Al's CR updates

[AlPater]

Neuronal SIRT1 regulates macronutrient-based diet selection through FGF21 and oxytocin signalling in mice.
Matsui S, Sasaki T, Kohno D, Yaku K, Inutsuka A, Yokota-Hashimoto H, Kikuchi O, Suga T, Kobayashi M, Yamanaka A, Harada A, Nakagawa T, Onaka T, Kitamura T.
Nat Commun. 2018 Nov 2;9(1):4604. doi: 10.1038/s41467-018-07033-z.
PMID: 30389922
https://www.nature.com/articles/s41467-018-07033-z
Abstract
Diet affects health through ingested calories and macronutrients, and macronutrient balance affects health span. The mechanisms regulating macronutrient-based diet choices are poorly understood. Previous studies had shown that NAD-dependent deacetylase sirtuin-1 (SIRT1) in part influences the health-promoting effects of caloric restriction by boosting fat use in peripheral tissues. Here, we show that neuronal SIRT1 shifts diet choice from sucrose to fat in mice, matching the peripheral metabolic shift. SIRT1-mediated suppression of simple sugar preference requires oxytocin signalling, and SIRT1 in oxytocin neurons drives this effect. The hepatokine FGF21 acts as an endocrine signal to oxytocin neurons, promoting neuronal activation and Oxt transcription and suppressing the simple sugar preference. SIRT1 promotes FGF21 signalling in oxytocin neurons and stimulates Oxt transcription through NRF2. Thus, neuronal SIRT1 contributes to the homeostatic regulation of macronutrient-based diet selection in mice.

Caloric restriction and cellular senescence.
Fontana L, Nehme J, Demaria M.
Mech Ageing Dev. 2018 Nov 2. pii: S0047-6374(18)30194-5. doi: 10.1016/j.mad.2018.10.005. [Epub ahead of print] Review.
PMID: 30395873
https://sci-hub.tw/10.1016/j.mad.2018.10.005
Abstract
Cellular senescence is a state of irreversible growth arrest characterized by hypertrophy and secretion of various bioactive molecules, a phenomenon defined the Senescence-Associated Secretory Phenotype (SASP). Senescent cells are implicated in a number of biological functions, from embryogenesis to aging. Significantly, excessive accumulation of senescent cells is associated to a decline of regenerative capacity and chronic inflammation. In accordance, the removal of senescent cells is sufficient to delay several pathologies and promote healthspan. Calorie restriction (CR) without malnutrition is currently the most effective non-genetic intervention to delay aging phenotypes. Recently, we have shown that CR can prevent accumulation of senescent cells in both mice and humans. Here, we summarize the current knowledge on the molecular and cellular events associated with CR, and define how these events can interfere with the induction of cellular senescence. We discuss the potential side effects of preventing senescence, and the possible alternative dietary interventions with potential senolytic properties.

[AlPater]

Energy restriction in renal protection.
Wang SY, Cai GY, Chen XM.
Br J Nutr. 2018 Nov;120(10):1149-1158. doi: 10.1017/S0007114518002684.
PMID: 30401006
https://sci-hub.tw/https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/energy-restriction-in-renal-protection/1B8B15E89F0BDDC6B9886DE6EB48C53F
Abstract
Energy restriction (ER) has been widely studied as a novel intervention, and its ability to prolong life has been fully demonstrated. For example, ER can significantly extend the lifespans of model flies, worms, rodents and other mammals. The role of ER in renal protection has also been elucidated. In preclinical studies, adjusting total energy intake or consumption of specific nutrients has prophylactic or therapeutic effects on ageing-related kidney disease and acute and chronic kidney injury. Amino acid restriction has gradually attracted attention. ER mimetics have also been studied in depth. The protective mechanisms of ER and ER mimetics for renal injury include increasing AMP-activated protein kinase and sirtuin type 1 (Sirt1) levels and autophagy and reducing mammalian target of rapamycin, inflammation and oxidative stress. However, the renal protective effect of ER has mostly been investigated in rodent models, and the role of ER in patients cannot be determined due to the lack of large randomised controlled trials. To protect the kidney, the mechanism of ER must be thoroughly researched, and more accurate diet or drug interventions need to be identified.
KEYWORDS:
AKI acute kidney injury; AMPK AMP-activated protein kinase; CKD chronic kidney disease; DN diabetic nephropathy; ER energy restriction; ERM energy restriction mimetics; ESRD end-stage renal disease; HIF hypoxia-inducible factor 1; PR protein restriction; Pi inorganic phosphate; ROS reactive oxygen species; Sirt1 sirtuin type 1; TGF-β transforming growth factor-β; mTOR mammalian target of rapamycin; Ageing; Energy restriction; Inflammation; Kidney injury; Oxidative stress; Sirtuin type 1: Autophagy

