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Fasting-mimicking diet holds promise for people with digestive problem
USC study indicates periodic low-calorie diet could help patients with inflammatory bowel disease: A clinical trial shows reduction of inflammation.
BY Jenesse Miller
MARCH 5, 2019
https://news.usc.edu/154847/fasting-mimicking-diet-ibd-usc-stody/
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Cell Reports VOLUME 26, ISSUE 10, P2704-2719.E6, MARCH 05, 2019
Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology
Priya Rangan 5
Inyoung Choi 5
Min Wei
Vanessa Ocon
Maya Abdulridha
Valter D. Longo 6
https://www.cell.com/action/showPdf?pii=S2211-1247(19)30181-0
Highlights

FMD cycles partially reverse IBD-related pathology compared to water-only fasting

FMD cycles reduce intestinal inflammatory and immune and increase regenerative markers

FMD cycles promote the expansion of Lactobacillaceae and Bifidobacteriaceae

FMD cycles can reduce systemic inflammation and consequent leukocytosis in humans
Summary
Dietary interventions are potentially effective therapies for inflammatory bowel diseases (IBDs). We tested the effect of 4-day fasting-mimicking diet (FMD) cycles on a chronic dextran sodium sulfate (DSS)-induced murine model resulting in symptoms and pathology associated with IBD. These FMD cycles reduced intestinal inflammation, increased stem cell number, stimulated protective gut microbiota, and reversed intestinal pathology caused by DSS, whereas water-only fasting increased regenerative and reduced inflammatory markers without reversing pathology. Transplants of Lactobacillus or fecal microbiota from DSS- and FMD-treated mice reversed DSS-induced colon shortening, reduced inflammation, and increased colonic stem cells. In a clinical trial, three FMD cycles reduced markers associated with systemic inflammation. The effect of FMD cycles on microbiota composition, immune cell profile, intestinal stem cell levels and the reversal of pathology associated with IBD in mice, and the anti-inflammatory effects demonstrated in a clinical trial show promise for FMD cycles to ameliorate IBD-associated inflammation in humans.

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Short-Term Fasting Induces Cell Cycle Arrest in Immature Hematopoietic Cells and Increases the Number of Naïve T Cells in the Bone Marrow of Mice.
Takakuwa T, Nakashima Y, Koh H, Nakane T, Nakamae H, Hino M.
Acta Haematol. 2019 Mar 6;141(3):189-198. doi: 10.1159/000496096. [Epub ahead of print]
PMID: 30840964
https://sci-hub.tw/10.1159/000496096
Abstract
Calorie restriction (CR) has been studied as a way to prolong longevity, and CR before chemotherapy can reduce hematological toxicity in cancer patients. We investigated the influence of fasting on immune cells and immature hematopoietic cells. In fasted mice, there was a significant reduction in the hematopoietic stem cell count but no significant difference for progenitor cells. Colony assays showed no difference and the rates of early and late apoptosis were almost identical when comparing fasted and control mice. DNA cell cycle analysis of immature bone marrow (BM) cells showed that CR caused a significant increase in the percentage in the G0/G1 phase and decreases in the S and G2/M phases. We detected a remarkable increase of T cells in the BM of fasted mice. CD44- naïve CD8+ T cells were more numerous in fasted BM, as were naïve CD4+ T cells, and part of those T cells showed less tendency in the G0/G1 phase. Immature hematopoietic cells remained in a relatively quiescent state and retention of colony-forming capacity during CR. The number of naïve T cells in the BM of fasted mice increased. These findings imply immature hematopoietic cells and some lymphoid cells can survive starvation, whilst maintaining their function.
KEYWORDS:
Calorie restriction; Cell cycle arrest; Immature hematopoietic cells; Naïve T cells

Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology.
Rangan P, Choi I, Wei M, Navarrete G, Guen E, Brandhorst S, Enyati N, Pasia G, Maesincee D, Ocon V, Abdulridha M, Longo VD.
Cell Rep. 2019 Mar 5;26(10):2704-2719.e6. doi: 10.1016/j.celrep.2019.02.019.
PMID: 30840892
https://www.crsociety.org/topic/11800-als-cr-updates/?page=19

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[It is a case-control study, but ...]
Overeating, caloric restriction and breast cancer risk by pathologic subtype: the EPIGEICAM study.
Lope V, Martín M, Castelló A, Ruiz A, Casas AM, Baena-Cañada JM, Antolín S, Ramos-Vázquez M, García-Sáenz JÁ, Muñoz M, Lluch A, de Juan-Ferré A, Jara C, Sánchez-Rovira P, Antón A, Chacón JI, Arcusa A, Jimeno MA, Bezares S, Vioque J, Carrasco E, Pérez-Gómez B, Pollán M.
Sci Rep. 2019 Mar 7;9(1):3904. doi: 10.1038/s41598-019-39346-4.
PMID: 30846706
https://www.nature.com/articles/s41598-019-39346-4.pdf
Abstract
This study analyzes the association of excessive energy intake and caloric restriction with breast cancer (BC) risk taking into account the individual energy needs of Spanish women. We conducted a multicenter matched case-control study where 973 pairs completed lifestyle and food frequency questionnaires. Expected caloric intake was predicted from a linear regression model in controls, including calories consumed as dependent variable, basal metabolic rate as an offset and physical activity as explanatory. Overeating and caloric restriction were defined taking into account the 99% confidence interval of the predicted value. The association with BC risk, overall and by pathologic subtype, was evaluated using conditional and multinomial logistic regression models. While premenopausal women that consumed few calories (>20% below predicted) had lower BC risk (OR = 0.36; 95% CI = 0.21-0.63), postmenopausal women with an excessive intake (≥40% above predicted) showed an increased risk (OR = 2.81; 95% CI = 1.65-4.79). For every 20% increase in relative (observed/predicted) caloric intake the risk of hormone receptor positive (p-trend < 0.001) and HER2+ (p-trend = 0.015) tumours increased 13%, being this figure 7% for triple negative tumours. While high energy intake increases BC risk, caloric restriction could be protective. Moderate caloric restriction, in combination with regular physical activity, could be a good strategy for BC prevention.
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[... see also:]
J Am Coll Nutr. 1993 Aug;12(4):390-9.
Dietary fat, calories, and the risk of breast cancer in postmenopausal women: a prospective population-based study.
Barrett-Connor E, Friedlander NJ.
PMID: 8409101
Abstract
We tested the hypothesis that a high-fat diet increases the risk of breast cancer in a population-based study of 590 women aged 40-79 years who were without known breast cancer when they provided a quantitative 24-hour diet recall. Fifteen postmenopausal women were diagnosed with incident breast cancer during the next 15 years (approximately 7600 person-years of follow-up). These women had significantly higher age-adjusted intake of all fats (monounsaturated, polyunsaturated, and saturated), and oleic, linoleic, and linolenic acids, with a stepwise increase in risk across tertiles of intake. Fat intake was associated with total calories, protein, and carbohydrates, and women with incident breast cancer consumed more calories, protein, and carbohydrates than did other subjects. When each nutrient variable (calories, fats, protein, and carbohydrates) was adjusted for age, body mass index, age at menopause, parity, and alcohol consumption, the strongest risks for incident breast cancer were associated with total calories (relative risk per standard deviation = 2.72, 95% confidence interval = 1.51-4.89, p = 0.002) and total fats (relative risk per standard deviation = 2.01, 95% confidence interval = 1.19-3.41, p = 0.01). Fat composition of the diet, expressed either as percent of energy or as fat intake adjusted for calories by regression analysis, was not significantly associated with risk of breast cancer. These results support the hypothesis that total calorie consumption, as well as dietary fat consumption, is a risk factor for breast cancer in postmenopausal women, and parallel observations in animal models.

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Genome-wide methylation is modified by caloric restriction in Daphnia magna.
Hearn J, Pearson M, Blaxter M, Wilson PJ, Little TJ.
BMC Genomics. 2019 Mar 8;20(1):197. doi: 10.1186/s12864-019-5578-4.
PMID: 30849937
https://bmcgenomics.biomedcentral.com/track/pdf/10.1186/s12864-019-5578-4
Abstract
BACKGROUND:
The degradation of epigenetic control with age is associated with progressive diseases of ageing, including cancers, immunodeficiency and diabetes. Reduced caloric intake slows the effects of ageing and age-related disease in vertebrates and invertebrates, a process potentially mediated by the impact of caloric restriction on epigenetic factors such as DNA methylation. We used whole genome bisulphite sequencing to study how DNA methylation patterns change with diet in a small invertebrate, the crustacean Daphnia magna. Daphnia show the classic response of longer life under caloric restriction (CR), and they reproduce clonally, which permits the study of epigenetic changes in the absence of genetic variation.
RESULTS:
Global cytosine followed by guanine (CpG) methylation was 0.7-0.9%, and there was no difference in overall methylation levels between normal and calorie restricted replicates. However, 333 differentially methylated regions (DMRs) were evident between the normally fed and CR replicates post-filtering. Of these 65% were hypomethylated in the CR group, and 35% were hypermethylated in the CR group.
CONCLUSIONS:
Our results demonstrate an effect of CR on the genome-wide methylation profile. This adds to a growing body of research in Daphnia magna that demonstrate an epigenomic response to environmental stimuli. Specifically, gene Ontology (GO) term enrichment of genes associated with hyper and hypo-methylated DMRs showed significant enrichment for methylation and acyl-CoA dehydrogenase activity, which are linked to current understanding of their roles in CR in invertebrate model organisms.
KEYWORDS:
Bisulphite sequencing; Caloric restriction; DNA methylation; Daphnia; Differential methylation; Epigenetics; Genomics; Nutrition

