Jump to content

Recommended Posts

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.

Share this post


Link to post
Share on other sites

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.
>>>>>>>>>>>>>>>>>>>
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

Share this post


Link to post
Share on other sites

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.

Share this post


Link to post
Share on other sites

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.

Share this post


Link to post
Share on other sites

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.

Share this post


Link to post
Share on other sites

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.

Share this post


Link to post
Share on other sites

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.

Share this post


Link to post
Share on other sites

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.

Share this post


Link to post
Share on other sites

Extent of food restriction affects probability but not delay-based decision-making.
Tapp DN, Zerkle HL, McMurray MS.
J Exp Anal Behav. 2020 Aug 10. doi: 10.1002/jeab.624. Online ahead of print.
PMID: 32776567
Abstract
Rodent studies on decision-making often use food rewards and food-restrict subjects in order to motivate performance. However, food restriction has widespread effects on brain and behavior, which depend on factors including extent of restriction and feeding schedule. These factors are well recognized for their effects on motivation, but may also cause effects on decision-making independent of motivation. We examined how the degree of weight-based food restriction in rats influenced decision-making on the probability and delay discounting tasks. Additionally, we examined how the method of food restriction (consistent amount vs. time constrained feeding schedule) influenced decision-making. Our results showed that the degree of weight-based food restriction significantly altered probability, but not delay discounting, and that these effects were not entirely explainable by differences in motivation. Additionally, the method of food restriction did not significantly influence discounting when animals were within the same range of weight-based restriction. Together, our findings suggest that the degree of food restriction may modulate the neural circuitry responsible for selective aspects of decision-making related to probability. Further, these data support the need for tight control and reporting of weight and feeding in studies relying on food restriction, and suggest that the effects of food restriction may be broader than previously considered.
Keywords: body weight; delay discounting; food restriction; probability discounting; rat; time constrained feeding schedule.

Does nutrition for cancer patients feed the tumour? A clinical perspective.
Bozzetti F, Stanga Z.
Crit Rev Oncol Hematol. 2020 Jul 12;153:103061. doi: 10.1016/j.critrevonc.2020.103061. Online ahead of print.
PMID: 32777729 Review.
Abstract
This review aims to answer to two basic questions: a) Which substrates does a tumour utilize and is there a regimen that might potentially favour the host over the tumour? and b) Does nutritional intervention disproportionally affect tumour growth? Literature to date focuses on humans; although some references to molecular mechanisms regulating cancer cells metabolism derive from studies on experimental tumours and cell biology. Literature shows that some tumours, especially those of the brain and head/neck and lung, are glucose-dependent, and patients with these tumours could benefit from a normocaloric ketogenic diet provided these tumours exhibit high fluorodeoxyglucose (18F-FDG) captation. A high fat-protein, low carbohydrate diet appears to better fulfil the nutritional requirements of the cancer patient. Current evidence shows no improvement in tumoral response after restricting patients' caloric intake; whereas malnutrition is acknowledged as an important negative predictive and prognostic factor in all cancer patients.
Keywords: Calorie restricted diet; Calorie restriction; Cancer cell metabolism; Ketogenic diet; Nutrition and tumour growth; Nutrition of cancer patients; Nutritive substrates of the cancer cell.

Share this post


Link to post
Share on other sites

Effect of 2 years of calorie restriction on liver biomarkers: results from the CALERIE phase 2 randomized controlled trial.
Dorling JL, Ravussin E, Redman LM, Bhapkar M, Huffman KM, Racette SB, Das SK, Apolzan JW, Kraus WE, Höchsmann C, Martin CK; CALERIE Phase 2 Study Group.
Eur J Nutr. 2020 Aug 14. doi: 10.1007/s00394-020-02361-7. Online ahead of print.
PMID: 32803412
Abstract
Purpose: Calorie restriction (CR) is an effective treatment for obesity-related liver and metabolic disease. However, CR studies in individuals without obesity are needed to see if CR could delay disease onset. Liver biomarkers indicate hepatic health and are linked to cardiometabolic disease. Our aim was to examine the effects of a 2-year CR intervention on liver biomarkers in healthy individuals without obesity.
Methods: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study was a 2-year randomized controlled trial. Overall, 218 participants (body mass index: 25.1 ± 1.7 kg/m2) were enrolled into a control group (n = 75) that ate ad libitum (AL), or a CR group (n = 143) that aimed to decrease energy intake by 25%. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and bilirubin were measured during the trial.
Results: At month 24, relative to the AL group, ALP (- 7 ± 1 IU/L; P < 0.01) and GGT (- 0.11 ± 0.04 log IU/L; P = 0.02) decreased and bilirubin increased (0.21 ± 0.06 log mg/dL; P < 0.01) in the CR group; no between-group differences in ALT (- 1 ± 1 IU/L; P > 0.99) or AST (2 ± 2 IU/L; P = 0.68) were revealed. However, sex-by-treatment-by-time interactions (P < 0.01) were observed, with CR (vs. control) inducing reduced ALT and GGT and increased AST in men only (P ≤ 0.02).
Conclusions: In metabolically healthy individuals without obesity, 2 years of CR improves several liver biomarkers, with potentially greater improvements in men. These data suggest that sustained CR may improve long-term liver and metabolic disease risk in healthy adults.
Keywords: Aging; Bilirubin; Cardiometabolic health; Energy restriction; Liver enzymes.

Share this post


Link to post
Share on other sites

Effects of dietary restriction on gut microbiota and CNS autoimmunity.
Cantoni C, Dorsett Y, Fontana L, Zhou Y, Piccio L.
Clin Immunol. 2020 Aug 18:108575. doi: 10.1016/j.clim.2020.108575. Online ahead of print.
PMID: 32822833 Review.
Abstract
Multiple sclerosis (MS) is the most common central nervous system (CNS) autoimmune disease. It is due to the interplay of genetic and environmental factors. Current opinion is that diet could play a pathogenic role in disease onset and development. Dietary restriction (DR) without malnutrition markedly improves health and increases lifespan in multiple model organisms. DR regimens that utilize continuous or intermittent food restriction can induce anti-inflammatory, immuno-modulatory and neuroendocrine adaptations promoting health. These adaptations exert neuroprotective effects in the main MS animal model, experimental autoimmune encephalomyelitis (EAE). This review summarizes the current knowledge on DR-induced changes in gut microbial composition and metabolite production and its impact on underlying functional mechanisms. Studies demonstrating the protective effects of DR regimens on EAE and people with MS, are also presented. This is a rapidly developing research field with important clinical implications for personalized dietary interventions in MS prevention and treatment.