24-h severe energy restriction impairs postprandial glycaemic control in young, lean males.
Clayton DJ, Biddle J, Maher T, Funnell MP, Sargeant JA, King JA, Hulston CJ, Stensel DJ, James LJ.
Br J Nutr. 2018 Nov;120(10):1107-1116. doi: 10.1017/S0007114518002568.
PMID: 30401004
https://sci-hub.tw/10.1017/S0007114518002568
Abstract
Intermittent energy restriction (IER) involves short periods of severe energy restriction interspersed with periods of adequate energy intake, and can induce weight loss. Insulin sensitivity is impaired by short-term, complete energy restriction, but the effects of IER are not well known. In randomised order, fourteen lean men (age: 25 (sd 4) years; BMI: 24 (sd 2) kg/m2; body fat: 17 (4) %) consumed 24-h diets providing 100 % (10 441 (sd 812) kJ; energy balance (EB)) or 25 % (2622 (sd 204) kJ; energy restriction (ER)) of estimated energy requirements, followed by an oral glucose tolerance test (OGTT; 75 g of glucose drink) after fasting overnight. Plasma/serum glucose, insulin, NEFA, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and fibroblast growth factor 21 (FGF21) were assessed before and after (0 h) each 24-h dietary intervention, and throughout the 2-h OGTT. Homoeostatic model assessment of insulin resistance (HOMA2-IR) assessed the fasted response and incremental AUC (iAUC) or total AUC (tAUC) were calculated during the OGTT. At 0 h, HOMA2-IR was 23 % lower after ER compared with EB (P<0·05). During the OGTT, serum glucose iAUC (P<0·001), serum insulin iAUC (P<0·05) and plasma NEFA tAUC (P<0·01) were greater during ER, but GLP-1 (P=0·161), GIP (P=0·473) and FGF21 (P=0·497) tAUC were similar between trials. These results demonstrate that severe energy restriction acutely impairs postprandial glycaemic control in lean men, despite reducing HOMA2-IR. Chronic intervention studies are required to elucidate the long-term effects of IER on indices of insulin sensitivity, particularly in the absence of weight loss.
KEYWORDS:
EB energy balance; EER estimated energy requirements; ER energy restriction; FGF21 fibroblast growth factor 21; GIP glucose-dependent insulinotropic peptide; GLP-1 glucagon-like peptide 1; HOMA2-IR homoeostatic model assessment of insulin resistance; IER intermittent energy restriction; OGTT oral glucose tolerance test; iAUC incremental AUC; tAUC total AUC; Insulin sensitivity; Intermittent energy restriction; Intermittent fasting; Type 2 diabetes; Weight management

[AlPater]