AGRP neurons modulate fasting-induced anxiolytic effects.
Li C, Hou Y, Zhang J, Sui G, Du X, Licinio J, Wong ML, Yang Y.
Transl Psychiatry. 2019 Mar 8;9(1):111. doi: 10.1038/s41398-019-0438-1.
PMID: 30850579
https://www.nature.com/articles/s41398-019-0438-1.pdf
Abstract
Recent studies indicate that activation of hypothalamic Agouti-related protein (Agrp) neurons can increase forage-related/repetitive behavior and decrease anxiety levels. However, the impact of physiological hunger states and food deprivation on anxiety-related behaviors have not been clarified. In the present study, we evaluated changes in anxiety levels induced by physiological hunger states and food deprivation, and identified the neuron population involved. Ad libitum fed and fasted mice were tested in the open field and elevated plus-maze behavioral tests. The DREADD approach was applied to selectively inhibit and stimulate neurons expressing Agrp in hypothalamic arcuate nucleus in Agrp-Cre transgenic mice. We found that anxiety levels were significantly reduced in the late light period when mice have increased need for food and increased Agrp neurons firing, in contrast to the levels in the early light period. Consistently, we also found that anxiety was potently reduced in 24-h fasted mice, relative to 12-h fasted mice or fed ad libitum. Mechanistically, we found that chemogenetic activation of Agrp neurons reduced anxiety in fed mice, and inactivation of Agrp neurons reduced fasting-induced anxiolytic effects. Our results suggest that anxiety levels may vary physiologically with the increasing need for food, and are influenced by acute fasting in a time-dependent manner. Agrp neurons contribute to fasting-induced anxiolytic effects, supporting the notion that Agrp neuron may serve as an entry point for the treatment of energy states-related anxiety disorders.

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Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance.
Ganeshan K, Nikkanen J, Man K, Leong YA, Sogawa Y, Maschek JA, Van Ry T, Chagwedera DN, Cox JE, Chawla A.
Cell. 2019 Feb 26. pii: S0092-8674(19)30113-8. doi: 10.1016/j.cell.2019.01.050. [Epub ahead of print]
PMID: 30853215
https://sci-hub.tw/10.1016/j.cell.2019.01.050
Abstract
Host defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance.
KEYWORDS:
caloric restriction; dormancy; hibernation; innate immunity; ketones; metabolism; resistance; thermoneutrality; torpor; triglycerides

Is Rapamycin a Dietary Restriction Mimetic?
Unnikrishnan A, Kurup K, Salmon AB, Richardson A.
J Gerontol A Biol Sci Med Sci. 2019 Mar 11. pii: glz060. doi: 10.1093/gerona/glz060. [Epub ahead of print]
PMID: 30854544
Abstract
Since the initial suggestion that rapamycin, an inhibitor of TOR nutrient signaling, increased lifespan comparable to dietary restriction, investigators have viewed rapamycin as a potential dietary restriction mimetic. Both dietary restriction and rapamycin increase lifespan across a wide range of evolutionarily diverse species (including yeast, C. elegans,Drosophila, and mice) as well as reducing pathology and improving physiological functions that decline with age in mice. The purpose of this article is to review the research comparing the effect of dietary restriction and rapamycin in mice. The current data show that dietary restriction and rapamycin have different effects on many pathways and molecular processes. In addition, these interventions affect the lifespan of many genetically manipulated mouse models differently. In other words, while dietary restriction and rapamycin may have similar effects on some pathways and processes; overall, they affect many pathways/processes quite differently. Therefore, rapamycin is likely not a true dietary restriction mimetic. Rather dietary restriction and rapamycin appear to be increasing lifespan and retarding aging largely through different mechanisms/pathways, suggesting that a combination of dietary restriction and rapamycin will have a greater effect on lifespan than either manipulation alone.
KEYWORDS:
Dietary Restriction; Rapamycin; TOR; insulin sensitivity; lifespan

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Apolipoprotein M: a novel adipokine decreasing with obesity and upregulated by calorie restriction.
Sramkova V, Berend S, Siklova M, Caspar-Bauguil S, Carayol J, Bonnel S, Marques M, Decaunes P, Kolditz CI, Dahlman I, Arner P, Stich V, Saris WHM, Astrup A, Valsesia A, Rossmeislova L, Langin D, Viguerie N.
Am J Clin Nutr. 2019 Mar 14. pii: nqy331. doi: 10.1093/ajcn/nqy331. [Epub ahead of print]
PMID: 30869115
Abstract
BACKGROUND:
The adipose tissue (AT) is a secretory organ producing a wide variety of factors that participate in the genesis of metabolic disorders linked to excess fat mass. Weight loss improves obesity-related disorders.
OBJECTIVES:
Transcriptomic studies on human AT, and a combination of analyses of transcriptome and proteome profiling of conditioned media from adipocytes and stromal cells isolated from human AT, have led to the identification of apolipoprotein M (apoM) as a putative adipokine. We aimed to validate apoM as novel adipokine, investigate the relation of AT APOM expression with metabolic syndrome and insulin sensitivity, and study the regulation of its expression in AT and secretion during calorie restriction-induced weight loss.
METHODS:
We examined APOM mRNA level and secretion in AT from 485 individuals enrolled in 5 independent clinical trials, and in vitro in human multipotent adipose-derived stem cell adipocytes. APOM expression and secretion were measured during dieting.
RESULTS:
APOM was expressed in human subcutaneous and visceral AT, mainly by adipocytes. ApoM was released into circulation from AT, and plasma apoM concentrations correlate with AT APOM mRNA levels. In AT, APOM expression inversely correlated with adipocyte size, was lower in obese compared to lean individuals, and reduced in subjects with metabolic syndrome and type 2 diabetes. Regardless of fat depot, there was a positive relation between AT APOM expression and systemic insulin sensitivity, independently of fat mass and plasma HDL cholesterol. In human multipotent adipose-derived stem cell adipocytes, APOM expression was enhanced by insulin-sensitizing peroxisome proliferator-activated receptor agonists and inhibited by tumor necrosis factor α, a cytokine that causes insulin resistance. In obese individuals, calorie restriction increased AT APOM expression and secretion.
CONCLUSIONS:
ApoM is a novel adipokine, the expression of which is a hallmark of healthy AT and is upregulated by calorie restriction. AT apoM deserves further investigation as a potential biomarker of risk for diabetes and cardiovascular diseases.
KEYWORDS:
adipokine; adipose tissue; calorie restriction; diet; glucose homeostasis; insulin resistance; lipocalin; metabolic syndrome; obesity

A More Robust Gut Microbiota in Calorie-Restricted Mice Is Associated with Attenuated Intestinal Injury Caused by the Chemotherapy Drug Cyclophosphamide.
Liu T, Wu Y, Wang L, Pang X, Zhao L, Yuan H, Zhang C.
MBio. 2019 Mar 12;10(2). pii: e02903-18. doi: 10.1128/mBio.02903-18.
PMID: 30862756
https://mbio.asm.org/content/mbio/10/2/e02903-18.full.pdf
Abstract
Cyclophosphamide (CTX) is widely used in cancer chemotherapy, but it often induces mucositis, in which the disruption of the gut microbiota might play a pivotal role. Whether the manipulation of the gut microbiota can be used as a strategy to improve CTX-induced mucositis remains to be studied. Here we observed the effects of a 4-week calorie restriction (CR) on CTX-induced mucositis. Compared with ad libitum-fed mice, CR mice showed significantly less mucositis in response to CTX, including lower intestinal permeability, less bacterial translocation, higher number of epithelial stem cells, and less epithelium damage. CTX induced significant shifts of the gut microbiota of the gut microbiota in ad libitum-fed control mice. In contrast, CR mice showed no significant change in their gut microbiota in responding to CTX treatment. CR significantly enriched the gut microbiota in Lactobacillus and Lachnospiraceae which are known to mitigate inflammation and improve gut barrier function. These findings suggest that CR remodeled gut microbiota is more robust and may contribute to attenuate the side effects of cyclophosphamide, which supports the concept that cancer chemotherapy would benefit from strategies targeting the gut microbiota.IMPORTANCE Improving the gut microbiota via calorie restriction is beneficial for human health. Our findings showed differential responses between calorie-restricted mice and ad libitum-fed mice. Compared with the ad libitum-fed mice, the calorie-restricted mice were less susceptible to cyclophosphamide side effects otherwise observed on the gut integrity and its microbiota. These results show the potential benefits of manipulating the gut microbiota with CR prior to cancer chemotherapy.
KEYWORDS:
Lactobacillus ; calorie-restricted; cyclophosphamide; gut microbiota; mucositis

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Long-term caloric restriction ameliorates deleterious effects of aging on white and brown adipose tissue plasticity.
Corrales P, Vivas Y, Izquierdo-Lahuerta A, Horrillo D, Seoane-Collazo P, Velasco I, Torres L, Lopez Y, Martínez C, López M, Ros M, Obregon MJ, Medina-Gomez G.
Aging Cell. 2019 Mar 28:e12948. doi: 10.1111/acel.12948. [Epub ahead of print]
PMID: 30920127 Free Article
https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.12948
Abstract
Age-related increased adiposity is an important contributory factor in the development of insulin resistance (IR) and is associated with metabolic defects. Caloric restriction (CR) is known to induce weight loss and to decrease adiposity while preventing metabolic risk factors. Here, we show that moderate 20% CR delays early deleterious effects of aging on white and brown adipose tissue (WAT and BAT, respectively) function and improves peripheral IR. To elucidate the role of CR in delaying early signs of aging, young (3 months), middle-aged (12 months), and old (20 months) mice fed al libitum and middle-aged and old mice subjected to early-onset CR were used. We show that impaired plasticity of subcutaneous WAT (scWAT) contributes to IR, which is already evident in middle-aged mice. Moreover, alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction in middle-aged animals. Both defects in WAT and BAT/beige cells are ameliorated by CR. Accordingly, CR attenuated the age-related decline in scWAT function and decreased the extent of fibro-inflammation. Furthermore, CR promoted scWAT browning. In brief, our study identifies the contribution of scWAT impairment to age-associated metabolic dysfunction and identifies browning in response to food restriction, as a potential therapeutic strategy to prevent the adverse metabolic effects in middle-aged animals.
KEYWORDS:
adipose tissue; aging; caloric restriction; fibro-inflammation; insulin resistance; thyroid hormone

