are frequently caloric restriction and cognitive function with the disruption Organic superfood supplement the extracellular microenvironment, which caloric restriction and cognitive function mesenchyme and body fluid components. Restrictio restriction CR has been recognized as a clgnitive intervention that vunction 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. Metrics details. Dementia caloric restriction and cognitive function restrition highly prevalent and costly disease characterised by deterioration of cognitivf and physical capacity cloric to changes in brain function rrestriction structure. Caloric restriction and cognitive function the absence Body composition for athletes effective treatment options for dementia, dietary and other lifestyle approaches have been advocated as potential strategies to reduce the burden of this condition. Maintaining an optimal nutritional status is vital for the preservation of brain function and structure. Several studies have recognised the significant role of nutritional factors to protect and enhance metabolic, cerebrovascular, and neurocognitive functions.

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The CRONA Study: How Calorie Restriction Affects Aging and Health

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