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Calorie restriction promotes remyelination in a Cuprizone-Induced demyelination mouse model of multiple sclerosis.
Mojaverrostami S, Pasbakhsh P, Madadi S, Nekoonam S, Zarini D, Noori L, Shiri E, Salama M, Zibara K, Kashani IR.
Metab Brain Dis. 2020 Jul 7. doi: 10.1007/s11011-020-00597-0. Online ahead of print.
PMID: 32638202
Abstract
Over the past few decades several attempts have been made to introduce a potential and promising therapy for Multiple sclerosis (MS). Calorie restriction (CR) is a dietary manipulation to reduce calorie intake which has been shown to improve neuroprotection and attenuate neurodegenerative disorders. Here, we evaluated the effect of 33% CR regimen for 4 weeks on the remyelination capacity of Cuprizone (CPZ) induced demyelination in a mouse model of MS. Results showed that CR induced a significant increase in motor coordination and balance performance in CPZ mice. Also, luxol fast blue (LFB) staining showed that CR regimen significantly improved the remyelination in the corpus callosum of CPZ + CR mice compared to the CPZ group. In addition, CR regimen significantly increased the transcript expression levels of BDNF, Sox2, and Sirt1 in the corpus callosum of CPZ mice, while decreasing the p53 levels. Moreover, CR regimen significantly decreased the apoptosis rate. Furthermore, astrogliosis (GFAP + astrocytes) and microgliosis (Iba-1 + microglia) were significantly decreased by CR regimen while oligodendrogenesis (Olig2+) and Sirt1 + cell expression were significantly increased in the corpus callosum of CPZ + CR mice compared to the CPZ group. In conclusion, CR regimen can promote remyelination potential in a CPZ-demyelinating mouse model of MS by increasing oligodendrocyte generation while decreasing their apoptosis.
Keywords: Calorie restriction; Cuprizone; Demyelination; Multiple sclerosis; Remyelination.

Lifespan Extension Via Dietary Restriction: Time to Reconsider the Evolutionary Mechanisms?
Moatt JP, Savola E, Regan JC, Nussey DH, Walling CA.
Bioessays. 2020 Jul 8:e1900241. doi: 10.1002/bies.201900241. Online ahead of print.
PMID: 32638410
Abstract
Dietary restriction (DR) is the most consistent environmental manipulation to extend lifespan. Originally thought to be caused by a reduction in caloric intake, recent evidence suggests that macronutrient intake underpins the effect of DR. The prevailing evolutionary explanations for the DR response are conceptualized under the caloric restriction paradigm, necessitating reconsideration of how or whether these evolutionary explanations fit this macronutrient perspective. In the authors' opinion, none of the current evolutionary explanations of DR adequately explain the intricacies of observed results; instead a context-dependent combination of these theories is suggested which is likely to reflect reality. In reviewing the field, it is proposed that the ability to track the destination of different macronutrients within the body will be key to establishing the relative roles of the competing theories. Understanding the evolution of the DR response and its ecological relevance is critical to understanding variation in DR responses and their relevance outside laboratory environments.
Keywords: adaptive plasticity; geometric framework of nutrition; nutrient recycling; resource reallocation; toxic protein; trade-off.

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Genetic and metabolomic architecture of variation in diet restriction-mediated lifespan extension in Drosophila.
Jin K, Wilson KA, Beck JN, Nelson CS, Brownridge GW 3rd, Harrison BR, Djukovic D, Raftery D, Brem RB, Yu S, Drton M, Shojaie A, Kapahi P, Promislow D.
PLoS Genet. 2020 Jul 9;16(7):e1008835. doi: 10.1371/journal.pgen.1008835. eCollection 2020 Jul.
PMID: 32644988
https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008835&type=printable
Abstract
In most organisms, dietary restriction (DR) increases lifespan. However, several studies have found that genotypes within the same species vary widely in how they respond to DR. To explore the mechanisms underlying this variation, we exposed 178 inbred Drosophila melanogaster lines to a DR or ad libitum (AL) diet, and measured a panel of 105 metabolites under both diets. Twenty four out of 105 metabolites were associated with the magnitude of the lifespan response. These included proteinogenic amino acids and metabolites involved in α-ketoglutarate (α-KG)/glutamine metabolism. We confirm the role of α-KG/glutamine synthesis pathways in the DR response through genetic manipulations. We used covariance network analysis to investigate diet-dependent interactions between metabolites, identifying the essential amino acids threonine and arginine as "hub" metabolites in the DR response. Finally, we employ a novel metabolic and genetic bipartite network analysis to reveal multiple genes that influence DR lifespan response, some of which have not previously been implicated in DR regulation. One of these is CCHa2R, a gene that encodes a neuropeptide receptor that influences satiety response and insulin signaling. Across the lines, variation in an intronic single nucleotide variant of CCHa2R correlated with variation in levels of five metabolites, all of which in turn were correlated with DR lifespan response. Inhibition of adult CCHa2R expression extended DR lifespan of flies, confirming the role of CCHa2R in lifespan response. These results provide support for the power of combined genomic and metabolomic analysis to identify key pathways underlying variation in this complex quantitative trait.
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Predicting longevity responses to dietary restriction: A stepping stone toward precision geroscience.
Perez-Matos MC, Mair WB.
PLoS Genet. 2020 Jul 9;16(7):e1008833. doi: 10.1371/journal.pgen.1008833. eCollection 2020 Jul.
PMID: 32644994 No abstract available.
https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008833&type=printable

