Caloric restriction improves health and survival of rhesus monkeys. Languille, S. The grey mouse lemur: a non-human primate model for ageing studies. Ageing Res. Hämäläinen, A. Losing grip: senescent decline in physical strength in a small-bodied primate in captivity and in the wild.

Article PubMed Google Scholar. Djelti, F. Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates.

Aging Albany, NY 9 , — Article Google Scholar. Picq, J. Age-related cerebral atrophy in nonhuman primates predicts cognitive impairments.

Aging 33 , — Mestre-Francès, N. Immunohistochemical analysis of cerebral cortical and vascular lesions in the primate Microcebus murinus reveal distinct amyloid β and β immunoreactivity profiles.

Dal-Pan, A. Caloric restriction or resveratrol supplementation and ageing in a non-human primate: first-year outcome of the RESTRIKAL study in Microcebus murinus. Age Dordr. Martin, B. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Yanai, S. Long-term dietary restriction causes negative effects on cognitive functions in rats.

Aging 25 , — Dirks, A. Caloric restriction in humans: potential pitfalls and health concerns. Ageing Dev. Redman, L. Caloric restriction in humans: impact on physiological, psychological, and behavioral outcomes. Redox Signal. Hedden, T. Insights into the ageing mind: a view from cognitive neuroscience.

Collino, S. Musculoskeletal system in the old age and the demand for healthy ageing biomarkers. Chetelat, G. Dissociating atrophy and hypometabolism impact on episodic memory in mild cognitive impairment. Brain , — Shamy, J. Volumetric correlates of spatiotemporal working and recognition memory impairment in aged rhesus monkeys.

Cortex 21 , — Bendlin, B. Effects of aging and calorie restriction on white matter in rhesus macaques. Aging 32 , Guo, J.

Early shifts of brain metabolism by caloric restriction preserve white matter integrity and long-term memory in aging mice. Aging Neurosci. PubMed PubMed Central Google Scholar. Bons, N. A stereotaxic atlas of the grey lesser mouse lemur brain Microcebus murinus. Brain Res. Brodmann, K.

London: Imperial College Press, original in Translated and edited by L. Le Gros Clark, W. The brain of Microcebus murinus. Proceedings of the Zoological Society of London. Sawiak, S. Voxel-based morphometry analyses of in vivo MRI in the aging mouse lemur primate.

Ashburner, J. A fast diffeomorphic image registration algorithm. Neuroimage 38 , Good, C. A Voxel-Based Morphometric Study of Ageing in Normal Adult Human Brains. Neuroimage 14 , Download references.

The authors are grateful to Mark A. Krasnow, Donald K. Ingram and Jean-Claude Baron for their invaluable editing contribution to this manuscript.

The authors also acknowledge the continuing assistance provided by Sandrine Chertouk, Lauriane Dezaire and Eric Guéton-Estrade for daily feeding and care provided to animals. Laurine Haro and Delphine Champeval are recognised for their expert technical assistance. This work was carried out with the financial support of the French National Research Agency project ANRPNRA and the Foundation for French Medical Research.

is funded by Université Paris Sorbonne Cité 'Dynamique du Vieillir' research program. Histology and Pathology Department, Veterinary School of Alfort, PRES Paris Est, , Maisons-Alfort, France. Université de Strasbourg, IPHC, 23 rue Becquerel, , Strasbourg, France.

CNRS, UMR, 23 rue Becquerel, , Strasbourg, France. Unité Mixte de Recherche en Santé INSERM, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, rue de la Santé, Paris, , France. Laboratoire de Psychopathologie et de Neuropsychologie, EA , Université Paris 8, 2 rue de la Liberté, , St Denis, France.

Neurodegenerative Diseases Laboratory, CNRS, CEA, Université Paris-Sud, Université Paris-Saclay UMR , , Fontenay-aux-Roses, France.

You can also search for this author in PubMed Google Scholar. and J. designed all experiments described here. and P. executed the experiments.

conducted data analyses. wrote the manuscript. Correspondence to Fabienne Aujard. Publisher's note: 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. Pifferi, F. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Commun Biol 1 , 30 Download citation. Received : 30 November Accepted : 21 February Published : 05 April 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. Bulletin of Experimental Biology and Medicine By submitting a comment you agree to abide by our Terms and Community Guidelines.

If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature.

nature communications biology articles article. Download PDF. Subjects Ageing Neural ageing. Abstract The health benefits of chronic caloric restriction resulting in lifespan extension are well established in many short-lived species, but the effects in humans and other primates remain controversial.

Introduction Caloric restriction, i. Full size image. Methods Animals and breeding All M. Dietary intervention The design of the Restrikal study has been previously described Spatial memory was assessed from Year 1 of treatment until natural death. As for spatial memory, working memory was assessed from Year 1 until natural death.

Accelerating rotarod task for motor performance evaluation For each trial, an animal was placed on a rotarod model , Ugo Basile, Italy , a motor-driven treadmill with a 5-cm-diameter cylinder. Motor performances were assessed from Year 1 of treatment until natural death.

MRI acquisition and analysis All the animals involved in the current study were studied by MRI from the age of 7. The study is published in The New England Journal of Medicine.