Sirtuin 1 genetic variation, energy balance and colorectal cancer risk by sex and subsite in the Netherlands Cohort Study.
Simons CCJM, Schouten LJ, Godschalk RW, van Schooten FJ, van den Brandt PA, Weijenberg MP.
Sci Rep. 2018 Nov 8;8(1):16540. doi: 10.1038/s41598-018-34728-6.
PMID: 30410074
https://www.nature.com/articles/s41598-018-34728-6
Abstract
Sirtuin 1 (SIRT1) is an energy-sensing protein, which may affect tumorigenesis. We used SIRT1 variants as time-independent indicators of SIRT1 involvement in carcinogenesis and we studied two tagging SIRT1 variants in relation to colorectal cancer (CRC) risk. We also evaluated known energy balance-related CRC risk factors within SIRT1 genotype strata. The Netherlands Cohort Study includes 120,852 individuals and has 20.3 years follow-up (case-cohort: nsubcohort = 5000; nCRC cases = 4667). At baseline, participants self-reported weight, weight at age 20, height, trouser/skirt size reflecting waist circumference, physical activity, and early life energy restriction. SIRT1 rs12778366 and rs10997870 were genotyped in toenail DNA available for ~75% of the cohort. Sex- and subsite-specific Cox hazard ratios (HRs) showed that the rs12778366 CC versus TT genotype decreased CRC and colon cancer risks in women (HRCRC = 0.53, 95% confidence interval: 0.30-0.94) but not men. Multiplicative interactions were observed between SIRT1 variants and energy balance-related factors in relation to CRC endpoints, but the direction of associations was not always conform expectation nor specific to one genotype stratum. In conclusion, these results support SIRT1 involvement in colon cancer development in women. No conclusions could be made regarding a modifying effect of SIRT1 variants on associations between energy balance-related factors and CRC risk.

[AlPater]

Identity Noise and Adipogenic Traits Characterize Dermal Fibroblast Aging.
Salzer MC, Lafzi A, Berenguer-Llergo A, Youssif C, Castellanos A, Solanas G, Peixoto FO, Stephan-Otto Attolini C, Prats N, Aguilera M, Martín-Caballero J, Heyn H, Benitah SA.
Cell. 2018 Nov 3. pii: S0092-8674(18)31320-5. doi: 10.1016/j.cell.2018.10.012. [Epub ahead of print]
PMID: 30415840
https://sci-hub.tw/10.1016/j.cell.2018.10.012
Abstract
During aging, stromal functions are thought to be impaired, but little is known whether this stems from changes of fibroblasts. Using population- and single-cell transcriptomics, as well as long-term lineage tracing, we studied whether murine dermal fibroblasts are altered during physiological aging under different dietary regimes that affect longevity. We show that the identity of old fibroblasts becomes undefined, with the fibroblast states present in young skin no longer clearly demarcated. In addition, old fibroblasts not only reduce the expression of genes involved in the formation of the extracellular matrix, but also gain adipogenic traits, paradoxically becoming more similar to neonatal pro-adipogenic fibroblasts. These alterations are sensitive to systemic metabolic changes: long-term caloric restriction reversibly prevents them, whereas a high-fat diet potentiates them. Our results therefore highlight loss of cell identity and the acquisition of adipogenic traits as a mechanism underlying cellular aging, which is influenced by systemic metabolism.
KEYWORDS:
adipogenesis; aging; caloric restriction; cell fate; dermis; epidermis; fibroblasts; high-fat diet; single-cell RNA-sequencing; stem cells

[AlPater]

The data on the aerobic training with or without calorie restriction and muscular levels of Irisin and muscular FNDC5 concentration in obese male Wistar rats.
Shirvani H, Delpasand A, Bazgir B.
Data Brief. 2018 Oct 22;21:888-892. doi: 10.1016/j.dib.2018.10.028. eCollection 2018 Dec.
PMID: 30426041
https://www.sciencedirect.com/science/article/pii/S2352340918312459?via%3Dihub
Abstract
The present data article aims at investigating the muscular levels of Irisin, FNDC5, and UCP1 in male Wistar rats during the aerobic exercise with or without calorie restriction (CR). Twenty four, 8-week-old male Wistar rats (190±16 g) were selected and purchased for the research. After obesity induction by high-fat diet, the animals were randomly divided into three groups: exercise EX (n = 8), EX-CR (n = ? and CO as control (n = 8). EX exercised 6 sessions per week and EXCR exercise 3 sessions + 3 days caloric restriction per week. The Irisin (Cat.No:CK-E91266 & Intra-Assay: CV<10%), FNDC5 (Cat.No:CK-E91393 & Intra-Assay: CV<10%) levels were assessed by the special Rat ELISA Kit (EASTBIOPHARM, China, under licensed by the United States). Muscular Irisin concentrations in EX group were higher than other groups. In addition, FNDC5 concentrations in EX group was higher than those in other groups.
KEYWORDS:
Animal model; Diet; Exercise; Training