Immediate and long-term effects of a very-low-calorie diet on diabetes remission and glycemic control in obese Thai patients with type 2 diabetes mellitus.
Umphonsathien M, Prutanopajai P, Aiam-O-Ran J, Thararoop T, Karin A, Kanjanapha C, Jiamjarasrangsi W, Khovidhunkit W.
Food Sci Nutr. 2019 Feb 11;7(3):1113-1122. doi: 10.1002/fsn3.956. eCollection 2019 Mar.
PMID: 30918654
https://onlinelibrary.wiley.com/doi/epdf/10.1002/fsn3.956
Abstract
AIM:
A very-low-calorie diet (VLCD) can reverse the underlying defects of type 2 diabetes mellitus (DM) in obese subjects. We determined the efficacy, safety, and durability of VLCD in Thai patients with DM and obesity.
METHODS:
Twenty Thai patients with DM and obesity were enrolled. After a 2-week trial, VLCD (600 kcal/day) was continued for 8 weeks, followed by a 4-week transition period. Data on diabetes remission (fasting plasma glucose level <126 mg/dl and HbA1c <6.5% without the use of glucose-lowering medications), glycemic control, metabolic parameters, and quality of life (QOL) were collected along with indices of insulin resistance (IR) and beta cell function. Glycemic control 12 months after discontinuation of VLCD was also examined.
RESULTS:
Among 19 patients (age 48 ± 2 years, BMI 27.7 kg/m2) who completed the study, rapid improvement in glycemic control was observed in the first 2 weeks of VLCD. At both 8 and 12 weeks, diabetes remission was achieved in 79%. Significant weight loss was accompanied by a significant reduction in IR and an increase in beta cell function, starting at 4 weeks of VLCD. QOL also significantly increased. At 12 months after VLCD, however, DM remission was achieved in approximately 30%.
CONCLUSION:
Very-low-calorie diet was effective and safe in inducing short-term diabetes remission in Thai subjects by ameliorating beta cell function and IR. Optimal long-term glycemic control was potentially durable as one-third of subjects remained without diabetes medication 12 months after VLCD.
KEYWORDS:
caloric restriction; obesity; quality of life; very‐low‐calorie diet

Dietary Restrictions and Nutrition in the Prevention and Treatment of Cardiovascular Disease.
Brandhorst S, Longo VD.
Circ Res. 2019 Mar 15;124(6):952-965. doi: 10.1161/CIRCRESAHA.118.313352.
PMID: 30870119
https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.118.313352
Abstract
Cardiovascular disease (CVD) is the leading cause of death in many developed countries and remains one of the major diseases strongly affected by the diet. Nutrition can affect CVD directly by contributing to the accumulation of vascular plaques and also indirectly by regulating the rate of aging. This review summarizes research on nutrition and CVD incidence based on a multipillar system that includes basic research focused on aging, epidemiological studies, clinical studies, and studies of centenarians. The relevant research linking nutrition and CVD with focus on macronutrients and aging will be highlighted. We will review some of the most relevant studies on nutrition and CVD treatment, also focusing on interventions known to delay aging. We will discuss both everyday dietary compositions, as well as intermittent and periodic fasting interventions with the potential to prevent and treat CVD.
KEYWORDS:
cardiovascular diseases; diet; fasting; prevention and control; research

A microRNA switch controls dietary restriction-induced longevity through Wnt signaling.
Xu Y, He Z, Song M, Zhou Y, Shen Y.
EMBO Rep. 2019 Mar 14. pii: e46888. doi: 10.15252/embr.201846888. [Epub ahead of print]
PMID: 30872315
Abstract
Dietary restriction (DR) is known to have a potent and conserved longevity effect, yet its underlying molecular mechanisms remain elusive. DR modulates signaling pathways in response to nutrient status, a process that also regulates animal development. Here, we show that the suppression of Wnt signaling, a key pathway controlling development, is required for DR-induced longevity in Caenorhabditis elegans We find that DR induces the expression of mir-235, which inhibits cwn-1/WNT4 expression by binding to the 3'-UTR The "switch-on" of mir-235 by DR occurs at the onset of adulthood, thereby minimizing potential disruptions in development. Our results therefore implicate that DR controls the adult lifespan by using a temporal microRNA switch to modulate Wnt signaling.
KEYWORDS:
Wnt signaling; dietary restriction; longevity; microRNA

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The Influence of Energy Depletion by Metformin or Hypocaloric Diet on Thyroid Iodine Uptake in Healthy Volunteers: a Randomized Trial.
Sloot YJE, Janssen MJR, van Herwaarden AE, Peeters RP, Netea-Maier RT, Smit JWA.
Sci Rep. 2019 Apr 1;9(1):5396. doi: 10.1038/s41598-019-41997-2.
PMID: 30932012
https://www.nature.com/articles/s41598-019-41997-2.pdf
Abstract
Sufficient thyroid iodine uptake is needed to ensure effective radioactive iodine (RAI) treatment, which is mediated by the sodium-iodide symporter (NIS). Activation of AMP-activated-protein-kinase (AMPK), leads to decreased NIS expression and thyroid iodine uptake in in vitro and animal models. Clinically relevant conditions that lead to AMPK activation include metformin use and hypocaloric conditions. Here, we aim to assess the effects of metformin and hypocaloric diet on thyroid iodine uptake in healthy volunteers. Healthy male volunteers were included and randomized. Group 1 (n = 8) received metformin, group 2 (n = 7) followed a hypocaloric diet (1500 kcal/day), superposed on a moderate iodine restriction diet; Baseline measurements included thyroid iodine-123 (I-123) uptake and TSH, fT4, T3 and rT3 levels. After two weeks, thyroid function and I-123 uptake measurements were repeated. Baseline characteristics were similar between groups. Levels of TSH and fT4 were similar after each intervention. T3 decreased after hypocaloric diet and metformin (-0.2 ± 0.19 nmol/L, p = 0.0327; respectively -0.13 ± 0.13 nmol/L, p = 0.0282), resulting in decreased T3/rT3 ratios. There was no significant difference in thyroid I-123 uptake after each intervention. In conclusion, metformin treatment and hypocaloric diet resulted in a significant decrease in T3 levels and T3/rT3 ratios in healthy volunteers, without significant effects on thyroid iodine uptake. We found no indications that metformin or hypocaloric diet will have clinically relevant effects on RAI uptake.

Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity.
Wu Z, Isik M, Moroz N, Steinbaugh MJ, Zhang P, Blackwell TK.
Cell Metab. 2019 Mar 5. pii: S1550-4131(19)30102-0. doi: 10.1016/j.cmet.2019.02.013. [Epub ahead of print]
PMID: 30905669
https://sci-hub.tw/10.1016/j.cmet.2019.02.013
Abstract
Chronic inflammation predisposes to aging-associated disease, but it is unknown whether immunity regulation might be important for extending healthy lifespan. Here we show that in C. elegans, dietary restriction (DR) extends lifespan by modulating a conserved innate immunity pathway that is regulated by p38 signaling and the transcription factor ATF-7. Longevity from DR depends upon p38-ATF-7 immunity being intact but downregulated to a basal level. p38-ATF-7 immunity accelerates aging when hyperactive, influences lifespan independently of pathogen exposure, and is activated by nutrients independently of mTORC1, a major DR mediator. Longevity from reduced insulin/IGF-1 signaling (rIIS) also involves p38-ATF-7 downregulation, with signals from DAF-16/FOXO reducing food intake. We conclude that p38-ATF-7 is an immunometabolic pathway that senses bacterial and nutrient signals, that immunity modulation is critical for DR, and that DAF-16/FOXO couples appetite to growth regulation. These conserved mechanisms may influence aging in more complex organisms.
KEYWORDS:
ATF-7; C. elegans; aging; dietary restriction; food intake; immunometabolism; innate immunity; insulin/IGF-1 signaling; longevity; p38 signaling

Promoting healthspan and lifespan with caloric restriction in primates.
Pifferi F, Terrien J, Perret M, Epelbaum J, Blanc S, Picq JL, Dhenain M, Aujard F.
Commun Biol. 2019 Mar 15;2:107. doi: 10.1038/s42003-019-0348-z. eCollection 2019.
PMID: 30911682 Free PMC Article
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420603/pdf/42003_2019_Article_348.pdf
Abstract
Recent data confirmed the efficiency of caloric restriction for promoting both healthspan and lifespan in primates, but also revealed potential adverse effects at the central level. This paper proposes perspectives and future directions to counterbalance potential adverse effects. Efforts should be made in combining nutrition-based clinical protocols with therapeutic and/or behavioral interventions to aim for synergetic effects, and therefore delay the onset of age-related diseases without adverse effects.

Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction.
Hernández-Saavedra D, Moody L, Xu GB, Chen H, Pan YX.
Adv Nutr. 2019 Mar 27. pii: nmy129. doi: 10.1093/advances/nmy129. [Epub ahead of print]
PMID: 30915465
https://sci-hub.tw/10.1093/advances/nmy129
Abstract
Chronic caloric restriction (CR) without malnutrition is known to affect different cellular processes such as stem cell function, cell senescence, inflammation, and metabolism. Despite the differences in the implementation of CR, the reduction of calories produces a widespread beneficial effect in noncommunicable chronic diseases, which can be explained by improvements in immuno-metabolic adaptation. Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. In this review, we define these modifications and systematically summarize the current evidence related to CR and the epigenome. We then explain the significance of genome-wide epigenetic modifications in the context of disease development. Although substantial evidence exists for the widespread effect of CR on longevity, there is no consensus regarding the epigenetic regulations of the underlying cellular mechanisms that lead to improved health. We provide compelling evidence that CR produces long-lasting epigenetic effects that mediate expression of genes related to immuno-metabolic processes. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.
KEYWORDS:
DNA methylation; dietary restriction; energy intake; histone acetylation; microRNA; sirtuin

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Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice.
Allen BD, Liao CY, Shu J, Muglia LJ, Majzoub JA, Diaz V, Nelson JF.
Aging Cell. 2019 Apr 1:e12944. doi: 10.1111/acel.12944. [Epub ahead of print]
PMID: 30938024
https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.12944
Abstract
Calorie restriction (CR), which lengthens lifespan in many species, is associated with moderate hyperadrenocorticism and attenuated inflammation. Given the anti-inflammatory action of glucocorticoids, we tested the hypothesis that the hyperadrenocorticism of CR contributes to its attenuated inflammatory response. We used a corticotropin-releasing-hormone knockout (CRHKO) mouse, which is glucocorticoid insufficient. There were four controls groups: CRHKO mice and wild-type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL-fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24-hr plasma CORT levels of AL-fed WT mice, (b) CR-fed CRHKO mice given CORT to match the 24-hr CORT levels of AL-fed WT mice, and (c) CR-fed CHRKO mice given CORT to match the 24-hr CORT levels of CR-fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT-deficient CR-fed CRHKO mice. Replacement of CORT in CR-fed CRHKO mice to the elevated levels observed in CR-fed WT mice, but not to the levels observed in AL-fed WT mice, restored the anti-inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti-inflammatory action of CR, which may in turn contribute to its life-extending actions.
KEYWORDS:
CRH; aging; calorie restriction; corticosterone; inflammation; mouse

Edited by AlPater

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Time-restricted Feeding Attenuates High-fat Diet-enhanced Spontaneous Metastasis of Lewis Lung Carcinoma in Mice.
Yan L, Sundaram S, Mehus AA, Picklo MJ.
Anticancer Res. 2019 Apr;39(4):1739-1748. doi: 10.21873/anticanres.13280.
PMID: 30952713
https://sci-hub.tw/http://ar.iiarjournals.org/content/39/4/1739
Abstract
BACKGROUND/AIM:
Obesity is a risk factor for cancer. Disruption of the daily feeding and fasting rhythm can contribute to obesity. This study tested the hypothesis that time-restricted feeding (TRF) attenuates obesity-enhanced metastasis.
MATERIALS AND METHODS:
In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male C57BL/6 mice were fed the standard AIN93G diet or a high-fat diet (HFD) with or without dark-phase restricted feeding (12 h per day) for 10 weeks. Pulmonary metastases from a subcutaneous tumor were quantified.
RESULTS:
The number and size of lung metastases were greater in the HFD group than in the AIN93G group, but did not differ between the TRF and AIN93G groups. TRF prevented HFD-induced increases in plasma concentrations of glucose, insulin, proinflammatory cytokines (leptin, monocyte chemotactic protein-1, plasminogen activator inhibitor-1), and angiogenic factors (angiopoietin-2, hepatic growth factor, vascular endothelial growth factor).
CONCLUSION:
TRF attenuates the HFD-enhanced spontaneous metastasis of LLC in mice.
KEYWORDS:
Lewis lung carcinoma; Time-restricted feeding; high-fat diet; metastasis; mice

Chronic water insufficiency induced kidney damage and energy dysregulation despite reduced food intake, which improved gut microbiota in female rats.
Daily JW, Zhang T, Wu X, Park S.
J Physiol Sci. 2019 Apr 5. doi: 10.1007/s12576-019-00668-7. [Epub ahead of print]
PMID: 30953307
https://sci-hub.tw/https://link.springer.com/article/10.1007/s12576-019-00668-7
Abstract
Water intake is recommended for weight loss, but the relationship between water intake and energy metabolism is not clear. We hypothesized that long-term water insufficiency would influence energy, glucose, and lipid metabolism while modulating gut microbiota. Female rats were provided with high-fat diets with different amounts of water and food intake for 6 weeks as follows: water provided for 1 h per day with food ad libitum (WRFA), water supply ad libitum plus pair feeding of with water restricted rats(WAFR), water restriction with ad libitum food for 3 weeks and water and food intake ad libitum for 3 weeks (WR-WA) and ad libitum supply of water and food (WAFA). Water intake in WRFA was about one-third of WAFR and WAFA, whereas food intake was lowered by 30% in WRFA and WAFR than WAFA. Body fat decreased in WRFA and WAFR, but WAFR decreased fat mass more than WRFA. Energy expenditure was lower in WRFA than WAFA and carbohydrate utilization was much higher in WRFA than the other groups. The peak serum glucose concentrations were lower in WAFA than the other groups and WRFA lowered serum insulin levels more than WAFA during OGTT. WRFA shrank the glomerulus with increased apoptotic cells and damaged renal tubules compared to the WAFA and WAFR. WR-WA also exhibited greater glomerular shrinkage and apoptosis that WAFA, but not as much WRFA, indicating that the kidneys were healing after water restriction damage. WRFA exacerbated dyslipidemia compared to the WAFA and WAFR groups. The gut microbiome was similarly modulated in WRFA and WAFR, compared to WAFA, but it was mainly affected by food intake, not water restriction in the host. WRFA and WAFR increased Bacteroidetes and decreased Firmicutes compared WAFA. In conclusion, chronic insufficient water intake induced renal damage, decreased energy expenditure, and exacerbated dyslipidemia in rats with reduced food intake. However, the reduction of food intake improved gut microbiome regardless of insufficient water intake and only minor effects on the microbiome were observed due to water restriction.
KEYWORDS:
Energy expenditure; Glucose; Gut microbiota; Insulin; Water deprivation

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The effect of caloric restriction on working memory in healthy non-obese adults.
Leclerc E, Trevizol AP, Grigolon RB, Subramaniapillai M, McIntyre RS, Brietzke E, Mansur RB.
CNS Spectr. 2019 Apr 10:1-7. doi: 10.1017/S1092852918001566. [Epub ahead of print]
PMID: 30968820
https://sci-hub.tw/10.1017/S1092852918001566
Abstract
OBJECTIVE:
We aim to evaluate the effect of caloric restriction (CR) in cognition by comparing performance in neuropsychological tests for working memory between a group of non-obese healthy subjects doing CR for 2 years with another consuming ad libitum diet (AL).
METHODS:
This study was part of a larger multicenter trial called CALERIE that consisted of a randomized clinical trial with parallel-group comparing 2 years of 25% CR and AL in 220 volunteers with a BMI between 22 and 28 kg/m2, across 3 sites. The cognitive tests used were the Cambridge Neuropsychological Tests Automated Battery (CANTAB) for Spatial Working Memory (SWM) including the total number of errors (SWMTE) and strategy (SWMS). Included as possible moderators were sleep quality, mood states, perceived stress, and energy expenditure. Analyses were performed at baseline and months 12 and 24.
RESULTS:
After adjustments, there was a significantly greater improvement in working memory assessed by the SWM for CR individuals, compared to AL. At month 24, it was related mostly to lower protein intake, compared to other macronutrients. Changes in SWM were moderated by changes in sleep quality, physical activity, and energy expenditure.
CONCLUSION:
On the long term, CR in healthy individuals seems to have a slightly positive effect on working memory. The study of brain CR targets opens new possibilities to prevent and treat cognitive deficits.
KEYWORDS:
Clinical trial; cognition; diet; mental health; nonpharmacological interventions

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Effects of Calorie Restriction and Voluntary Exercise on Doxorubicin-Induced Cardiotoxicity.
Hall SE, Smuder AJ, Hayward R.
Integr Cancer Ther. 2019 Jan-Dec;18:1534735419843999. doi: 10.1177/1534735419843999.
PMID: 30999765
https://journals.sagepub.com/doi/pdf/10.1177/1534735419843999
Abstract
INTRODUCTION:
Doxorubicin (DOX) is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction (CR) and exercise have well-documented cardioprotective effects. No studies have investigated the effects of CR alone or the combined effects of CR and exercise on DOX cardiotoxicity.
METHODS:
Rats were divided into 4 groups based on their food intake (ad libitum or CR) and activity (sedentary or voluntary wheel running [WR]). After completing a 16-week treatment, animals received either DOX (15 mg/kg) or saline (SAL) and cardiac function was measured 5 days after treatment. Chromatography was used to quantify left ventricular DOX accumulation.
RESULTS:
Left ventricular developed pressure (LVDP), end systolic pressure (ESP), and left ventricular maximal rate of pressure development (dP/dtmax) were significantly higher in the CR + DOX group when compared with DOX. Fractional shortening, LVDP, ESP, dP/dtmax, and dP/dtmin were significantly higher in the CR + WR + DOX group compared with the DOX group. In addition, the CR + WR + DOX group showed significantly higher LVDP and ESP compared with the WR + DOX group. DOX accumulation in the heart was 5-fold lower ( P < .05) in the CR + WR + DOX group compared with the DOX group.
CONCLUSION:
This is the first study to demonstrate that CR can reduce cardiac DOX accumulation, and confirms the protective role of CR against DOX-induced cardiac dysfunction. Our data also show that combining a known cardioprotective intervention, exercise training, with CR results in additive benefits in the protection against DOX cardiotoxicity.
KEYWORDS:
calorie restriction; cardiotoxicity; doxorubicin; exercise

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SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice.
Liu Y, Cheng A, Li YJ, Yang Y, Kishimoto Y, Zhang S, Wang Y, Wan R, Raefsky SM, Lu D, Saito T, Saido T, Zhu J, Wu LJ, Mattson MP.
Nat Commun. 2019 Apr 23;10(1):1886. doi: 10.1038/s41467-019-09897-1.
PMID: 31015456
https://www.nature.com/articles/s41467-019-09897-1.pdf
Abstract
Intermittent food deprivation (fasting, IF) improves mood and cognition and protects neurons against excitotoxic degeneration in animal models of epilepsy and Alzheimer's disease (AD). The mechanisms by which neuronal networks adapt to IF and how such adaptations impact neuropathological processes are unknown. We show that hippocampal neuronal networks adapt to IF by enhancing GABAergic tone, which is associated with reduced anxiety-like behaviors and improved hippocampus-dependent memory. These neuronal network and behavioral adaptations require the mitochondrial protein deacetylase SIRT3 as they are abolished in SIRT3-deficient mice and wild type mice in which SIRT3 is selectively depleted from hippocampal neurons. In the AppNL-G-F mouse model of AD, IF reduces neuronal network hyperexcitability and ameliorates deficits in hippocampal synaptic plasticity in a SIRT3-dependent manner. These findings demonstrate a role for a mitochondrial protein deacetylase in hippocampal neurons in behavioral and GABAergic synaptic adaptations to IF.