The researchers enrolled a total of people in the study. All participants had a body mass index BMI over 25 overweight. They randomly divided the participants into two groups: people were allocated to the MIND diet, and the remaining remained on their normal diet.

The participants were told to remain on their diet for three years, during which time they had regular dietary counseling over the phone and in person.

Both groups were advised about portion size to ensure their calorie intake was correct. Those on the MIND diet were also told which new foods to include and which foods they should not eat, a key tenet of this eating pattern that is said to help slow cognitive decline.

The researchers followed up with the participants four times during the three years to assess their mental abilities, blood pressure, diet, physical activity, health conditions, and medication use. After six months, then 12, 24, and 36 months, participants undertook a range of cognition tests run by researchers who were unaware of which diet group they were in.

Some also underwent magnetic resonance imaging MRI scans to identify any brain changes. Both showed small improvements in cognitive scores, but there was no significant difference between the two groups at the end of the three years in either cognitive performance or MRI scans.

The participants lost, on average, 5kg over the course of the trial, which the researchers suggest may have caused the improvements in cognition. Previous studies have reported an association between weight loss and improved cognitive function.

Studies have also shown that weight loss reduces overall inflammation and that limiting calories is likely to have an anti-inflammatory effect — both of which occurred in this study.

The researchers also suggest that practice effects may explain the improvement in cognitive tests in the first year for both groups. Although the researchers expected to see greater improvements in the MIND group than the control group, they suggest that their results may have been affected by the fact that the control group also had a relatively healthy diet.

So, perhaps any improvement in diet could benefit cognitive health. To remain healthy and active even in old age, the Centers for Disease Control and Prevention CDC also advises six lifestyle choices that can increase the likelihood of aging healthily:.

These measures will not only help maintain physical health but will help keep your brain healthy and functioning, too. 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. Guo J, Bakshi V, Lin AL. Early shifts of brain metabolism by caloric restriction preserve white matter integrity and long-term memory in aging mice.

Front Aging Neurosci. Lin AL, Zhang W, Gao X, Watts L. Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain. Parikh I, Guo J, Chuang KH, Zhong Y, Rempe RG, Hoffman JD, et al.

Caloric restriction preserves memory and reduces anxiety of aging mice with early enhancement of neurovascular functions. Hoffman JD, Parikh I, Green SJ, Chlipala G, Mohney RP, Keaton M, et al.

Age drives distortion of brain metabolic, vascular and cognitive functions, and the gut microbiome. Redman LM, Smith SR, Burton JH, Martin CK, Il'yasova D, Ravussin E. Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging.

Cell Metab. Dhahbi JM, Mote PL, Wingo J, Rowley BC, Cao SX, Walford RL, et al. Caloric restriction alters the feeding response of key metabolic enzyme genes.

Mech Ageing Dev. Huffman KM, Redman LM, Landerman LR, Pieper CF, Stevens RD, Muehlbauer MJ, et al. Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial. PLoS ONE. Khoo CM, Muehlbauer MJ, Stevens RD, Pamuklar Z, Chen J, Newgard CB, et al.

Postprandial metabolite profiles reveal differential nutrient handling after bariatric surgery compared with matched caloric restriction. Ann Surg. Flurkey K, Currer J, Harrison D.

Mouse models in aging research. In: Fox JG, Davisson MT, Quimby FW, Barthold SW, Newcomer CE, Smith AL, editors.

The Mouse in Biomedical Research , 2nd ed. Academic Press Google Scholar. Evans AM, Dehaven CD, Barrett T, Mitchell M, Milgram E. Anal Chem. Ohta T, Masutomi N, Tsutsui N, Sakairi T, Mitchell M, Milburn MV, et al. Untargeted metabolomic profiling as an evaluative tool of fenofibrate-induced toxicology in Fischer male rats.

Toxicol Pathol. Dehaven CD, Evans AM, Dai H, Lawton KA. J Cheminform. Siegel GJ. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Baslow MH. The vertebrate brain, evidence of its modular organization and operating system: insights into the brain's basic units of structure, function, and operation and how they influence neuronal signaling and behavior.

Front Behav Neurosci. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology.

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. Inter-individual variability as well as repetition of measurements over years were included in the random effect.

The effects of treatments i. Survival time was the time between onset of treatment and any cause of death for overall mortality analyses or age-related death for age-related mortality analyses. The cut-off date was set as December 1, The PH assumption was tested by fitting a PH Cox regression with linear treatment—time interactions; these interaction terms did not significantly differ from zero for both analyses, and the proportional hazard assumptions were therefore considered as valid.

SAS V9. Type-1 error was set at 0. McCay, C. The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure.

Article CAS Google Scholar. Fontana, L. Extending healthy life span--from yeast to humans. Science , — Article CAS PubMed PubMed Central Google Scholar. Colman, R. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys.

Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Article PubMed PubMed Central Google Scholar. Mattison, J. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature , — Article CAS PubMed Google Scholar.

Caloric restriction improves health and survival of rhesus monkeys. Languille, S. The grey mouse lemur: a non-human primate model for ageing studies.