Share this post


Link to post
Share on other sites

SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1.
Simonet NG, Thackray JK, Vazquez BN, Ianni A, Espinosa-Alcantud M, Morales-Sanfrutos J, Hurtado-Bagès S, Sabidó E, Buschbeck M, Tischfield J, De La Torre C, Esteller M, Braun T, Olivella M, Serrano L, Vaquero A.
Sci Adv. 2020 Jul 24;6(30):eaaz2590. doi: 10.1126/sciadv.aaz2590. eCollection 2020 Jul.
PMID: 32832656 Free PMC article.
Abstract
Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono-adenosine 5'-diphosphate (ADP)-ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.1 axis in glucose homeostasis and aging.

Caloric Restriction recovers impaired β-cell-β-cell gap junction coupling, calcium oscillation coordination and insulin secretion in prediabetic mice.
do Amaral MEC, Kravets V, Dwulet JM, Farnsworth NL, Piscopio R, Schleicher WE, Miranda JG, Benninger RKP.
Am J Physiol Endocrinol Metab. 2020 Aug 24. doi: 10.1152/ajpendo.00132.2020. Online ahead of print.
PMID: 32830549
Abstract
Caloric restriction can decrease the incidence of metabolic diseases such as obesity and type 2 diabetes mellitus (T2DM). The mechanisms underlying the benefits of caloric restriction involved in insulin secretion and glucose homeostasis are not fully understood. Intercellular communication within the islets of Langerhans, mediated by Connexin36 (Cx36) gap junctions, regulates insulin secretion dynamics and glucose homeostasis. The goal of this study was to determine if caloric restriction can protect against decreases in Cx36 gap junction coupling and altered islet function induced in models of obesity and prediabetes. C57BL6 mice were fed with a high fat diet (HFD), showing indications of prediabetes after 2 months, including weight gain, insulin resistance, and elevated fasting glucose and insulin levels. Subsequently, mice were submitted to one month of 40% caloric restriction (2g/day of HFD). Mice under 40% caloric restriction showed reversal in weight gain and recovered insulin sensitivity, fasting glucose and insulin levels. In islets of mice fed the HFD, caloric restriction protected against obesity-induced decreases in gap junction coupling and preserved glucose-stimulated calcium signaling, including Ca2+ oscillation coordination and oscillation amplitude. Caloric restriction also promoted a slight increase in glucose metabolism, as measured by increased NAD(P)H autofluorescence, as well as recovering glucose-stimulated insulin secretion. We conclude that declines in Cx36 gap junction coupling that occur in obesity can be completely recovered by caloric restriction and obesity reversal, improving Ca2+ dynamics and insulin secretion regulation. This suggests a critical role for caloric restriction in the context of obesity to prevent islet dysfunction.
Keywords: calcium; caloric restriction; diabetes; gap junctions; islets of langerhans.

Share this post


Link to post
Share on other sites

Fasting, Dietary Restriction, and Immunosenescence.
Longo VD, Cortellino S.
J Allergy Clin Immunol. 2020 Aug 24:S0091-6749(20)31173-8. doi: 10.1016/j.jaci.2020.07.035. Online ahead of print.
PMID: 32853639 No abstract available.
https://www.jacionline.org/article/S0091-6749(20)31173-8/pdf

The effect of fasting or calorie restriction on mitophagy induction: a literature review.
Mehrabani S, Bagherniya M, Askari G, Read MI, Sahebkar A.
J Cachexia Sarcopenia Muscle. 2020 Aug 27. doi: 10.1002/jcsm.12611. Online ahead of print.
PMID: 32856431 Review.
Abstract
Mitochondrial dysfunction can be a major cause of a wide range of age-related diseases. Maintaining the normal homeostasis of mitochondria population plays an important role in ensuring people's health, which is done through the mitophagy process. Among the various stimuli for the onset of mitophagy, caloric restriction (CR) is one of the strongest non-genetic triggers for initiating the mitophagy process. The primary objective of this paper is to review the literature assessing the effect of CR on mitophagy. Medline, Web of Science, Scopus, and Google Scholar databases was searched from inception to 1 August 2019. Reference lists from all selected articles were also examined for additional relevant studies. The evidence regarding the effect of fasting or CR on mitophagy is still limited. In addition, the methodological approaches of the studies are too heterogeneous in terms of types of food restriction, study duration, and targeted tissues. Most of the studies showed that fasting or CR induced mitophagy and mitophagy-related markers such as Binp3 and Parkin. However, some studies demonstrated that mitophagy occurred both in fasting and fed state with no significant differences or may be induced in fed state. Study on the muscle tissue of subjects after exercise showed that mitophagy was upregulated in the fed state. It has been demonstrated that mitophagy in the muscle was lowered in the absence of AMP-dependent kinase and fibroblast growth factor 21 genes, both in fasted and fed conditions. Current evidence overwhelmingly suggests that CR and fasting induce mitophagy and mitophagy-related markers. Based on the current evidence that we reviewed here, it could be concluded that fasting or CR has a promising role as a novel and practical approach in the prevention of age-related diseases without any side effects by inducing mitophagy in different organs of the body. More studies will be required in future to clarify the relationship between food deprivation and mitophagy. Further studies using a variety of different types of CR and fasting states are also warranted to determine the best approach for inducing mitophagy and improving health.
Keywords: BNip3; Calorie restriction; Fasting; Mitophagy; PINK1.

Share this post


Link to post
Share on other sites

Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice.
Ke Z, Firsanov D, Spencer B, Seluanov A, Gorbunova V.
NPJ Aging Mech Dis. 2020 Aug 14;6:9. doi: 10.1038/s41514-020-00047-2. eCollection 2020.
PMID: 32864160 Free PMC article.
Abstract
Calorie restriction (CR) improves health, reduces cancer incidence and extends lifespan in multiple organisms including mice. CR was shown to enhance base excision repair and nucleotide excision repair pathways of DNA repair, however, whether CR improves repair of DNA double-strand breaks has not been examined in in vivo system. Here we utilize non-homologous end joining (NHEJ) reporter mice to show that short-term CR strongly enhances DNA repair by NHEJ, which is associated with elevated levels of DNA-PK and SIRT6.
Keywords: Medical research; Molecular biology.