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The effect of caloric restriction on blood pressure and cardiovascular function: A systematic review and meta-analysis of randomized controlled trials
Kirkham AA, Beka V, Prado, CM.
Clinical Nutrition|July 10, 2020
Researchers investigated how caloric restriction can impact blood pressure (BP) and cardiovascular function by analyzing human randomized control trials (RCTs). They identified RCTs where adults got a calorie-restricted intervention vs a control/standard diet by exploring Medline, EMBASE, CINAHL (up to June 2017). Overall, 32 RCTs with 1,722 participants were included in the analysis. They found the largest impact on systolic and diastolic BP with calorie-restricted interventions lasting 1–4 weeks, but HR remained unaffected with these diets. Findings revealed that the observed changes in BP in response to 1–4 weeks of calorie restriction were comparable to that anticipated with medications, and greater than that documented for other lifestyle interventions or supplements. Comparable effects on BP with a reduction in HR as well was seen with interventions lasting 1.5–6 months had. An improved relative VO2 peak improved and possible beneficial effects on MSNA and endothelial function was also seen with the longer intervention.

Protein and calorie restriction may improve outcomes in living kidney donors and kidney transplant recipients.
Jongbloed F, de Bruin RWF, Steeg HV, Beekhof P, Wackers P, Hesselink DA, Hoeijmakers JHJ, Dollé MET, IJzermans JNM.
Aging (Albany NY). 2020 Jul 11;12. doi: 10.18632/aging.103619. Online ahead of print.
PMID: 32652516
Abstract
Previously, we and others showed that dietary restriction protects against renal ischemia-reperfusion injury in animals. However, clinical translation of preoperative diets is scarce, and in the setting of kidney transplantation these data are lacking. In this pilot study, we investigated the effects of five days of a preoperative protein and caloric dietary restriction (PCR) diet in living kidney donors on the perioperative effects in donors, recipients and transplanted kidneys. Thirty-five kidney donors were randomized into either the PCR, 30% calorie and 80% protein reduction, or control group without restrictions. Adherence to the diet and kidney function in donors and their kidney recipients were analyzed. Perioperative kidney biopsies were taken in a selected group of transplanted kidneys for gene expression analysis. All donors adhered to the diet. From postoperative day 2 up until month 1, kidney function of donors was significantly better in the PCR-group. PCR-donor kidney recipients showed significantly improved kidney function and lower incidence of slow graft function and acute rejection. PCR inhibited cellular immune response pathways and activated stress-resistance signaling. These observations are the first to show that preoperative dietary restriction induces postoperative recovery benefits in humans and may be beneficial in clinical settings involving ischemia-reperfusion injury.
Keywords: acute rejection; dietary restriction; kidney function; kidney transplantation; living kidney donation.