Ageing Res. Now, a study has compared the effect of the MIND diet — a hybrid of the Mediterranean and DASH Dietary Approaches to Stop Hypertension diets — and mild caloric restriction on cognition. The study found that both diets had a small positive effect on cognition, with neither being significantly better than the other.

The study is published in The New England Journal of Medicine. The researchers enrolled a total of people in the study. All participants had a body mass index BMI over 25 overweight. They randomly divided the participants into two groups: people were allocated to the MIND diet, and the remaining remained on their normal diet.

The participants were told to remain on their diet for three years, during which time they had regular dietary counseling over the phone and in person. Both groups were advised about portion size to ensure their calorie intake was correct. Those on the MIND diet were also told which new foods to include and which foods they should not eat, a key tenet of this eating pattern that is said to help slow cognitive decline.

The researchers followed up with the participants four times during the three years to assess their mental abilities, blood pressure, diet, physical activity, health conditions, and medication use. After six months, then 12, 24, and 36 months, participants undertook a range of cognition tests run by researchers who were unaware of which diet group they were in.

Some also underwent magnetic resonance imaging MRI scans to identify any brain changes. Both showed small improvements in cognitive scores, but there was no significant difference between the two groups at the end of the three years in either cognitive performance or MRI scans.

The participants lost, on average, 5kg over the course of the trial, which the researchers suggest may have caused the improvements in cognition.

Previous studies have reported an association between weight loss and improved cognitive function. Studies have also shown that weight loss reduces overall inflammation and that limiting calories is likely to have an anti-inflammatory effect — both of which occurred in this study.

The researchers also suggest that practice effects may explain the improvement in cognitive tests in the first year for both groups. Although the researchers expected to see greater improvements in the MIND group than the control group, they suggest that their results may have been affected by the fact that the control group also had a relatively healthy diet.

So, perhaps any improvement in diet could benefit cognitive health. Clinical studies have revealed altered expression levels of multiple microRNAs in the blood of aging people, and the biological functions of these differentially regulated microRNAs include cell growth, development, and aging by regulating the expression of the telomerase, p53, and p16 signaling pathways Pourrajab et al.

Therefore, the role of lncRNA in aging and aging-related diseases should not be underestimated. For example, lncRNA-p21, which is a key target of the p53 signaling pathway, plays a role in regulating age-related diseases Yang et al.

We briefly summarized the effect of various factors on the brain microenvironment during aging and neurodegeneration. Based on this, different drugs and non-drug protocols may help restore homeostasis of the brain microenvironment to recover neural functions.

As an extensively studied lifestyle strategy, CR has been interrogated for its potential role in alleviating aging-related cognitive deficits. For example, CR in aging mice protects against neural progenitor cell loss, likely via alleviating chronic inflammation Apple et al.

In the following sections, we discuss the potential mechanisms of CR for improving extracellular homeostasis to recover aging-related deficits at the molecular, cellular, and tissue levels. The mTOR and insulin receptor pathways are critical for sensing cellular energy metabolism and coordinate anabolism, which leads to the potentiation of protein or lipid synthesis, ribosome neogenesis, mitochondrial metabolism, cell growth, and mitosis Ben-Sahra and Manning, Under excess nutritional status, tissue mTOR is hyperactivated, which results in a change in protein catabolism and an elevated production of mitochondrial ROS; simultaneously, autophagy is inhibited, which results in an inflammatory response Kapahi et al.

Therefore, a persistently activated mTOR pathway accelerates the aging process, and the inhibition of mTOR signaling mimics the effect of CR in potentiating the immune response and extends the lifespan Harrison et al.

Adenosine monophosphate-activated protein kinase AMPK is a signaling protein for sensing low-energy status, and it can inhibit the mTOR cascade reaction by phosphorylating the tuberous sclerosis complex 2 TSC2 complex Inoki et al. Thus, the AMPK and mTOR pathways antagonize each other to maintain the metabolic homeostasis of tissues.

Both mTOR and AMPK pathways play important roles in the pathogenesis of aging-related neurodegenerative diseases and are responsive to CR.

For example, the deposition of Aβ proteins has been shown to activate neuronal mTOR, which facilitates de novo protein synthesis and inhibits autophagy, accelerating the aggregation of Aβ and Tau proteins. Therefore, as a specific mTOR inhibitor, rapamycin can improve cognitive functions, as demonstrated in AD animal models Caccamo et al.

Similarly, the inhibition of mTOR can induce cell autophagy to relieve disease symptoms Ravikumar et al. A further mechanistic link was provided by the induction of neuronal AMPK phosphorylation by CR via the upregulation of fibroblast growth factor 21 to suppress mTOR activity and relieve the hyperphosphorylation of tau proteins Rühlmann et al.

In examinations of Aβ, although no study has directly investigated the relationship between CR and Aβ deposition, the known effect of AMPK activation in relieving Aβ aggregates Chen et al. Thus, the regulation of cellular homeostasis by mTOR and AMPK prevents the body from metabolic imbalance González et al.

Moreover, both AMPK and mTOR play important roles in the hypothalamic regulation of body metabolism Martínez de Morentin et al. However, further studies are needed to understand how the coordination between these two molecular pathways influences energy metabolism and the brain aging process.