Share this post


Link to post
Share on other sites

Amyloidosis increase is not attenuated by long-term calorie restriction or related to neuron density in the prefrontal cortex of extremely aged rhesus macaques.
Stonebarger GA, Urbanski HF, Woltjer RL, Vaughan KL, Ingram DK, Schultz PL, Calderazzo SM, Siedeman JA, Mattison JA, Rosene DL, Kohama SG.
Geroscience. 2020 Sep 2. doi: 10.1007/s11357-020-00259-0. Online ahead of print.
PMID: 32876855
Abstract
As human lifespan increases and the population ages, diseases of aging such as Alzheimer's disease (AD) are a major cause for concern. Although calorie restriction (CR) as an intervention has been shown to increase healthspan in many species, few studies have examined the effects of CR on brain aging in primates. Using postmortem tissue from a cohort of extremely aged rhesus monkeys (22-44 years old, average age 31.8 years) from a longitudinal CR study, we measured immunohistochemically labeled amyloid beta plaques in Brodmann areas 32 and 46 of the prefrontal cortex, areas that play key roles in cognitive processing, are sensitive to aging and, in humans, are also susceptible to AD pathogenesis. We also evaluated these areas for cortical neuron loss, which has not been observed in younger cohorts of aged monkeys. We found a significant increase in plaque density with age, but this was unaffected by diet. Moreover, there was no change in neuron density with age or treatment. These data suggest that even in the oldest-old rhesus macaques, amyloid beta plaques do not lead to overt neuron loss. Hence, the rhesus macaque serves as a pragmatic animal model for normative human aging but is not a complete model of the neurodegeneration of AD. This model of aging may instead prove most useful for determining how even the oldest monkeys are protected from AD, and this information may therefore yield valuable information for clinical AD treatments.
Keywords: Aging; Alzheimer’s disease; Amyloid plaques; Diet; Neurodegeneration; Neuron number.

Improvement of intestinal stem cells and barrier function via energy restriction in middle-aged C57BL/6 mice.
Di W, Lv Y, Xia F, Sheng Y, Liu J, Ding G.
Nutr Res. 2020 Jun 26;81:47-57. doi: 10.1016/j.nutres.2020.06.015. Online ahead of print.
PMID: 32877836
Abstract
This study aimed to reveal the impact of energy restriction on the intestine via structural and molecular changes in terms of intestinal stem cell (ISC) function, ISC niche, intestinal epithelial barrier function, and intestinal immune function. Female C57BL/6J mice, aged 12 months, fed a commercial chow were used in this study. The ISC function, ISC niche, intestinal epithelial barrier function, and intestinal immune function were assessed. Energy restriction reversed aging-induced intestinal shortening and made the crypts shallower. The intestinal epithelial cells isolated from the intestine showed a significant increase in the expression levels of stem cell-associated genes in small intestinal epithelial cells as detected by flow cytometry. Despite the increase in the number of stem cells and the expression levels of markers, no increase or decrease was found in the enteroid complexity of the small intestine and colonic enteroid formation in vitro. The colonic mucous layer was measured in mice of the energy restricted (ER)-treated group to investigate the epithelial barrier function in the colon. The results revealed that the barrier was more complete. The fluorescence intensity of tight junction markers claudin-2 and zonula occludens-1 increased and the mRNA expression profiles of monocyte chemotactic protein 1 and interleukin-6 decreased in the colon of mice in the ER-treated group. The beneficial effects of ER on the colon in terms of the integrity of the mucosal barrier and alleviation of inflammation were confirmed, thus highlighting the importance of modulating the intestinal function in developing effective antiaging dietary interventions.
Keywords: Aging; Energy restriction; Intestinal barrier; Intestinal epithelial cell; Intestinal epithelial stem cell.

Share this post


Link to post
Share on other sites

Dietary restriction and/or exercise training impairs spermatogenesis in normal rats.
Li Y, Zhang L, Zheng X, Qian J, Li Y, Xie C, Zhang X, Zhou Y, Huang H.
Appl Physiol Nutr Metab. 2020 Sep 9. doi: 10.1139/apnm-2020-0477. Online ahead of print.
PMID: 32905708
Abstract
Dietary restriction and/or exercise has been shown to have multiple benefits for health. However, its effects on reproductive health and the mechanisms by which it regulates reproductive function remain unclear. Here, in order to evaluate its effects on spermatogenesis and sperm function, rats were divided into four groups: ad libitum-fed sedentary control (CO), dietary restriction (DR), exercise training (ET), and dietary restriction plus exercise training (DR+ET) groups. Results indicated that body weight, epididymal fat pad weight, and sperm counts were significantly reduced in the DR, ET, and DR+ET groups. Moreover, sperm motility and capacitation-associated protein tyrosine phosphorylation were suppressed in the DR and DR+ET groups, but not the ET group. Microarray analysis revealed that the number of downregulated genes was higher than that of upregulated genes in the DR and/or ET groups. About half of the downregulated genes are common after exercise training and/or diet restriction. Gene ontology analysis showed that downregulated genes in the DR, ET, and DR+ET groups affected spermatogenesis through overlapping pathways, including glucocorticoid, corticosteroid, extracellular structure organization, and estradiol responses. Our findings suggest that diet restriction and/or exercise training may present potential risks to male reproductive dysfunction by disrupting normal gene expression patterns in the testis. Novelty bullets: 1. Dietary restriction and/or exercise can lead to the damage of spermatogenesis as well as sperm maturation. 2. Sperm functional changes are more sensitive to dietary restriction than exercise training. 3. Dietary restriction and exercise impair spermatogenesis through overlapping biological pathways in the testis.

Share this post


Link to post
Share on other sites

Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers.
Di Tano M, Raucci F, Vernieri C, Caffa I, Buono R, Fanti M, Brandhorst S, Curigliano G, Nencioni A, de Braud F, Longo VD.
Nat Commun. 2020 May 11;11(1):2332. doi: 10.1038/s41467-020-16243-3.
PMID: 32393788 Free PMC article.
Abstract
Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS-mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors.
>>>>>>>>>>>>>>>>>>
A fasting-mimicking diet and vitamin C turning anti-aging strategies against cancer.
Di Tano M, Longo VD.
Mol Cell Oncol. 2020 Jul 29;7(5):1791671. doi: 10.1080/23723556.2020.1791671. eCollection 2020.
PMID: 32944646
Abstract
In search of anti-aging interventions with differential effects on normal and cancer cells, we show that cycles of a fasting-mimicking diet plus pharmacological doses of vitamin C can be effective in targeting KRAS-mutant cancers. This approach represents a promising strategy able to protect the organism while killing cancer cells.
Keywords: Fasting-mimicking diet; KRAS-mutant cancers; iron metabolism; vitamin C.