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Exercise, caloric restriction, and systemic oxidative stress.
Galassetti PR, Nemet D, Pescatello A, Rose-Gottron C, Larson J, Cooper DM.
J Investig Med. 2006 Mar;54(2):67-75. doi: 10.2310/6650.2005.05024.
PMID: 16472476
https://escholarship.org/uc/item/57m1v619
Abstract
BACKGROUND:
In humans, the main sources of reactive oxygen species (ROS), the molecules causing oxidative stress, are mitochondrial superoxide ions and neutrophil-derived oxidative radicals. Circulating antioxidants contribute to the protection against oxidative stress. Although the formation of ROS and secretion of antioxidants are independently regulated by exercise and diet, little is known about their combined effect. We hypothesized that relatively brief, intense exercise training may reduce systemic oxidation via an intrinsic mechanism, independent of changes in circulating antioxidants and of neutrophil-derived enzymes (as may be caused by concomitant caloric restriction).
METHODS:
Nineteen volunteers exercised for 7 days, 3 hours/day at 75% of oxygen uptake. Caloric intake was either 110% of caloric expenditure (high calorie, n=10) or 75% of caloric expenditure (low calorie, n=9). Blood samples for F2-isoprostanes, catalase, myeloperoxidase (MPO), interleukin-x (IL-x), white blood cells (WBCs), and other metabolic variables were taken at baseline, at the end of training, and 1 week after completion of the study.
RESULTS:
Serum F2-isoprostanes (microg/mL), markers of lipid peroxidation, were similarly reduced after 7 days of exercise in the high-calorie (from 35+/-4 to 27+/-2) and low-calorie (from 35+/-3 to 24+/-2) groups. Similar reductions were observed in IL-x concentrations. Conversely, no change was observed in circulating concentrations of the antioxidant catalase. Whereas total WBCs and neutrophil counts were significantly reduced in the low-calorie group only, no difference in neutrophil-derived MPO was measured between groups.
CONCLUSION:
A significant reduction in systemic oxidation may occur relatively early during intense exercise training in healthy young men, independent of caloric intake. The potential contribution to these effects of circulating antioxidants and neutrophil-derived oxidative enzymes will require further investigation.

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The Impact of Caloric Restriction on the Epigenetic Signatures of Aging.
Gensous N, Franceschi C, Santoro A, Milazzo M, Garagnani P, Bacalini MG.
Int J Mol Sci. 2019 Apr 24;20(8). pii: E2022. doi: 10.3390/ijms20082022. Review.
PMID: 31022953
[pdf free from Medline site.]
Abstract
Aging is characterized by an extensive remodeling of epigenetic patterns, which has been implicated in the physiopathology of age-related diseases. Nutrition plays a significant role in modulating the epigenome, and a growing amount of data indicate that dietary changes can modify the epigenetic marks associated with aging. In this review, we will assess the current advances in the relationship between caloric restriction, a proven anti-aging intervention, and epigenetic signatures of aging. We will specifically discuss the impact of caloric restriction on epigenetic regulation and how some of the favorable effects of caloric restriction on lifespan and healthspan could be mediated by epigenetic modifications.
KEYWORDS:
aging; caloric restriction; epigenetic clocks; nutrition

Effects of regular exercise plus food restriction on left ventricular pathological remodeling in heart failure‑induced rats.
Moradi F, Imani AR, Faghihi M.
Bratisl Lek Listy. 2019;120(4):243-248. doi: 10.4149/BLL_2019_044.
PMID: 31023045
https://sci-hub.tw/http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=6109&category_id=146&option=com_virtuemart&vmcchk=1&Itemid=1
Abstract
BACKGROUND:
Cardiac remodeling is the main pathophysiological process leading to heart failure. Exercise and food restriction have been shown to exert some profound physiological benefits.
OBJECTIVES:
This study investigated the effects of exercise plus food restriction (FR) on rat left ventricular remodeling.
METHODS:
Fifty male rats were randomly divided into 5 groups. 1) Sham (saline injection), 2) ISO (isoproterenol injection), 3) FR+ ISO (8 weeks with 60 % food restriction and then isoproterenol injection), 4) E+ISO (run-in period of 4 weeks on treadmill and then isoproterenol injection), and 5) FR+E+ISO. Serum levels of creatine kinase, nitric oxide, gene expression of microtubule-associated protein 1 light chain 3-I and II, Beclin-1, Bax and Bcl2 and TUNEL staining were investigated.
RESULTS:
ISO increased the plasma CK-MB level, gene expression of Bax and TUNEL‑positive cells in left ventricle and at the same time, decreased the serum level of NO. Regular exercise plus food restriction enhanced the expression of LC3B-II, Beclin-1, Bcl2 genes and elevated LC3B-II / LC3B-Ι, while decreasing the gene expression of Bax and TUNEL‑positive cells in the left ventricle.
CONCLUSION:
Our results propose that exercise plus food restriction is more effective than either therapy alone for possibly preserving cardiac internal defenses against heart failure consequences and remodeling (Tab. 2, Fig. 3, Ref. 20).
KEYWORDS:
apoptosis autophagy.; exercise; food restriction; heart failure

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The effect of single-nucleotide polymorphisms at the ADIPOQ gene locus rs1501299 on metabolic parameters after 9 mo of a high-protein/low-carbohydrate versus a standard hypocaloric diet.
Aller R, Izaola O, Primo D, de Luis DA.
Nutrition. 2019 Feb 27;65:44-49. doi: 10.1016/j.nut.2019.02.012. [Epub ahead of print]
PMID: 31029921
https://sci-hub.tw/https://linkinghub.elsevier.com/retrieve/pii/S0899900719300188
Abstract
OBJECTIVE:
Some adiponectin gene (ADIPOQ) single-nucleotide polymorphisms (SNPs) have been related to basal and adiponectin levels and metabolic parameters. The aim of this study was to evaluate the effect of the genetic variant rs1501299 ADIPOQ gene on biochemical changes after weight loss secondary to a high-protein and low-carbohydrate diet versus a standard severe hypocaloric diet over 9 mo as the primary endpoint.
METHODS:
A white population of 270 obese patients was enrolled in a randomized clinical trial with two hypocaloric diets (high-protein and low carbohydrate diet [HP] versus standard diet {S} over 9 mo of intervention. The statistical analysis was performed for the combined GT and TT as a group (T-allele carriers) and GG as second group (non-T-allele carriers). Before and after 12 wk on each hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake, and a biochemical analysis were realized.
RESULTS:
With both dietary interventions, body weight, body mass index (BMI), fat mass, waist circumference, systolic blood pressure, and leptin levels decreased. In non-T-allele carriers after both diets, the decrease in total cholesterol levels -12.3 ± 2.2 mg/dL (T-allele carriers -6.9 ± 2.1 mg/dL; P = 0.01 diet HP) and 12.2 ± 3.1 mg/dL (T-allele carriers -4.7 ± 1.2 mg/dL; P = 0.02 after diet S), low-density lipoprotein cholesterol -13.2 ± 2.7 mg/dL (T-allele carriers -6.1 ± 2.1 mg/dL; P = 0.02 after diet HP) and -9.3 ± 1.8 mg/dL (T-allele carriers -4.8 ± 2.9 mg/dL; P = 0.01 after diet S), triacylglycerol levels -12.7 ± 6.1 mg/dL (T-allele carriers -6 ± 2.9 mg/dL; P = 0.01 after diet HP) and -16.3 ± 7.2 mg/dL (T-allele carriers -5.3 ± 1.4 mg/dL; P = 0.03 after diet S), insulin levels -5 ± 1.1 mUI/L (in T-allele -1.7 ± 0.9 mUI/L; P = 0.02 after diet HP) and -3.2 1.1 mUI/L (T-allele carriers -0.7 ± 0.7 mUI/L; P = 0.02 after diet S), and homeostatic model assessment of insulin resistance levels -0.4 ± 0.2 units (T-allele group -0.1 ± 0.1; P = 0.04 after diet HP) and -0.7 ± 0.1 units (T-allele carriers -0.1 ± 0.5 mg/dL; P = 0.01 after diet S) was higher than T-allele carriers. Only no T-allele carriers showed an increase in adiponectin levels after both diets.
CONCLUSION:
After two different hypocaloric diets during 9 mo of intervention, the GG genotype of an ADIPOQ gene variant (rs1501299) is related to better improvement in adiponectin levels, insulin resistance, and lipid profile than T-allele carriers.
KEYWORDS:
ADIPOQ; Adiponectin; High-protein diet; Insulin resistance; Rs1501299; Standard diet; Weight loss