Sirtuin is an evolutionally conserved family of deacetylase that plays specific roles in extending the lifespan Bishop and Guarente, Allosteric regulation of nicotinamide adenine dinucleotide NAD activates Sirtuin, which further affects histones and transcription factors to regulate gene expression, and CR can also activate this deacetylase to relieve oxidative stress Qiu X.

Moreover, Sirtuin works synergistically with other nutrition-sensitive proteins that are activated by CR, such as AMPK Cantó et al. Moreover, CR has been reported to relieve post-surgical memory deficits in aging mice by activating deacetylase to relieve endoplasmic reticulum stress in the hippocampus Yao et al.

Furthermore, the effect of Sirtuin on the cellular microenvironment has been demonstrated by previous studies that showed that the activation of cellular autophagy Lee et al. Different environmental and internal stimuli, such as nutrition, hormones, and growth factors, can activate the cAMP-responsive element-binding CREB protein family, which profoundly affects the expression of brain-derived neurotrophic factor BDNF to mediate the survival, growth, differentiation, and plasticity of neurons Lonze and Ginty, CREB also modulates the transcriptional activation of tyrosine receptor kinase B, which is the major receptor for BDNF Tabuchi et al.

CR potentiates CREB expression and activation via the AMPK cascade pathways; thus, CREB is a hub for nutritional sensors and neuronal growth.

However, CREB can directly activate Sirtuin1 in the mouse hippocampus Fusco et al. In neurodegenerative diseases, Sirtuin1 can potentiate CREB-target of rapamycin complex 1 transcriptional activity to improve disease symptoms Jeong et al.

Therefore, the CREB—Sirtuin1 axis is critical for multi-layered brain responses under CR; however, upstream hormonal factors that induce the CREB cascade require further investigation.

Neurotrophic factors NTFs are a group of naturally occurring proteins that regulate the development, maturation, and functional integration of the nervous system. During CR, the expression level of NTFs, such as BDNF, neurotrophic factor 3 NT3 , glial cell line-derived neurotrophic factor GDNF , and fibroblast growth factor 2 FGF2 , are increased in the brain, which is likely a compensatory mechanism against physiological stress Qiu G.

Numerous studies have shown that BDNF plays a critical role in mediating synaptic plasticity, neurogenesis, and neuronal stress resistance, especially during learning and memory.

For example, the hippocampal BDNF level was positively correlated with the performance of a spatial learning task Hall et al. In addition, Type 2 diabetes mellitus T2DM is known to be associated with an increased risk of dementia, and week fasting in T2DM rats improves behavior and brain function by increasing the levels of NT3 and BDNF.

NT3 is involved in the synaptic release of numerous neurotransmitters in both peripheral and central nervous systems and affects tissue development Tyler et al. Similar to BDNF, GDNF has been shown to exert neuroprotective effects in primate PD models and is currently being used in clinical trials in PD patients Gill et al.

CR significantly increases the concentration of GDNF by almost three times that in the control group and leads to activated neuroprotective signaling pathways of DA neurons Maswood et al. Both in vivo and in vitro studies have shown that GDNF and BDNF protect neurons from excitatory toxicity and metabolic and oxidative damage Maswood et al.

Moreover, other NTFs are likely related to brain aging, such as FGF2, which has been suggested to be involved in modulating synaptic plasticity during food deprivation, although its specific mechanisms remain unclear Graham and Richardson, ; Mattson et al.

Insulin-like growth factor 1 IGF-1 is a phylogenetically ancient neurotrophic hormone that plays a crucial role in central nervous system development and maturation.

Fasting mimicking diet FMD increases the expression of IGF-1 and its receptor in the dentate gyrus DG of the hippocampus and subsequently potentiates adult neurogenesis Brandhorst et al. Taken together, the elevated NTFs induced by CR are essential for the effects of CR on brain aging and nerve regeneration.

Recent epigenetics research has revealed that CR affects the progression of aging and related diseases by regulating gene expression through epigenetic modifications Molina-Serrano and Kirmizis, As an environmental stimulus, CR affects DNA methylation levels to alter chromosome structure, which modulates the expression of genes related to aging and neurodegenerative diseases Hahn et al.

With CR in aging mice, DNA methyltransferases DNMT 1 activity increases to relieve the hypomethylation of senescent DNA, whereas the DNMT3a expression level in the hippocampus changes to protect brain function Chouliaras et al.

Numerous experiments have demonstrated the role of SIRT1 in mediating the anti-aging effect of CR, such as deacetylation effect of histones at H4K16 and H3K9 sites, to maintain gene silencing for resisting environmental stress and aging Gong et al.

In addition to gene transcripts, non-coding RNAs, such as microRNAs and lncRNAs, are critical for maintaining homeostasis of the body as well as for the development of neurodegenerative diseases. CR increases the expression of microRNA necessary for mitochondrial protein translation Zhang et al.

CR markedly increases global and mitochondrial microRNA levels; moreover, microRNA has been found to specifically activate mitochondrial translation Zhang et al.

In a second study, microRNA was induced by CR to mediate body longevity via the Wnt signaling pathway Xu et al. In brain tissues of CR-treated mice, the downregulation of three microRNAs, 34a, 30e, and a, helped maintain neuronal survival Khanna et al.