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Intermittent fasting, a possible priming tool for host defense against SARS-CoV-2 infection: crosstalk among calorie restriction, autophagy and immune response.
Hannan MA, Rahman MA, Rahman MS, Al Mamun Sohag A, Dash R, Hossain KS, Farjana M, Uddin MJ.
Immunol Lett. 2020 Jul 10:S0165-2478(20)30349-7. doi: 10.1016/j.imlet.2020.07.001. Online ahead of print.
PMID: 32659267 Review.
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of deadly Coronavirus disease-19 (COVID-19) pandemic, which emerged as a major threat to public health across the world. Although there is no clear gender or socioeconomic discrimination in the incidence of COVID-19, individuals who are older adults and/or with comorbidities and compromised immunity have a relatively higher risk of contracting this disease. Since no specific drug has yet been discovered, strengthening immunity along with maintaining a healthy living is the best way to survive this disease. As a healthy practice, calorie restriction in the form of intermittent fasting (IF) in several clinical settings has been reported to promote several health benefits, including priming of the immune response. This dietary restriction also activates autophagy, a cell surveillance system that boosts up immunity. With these prevailing significance in priming host defense, IF could be a potential strategy amid this outbreak to fighting off SARS-CoV-2 infection. Currently, no review so far available proposing IF as an encouraging strategy in the prevention of COVID-19. A comprehensive review has therefore been planned to highlight the beneficial role of fasting in immunity and autophagy, that underlie the possible defense against SARS-CoV-2 infection. The COVID-19 pathogenesis and its impact on host immune response have also been briefly outlined. This review aimed at revisiting the immunomodulatory potential of IF that may constitute a promising preventive approach against COVID-19.
Keywords: Autophagy; COVID-19; Calorie restriction; Cytokine storm; Immune responses; SARS-COV-2.

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Dynamics of breast tumor incidence, tumor volume and serum metabolic hormones in calorie restricted rats.
Koc Yildirim E, Balkaya M.
Biotech Histochem. 2020 Jul 16:1-8. doi: 10.1080/10520295.2020.1791955. Online ahead of print.
PMID: 32672075
Abstract
Reports of the effects of calorie restriction on tumors after the tumor has developed are uncommon and limited to a few tumor types. We investigated the effects of calorie restriction on tumor growth in breast cancer after tumor growth had progressed. We used the N-nitroso-N-methylurea (NMU) induced breast cancer model in rats. In addition to a healthy control group (C), rats with 10 - 12 mm tumors were divided into three groups: cancer control group (CC), alternate day feeding group (ADF) and calorie restriction group (CR-50%). At the end of the experimental period the volume of tumors was decreased in the CR-50% group compared to the CC group. Serum adiponectin concentrations for the C and ADF groups were higher than for the CC group. All tumors of the CR-50% group were benign. The highest incidence of malignant and invasive tumors occurred in the CC group. A 50% calorie restriction appears to be an effective dietary intervention for advanced tumors.
Keywords: Breast; N-nitroso-N-methylurea; calorie restriction; cancer; fasting; rats.

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Calorie Restriction Increases the Number of Competing Stem Cells and Decreases Mutation Retention in the Intestine.
Bruens L, Ellenbroek SIJ, Suijkerbuijk SJE, Azkanaz M, Hale AJ, Toonen P, Flanagan DJ, Sansom OJ, Snippert HJ, van Rheenen J.
Cell Rep. 2020 Jul 21;32(3):107937. doi: 10.1016/j.celrep.2020.107937.
PMID: 32698002
https://www.cell.com/cell-reports/pdf/S2211-1247(20)30918-9.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124720309189%3Fshowall%3Dtrue
Abstract
Calorie restriction (CR) extends lifespan through several intracellular mechanisms, including increased DNA repair, leading to fewer DNA mutations that cause age-related pathologies. However, it remains unknown how CR acts on mutation retention at the tissue level. Here, we use Cre-mediated DNA recombination of the confetti reporter as proxy for neutral mutations and follow these mutations by intravital microscopy to identify how CR affects retention of mutations in the intestine. We find that CR leads to increased numbers of functional Lgr5+ stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying neutral or Apc mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine.
Keywords: Lgr5; calorie restriction; competition; diet; intestine; mutation retention; stem cells.