 

Effects of caloric restriction on human physiological, psychological, and behavioral outcomes: highlights from CALERIE phase 2.
Dorling JL, van Vliet S, Huffman KM, Kraus WE, Bhapkar M, Pieper CF, Stewart T, Das SK, Racette SB, Roberts SB, Ravussin E, Redman LM, Martin CK.
Nutr Rev. 2020 Sep 17:nuaa085. doi: 10.1093/nutrit/nuaa085. Online ahead of print.
PMID: 3294069
Abstract
Caloric restriction (CR) is a strategy that attenuates aging in multiple nonhuman species. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trials are part of a research program aiming to test the effects of CR on aging and longevity biomarkers in humans. Building on CALERIE phase 1, CALERIE phase 2 (CALERIE 2) was the largest study to date to assess sustained CR in healthy humans without obesity. In a 24-month randomized controlled trial comprising 218 participants at baseline, CALERIE 2 showed that moderate CR, 11.9% on average, induced improvements in aging-related biomarkers without adversely affecting psychological or behavioral outcomes. The objectives of this report are to summarize and review the highlights of CALERIE 2 and report previously unpublished results on eating disorder symptoms and cognitive function. This article specifically summarizes the physiological, psychological, aging, behavioral, and safety results of the trial. Also provided are research directions beyond CALERIE 2 that highlight important opportunities to investigate the role of CR in aging, longevity, and health span in humans.
Keywords: aging; longevity; metabolism; quality of life; randomized controlled trial.

 

Long-term mid-onset dietary restriction rejuvenates hematopoietic stem cells and improves regeneration capacity of total bone marrow from aged mice.
Tao S, Wang Y, Wu J, Zeng T, Cui H, Tao Z, Lei L, Yu L, Liu A, Wang H, Zhang L, Tang D.
Aging Cell. 2020 Sep 15:e13241. doi: 10.1111/acel.13241. Online ahead of print.
PMID: 32935456
Abstract
Currently, the world's aging population is expanding rapidly, leading to a rise in aged hematopoietic cell transplantation (HCT) recipients and aged donors. However, the age of donors is negatively related to the prognosis after transplantation due to functional decline in hematopoietic stem cells (HSCs) during aging. Previously, we showed that an early-onset dietary restriction (DR) significantly retards early aging of HSCs. However, the effects of a mid-onset DR on HSCs remain unknown. In the current study, we performed 30% DR in 15- to 18-month-old mice (equivalent to 50-60 human years) for short-term (4 months) and long-term (9 months). We show that DR reduces and rectifies the imbalance of the HSC pool in aged mice. Short-term DR improves hematopoietic reconstitution in purified HSC transplantations, but not in bone marrow transplantations. Intriguingly, long-term mid-onset DR improves the hematopoietic regeneration of aging HSCs with a particular enhancement of lymphoid outputs even in total bone marrow transplantation settings. Mechanistically, long-term DR rejuvenates the aberrantly regulated mitochondrial pathways in aging HSCs and is accompanied by increased quiescence and reduced DNA damage signaling in HSCs. Short-term DR showed a similar trend of rescuing these aging hallmarks but to a much lesser extent. Together, the current study suggests that mid-onset DR ameliorates the function of aging HSCs and long-term DR even improved hematopoietic reconstitution in bone marrow transplantation, which could potentially have considerable implications in HCT of humans when only old donors are available.
Keywords: aging; bone marrow transplantation; dietary restriction; hematopoietic stem cells.

Edited by AlPater

Share this post


Link to post
Share on other sites

Caloric restriction alleviates aging-related fibrosis of kidney through downregulation of miR-21 in extracellular vesicles.
Liu JR, Cai GY, Ning YC, Wang JC, Lv Y, Guo YN, Fu B, Hong Q, Sun XF, Chen XM.
Aging (Albany NY). 2020 Aug 27;12. doi: 10.18632/aging.103591. Online ahead of print.
PMID: 32963130
Abstract
Glomerulosclerosis and renal interstitial fibrosis occur with the aging kidney. In this study, we examined the expression of miR-21, peroxisome proliferator-activated receptor(PPARα), hypoxia-inducible factor(HIF-1α) in the kidney of 3-month-old rats fed ad libitum (YAL), 24-month-old rats fed ad libitum (OAL) and 24-month-old rats subjected to a 70% calorie-restricted diet for 8 months (OCR). We found long-term caloric restriction (CR) ameliorated aging and aging-related fibrosis. CR ameliorated the increment of miR-21 and HIF-1α, as well as the decrement of PPARα in old ad libitum group. Human proximal tubular cells (HPTCs) presented phenotypes of senescence and epithelial to mesenchymal transition (EMT) under high-glucose conditions, in which senescence occurred earlier than EMT. Senescent cells secreted extracellular vesicles (EVs) which contained miR-21 into the recipient cells. Inhibiting miR-21 of donor cells prevented the occurrence of EMT in recipient cells. In addition, miR-21 induced EMT through targeting PPARα protein and consequently enhancing HIF-1α expression, although other pathways cannot be ruled out. These findings demonstrated that miR-21-containing EVs derived from the senescent cells could facilitate EMT of HPTCs via PPARα-HIF-1α signaling pathway. Long-term caloric restriction and caloric restriction mimetics alleviated aging-related-fibrosis of kidney through downregulation of miR-21.
Keywords: EMT; age; caloric restriction; extracellular vesicles; miR-21.

Effects of caloric restriction on retinal aging and neurodegeneration.
Adornetto A, Morrone LA, Satriano A, Laganà ML, Licastro E, Nucci C, Corasaniti MT, Tonin P, Bagetta G, Russo R.
Prog Brain Res. 2020;256(1):189-207. doi: 10.1016/bs.pbr.2020.07.005. Epub 2020 Aug 18.
PMID: 32958212
Abstract
Glaucoma is the most common neurodegenerative cause of irreversible blindness worldwide. Restricted caloric regimens are an attractive approach for delaying the progression of neurodegenerative diseases. Here we review the current literature on the effects of caloric restriction on retinal neurons, under physiological and pathological conditions. We focused on autophagy as one of the mechanisms modulated by restricted caloric regimens and involved in the death of retinal ganglion cells (RGCs) over the course of glaucoma.
Keywords: AMPK; Aging; Autophagy; Caloric restriction; Glaucoma; Neurodegeneration; Retina; SIRT1.

Share this post


Link to post
Share on other sites

Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction.
Chamoli M, Goyala A, Tabrez SS, Siddiqui AA, Singh A, Antebi A, Lithgow GJ, Watts JL, Mukhopadhyay A.
Nat Commun. 2020 Sep 25;11(1):4865. doi: 10.1038/s41467-020-18690-4.
PMID: 32978396
https://www.nature.com/articles/s41467-020-18690-4.pdf
Abstract
The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of "Xenobiotic Detoxification Program" (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.