Recent studies Khanna et al. In examinations of lncRNA, CR helped protect cardiomyocytes by mediating lncRNA metastasis associate lung adenocarcinoma transcript 1 MALAT1 and GAS5 Rajagopalan et al.

In addition, in a Drosophila model, lncRNAs mediated the aging pathway during CR treatment Yang et al. In sum, non-coding RNAs participate in the process of cell growth, development, and aging primarily by affecting the p53 and P16 signaling pathways.

When the body faces increased demands of oxidation or damaged mitochondria, mitochondrial biogenesis MB is induced via the PGC-1α pathway López-Lluch et al.

Two CR-related cellular metabolic sensors are AMPK and Sirtuin1, which modulate PGC-1α activity by phosphorylation and deacetylation, respectively. Mouse models have shown that PGC-1α inhibition relieves brain oxidative injury and neurodegeneration St-Pierre et al. For example, the mutant huntingtin protein inhibits the transcription of PGC-1α to induce mitochondrial damage, which leads to oxidative stress and metabolic failure, whereas overexpression of PGC-1α prevents such cellular damage Cui et al.

CR can potentiate MB via the upregulation of nitric oxide synthase NOS to enhance cellular respiration to improving neuronal survival during brain aging Nisoli et al. Moreover, MB participates in hippocampal synaptogenesis and plasticity Wrann et al.

Autophagy is a widely studied catabolic process in which damaged organelles or large biomolecules are encapsulated by autophagosomes, which are subsequently fused with lysosomes to digest cell debris Mizushima and Komatsu, The dual roles of autophagy of cellular debris degradation and byproduct recycling provide substrates for the biosynthesis of large molecules as well as energy resources under conditions of nutritional deficiency Mizushima and Komatsu, As a mechanism that counteracts energy insufficiency, autophagy restores cellular activity by clearing damaged mitochondria, abnormally folded proteins, and deposited lipids Tschopp, For example, in an AD model, CR facilitated autophagy and activated glial cells to reduce neuronal Aβ loads Gregosa et al.

Moreover, recent studies have revealed that CR activates cellular autophagy in hepatocytes, adipocytes, skeletal muscle, and hypothalamic tissues, which indicates a close relationship between autophagy and CR Martinez-Lopez et al.

One study also showed that short-term fasting leads to a dramatic upregulation in neuronal autophagy Alirezaei et al. A summary of the major molecular pathways of CR is provided in Figure 2.

Figure 2. Molecular pathways of CR on neuroprotection Created with BioRender. As the energy sensor, AMPK-mTOR pathways respond to CR by reacting to the metabolic status of cells.

As the intracellular pathway, nicotinamide adenine dinucleotide-mediated sirtuin affects gene expression to generate neurotrophic factors such as BDNF.

Downstream of Sirtuin 1, PGC-1α modulates mitochondrial biogenesis and function, which affects cellular metabolism. The brain—gut axis is a complex bidirectional communication system that includes neuroimmune, neuroendocrine, and neural pathways Osadchiy et al. The communication between gut microbes and the central nervous system affects mood, behavior, and cognitive functions as well as the processes of aging and neurodegenerative diseases Zarrinpar et al.

Dietary factors, such as food types and dietary patterns, not only directly affect the central nervous system by influencing nerve cell membranes, neurotransmitters, and cerebrovascular functions but also interact with the central nervous system through the intestinal microbiome.

Therefore, interventions of dietary style can significantly alter the composition and function of gut microbes Attaye et al. Caloric restriction can alleviate neuroinflammation and neurodegeneration through intestinal flora and its metabolites, which then relieve the symptoms of aging and neurodegenerative diseases.

On one hand, dietary patterns may alter the composition and metabolites of the gut microbiome, some of which activate immune cells and microglia in the brain to affect neuroinflammation Zhang et al.

Furthermore, CR can decrease the biosynthesis of lipid A, a critical component of lipopolysaccharides, and its downregulation further facilitates the infiltration of eosinophils that originate from adipose tissues and the polarization of anti-inflammatory macrophages Fabbiano et al.

In PD mice, FMD was shown to lower the number of glial cells to reduce the release of TNF-α and IL-1β by altering the intestinal flora and its metabolites Zhou et al.

On the other hand, CR can affect the metabolism of intestinal microorganisms, which alters the generation of neurotransmitters, neurotransmitter precursors, and other metabolites, such as serotonin, tryptophan, and short-chain fatty acids SCFAs. Intestinal microbial metabolites have been widely recognized to affect emotional behavior, neurogenesis, and the integrity of the BBB Luczynski et al.

For example, SCFAs produced by the intestinal microbiota can cross the BBB, and butyrate has been found to exert neuroprotective effects by relieving neuroinflammation and increasing BDNF Zhou et al. In addition, the intestinal and vagus nerves are important signal communication pathways in the gut—brain axis and warrant further study; the effect of CR remains unexplored.

The possible mechanism of CR in alleviating aging and neurodegenerative diseases through the gut—brain axis is summarized in Figure 3. Figure 3. CR improves aging and neurodegenerative diseases via the gut—brain axis.