[AlPater]

Time-restricted feeding mitigates high-fat diet-enhanced mammary tumorigenesis in MMTV-PyMT mice.
Sundaram S, Yan L.
Nutr Res. 2018 Nov;59:72-79. doi: 10.1016/j.nutres.2018.07.014. Epub 2018 Jul 31.
PMID: 30442235
https://sci-hub.tw/10.1016/j.nutres.2018.07.014
Abstract
Erratic eating behavior disrupts the daily feeding and fasting pattern and leads to metabolic dysfunction and chronic diseases including cancer. In the present study, we tested the hypothesis that time-restricted feeding of a high-fat diet (HFD) to the dark phase does not enhance mammary tumorigenesis in MMTV-PyMT mice. Female mice were assigned to 3 groups and fed the standard AIN93G diet or an HFD with or without dark phase restricted feeding (12 hours). The duration of restricted feeding was 8 weeks. The HFD group had 24% more body fat mass than the AIN93G group; the body fat mass of the restricted group remained similar to that of the AIN93G group. Energy intake of the restricted group was similar to that of the HFD and AIN93G groups. The median mammary tumor latency was 5.8, 7.0, and 6.4 weeks for the AIN93G, HFD, and restricted groups, respectively. Mammary tumor progression was 241% higher in the HFD group than that in the AIN93G group; there was no significant difference in tumor progression between the restricted and AIN93G groups. Plasma concentrations of leptin, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, angiopoietin-2, vascular endothelial growth factor, and hepatocyte growth factor were significantly higher in the HFD group than those in the control group; these measurements were similar between the restricted and control groups. In conclusion, feeding restricted to the dark phase mitigates the HFD-enhanced mammary tumorigenesis; this may be related to the lower body adiposity and associated inflammatory and angiogenic signals.
KEYWORDS:
High-fat diet; MMTV-PyMT; Mammary tumor; Mice; Restricted feeding

Calorie restriction and its impact on gut microbial composition and global metabolism.
Zheng X, Wang S, Jia W.
Front Med. 2018 Nov 16. doi: 10.1007/s11684-018-0670-8. [Epub ahead of print] Review.
PMID: 30446879
https://sci-hub.tw/10.1007/s11684-018-0670-8
Abstract
Calorie restriction (CR) is a dietary regimen that reduces calorie intake without incurring malnutrition or a reduction in essential nutrients. It has long been recognized as a natural strategy for promoting health, extending longevity, and prevents the development of metabolic and age-related diseases. In the present review, we focus on the general effect of CR on gut microbiota composition and global metabolism. We also propose mechanisms for its beneficial effect. Results showed that probiotic and butyrate-producing microbes increased their relative abundance, whereas proinflammatory strains exhibited suppressed relative abundance following CR. Analyses of the gut microbial and host metabolisms revealed that most host microbial co-metabolites were changed due to CR. Examples of dramatic CR-induced changes in host metabolism included a decrease in the rate of lipid biosynthesis and an increase in the rates of fatty acid catabolism, β-oxidation, glycogenolysis, and gluconeogenesis. The observed phenotypes and the further verification of the direct link between gut microbiota and metabolome may benefit patients that are at risk for developing metabolic disease. Thus, improved gut microbiota composition and metabolome are potential biomarkers for determining the effectiveness of dietary interventions for age-related and metabolic diseases.
KEYWORDS:
caloric restriction; gut microbiota; metabolome

[AlPater]