Resemblance and differences in dietary restriction nephroprotective mechanisms in young and old rats.
Andrianova NV, Zorova LD, Pevzner IB, Popkov VA, Chernikov VP, Silachev DN, Plotnikov EY, Zorov DB.
Aging (Albany NY). 2020 Sep 24;12. doi: 10.18632/aging.103960. Online ahead of print.
PMID: 32970613
https://paperchase-aging.s3-us-west-1.amazonaws.com/pdf/eYPXbdLKxHZT7JgwD.pdf
Abstract
Dietary restriction (DR) is the strategy ameliorating the morbidity of various pathologies, including age-associated diseases. Acute kidney injury (AKI) remains a problem for the elderly with DR being a promising approach for diminishing its consequences. We evaluated the possible nephroprotective potential of short-term DR in young and old rats. DR in young rats resulted in pronounced beneficial effects normalizing lipid metabolism (triglycerides concentration, adiponectin level) activating autophagic-lysosomal system evaluated by LC3II/LC3I ratio, LAMP1, p62/SQSTM1 levels, and LysoTracker Green staining. DR had a remarkable recovering effect on mitochondrial structure and functions including regaining of mitochondrial membrane potential, the elevation of SIRT-3, PGC-1α, Bcl-XL levels and partial restoration of ultrastructure. The beneficial effects of DR resulted in the mitigation of oxidative stress including a decrease in levels of protein carbonylation and lipid peroxidation. Aging led to decreased activity of autophagy, elevated oxidative stress and impaired kidney regenerative capacity. Eventually, in old rats, even 8-week DR was not able to ameliorate AKI, but it caused some rejuvenating effects including elevation of mitochondrial membrane potential and Bcl-XL levels, as well as lowered severity of the oxidative stress. Thus, the age-associated decline of protective signaling demands extended DR to achieve nephroprotective potential in old animals.
Keywords: aging; caloric restriction; ischemia/reperfusion; kidney injury; mitochondria.
"In addition, we estimated the intensity of lipid
peroxidation ... revealed the decrease in ... DR
rats, but only in young animals (Figure 6G)."

Share this post


Link to post
Share on other sites

Calorie restriction changes muscle satellite cell proliferation in a manner independent of metabolic modulation.
Abreu P, Serna JDC, Munhoz AC, Kowaltowski AJ.
Mech Ageing Dev. 2020 Sep 30:111362. doi: 10.1016/j.mad.2020.111362. Online ahead of print.
PMID: 33010305
Abstract
Calorie restriction is known to promote healthy aging, which includes prevention of muscle loss. We investigated the effect of rodent calorie restriction on mitochondrial respiration and clonogenic capacity of muscle satellite stem cells, since metabolic alterations are known to regulate stem cell activity. Surprisingly, short or long-term calorie restriction do not change mitochondrial or glycolytic function. Nevertheless, both short- and long-term calorie restriction enhance myogenic colony formation. Overall, our results show that not all changes in satellite stem cell function are accompanied by metabolic remodeling.
Keywords: Bioenergetics; Diet; Metabolism; Mitochondria; Muscle stem cells.

Impacts of Calorie Restriction and Intermittent Fasting on Health and Diseases: Current Trends.
Chung HY, Kim DH, Bang E, Yu BP.
Nutrients. 2020 Sep 25;12(10):E2948. doi: 10.3390/nu12102948.
PMID: 32992924
[pdf availed from Medline abstract site.]
Abstract
This special issue on the effects of calorie restriction (CR) and intermittent fasting (IF) on health and diseases includes five scholarly reviews and four original articles that provide an insight into the molecular and cellular action mechanisms of epigenetically manipulated dietary paradigms [...].

Time-restricted feeding (TRF) for prevention of age-related vascular cognitive impairment and dementia.
Balasubramanian P, DelFavero J, Ungvari A, Papp M, Tarantini A, Price N, de Cabo R, Tarantini S.
Ageing Res Rev. 2020 Sep 27:101189. doi: 10.1016/j.arr.2020.101189. Online ahead of print.
PMID: 32998063
Abstract
Aging is the most significant risk factor for vascular cognitive impairment (VCI), and the number of individuals affected by VCI is expected to exponentially increase in the upcoming decades. Yet, there are no current preventative or therapeutic treatments available against the development and progression of VCI. Therefore, there is a pressing need to better understand the pathophysiology underlying these conditions, for the development of novel tools and interventions to improve cerebrovascular health and delay the onset of VCI. There is strong epidemiological and experimental evidence that lifestyle factors, including nutrition and dietary habits, significantly affect cerebrovascular health and thereby influence the pathogenesis of VCI. Here, recent evidence is presented discussing the effects of lifestyle interventions against age-related diseases which in turn, inspired novel research aimed at investigating the possible beneficial effects of dietary interventions for the prevention of cognitive decline in older adults.
Keywords: Aging; Cognitive function; Dementia; Neurodegeneration Geroscience; Neurovascular coupling; Time restricted feeding.

Share this post


Link to post
Share on other sites

Effects of intermittent fasting or calorie restriction on markers of lipid metabolism in human skeletal muscle.
Liu B, Hutchison AT, Thompson CH, Lange K, Wittert GA, Heilbronn LK.
J Clin Endocrinol Metab. 2020 Oct 8:dgaa707. doi: 10.1210/clinem/dgaa707. Online ahead of print.
PMID: 33031557
Abstract
Context: Impaired lipid metabolism is linked with obesity-associated insulin resistance, which may be reversed by caloric restriction (CR).
Objective: In a secondary analysis of a randomized controlled trial, we compared the effects of intermittent fasting (IF) and CR on markers of lipid metabolism in muscle.
Design: Seventy-six women (BMI 25-40 kg/m2) were randomized to one of three diets for eight weeks and provided with foods at 70% (CR70 and IF70) or 100% (IF100) of energy requirements. IF groups ate breakfast, prior to a 24-hour fast on 3 non-consecutive days per week. On non-fasting days, IF70 ate at 100% and IF100 ate at 145% of energy requirements to achieve the prescribed target. Weight, body composition, insulin sensitivity by clamp, non-esterified fatty acids (NEFA), β-hydroxybutyrate, and markers of lipid metabolism and oxidative stress in muscle by qPCR were measured at baseline and week 8 following a 12-hour overnight fast (all groups) and 24-hour fast (IF groups).
Results: IF70 resulted in greater weight and fat losses and reduced NEFA versus CR70 and IF100 after an overnight fast. IF70 and IF100 induced a greater reduction only in mRNA levels of antioxidant enzymes GPX1, SOD1 and SOD2 versus CR70. Fasting for 24-hours increased NEFA and β-hydroxybutyrate in IF groups, but impaired insulin sensitivity and increased PLIN5 mRNA levels.
Conclusions: In comparison to CR, IF did not increase markers of lipid metabolism in muscle, but reduced expression of antioxidant enzymes. However, fasting-induced insulin resistance was detected, alongside increased PLIN5 expression, potentially reflecting transient lipid storage.
Keywords: calorie restriction; intermittent fasting; lipid metabolism; mitochondria; muscle; obesity.