CR significantly changes the composition and metabolism of gut microbes, which results in the production of various neurotransmitters and their precursors, inducing a neuroprotection effect.

When inflammatory cytokine levels are repressed locally, neuroinflammation is further relieved. In addition to immune and endocrine regulation, gut microbes send signals directly to the central region via vagal afferent nerves.

SCFAs, short-chain fatty acids. Chronic inflammation is the common pathological feature of various metabolic disorders Hotamisligil and Erbay, During the aging process, persistent systemic inflammation aggravates tissue degeneration Franceschi and Campisi, Moreover, chronic inflammation induces metabolic disorders, such as insulin resistance, which leads to the disruption of neuronal functions and the acceleration of neurodegeneration Heneka et al.

In addition, neuroinflammation damages hypothalamic nuclei, which are the centers responsible for the homeostasis of energy and blood glucose; thus, causing obesity and diabetes Jordan et al. The anti-inflammatory effects of CR have been demonstrated in both animal models and human patients Mercken et al.

For example, CR and intermittent feeding relieve neuroinflammation in the rodent hypothalamus and hippocampus Radler et al. CR also decreases serum and brain concentrations of proinflammatory cytokines via the suppression of NF-kB activity and elevates BDNF expression Vasconcelos et al.

In addition to the suppression of neuroinflammation discussed above, CR also helps to maintain normal BBB permeability and function primarily by improving cerebral vascular homeostasis and the gut—brain axis. Recent studies have revealed a beneficial effect of CR on brain vascular health.

Low caloric diets help to maintain blood vessel homeostasis, which includes the reduction of oxidative stress, enhancement of nitric oxide bioactivity, and the suppression of vascular inflammation.

Studies on the molecular mechanisms showed that critical cytokines and pathways, such as AMPK, mTOR, and endothelial nitric oxide synthase eNOS pathways, all participated in the maintenance of vascular homeostasis Liu et al.

CR attenuates neuronal loss, induction of heme oxygenase-1, and BBB breakdown induced by impaired oxidative metabolism Calingasan and Gibson, Furthermore, moderate CR has neuroprotective effects: it reduces pmediated neurovascular damage and microglia activation after hypoxic ischemia to maintain normal permeability of the BBB Tu et al.

However, the protein and ion channels mediated by CR responsible for the protection of BBB permeability require further study. Both long- and short-term CR potentiates eNOS expression in endothelial vascular cells Minamiyama et al. Such information from peripheral vessels indicates the beneficial effects of CR on cerebral vessels.

In a high-fat diet mouse model, CR treatment significantly relieved BBB leakage Kim et al. Another aging mouse model showed that CR significantly preserved cerebral blood flow at 20 months of age when cerebrovascular function should be compromised under normal feeding conditions Parikh et al.

In addition, intestinal flora promotes the integrity and functional stability of the BBB, and CR has been shown to have positive effects on intestinal flora. Specifically, CR promotes the expression of tight junction proteins in brain endothelial cells by changing SCFA production in the intestinal flora and thus maintaining the integrity of the BBB Logsdon et al.

These data illustrate the potentially important role of CR in maintaining the integrity of the BBB and cerebrovascular functions.

Overall, the integrity and normal function of the BBB increase the stability of the brain microenvironment, which alleviates the symptoms of aging and neurodegenerative diseases.

Synaptic plasticity is critical for learning and memory functions Mattson, , which are dependent on synaptic density, morphology, and function. In rodents, brain aging is accompanied by weakened synaptic plasticity, as reflected by impaired long-term potentiation in the hippocampus, down-expression of synaptic proteins, and impaired BDNF expression or receptors.

CR can prevent these aging-related adverse effects and improve cognitive deficits Fontán-Lozano et al. Specifically, in mice, CR enhances cognitive functions by increasing the spine density of the hippocampal DG region Wahl et al.

Because synaptic plasticity is highly dependent on the mitochondrial activity at axonal terminals Levy et al. Moreover, CR can also benefit synaptic plasticity by activating anti-inflammatory pathways under brain aging or acute cerebral injury conditions Pani, In addition to the enhancement of synaptic plasticity, CR may also facilitate adult neurogenesis, which occurs in specific brain regions including the subventricular zone SVZ and hippocampal DG nuclei.

The constitutive proliferation and differentiation of neural progenitor cells generate both neurons and glial cells, which actively replace damaged cells and participate in the homeostatic regulation of the brain microenvironment and thus, play specific roles in learning and motor regulation Zhang et al.

It has also been shown that CR increases the expression of BDNF in the hippocampus Kaptan et al. Neural autoimmunity refers to the autoimmune response that specifically targets the nervous system, leading to neurodegenerative diseases, such as MS and AD Singh, During these responses, cellular immunity plays a key role in the development of autoimmunity and inflammation.

For example, MS is characterized by T cell-mediated demyelination and neurodegeneration in the central nervous system Friese and Fugger, ; Sospedra and Martin, In experimental autoimmune encephalomyelitis EAE animal models, activated myelin-specific TH1 and TH17 cells were shown to cross the BBB and migrate to the central nervous system, where they were subsequently activated by local antigen-presenting cells to promote inflammation Dhib-Jalbut, ; Goverman, Recent studies have found that CR can reverse immunosuppression or immune aging associated with chemotherapy or hematopoietic stem cell-based regeneration Cheng et al.