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Astroglia-Derived BDNF and MSK-1 Mediate Experience- and Diet-Dependent Synaptic Plasticity.
Lalo U, Bogdanov A, Moss GW, Pankratov Y.
Brain Sci. 2020 Jul 18;10(7):E462. doi: 10.3390/brainsci10070462.
PMID: 32708382
Abstract
Experience- and diet-dependent regulation of synaptic plasticity can underlie beneficial effects of active lifestyle on the aging brain. Our previous results demonstrate a key role for brain-derived neurotrophic factor (BDNF) and MSK1 kinase in experience-related homeostatic synaptic scaling. Astroglia has been recently shown to release BDNF via a calcium-dependent mechanism. To elucidate a role for astroglia-derived BDNF in homeostatic synaptic plasticity in the aging brain, we explored the experience- and diet-related alterations of synaptic transmission and plasticity in transgenic mice with impairment of the BDNF/MSK1 pathway (MSK1 kinase dead knock-in mice, MSK1 KD) and impairment of glial exocytosis (dnSNARE mice). We found that prolonged tonic activation of astrocytes caused BDNF-dependent increase in the efficacy of excitatory synapses accompanied by enlargement of synaptic boutons. We also observed that exposure to environmental enrichment (EE) and caloric restriction (CR) enhanced the Ca2+ signalling in cortical astrocytes and strongly up-regulated the excitatory and down-regulated inhibitory synaptic currents in old wild-type mice, thus counterbalancing the impact of ageing on astroglial and synaptic signalling. The EE- and CR-induced up-scaling of excitatory synaptic transmission in neocortex was accompanied by the enhancement of long-term synaptic potentiation. Importantly, effects of EE and CR on synaptic transmission and plasticity was significantly reduced in the MSK1 KD and dnSNARE mice. Combined, our results suggest that astroglial release of BDNF is important for the homeostatic regulation of cortical synapses and beneficial effects of EE and CR on synaptic transmission and plasticity in aging brain.

Keywords: AMPA receptors; Arc/Arg3.1; GABA receptors; TrkB receptors; aging; calcium signalling; dendritic spines; diet; enriched environment; glia-neuron interactions; ion conductance microscopy; synaptic scaling; synaptic strength.

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Two weeks of early time-restricted feeding (eTRF) improves skeletal muscle insulin and anabolic sensitivity in healthy men.
Jones R, Pabla P, Mallinson J, Nixon A, Taylor T, Bennett A, Tsintzas K.
Am J Clin Nutr. 2020 Jul 30:nqaa192. doi: 10.1093/ajcn/nqaa192. Online ahead of print.
PMID: 32729615
Abstract
Background: Altering the temporal distribution of energy intake (EI) and introducing periods of intermittent fasting (IF) exert important metabolic effects. Restricting EI to earlier in the day [early time-restricted feeding (eTRF)] is a novel type of IF.
Objectives: We assessed the chronic effects of eTRF compared with an energy-matched control on whole-body and skeletal muscle insulin and anabolic sensitivity.
Methods: Sixteen healthy males (aged 23 ± 1 y; BMI 24.0 ± 0.6 kg·m-2) were assigned to 2 groups that underwent either 2 wk of eTRF (n = 😎 or control/caloric restriction (CON:CR; n = 😎 diet. The eTRF diet was consumed ad libitum and the intervention was conducted before the CON:CR, in which the diet was provided to match the reduction in EI and body weight observed in eTRF. During eTRF, daily EI was restricted to between 08:00 and 16:00, which prolonged the overnight fast by ∼5 h. The metabolic responses to a carbohydrate/protein drink were assessed pre- and post-interventions following a 12-h overnight fast.
Results: When compared with CON:CR, eTRF improved whole-body insulin sensitivity [between-group difference (95% CI): 1.89 (0.18, 3.60); P = 0.03; η2p = 0.29] and skeletal muscle uptake of glucose [between-group difference (95% CI): 4266 (261, 8270) μmol·min-1·kg-1·180 min; P = 0.04; η2p = 0.31] and branched-chain amino acids (BCAAs) [between-group difference (95% CI): 266 (77, 455) nmol·min-1·kg-1·180 min; P = 0.01; η2p = 0.44]. eTRF caused a reduction in EI (∼400 kcal·d-1) and weight loss (-1.04 ± 0.25 kg; P = 0.01) that was matched in CON:CR (-1.24 ± 0.35 kg; P = 0.01).
Conclusions: Under free-living conditions, eTRF improves whole-body insulin sensitivity and increases skeletal muscle glucose and BCAA uptake. The metabolic benefits of eTRF are independent of its effects on weight loss and represent chronic adaptations rather than the effect of the last bout of overnight fast. This trial was registered at clinicaltrials.gov as NCT03969745.
Keywords: body composition; energy balance and metabolism; free-living intervention; insulin sensitivity; skeletal muscle; time-restricted feeding.

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