Share this post


Link to post
Share on other sites

The effects of graded levels of calorie restriction: XVI. Metabolomic changes in the cerebellum indicate activation of hypothalamocerebellar connections driven by hunger responses.
Green CL, Mitchell SE, Derous D, García-Flores LA, Wang Y, Chen L, Han JJ, Promislow DEL, Lusseau D, Douglas A, Speakman JR.
J Gerontol A Biol Sci Med Sci. 2020 Oct 14:glaa261. doi: 10.1093/gerona/glaa261. Online ahead of print.
PMID: 33053185
Abstract
Calorie restriction (CR) remains the most robust intervention to extend lifespan and improve healthspan. Though the cerebellum is more commonly associated with motor control, it has strong links with the hypothalamus and is thought to be associated with nutritional regulation and adiposity. Using a global mass spectrometry-based metabolomics approach, we identified 756 metabolites that were significantly differentially expressed (SDE) in the cerebellar region of the brain of C57BL/6J mice, fed graded levels of calorie restriction (10, 20, 30 and 40% CR) compared to mice fed ad libitum for 12 hours a day. Pathway enrichment indicated changes in the pathways of adenosine and guanine, which are precursors of DNA production, in addition to changes in pathways of metabolism of in aromatic amino acids, tyrosine, phenylalanine, and tryptophan, and the sulphur-containing amino acid methionine. We also saw increases in TCA cycle, electron donor, and dopamine and histamine pathways. In particular, changes in L-histidine and homocarnosine correlated positively with level of CR and food anticipatory activity and negatively with insulin and body temperature. Several metabolic and pathway changes acted against changes seen in age-associated neurodegenerative disorders, including increases in the TCA cycle and reduced L-proline. Carnitine metabolites contributed to discrimination between CR groups, which corroborates previous work in the liver and plasma. These results indicate the conservation of certain aspects of metabolism across tissues with CR. Moreover, this is the first study to indicate CR alters the cerebellar metabolome, and does so in a graded fashion, after only a short period of restriction.
Keywords: Brain; Mass-spectrometry; Metabolome; Neurodegeneration; Nutritional regulation.

Fasting and refeeding cycles alter subcutaneous white depot growth dynamics and the morphology of brown adipose tissue in female rats.
Rosas Fernández M, Concha Vilca C, Batista LO, Souza Figueiredo L, Ribeiro RA, Tavares do Carmo MDG, de Albuquerque KT.
Br J Nutr. 2020 Oct 15:1-23. doi: 10.1017/S0007114520004055. Online ahead of print.
PMID: 33054875
Abstract
Intermittent food restriction (IFR) is used mainly for weight loss, however, its effects on adipose tissue are not known when alternating with obesogenic diet. To demonstrate its effects on morphological dynamics of fat deposits, female Wistar were distributed into the groups: standard control (ST-C), with commercial diet; DIO control (DIO-C), with a diet that induces obesity (DIO) during the first and last 15 days, replaced by a standard diet for 30 intermediate days; standard restricted (ST-R), with standard diet during the first and last 15 days, with six cycles of IFR at 50% of ST-C; and DIO restricted (DIO-R), in DIO during the first and last 15 days, with six cycles of IFR at 50% of DIO-C. At 105 days of life, white adipose tissue (WAT) and brown adipose tissue (BAT) deposits were collected, weighed and histology performed. IFR groups showed higher food intake (DIO-R: 670.8±31.86kcal/g vs DIO-C: 606.5±26.23kcal/g, p<0.0001), energy efficiency (DIO-R: 3.80±0.15 g/kcal vs DIO-C: 3.26±0.17 g/kcal, p<0.0001), WAT (DIO-R: 5.65±0.30g/100g, ST-R: 3.64±0.23g/100g vs. DIO-C: 4.56±0.30g/100g, ST-C: 2.87±0.31g/100g, p<0.0001) and BAT (DIO-R: 0.13±0.004g/100g vs DIO-C: 0.13±0.005g/100g, p<0.0001) than its respective controls. Furthermore, IFR groups presented hypertrophy of WAT and BAT, as well as fibrosis in BAT. Thus, IFR can establish prospective resistance to weight loss by favoring changes in adipose tissue morphology, increased energy intake, and efficiency. Finally, the DIO diet before and after IFR aggravates the damages caused by the restriction.
Keywords: Brown adipose tissue fibrosis; Diet-induced obesity (DIO) model; Energy efficiency; Fat tissue; Intermittent fasting.

The Potential of Fasting and Caloric Restriction to Mitigate Radiation Damage-A Systematic Review.
Valayer S, Kim D, Fogtman A, Straube U, Winnard A, Caplan N, Green DA, van Leeuwen FHP, Weber T.
Front Nutr. 2020 Sep 18;7:584543. doi: 10.3389/fnut.2020.584543. eCollection 2020.
PMID: 33072801 Free PMC article.
Abstract
Detrimental health effects from ionizing radiation to living organisms is one of the key concerns identified and addressed by Radiation Protection institutions, nationally and internationally on Earth and for human spaceflight. Thus, new methods for mitigating the adverse effects of ionizing radiation are urgently needed for terrestrial health and deep space exploration. Caloric restriction and (intermittent-) fasting have been reported to elicit a variety of immediate and long-term physiological effects. The rapidly growing body of evidence of research studies investigating the effects of caloric restriction and dietary fasting points toward a multitude of benefits affecting numerous physiological systems. Therefore, a systematic review was performed to evaluate the evidence of caloric restriction and dietary fasting on the physiological response to ionizing radiation in humans and animals. All experimental studies of humans, animals, and eukaryotic cell lines available in PubMed, Cochrane library, and specialized databases were searched comparing irradiation post-caloric restriction or fasting to a non-nutritionally restricted control group on a broad range of outcomes from molecular to clinical responses. The initial search yielded 2,653 records. The final analysis included 11 studies. Most studies investigated survival rate or cancer occurrence in animals. Included studies did not reveal any benefit from pre exposure caloric restriction, except when performed with post radiation caloric restriction. However, the effects of pre-exposure fasting suggest increased resilience to ionizing radiation.
Keywords: SIRTUIN; caloric restriction; deep space; fasting; irradation; radio-protection; radiology; space flight.