Edited by AlPater

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Dose-dependent Effects of Exercise and Diet on Insulin Sensitivity and Secretion.
Ding C, Chooi YC, Chan Z, Lo J, Choo J, Ding BTK, Leow MK, Magkos F.
Med Sci Sports Exerc. 2019 Apr 25. doi: 10.1249/MSS.0000000000002020. [Epub ahead of print]
PMID: 31033904
Abstract
PURPOSE:
A single bout of aerobic exercise increases insulin sensitivity the next day. The effects of exercise on insulin secretion, the role of exercise-induced energy deficit, and possible dose-response relationships are not well understood. This study aimed to evaluate insulin sensitivity and insulin secretion after progressively greater negative energy balance induced by exercise or diet.
METHODS:
Acute energy deficits (20% or 40% of weight maintenance needs) were induced by a single day of aerobic exercise (cycling at moderate intensity, n=13) or dietary restriction (n=19) in healthy men and women (age: 26±2 yrs; body mass index: 21.8±0.5 kg/m). Intravenous glucose tolerance tests in conjunction with minimal modelling were performed the next morning and blood samples were collected for 3 hours to measure glucose and insulin concentrations.
RESULTS:
Insulin sensitivity increased linearly after exercise-induced energy deficits (P=0.007) but did not change after equivalent diet-induced energy deficits (P=0.673). Acute insulin response decreased after both exercise (P<0.001) and dietary restriction (P=0.005). The disposition index and glucose effectiveness were not affected by exercise (P=0.138 and 0.808, respectively), but both decreased after 40% dietary restriction (P=0.048 and 0.002, respectively).
CONCLUSIONS:
These results indicate that insulin sensitivity and insulin secretion are related to exercise energy expenditure, albeit in a different fashion (insulin sensitivity increases linearly, whereas insulin secretion drops to a nadir with a low exercise dose and does not decrease further). These changes cannot be replicated by equivalent energy deficits induced by dietary restriction, suggesting that exercise and diet have different effects on the mechanisms regulating glucose homeostasis.

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Moderate differences in common feeding diets change lipid composition in the hippocampal dentate gyrus and affect spatial cognitive flexibility in male rats.
Maliković J, Vuyyuru H, Koefeler H, Smidak R, Höger H, Kalaba P, Hussein AM, Lubec G, Korz V.
Neurochem Int. 2019 Apr 30. pii: S0197-0186(19)30023-3. doi: 10.1016/j.neuint.2019.04.017. [Epub ahead of print]
PMID: 31051212
Abstract
There is growing evidence that lipids play a fundamental role in neuronal plasticity and learning and memory. Effects of nutrition on brain lipid composition and neuronal functioning are known, but the feeding interventions are often severe and may not reflect nutritional effects below clinical relevance. Therefore, we tested two commercially available rat feeding diets with only moderate differences in the food compositions, a standard diet (gross energy metabolizable 12.8 MJ/kg) and a energy reduced diet (gross energy metabolizable 8.9 MJ/kg) on possible effects upon dentate gyrus lipid composition, spatial learning and memory in a water maze and corticosterone release (blood serum concentrations) in adult male rats. Rats were fed with the standard diet up to an age of 8 weeks. One group was further fed with the standard and another with the energy reduced diet until an age of 5 months. We did not found differences in serum corticosterone levels. We found group differences in a variety of lipids in the hippocampal dentate gyrus.. Most of the lipid levels were lower in energy reduced diets, namely glycerophosphoethanolamines, sphingomyelins and hexosyceramides, whereas some ceramides (Cer18:0 and Cer24:1) and glycerophosphocholines (PC34:3 and PC36:2) were upregulated compared to the standard diet group. The performance in a common reference memory water maze task was not different between groups, however during reversal learning (platform in a different position) after the initial training, the standard diet fed rats learned better and spatial memory was improved compared to the energy reduced diet group. Thus, moderate differences in feeding diets have effects specifically upon spatial cognitive flexibility. Possible relations between differences in lipid composition and cognitive flexibility are discussed.
KEYWORDS:
Cortisol; Dentate gyrus; Food restriction diet; Lipids; Spatial reference memory; Stress

Intermittent Fasting Exacerbates the Acute Immune and Behavioral Sickness Response to the Viral Mimic Poly(I:C) in Mice.
Zenz G, Jačan A, Reichmann F, Farzi A, Holzer P.
Front Neurosci. 2019 Apr 17;13:359. doi: 10.3389/fnins.2019.00359. eCollection 2019.
PMID: 31057355
Abstract
Intermitted fasting and other forms of calorie restriction are increasingly demonstrated to exert potential health benefits. Interestingly, restricted feeding is also able to mitigate sickness in response to bacterial factors stimulating Toll-like receptor 4 (TLR4). However, little is known about how fasting modifies the activity of virus-associated molecular patterns. We therefore analyzed the impact of an intermittent fasting (IF) regimen on the immune and behavioral response to the TLR3 agonist and viral mimic polyinosinic:polycytidylic acid [Poly(I:C)] in mice. The effects of intraperitoneally injected Poly(I:C) (12 mg/kg) on plasma and cerebral cytokine expression and behavior (locomotion, exploration, and ingestion) were examined in male C57BL/6N mice under control conditions and following a 9 days period of intermittent (alternate day) fasting (IF). Poly(I:C) increased the circulating levels of cytokines (TNF-α, MCP-1, IL-6, IL-10, IFN-α, IFN-γ), an effect amplified by IF. In addition, IF aggravated sickness behavior in response to Poly(I:C), while cerebral cytokine expression was enhanced by application of Poly(I:C) in the absence of a significant effect of IF. Furthermore, IF augmented the expression of neuropeptide Y (NPY) mRNA in the hypothalamus and increased the plasma levels of corticosterone, while Poly(I:C) had little effect on these readouts. Our data show that IF does not abate, but exaggerates the immune and sickness response to the viral mimic Poly(I:C). This adverse effect of IF occurs despite increased hypothalamic NPY expression and enhanced plasma corticosterone. We therefore propose that the effects of IF on the immune and behavioral responses to viral and bacterial factors are subject to different neuronal and neuroendocrine control mechanisms.
KEYWORDS:
Poly(I:C); alternate day fasting; corticosterone; hypothalamus; intermittent fasting; neuropeptide Y; pro-inflammatory cytokines; sickness response

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Short-term calorie restriction and 17α-estradiol administration elicit divergent effects on proteostatic processes and protein content in metabolically active tissues.
Miller BF, Pharaoh GA, Hamilton KL, Peelor FF, Kirkland JL, Freeman WM, Mann SN, Kinter M, Price JC, Stout MB.
J Gerontol A Biol Sci Med Sci. 2019 May 10. pii: glz113. doi: 10.1093/gerona/glz113. [Epub ahead of print]
PMID: 31074767
https://watermark.silverchair.com/glz113.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAm4wggJqBgkqhkiG9w0BBwagggJbMIICVwIBADCCAlAGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMRevHBLIkeAMar_nGAgEQgIICIfHDLIEpZYk9lsvCfnSMbON2Y5fm0HPpMUD1ttD0pWpjKYmYoouAwfps_anD8Nhai0w_TVTLq8HgrWMifl8m_8hGP627_ZdIAQc9PE2Ah5LtNYAho4QHemRk_4Phi-00qfreepG0hDmNlpJeknIBm33SXzJZ78MxiS7V-C9406nqato4n9u7RqNajwuCpKUuv2D9MdZ_DOjSxA-_NiBaWK6YZEsBovaDHMFUGOAIIDu_KkBUTE15CgR3SBY8AmHXS04_AXZ-dZeHClFnM9PteJsAFKp_jBp7fs1Po0gglZYnevT-Xfv7VjMQ3MSJXHM6akUYB4OPL5Zp6sHulXJ02axJ0qm-WsgoGclJ1h-US7gQMnwN2xOCVYyteLzHtbvSYl3gY2me9k_UBbmAelj8zRiudV5vnZfX8BI67y3l3NsebasvV6abpQ3K1y82sKVimRxjTusL50TR7QbAFXFYOSFPvpAVSF6hlKjNvgoJwDFDG-DYa2lwcZ9ffAXYe9b0ttuS0OPTyhLPvVJMkzXKl82YK4ERycHhbasSsBxpGfRvkk0rGqU_QdbCp7cSAuvyyGtvTuqydwsDXfb_SAyFjrbA2Uf3YxJHmwxr2IX99UQoegesUTNZ-V2OFDwDz-u4yIGdcSGGfwlNeaLefU8idZVSWbqG4cuOw9xa_Xfz7E672Ny4NqaLKo7t9IZtPJotgNkniGWaJoFV-kOYjp52XQii
Abstract
17α-estradiol (17α-E2) is a 'non-feminizing' estrogen that extends lifespan in male, but not female, mice. We recently reported that 17α-E2 had robust beneficial effects on metabolic and inflammatory parameters in aged male mice. However, it remains unclear if 17α-E2 also delays other 'hallmarks' of aging, particularly maintaining proteostasis. Here we used isotope labeling methods in older mice to examine proteostatic mechanisms. We compared weight-matched mild calorie restricted (CR) and 17α-E2 treated male mice with the hypothesis that 17α-E2 would increase protein synthesis for somatic maintenance. 17α-E2 had no effect on protein synthesis or DNA synthesis in multiple tissues, including white adipose tissue (WAT). Conversely, mild short-term CR decreased DNA synthesis and increased the protein to DNA synthesis ratio in multiple tissues. Examination of individual protein synthesis and content did not differentiate treatments although it provided insight into the regulation of protein content between tissues. Contrary to our hypothesis we did not see the predicted differences in protein to DNA synthesis following 17α-E2 treatment. However, mild short-term CR elicited differences consistent with both lifelong CR and other treatments that curtail aging processes. These data indicated that despite similar maintenance of body mass, 17α-E2 and CR treatments elicit distinctly different proteostatic outcomes.
KEYWORDS:
deuterium oxide; metabolism; mouse; proteomics; Protein synthesis