A time to fast.
Di Francesco A, Di Germanio C, Bernier M, de Cabo R.
Science. 2018 Nov 16;362(6416):770-775. doi: 10.1126/science.aau2095. Review.
PMID: 30442801
http://science.sciencemag.org/content/362/6416/770.full
Abstract
Nutrient composition and caloric intake have traditionally been used to devise optimized diets for various phases of life. Adjustment of meal size and frequency have emerged as powerful tools to ameliorate and postpone the onset of disease and delay aging, whereas periods of fasting, with or without reduced energy intake, can have profound health benefits. The underlying physiological processes involve periodic shifts of metabolic fuel sources, promotion of repair mechanisms, and the optimization of energy utilization for cellular and organismal health. Future research endeavors should be directed to the integration of a balanced nutritious diet with controlled meal size and patterns and periods of fasting to develop better strategies to prevent, postpone, and treat the socioeconomical burden of chronic diseases associated with aging.

[AlPater]

Low-protein high-carb diet shows promise for healthy brain aging
November 20, 2018, University of Sydney
https://medicalxpress.com/news/2018-11-low-protein-high-carb-diet-healthy-brain.html
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Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice.
Wahl D, Solon-Biet SM, Wang QP, Wali JA, Pulpitel T, Clark X, Raubenheimer D, Senior AM, Sinclair DA, Cooney GJ, de Cabo R, Cogger VC, Simpson SJ, Le Couteur DG.
Cell Rep. 2018 Nov 20;25(8):2234-2243.e6. doi: 10.1016/j.celrep.2018.10.070.
PMID: 30463018
https://www.cell.com/cell-reports/pdf/S2211-1247(18)31674-7.pdf
Abstract
Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.
KEYWORDS:
brain aging; calorie restriction; cardiometabolic health; cognitive function; hippocampus; protein restriction

Voluntary Wheel Running Exercise Evoked by Food-Restriction Stress Exacerbates Weight Loss of Adolescent Female Rats But Also Promotes Resilience by Enhancing GABAergic Inhibition of Pyramidal Neurons in the Dorsal Hippocampus.
Chowdhury TG, Wable GS, Chen YW, Tateyama K, Yu I, Wang JY, Reyes AD, Aoki C.
Cereb Cortex. 2018 Nov 14. doi: 10.1093/cercor/bhy283. [Epub ahead of print]
PMID: 30462186
Abstract
Adolescence is marked by increased vulnerability to mental disorders and maladaptive behaviors, including anorexia nervosa. Food-restriction (FR) stress evokes foraging, which translates to increased wheel running exercise (EX) for caged rodents, a maladaptive behavior, since it does not improve food access and exacerbates weight loss. While almost all adolescent rodents increase EX following FR, some then become resilient by suppressing EX by the second-fourth FR day, which minimizes weight loss. We asked whether GABAergic plasticity in the hippocampus may underlie this gain in resilience. In vitro slice physiology revealed doubling of pyramidal neurons' GABA response in the dorsal hippocampus of food-restricted animals with wheel access (FR + EX for 4 days), but without increase of mIPSC amplitudes. mIPSC frequency increased by 46%, but electron microscopy revealed no increase in axosomatic GABAergic synapse number onto pyramidal cells and only a modest increase (26%) of GABAergic synapse lengths. These changes suggest increase of vesicular release probability and extrasynaptic GABAA receptors and unsilencing of GABAergic synapses. GABAergic synapse lengths correlated with individual's suppression of wheel running and weight loss. These analyses indicate that EX can have dual roles-exacerbate weight loss but also promote resilience to some by dampening hippocampal excitability.

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity.
Hahn O, Stubbs TM, Reik W, Grönke S, Beyer A, Partridge L.
PLoS Genet. 2018 Nov 21;14(11):e1007766. doi: 10.1371/journal.pgen.1007766. [Epub ahead of print]
PMID: 30462643
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007766
Abstract
Dietary, pharmacological and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, whole-genome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.