Dietary Restriction Suppresses Steatosis-Associated Hepatic Tumorigenesis in Hepatitis C Virus Core Gene Transgenic Mice.
Jia F, Diao P, Wang X, Hu X, Kimura T, Nakamuta M, Nakamura I, Shirotori S, Sato Y, Moriya K, Koike K, Gonzalez FJ, Nakayama J, Aoyama T, Tanaka N.
Liver Cancer. 2020 Sep;9(5):529-548. doi: 10.1159/000508308. Epub 2020 Jul 10.
PMID: 33083279 Free PMC article.
Abstract
Background and aims: Dietary restriction (DR) is a preventive strategy for obesity, metabolic syndrome, cardiovascular disease, and diabetes. Although an interconnection between obesity, metabolic syndrome, fatty liver, and hepatocellular carcinoma has been documented, the mechanism and impact of DR on steatosis-derived hepatocarcinogenesis are not fully understood. This study aimed to evaluate whether DR can prevent hepatic tumorigenesis.
Methods: Male hepatitis C virus core gene transgenic (HCVcpTg) mice that develop spontaneous age-dependent insulin resistance, hepatic steatosis, and ensuing liver tumor development without apparent hepatic fibrosis, were fed with either a control diet ad libitum (control group) or 70% of the same control diet (DR group) for 15 months, and liver phenotypes were investigated.
Results: DR significantly reduced the number and volume of liver tumors. DR attenuated hepatic oxidative and endoplasmic reticulum stress and markedly suppressed nuclear factor-κB, signal transducer and activator of transcription 3 (STAT3) and STAT5, and phosphorylation of extracellular signal-regulated kinase, leading to downregulation of several pro-oncogenic mediators, such as cyclin D1. Serum insulin and insulin-like growth factor 1 levels, as well as hepatic expression of insulin receptor substrate 1/2, phosphatidylinositol-3 kinase, and serine/threonine-protein kinase AKT, were downregulated by DR. A transcriptome analysis revealed that STAT3 signaling and lipogenesis were the most suppressed hepatocarcinogenic pathways affected by DR. Additionally, DR stimulated autophagy and p62/sequestosome 1 degradation, enhanced phosphorylation of AMP-activated protein kinase α, increased fibroblast growth factor 21 expression, and attenuated expression of senescence-associated secretory phenotypes.
Conclusion: DR suppressed steatosis-associated hepatic tumorigenesis in HCVcpTg mice, mainly due to attenuation of pathways involved in inflammation, cellular stress, cell proliferation, insulin signaling, and senescence. These findings support the notion that persistent 30% reduction of daily food intake is beneficial for preventing steatosis-associated hepatocarcinogenesis caused by HCV core protein.
Keywords: Cyclin D1; NF-κB; STAT3; Senescence; p62/SQSTM1.

Share this post


Link to post
Share on other sites

CR reprograms acetyl-CoA metabolism and induces long-chain acyl-CoA dehydrogenase and CrAT expression.
Mezhnina V, Pearce R, Poe A, Velingkaar N, Astafev A, Ebeigbe OP, Makwana K, Sandlers Y, Kondratov RV.
Aging Cell. 2020 Oct 26:e13266. doi: 10.1111/acel.13266. Online ahead of print.
PMID: 33105059
Abstract
Calorie restriction (CR), an age delaying diet, affects fat oxidation through poorly understood mechanisms. We investigated the effect of CR on fat metabolism gene expression and intermediate metabolites of fatty acid oxidation in the liver. We found that CR changed the liver acylcarnitine profile: acetylcarnitine, short-chain acylcarnitines, and long-chain 3-hydroxy-acylcarnitines increased, and several long-chain acylcarnitines decreased. Acetyl-CoA and short-chain acyl-CoAs were also increased in CR. CR did not affect the expression of CPT1 and upregulated the expression of long-chain and very-long-chain Acyl-CoA dehydrogenases (LCAD and VLCAD, respectively). The expression of downstream enzymes such as mitochondrial trifunctional protein and enzymes in medium- and short-chain acyl-CoAs oxidation was not affected in CR. CR shifted the balance of fatty acid oxidation enzymes and fatty acid metabolites in the liver. Acetyl-CoA generated through beta-oxidation can be used for ketogenesis or energy production. In agreement, blood ketone bodies increased under CR in a time of the day-dependent manner. Carnitine acetyltransferase (CrAT) is a bidirectional enzyme that interconverts short-chain acyl-CoAs and their corresponding acylcarnitines. CrAT expression was induced in CR liver supporting the increased acetylcarnitine and short-chain acylcarnitine production. Acetylcarnitine can freely travel between cellular sub-compartments. Supporting this CR increased protein acetylation in the mitochondria, cytoplasm, and nucleus. We hypothesize that changes in acyl-CoA and acylcarnitine levels help to control energy metabolism and contribute to metabolic flexibility under CR.

Share this post


Link to post
Share on other sites

Caloric restriction modulates the monoaminergic system and metabolic hormones in aged rats.
Portero-Tresserra M, Rojic-Becker D, Vega-Carbajal C, Guillazo-Blanch G, Vale-Martínez A, Martí-Nicolovius M.
Sci Rep. 2020 Nov 9;10(1):19299. doi: 10.1038/s41598-020-76219-7.
PMID: 33168891
Abstract
Caloric restriction (CR) can attenuate the general loss of health observed during aging, being one of the mechanisms involved the reduction of hormonal alteration, such as insulin and leptin. This change could also prevent age-specific fluctuations in brain monoamines, although few studies have addressed the effects of CR on peripheral hormones and central neurotransmitters exhaustively. Therefore, the variations in brain monoamine levels and some peripheral hormones were assessed here in adult 4-month old and 24-month old male Wistar rats fed ad libitum (AL) or maintained on a 30% CR diet from four months of age. Noradrenaline (NA), dopamine (DA), serotonin (5-HT) and its metabolites were measured by high-performance liquid chromatography with electrochemical detection (HPLC-ED) in nine brain regions: cerebellum, pons, midbrain, hypothalamus, thalamus, hippocampus, striatum, frontal cortex, and occipital cortex. In addition, the blood plasma levels of hormones like corticosterone, insulin and leptin were also evaluated, as were insulin-like growth factor 1 and other basal metabolic parameters using enzyme-linked immunosorbent assays (ELISAs): cholesterol, glucose, triglycerides, albumin, low-density lipoprotein, calcium and high-density lipoprotein (HDLc). CR was seen to increase the NA levels that are altered by aging in specific brain regions like the striatum, thalamus, cerebellum and hypothalamus, and the DA levels in the striatum, as well as modifying the 5-HT levels in the striatum, hypothalamus, pons and hippocampus. Moreover, the insulin, leptin, calcium and HDLc levels in the blood were restored in old animals maintained on a CR diet. These results suggest that a dietary intervention like CR may have beneficial health effects, recovering some negative effects on peripheral hormones, metabolic parameters and brain monoamine concentrations.