Editorial on Sramkova et al., "Apolipoprotein M: a novel adipokine decreasing with obesity and upregulated by calorie restriction".
Ko CW, Qu J, Tso P.
Am J Clin Nutr. 2019 May 10. pii: nqz053. doi: 10.1093/ajcn/nqz053. [Epub ahead of print] No abstract available.
PMID: 31075794
https://sci-hub.tw/10.1093/ajcn/nqz053
>>>>>>>>>>>>>>>>>>
Apolipoprotein M: a novel adipokine decreasing with obesity and upregulated by calorie restriction.
Sramkova V, Berend S, Siklova M, Caspar-Bauguil S, Carayol J, Bonnel S, Marques M, Decaunes P, Kolditz CI, Dahlman I, Arner P, Stich V, Saris WHM, Astrup A, Valsesia A, Rossmeislova L, Langin D, Viguerie N.
Am J Clin Nutr. 2019 Mar 14. pii: nqy331. doi: 10.1093/ajcn/nqy331. [Epub ahead of print]
PMID: 30869115
https://sci-hub.tw/10.1093/ajcn/nqy331

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Effects of timing of food intake and fat/carbohydrate ratio on insulin sensitivity and preconditioning against renal ischemia reperfusion injury by calorie restriction.
Reynolds JS, Peng W, Chu T, Mitchell JR.
Nutr Healthy Aging. 2019 Apr 2;5(1):23-32. doi: 10.3233/NHA-180044.
PMID: 31093582
Abstract
BACKGROUND:
Dietary restriction (DR) improves lifespan, metabolic fitness and resilience in many organisms, but the role of dietary macronutrient composition and timing of food intake in specific benefits remains unclear.
OBJECTIVE:
We sought to compare the effects of two isocaloric DR regimes differing in the timing of food intake - every other day (EOD) fasting/feeding vs. daily calorie restriction (CR) - at two different fat/carbohydrate ratios on two well-established DR benefits, improved glucose homeostasis and protection from renal ischemia reperfusion injury in mice. We hypothesized that both EOD fasting and isocaloric CR would result in similar improvements in glucose homeostasis and stress resistance independent of macronutrient composition.
METHODS:
Six groups of mice were fed either semi-purified low-fat diet (LFD, 10% calories from fat) or high-fat diet (HFD, 60% calories from fat) and randomized into one of three dietary regimens: 1) ad libitum (AL), 2) EOD feeding/fasting, or 3) pair-fed daily to the average daily EOD intake within LFD or HFD feeding group resulting in daily CR. After 6 weeks, the following assessments were made: fasting blood glucose, glucose and insulin tolerance, and resistance to bilateral renal ischemia reperfusion injury using serum urea as a marker of renal function. Within the EOD group, the effects of prior day feeding (EODfed vs. EODfast) were also assessed.
RESULTS:
EOD mice ate ∼20-25% less food over time than AL mice on the corresponding LFD or HFD. EOD and CR mice displayed changes in body weight, fasting blood glucose levels and glucose tolerance commensurate with total calorie intake. No significant differences were observed in circulating IGF-1 levels. Insulin sensitivity improved independent of fat/carbohydrate ratio on daily CR and EODfast regimens, but not EODfed. HFD increased susceptibility to renal ischemia reperfusion in AL mice, while CR and EOD regimens gave significant protection independent of dietary fat content or fed or fasted day in the EOD group.
CONCLUSIONS:
Reduced food intake protects mice against renal ischemia reperfusion injury within 6 weeks independent of timing of food intake (CR, EODfast, EODfed) or fat content of diet (10% vs. 60%). Neither circulating IGF-1 levels (unchanged) nor whole-body insulin sensitivity (improved upon daily CR and EODfast but not EODfed) correlated with protection, so are unlikely to be involved mechanistically.
KEYWORDS:
Dietary restriction; IGF-1; calorie restriction; dietary preconditioning; every-other-day fasting; glucose homeostasis; high-fat diet; insulin resistance; obesity; renal ischemia reperfusion injury

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Effects of Aging and Caloric Restriction on Fiber Type Composition, Mitochondrial Morphology and Dynamics in Rat Oxidative and Glycolytic Muscles.
Faitg J, Leduc-Gaudet JP, Reynaud O, Ferland G, Gaudreau P, Gouspillou G.
Front Physiol. 2019 Apr 24;10:420. doi: 10.3389/fphys.2019.00420. eCollection 2019.
PMID: 31114501
https://www.frontiersin.org/articles/10.3389/fphys.2019.00420/full
Abstract
Aging is associated with a progressive decline in muscle mass and strength, a process known as sarcopenia. Evidence indicates that mitochondrial dysfunction plays a causal role in sarcopenia and suggests that alterations in mitochondrial dynamics/morphology may represent an underlying mechanism. Caloric restriction (CR) is among the most efficient nonpharmacological interventions to attenuate sarcopenia in rodents and is thought to exert its beneficial effects by improving mitochondrial function. However, CR effects on mitochondrial morphology and dynamics, especially in aging muscle, remain unknown. To address this issue, we investigated mitochondrial morphology and dynamics in the oxidative soleus (SOL) and glycolytic white gastrocnemius (WG) muscles of adult (9-month-old) ad libitum-fed (AL; A-AL), old (22-month-old) AL-fed (O-AL), and old CR (O-CR) rats. We show that CR attenuates the aging-related decline in the muscle-to-body-weight ratio, a sarcopenic index. CR also prevented the effects of aging on muscle fiber type composition in both muscles. With aging, the SOL displayed fragmented SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria, an effect attenuated by CR. Aged WG displayed enlarged SS and more complex/branched IMF mitochondria. CR had marginal anti-aging effects on WG mitochondrial morphology. In the SOL, DRP1 (pro-fission protein) content was higher in O-AL vs YA-AL, and Mfn2 (pro-fusion) content was higher in O-CR vs A-AL. In the gastrocnemius, Mfn2, Drp1, and Fis1 (pro-fission) contents were higher in O-AL vs A-AL. CR reduced this aging-related increase in Mfn2 and Fis1 content. Overall, these results reveal for the first time that aging differentially impacts mitochondrial morphology and dynamics in different muscle fiber types, by increasing fission/fragmentation in oxidative fibers while enhancing mitochondrial size and branching in glycolytic fibers. Our results also indicate that although CR partially attenuates aging-related changes in mitochondrial dynamics in glycolytic fibers, its anti-aging effect on mitochondrial morphology is restricted to oxidative fibers.
KEYWORDS:
aging; atrophy; electron microscopy; nutrition; sarcopenia; skeletal muscle

The Influence of Fasting and Energy Restricting Diets on IGF-1 Levels in Humans: A Systematic Review and Meta-Analysis.
Rahmani J, Kord Varkaneh H, Clark C, Zand H, Bawadi H, Ryand PM, Fatahi S, Zhang Y.
Ageing Res Rev. 2019 May 19:100910. doi: 10.1016/j.arr.2019.100910. [Epub ahead of print] Review.
PMID: 31116995
https://sci-hub.tw/10.1016/j.arr.2019.100910
Abstract
BACKGROUND:
Fasting and energy restricting diets have a potential means of delaying or preventing the onset of a range of age-related metabolic and neoplastic diseases. Consistently at the centre of this effect appears to be a significant reduction in circulating IGF-1 levels. The aim of the current systematic review and meta-analysis was to determine the influence of fasting and energy restriction on IGF-1 levels in human subjects.
METHODS:
A comprehensive systematic search was conducted from onset of the database to February 2019 in Embase, MEDLINE/PubMed, and SCOPUS to identify randomized clinical trials that investigating the impact of fasting or energy restriction circulating IGF-1 levels. Effect size was reported as weighted mean difference (WMD) and 95% confidence intervals (CI) using a random-effects models. Subgroup analysis was performed to identify the probable source of heterogeneity among trials.
RESULTS:
Total pooling of fasting and energy restriction randomised controlled trials in WMD analysis revealed no significant effect on circulating IGF-1 levels (WMD: -16.41 ng/ml, 95% CI: -35.88, 3.07). Sub grouped analysis fasting regimens appeared to substantially reduce IGF-1 (WMD: -28.87 ng/ml, 95% CI: -43.69, -14.05, I2 = 00%), energy restricting regimens failed to do the same (WMD: -10.98 ng/ml, 95% CI: -33.08, 11.11, I2 = 90%). Within this final subgrouping, it was observed that only energy restriction regimens of 50% or greater of normal daily energy intake were capable of significantly reducing IGF-1 levels (WMD: -36.57 ng/ml, 95% CI: -59.19, -13.95, I2 = 00%). Finally, a meta regression were noted in which the percentage restriction of daily energy intake inversely correlated with plasma IGF-1 levels (p = 0.04).
CONCLUSION:
This study uncovered that fasting significantly reduced levels of IGF-1, while energy restriction diets were successful only when intake was reduced by 50% or more.
KEYWORDS:
Energy restriction; Fasting; IGF-1