Similarly, animal experiments have indicated that FMD reduces the number of dendritic cells and increases the relative number of naive T cells, which reduces the infiltration of immune cells into the spinal cord Choi et al.

Moreover, FMD reduces the clinical severity of EAE in mice, and these improvements were associated with an increase in the number of regulatory T cells and decreases in the levels of proinflammatory cytokines, TH1 and TH 17 cells, and antigen-presenting cells Choi et al.

In addition, FMD promotes oligodendrocyte progenitor cell regeneration and myelin regeneration in both MS and EAE models, which supports its inhibitory effect on autoimmunity and myelin regeneration Choi et al.

Numerous studies have confirmed the effects of CR on systemic immunity and chronic inflammation, although further evidence is needed to validate the effect of CR on neural autoimmunity.

As stated above, the CR paradigm can affect the brain microenvironment at molecular, cellular, and tissue levels. Although most of those mechanistic models were established using rodent models, the beneficial clinical effects of CR have been reported across various disease conditions.

In general, CR exerts neuroprotective effects by modulating metabolism and neuroinflammatory environments to preserve the existing neural network, which may help recover synaptic connections to regain neural functions. Neurogenesis is a process in which progenitor cells develop into intact neurons, and it occurs in embryonic brains and discrete regions of adult brains Gross, ; Lie et al.

In most mammalian species, active neurogenesis occurs throughout life in the SVZ of the lateral ventricle and the subgranular zone of the DG in the hippocampus Ming and Song, ; Qiu G. In addition, adult hippocampal neurogenesis is enhanced by CR and is associated with circulating auxin-releasing peptide levels.

However, studies have also reported that long-term CR does not delay the age-related decline of hippocampal neurogenesis, but instead increases the survival rate of glial precursors in the hilus Bondolfi et al.

Further systematic studies are needed to gain a full understanding of the effects of CR on hippocampal neurogenesis. During AD pathogenesis, mitochondrial dysregulation is considered a critical factor for maintaining cellular, metabolic, and redox homeostasis, which affects neurite growth and synaptic function Cheng et al.

CR paradigms have been shown to increase the calcium retention capacity of brain mitochondria Amigo et al. Moreover, autophagy has been suggested as a mechanism to facilitate the recovery from AD-related symptoms because CR promotes cellular autophagy Yang and Zhang, The molecular pathway involved is likely the CR-modulated mTOR pathway Van Cauwenberghe et al.

Investigations have reported a correlation between PD risk and dietary habits Gardener and Caunca, Using a cell model, CR rescued cells from synucleinopathy Sampaio-Marques et al.

In a primate PD model, CR increased NTFs, which attenuated the pathological and behavioral deficits of the disease Maswood et al.

By suppressing the cellular stress response, CR helps to facilitate NTFs, chaperone proteins, DNA repair, and MB Mattson, , all of which contribute to the relief of disease symptoms. Multiple sclerosis is an autoimmune disease that can cause demyelination of the central nervous system, leading to varying degrees of axonal and neuronal damage.

IF improves the clinical course and pathology in MS and EAE animal models by relieving demyelination or axonal damage Cignarella et al. In MS animal models, IF provides protection by affecting the intestinal microbiota, and similar effects on gut microbiota have been observed in patients with recurrent MS following short-term IF intervention Cignarella et al.

In a clinical trial, participants who did not follow a low-sugar, low-carb, low-calorie diet were more likely to have progressive MS, accompanied by obesity and weight gain Fitzgerald et al. Although the CR diet temporarily improved motor performance in G93A mice, an animal model of amyotrophic lateral sclerosis ALS , it accelerated the clinical onset of the disease, which suggested that the CR diet may not be a protective strategy for patients with ALS Hamadeh et al.

Both HD patients and transgenic mouse models exhibit reduced levels of BDNF and metabolic disorders, in addition to the mutated human Huntingtin protein.

CR increases BDNF levels and the protein concentration of chaperone heat-shock protein in the striatum and cortex and prolongs the life span of HD patients by alleviating neuropathological, movement, and metabolic abnormalities Duan et al. Similarly, a ketogenic diet in a mouse model has been shown to interfere with HD, where weight loss was delayed; however, improvements in movement disorders or longevity were not observed Ruskin et al.

Currently, studies on the detailed molecular mechanism of CR interventions on HD remain limited. Both TBI and stroke are complex pathological processes that comprise primary and secondary injuries Lončarević-Vasiljković et al. CR has been shown to improve behavioral outcomes after ischemic brain injury.

The cellular and molecular mechanisms underlying the protection of brain cells against stroke and TBI by CR involve the up-regulated expression of neurotrophic factors BDNF and FGF2 , antioxidant enzymes, and protein chaperones Arumugam et al.

Decreased leptin and increased ketone levels may also contribute to the neuroprotective effects of CR in stroke models Manzanero et al. In addition, CR is currently considered a preventive lifestyle that reduces the severity of TBI outcomes and tissue damage and improves recovery after injury Roberge et al.