Effects of dietary restriction on metabolic and cognitive health.
Matos MS, Platt B, Delibegovic M.
Proc Nutr Soc. 2020 Nov 3:1-34. doi: 10.1017/S0029665120007910. Online ahead of print.
PMID: 33138875 No abstract available.
https://sci-hub.se/10.1017/S0029665120007910

Share this post


Link to post
Share on other sites

Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories.
Mitchell SJ, Bernier M, Mattison JA, Aon MA, Kaiser TA, Anson RM, Ikeno Y, Anderson RM, Ingram DK, de Cabo R.
Cell Metab. 2019 Jan 8;29(1):221-228.e3. doi: 10.1016/j.cmet.2018.08.011. Epub 2018 Sep 6.
PMID: 30197301 Free PMC article.
https://www.cell.com/cell-metabolism/pdf/S1550-4131(18)30512-6.pdf
Abstract
The importance of dietary composition and feeding patterns in aging remains largely unexplored, but was implicated recently in two prominent nonhuman primate studies. Here, we directly compare in mice the two diets used in the primate studies focusing on three paradigms: ad libitum (AL), 30% calorie restriction (CR), and single-meal feeding (MF), which accounts for differences in energy density and caloric intake consumed by the AL mice. MF and CR regimes enhanced longevity regardless of diet composition, which alone had no significant impact within feeding regimens. Like CR animals, MF mice ate quickly, imposing periods of extended daily fasting on themselves that produced significant improvements in morbidity and mortality compared with AL. These health and survival benefits conferred by periods of extended daily fasting, independent of dietary composition, have major implications for human health and clinical applicability.
Keywords: aging; caloric restriction; diet composition; dietary restriction; fasting; lifespan extension; longevity; time-restricted feeding.

Hypocaloric Diet Initiated Post-Ischemia Provides Long-Term Neuroprotection and Promotes Peri-Infarct Brain Remodeling by Regulating Metabolic and Survival-Promoting Proteins.
de Carvalho TS, Sanchez-Mendoza EH, Schultz Moreira AR, Nascentes Melo LM, Wang C, Sardari M, Hagemann N, Doeppner TR, Kleinschnitz C, Hermann DM.
Mol Neurobiol. 2020 Nov 17. doi: 10.1007/s12035-020-02207-7. Online ahead of print.
PMID: 33200399
Abstract
Calorie restriction confers post-ischemic neuroprotection, when administered in a defined time window before ischemic stroke. How a hypocaloric diet influences stroke recovery when initiated after stroke has not been investigated. Male C57BL6/j mice were exposed to transient intraluminal middle cerebral artery occlusion. Immediately post-ischemia, mice were randomized to two groups receiving moderately hypocaloric (2286 kcal/kg food) or normocaloric (3518 kcal/kg) diets ad libitum. Animals were sacrificed at 3 or 56 days post-ischemia (dpi). Besides increased low density lipoprotein at 3 days and reduced alanine aminotransferase and increased urea at 56 days, no alterations of plasma markers were found in ischemic mice on hypocaloric diet. Body weight mildly decreased over 56 dpi by 7.4%. Hypocaloric diet reduced infarct volume in the acute stroke phase at 3 dpi and decreased brain atrophy, increased neuronal survival and brain capillary density in peri-infarct striatum and reduced motor coordination impairment in tight rope tests in the post-acute stroke phase over up to 56 dpi. The abundance of brain-derived neurotrophic factor, the NAD-dependent deacetylase and longevity protein sirtuin-1, the anti-oxidant glutathione peroxidase-3, and the ammonium detoxifier glutamine synthetase in the peri-infarct brain tissue was increased by hypocaloric diet. This study shows that a moderately hypocaloric diet that is initiated after stroke confers long-term neuroprotection and promotes peri-infarct brain remodeling.
Keywords: Calorie restriction; Ischemic stroke; Neurological recovery; Neuroprotection; Sirtuin-1.

S-adenosyl methionine synthetase SAMS-5 mediates dietary restriction-induced longevity in Caenorhabditis elegans.
Chen CC, Lim CY, Lee PJ, Hsu AL, Ching TT.
PLoS One. 2020 Nov 11;15(11):e0241455. doi: 10.1371/journal.pone.0241455. eCollection 2020.
PMID: 33175851
Abstract
S-adenosyl methionine synthetase (SAMS) catalyzes the biosynthesis of S-adenosyl methionine (SAM), which serves as a universal methyl group donor for numerous biochemical reactions. Previous studies have clearly demonstrated that SAMS-1, a C. elegans homolog of mammalian SAMS, is critical for dietary restriction (DR)-induced longevity in Caenorhabditis elegans. In addition to SAMS-1, three other SAMS paralogs have been identified in C. elegans. However, their roles in longevity regulation have never been explored. Here, we show that depletion of sams-5, but not sams-3 or sams-4, can extend lifespan in worms. However, the phenotypes and expression pattern of sams-5 are distinct from sams-1, suggesting that these two SAMSs might regulate DR-induced longevity via different mechanisms. Through the genetic epistasis analysis, we have identified that sams-5 is required for DR-induced longevity in a pha-4/FOXA dependent manner.

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting.
Brocker CN, Kim D, Melia T, Karri K, Velenosi TJ, Takahashi S, Aibara D, Bonzo JA, Levi M, Waxman DJ, Gonzalez FJ.
Nat Commun. 2020 Nov 17;11(1):5847. doi: 10.1038/s41467-020-19554-7.
PMID: 33203882
Abstract
Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARα directly upregulates the long non-coding RNA gene Gm15441 through PPARα binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1β (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to PPARα agonism and fasting. These findings provide evidence for a mechanism by which PPARα attenuates hepatic inflammasome activation in response to metabolic stress through induction of lncRNA Gm15441.

Share this post


Link to post
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now

×