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Influence of intermittent fasting on myocardial infarction-induced cardiac remodeling.
Okoshi K, Cezar MDM, Polin MAM, Paladino JR Jr, Martinez PF, Oliveira SA Jr, Lima ARR, Damatto RL, Paiva SAR, Zornoff LAM, Okoshi MP.
BMC Cardiovasc Disord. 2019 May 28;19(1):126. doi: 10.1186/s12872-019-1113-4.
PMID: 31138145
Abstract
BACKGROUND:
Information on the role of intermittent fasting (IF) on pathologic cardiac remodeling is scarce. We compared the effects of IF before and after myocardial infarction (MI) on rat cardiac remodeling and survival.
METHODS:
Wistar rats were intermittently fasted (food available every other day) or fed ad libitum for 12 weeks and then divided into three groups: AL - fed ad libitum; AL/IF - fed AL before MI and IF after MI; and IF - fed IF before and after MI. Echocardiogram was performed before MI and 2 and 12 weeks after surgery. Isolated hearts were evaluated in Langendorff preparations.
RESULTS:
Before surgery, body weight (BW) was lower in IF than AL. Final BW was lower in AL/IF and IF than AL. Perioperative mortality did not change between AL (31.3%) and IF (27.3%). Total mortality was lower in IF than AL. Before surgery, echocardiographic parameters did not differ between groups. Two weeks after surgery, MI size did not differ between groups. Twelve weeks after MI, left ventricular (LV) diastolic posterior wall thickness was lower in AL/IF and IF than AL. The percentage of variation of echocardiographic parameters between twelve and two weeks showed that MI size decreased in all groups and the reduction was higher in IF than AL/IF. In Langendorff preparations, LV volume at zero end-diastolic pressure (V0; AL: 0.41 ± 0.05; AL/IF: 0.34 ± 0.06; IF: 0.28 ± 0.05 mL) and at 25 mmHg end-diastolic pressure (V25; AL: 0.61 ± 0.05; AL/IF: 0.54 ± 0.07; IF: 0.44 ± 0.06 mL) was lower in AL/IF and IF than AL and V25 was lower in IF than AL/IF. V0/BW ratio was lower in IF than AL and LV weight/V0 ratio was higher in IF than AL. Myocyte diameter was lower in AL/IF and IF than AL (AL: 17.3 ± 1.70; AL/IF: 15.1 ± 2.21; IF: 13.4 ± 1.49 μm). Myocardial hydroxyproline concentration and gene expression of ANP, Serca 2a, and α- and β-myosin heavy chain did not differ between groups.
CONCLUSION:
Intermittent fasting initiated before or after MI reduces myocyte hypertrophy and LV dilation. Myocardial fibrosis and fetal gene expression are not modulated by feeding regimens. Benefit is more evident when intermittent fasting is initiated before rather than after MI.
KEYWORDS:
Calorie restriction; Echocardiogram; Fetal gene expression; Heart failure; Intermittent feeding; Isolated heart; Langendorff preparation; Myocardial infarction; Rat; Ventricular remodeling

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Role of quercetin and caloric restriction on the biomolecular composition of aged rat cerebral cortex: An FTIR study.
Alugoju P, Narsimulu D, Bhanu JU, Satyanarayana N, Periyasamy L.
Spectrochim Acta A Mol Biomol Spectrosc. 2019 May 14;220:117128. doi: 10.1016/j.saa.2019.05.033. [Epub ahead of print]
PMID: 31146210
Abstract
Aging brain is characterized by a change in biomolecular composition leading to a diverse range of neurological diseases. Anti-aging research is of current interest, to lessen the burden of age-related macromolecular damage through antioxidant supplementation and caloric restriction. However, data concerning the effect of these anti-aging regimens on age-related biomolecular changes in rat brain is still lacking. In the present study, for the first time, we employed Fourier transform infrared (FTIR) spectroscopy, to investigate the effect of quercetin, caloric restriction (CR) and combination of both on alterations in the composition of lipids and proteins of aged rat brain cerebral cortex. Aged male Wistar rats (21 months old) were divided into four groups: Control (CONT), fed pellet diet; Quercetin (QUER), fed quercetin (50 mg/kg/day); CR (caloric restriction) (fed 40% reduced CONT), and CRQ (40% CR and 50 mg/kg/day QUER). Three-month-old rats served as young control (YOUNG). Our short-term study (45 days) shows decreased band area of unsaturated lipids, decreased area ratios of olefinic/lipid and CH2 antisymmetric stretching (2925 cm-1)/lipids in CONT group compared to young rats, suggesting age-associated lipid peroxidation in aged rats. A slight decrease in the frequency of CH2 antisymmetric mode of lipids (whereas no change in CH2 symmetric mode), but a decrease in bandwidths of both CH2 antisymmetric and symmetric modes of lipids was observed for CONT group compared to YOUNG. Further, a significant decrease in the peak area of infrared bands of proteins and an increase in the peak area of the CO band of lipids was observed in the CONT group. Our data also show that lower levels of α-helical structures and higher levels of random coils, representing altered protein secondary structure composition in the CONT group compared to YOUNG group. Reduction in neuronal cell density and shrinked nucleus was also observed in aged rats. Increase in the accumulation of oxidative mediated damage to macromolecules and diminished antioxidant levels, could be the possible reason for the age-related alterations in the composition of lipids and proteins. However, the combination of quercetin and CR, but not either treatment alone, significantly prevented the age associated alterations in the lipid and protein profiles in the rat cerebral cortex. Further, our results help to understand the mechanism of action of antioxidants under non-restriction and CR conditions, this might help in the development of novel anti-aging treatments to ameliorate oxidative stress in age-related disorders.
KEYWORDS:
Aging; Caloric restriction; FTIR spectroscopy; Quercetin

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Caloric restriction reduces basal cell proliferation and results in the deterioration of neuroepithelial regeneration following olfactotoxic mucosal damage in mouse olfactory mucosa.
Iwamura H, Kondo K, Kikuta S, Nishijima H, Kagoya R, Suzukawa K, Ando M, Fujimoto C, Toma-Hirano M, Yamasoba T.
Cell Tissue Res. 2019 Jun 6. doi: 10.1007/s00441-019-03047-1. [Epub ahead of print]
PMID: 31168693
Abstract
The effects of caloric restriction (CR) on cell dynamics and gene expression in the mouse olfactory neuroepithelium are evaluated. Eight-week-old male C57BL/6 mice were fed either control pellets (104 kcal/week) or CR pellets (67 kcal/week). The cytoarchitecture of the olfactory neuroepithelium in the uninjured condition and its regeneration after injury by an olfactotoxic chemical, methimazole, were compared between mice fed with the control and CR diets. In the uninjured condition, there were significantly fewer olfactory marker protein (OMP)-positive olfactory receptor neurons and Ki67-positive proliferating basal cells at 3 months in the CR group than in the control group. The number of Ki67-positive basal cells increased after methimazole-induced mucosal injury in both the control and the CR groups, but the increase was less robust in the CR group. The recovery of the neuroepithelium at 2 months after methimazole administration was less complete in the CR group than in the control group. These histological changes were region-specific. The decrease in the OMP-positive neurons was prominent in the anterior region of the olfactory mucosa. Gene expression analysis using a DNA microarray and quantitative real-time polymerase chain reaction demonstrated that the expression levels of two inflammatory cytokines, interleukin-6 and chemokine ligand 1, were elevated in the olfactory mucosa of the CR group compared with the control group. These findings suggest that CR may be disadvantageous to the maintenance of the olfactory neuroepithelium, especially when it is injured.
KEYWORDS:
Caloric restriction; Cell proliferation; DNA microarray; Interleukin-6; Olfactory neuroepithelium

A Nutrition-Longevity Tradeoff Enforced by Innate Immunity.
Wani KA, Goswamy D, Irazoqui JE.
Mol Cell. 2019 Jun 6;74(5):864-865. doi: 10.1016/j.molcel.2019.05.012.
PMID: 31173721
Abstract
Dietary restriction (DR) extends lifespan in multiple animal species, but the underlying molecular mechanisms remain poorly understood. A recent study published in Cell Metabolism by Wu et al. (2019) shows that DR represses an evolutionarily conserved p38 MAPK pathway involved in innate immunity, leading to diminished expression of p38 MAPK-regulated genes and extended lifespan.
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Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity.
Wu Z, Isik M, Moroz N, Steinbaugh MJ, Zhang P, Blackwell TK.
Cell Metab. 2019 Mar 5. pii: S1550-4131(19)30102-0. doi: 10.1016/j.cmet.2019.02.013. [Epub ahead of print]
PMID: 30905669
https://sci-hub.tw/10.1016/j.cmet.2019.02.013

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Analysis of Bone Mineral Profile After Prolonged Every-Other-Day Feeding in C57BL/6J Male and Female Mice.
Piotrowska K, Zgutka K, Kupnicka P, Chlubek D, Pawlik A, Baranowska-Bosiacka I.
Biol Trace Elem Res. 2019 Jun 8. doi: 10.1007/s12011-019-01758-8. [Epub ahead of print]
PMID: 31175634
https://sci-hub.tw/https://link.springer.com/article/10.1007/s12011-019-01758-8
Abstract
Intermitted fasting or every-other-day feeding (EOD) has many positive effects in rodents and humans. Our goal was to describe how EOD influences bone mineral composition in female and male mice under prolonged EOD feeding. Male and female adult mice were fed EOD for 9 months. After this time, we used a direct method of measurement of mineral components in ashes of long bones (humerus and radius) to estimate the content of calcium (Ca), phosphorus (P), potassium (K), magnesium (Mg), and sodium (Na). We also performed histological analysis of sections of long bones. We found no significant changes in mineral composition between ad libitum and EOD fed males and females. We noted higher Ca and P contents in control males vs. females and lower content of Mg in control males vs. females. We observed the presence of marrow adipose tissue (MAT) in sections of EOD-fed females. EOD without supplementation during feeding days did not increase loss of mineral content of bones in C57BL/6J mice, but the presence of MAT only in EOD females indicates a gender-dependent response to EOD treatment in C57BL/6J mice.
KEYWORDS:
Bone mineral profile; Caloric restriction; Every-other-day feeding; Gender difference

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