One study showed that CR for 3 months before TBI eliminates TNFα-dependent caspase-3 activation and secondary neuronal apoptosis, which suggests that DR strongly influences external apoptotic pathways Loncarevic-Vasiljkovic et al.

However, it was speculated that CR, as an additional external pressure, further aggravates the energy crisis caused by TBI and stroke Lončarević-Vasiljković et al.

In retinal aging, CR protects the structural and functional integrity of retinal ganglion cells by facilitating cellular autophagy, which improves the progression of glaucoma that occurs commonly in aging people Adornetto et al.

In regard to age-related changes in retinal tissues, CR has been shown to reduce certain metabolites, such as glutathione and ascorbic acid levels Li et al. Such metabolic regulatory effects may be related to transcriptional factors such as nuclear factor-erythroid factor 2-related factor 2 Nrf2; Izuta et al.

In the future, additional studies to investigate the value of CR in counteracting retinal aging are warranted. We have summarized the major findings regarding the application of CR in alleviating neurodegenerative diseases Table 2.

In practice, dietary plans may be combined with anti-aging drugs to synergistically counteract brain degeneration. For example, resveratrol has been found to function as a mimetic compound that partially substitutes the effects of CR Barger, In addition, a similar observation was made for the SIRT1 activator drug, SRT Suzuki et al.

Further knowledge can be gained from neuroendocrine studies, such as the role of ghrelin in mediating CR-induced neuroprotective effects Bayliss et al. Taken together, further investigations on the mechanisms underlying the neuroprotective effects of CR may reveal potentially additive effects of combing both drugs and dietary plans, which will enable the development of more effective interventions.

Table 2. Recent studies of dietary interventions for different neurodegenerative diseases. The extracellular microenvironment is critical for maintaining normal physiological functions of cells because of its role in the homeostatic regulation of various components.

Various factors, such as inflammation, metabolic waste, and the BBB, can disrupt normal brain microenvironments.

Thus, the maintenance of the extracellular environment is vital for brain health. Current studies have suggested that lifestyle interventions, such as regular exercise training, a healthy diet, and sufficient sleep, protect the brain by improving the microenvironment balance under pathological conditions.

Caloric restriction effectively protects the brain microenvironment via multiple mechanisms at molecular, cellular, and tissue levels. Major benefits obtained by CR are based on recent findings in aging and neuropathological models. However, there is currently no consensus on a unified protocol for CR because the duration or starting age of CR has not been clarified in animals.

Currently, IF and CR are the two predominant approaches. For the CR scheme, several precautions need to be specified, which include the avoidance of artificial sweeteners and the supplementation of probiotics.

Specifically, the ketogenic diet has been shown to significantly affect gut microbes, whereby its composition is prominently altered to induce metabolic disorders, leading to brain dysfunctions Paoli et al.

Thus, further investigations on the gut microbial diversity under the CR paradigm are needed to develop guidelines for monitoring and treating the gut—brain axis.

Reports have shown that the initiation age and duration of CR are critical factors that influence overall efficiency. Specifically, CR started at middle-age has the most potent neuroprotective effect Todorovic et al. Current studies on the neuroprotective effects of CR have various weaknesses, which include the lack of a precise description of the dosage curve i.

These factors limit the large-scale promotion of CR in aging and high-risk populations with neurodegenerative diseases. Therefore, future explorations are required to understand the neuroprotective mechanisms underlying CR to develop alternative pharmaceutical or non-drug interventions for brain aging and neurodegeneration.

ND prepared materials for the writing. ND, XL, and LZ wrote the manuscript. LZ and ZC revised the manuscript. All authors contributed to the article and approved the submitted version.

This study was supported by National Key Research and Development Program of China YFA to LZ, Guangdong Natural Science Foundation A to LZ, Science and Technology Program of Guangzhou, China to LZ, and National Natural Science Foundation of China to LZ.

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. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Adornetto, A. Effects of caloric restriction on retinal aging and neurodegeneration. Brain Res. doi: PubMed Abstract CrossRef Full Text Google Scholar.

Alirezaei, M. Short-term fasting induces profound neuronal autophagy. Autophagy 6, — Amigo, I. Caloric restriction increases brain mitochondrial calcium retention capacity and protects against excitotoxicity. Aging Cell 16, 73— Apple, D.

Calorie restriction protects neural stem cells from age-related deficits in the subventricular zone. Aging 11, — Armentero, M. Arumugam, T. Age and energy intake interact to modify cell stress pathways and stroke outcome.

Attaye, I. A crucial role for diet in the relationship between gut microbiota and cardiometabolic disease. Barger, J. An adipocentric perspective of resveratrol as a calorie restriction mimetic. Bayliss, J.

Ben-Sahra, I. mTORC1 signaling and the metabolic control of cell growth. Cell Biol. Google Scholar. Berti, V. Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults.

Neurology 90, e—e Birch, J. Senescence and the SASP: many therapeutic avenues. Genes Dev. Bishop, N. Genetic links between diet and lifespan: shared mechanisms from yeast to humans.

Boland, B. Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Drug Discov. Bondolfi, L. Aging 25, — CrossRef Full Text Google Scholar. Brandhorst, S.