Interleukin-12 as a biomarker of the beneficial effects of food restriction in mice receiving high fat diet or high carbohydrate diet.
de Almeida-Souza CB, Antunes MM, Godoy G, Schamber CR, Silva MARCP, Bazotte RB.
Braz J Med Biol Res. 2018 Nov 14;51(12):e7900. doi: 10.1590/1414-431X20187900.
PMID: 30462775
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2018001200606&lng=en&tlng=en
Abstract
The impact of food restriction (FR) during 56 days on serum levels of cytokines in mice fed a high-fat diet (HFD) or high-carbohydrate diet (HCD) were evaluated. The amount of food was reduced 50% for HFD-FR and HCD-FR groups compared to mice receiving free access to HFD (HFD group) or HCD (HCD group). We quantified the serum levels of basic fibroblast growth factor, granulocyte-macrophage colony-stimulating factor, inducible protein 10, interferon γ, interleukin 1α (IL-1α), IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, keratinocyte chemoattractant, macrophage inflammatory protein-1α, monocyte chemotactic protein 1, monokine induced by IFN-γ, and tumor necrosis factor α. Only IL-12 levels were lower (P<0.05), for both HFD-FR (HFD-FR vs HFD) and HCD-FR (HCD-FR vs HCD). Therefore, IL-12 levels could be considered a biological marker of the beneficial effects of FR.

[AlPater]

Lipoprotein Subclass Profile after Progressive Energy Deficits Induced by Calorie Restriction or Exercise.
Chooi YC, Ding C, Chan Z, Lo J, Choo J, Ding BTK, Leow MK, Magkos F.
Nutrients. 2018 Nov 21;10(11). pii: E1814. doi: 10.3390/nu10111814.
PMID: 30469333
https://www.mdpi.com/2072-6643/10/11/1814/htm
Abstract
Weight loss, induced by chronic energy deficit, improves the blood lipid profile. However, the effects of an acute negative energy balance and the comparative efficacy of diet and exercise are not well-established. We determined the effects of progressive, acute energy deficits (20% or 40% of daily energy requirements) induced by a single day of calorie restriction (n = 19) or aerobic exercise (n = 13) in healthy subjects (age: 26 ± 9 years; body mass index (BMI): 21.8 ± 2.9 kg/m²). Fasting plasma concentrations of very low-, intermediate-, low-, and high-density lipoprotein (VLDL, LDL, IDL, and HDL, respectively) particles and their subclasses were determined using nuclear magnetic resonance. Total plasma triglyceride and VLDL-triglyceride concentrations decreased after calorie restriction and exercise (all p ≤ 0.025); the pattern of change was linear with an increasing energy deficit (all p < 0.03), with no evidence of plateauing. The number of circulating large and medium VLDL particles decreased after diet and exercise (all p < 0.015), with no change in small VLDL particles. The concentrations of IDL, LDL, and HDL particles, their relative distributions, and the particle sizes were not altered. Our data indicate that an acute negative energy balance induced by calorie restriction and aerobic exercise reduces triglyceride concentrations in a dose-dependent manner, by decreasing circulating large and medium VLDL particles.
KEYWORDS:
cholesterol; lipoproteins; negative energy balance; triglyceride

Dorsal-zone-specific reduction of sensory neuron density in the olfactory epithelium following long-term exercise or caloric restriction.
Tuerdi A, Kikuta S, Kinoshita M, Kamogashira T, Kondo K, Iwasaki S, Yamasoba T.
Sci Rep. 2018 Nov 23;8(1):17300. doi: 10.1038/s41598-018-35607-w.
PMID: 30470811
https://www.nature.com/articles/s41598-018-35607-w
Abstract
Exercise (Ex) and caloric restriction (CR) reduce oxidative stress and improve organ function. For instance, voluntary Ex or CR is known to reduce age-related cochlear damage in male C57BL/6J mice. However, the effect of Ex and CR on the olfactory system is unknown. In this study, we confirmed the positive effect of Ex and CR on age-related cochlear damage, but found that Ex and CR affected negatively cell dynamics in the olfactory epithelium (OE) by reducing the number of mature olfactory sensory neurons (OSNs) and increasing the number of proliferative basal cells and apoptotic OSNs in the dorsal zone of the olfactory epithelium (OE), which contains neurons expressing NADPH quinone oxido-reductase 1 (NQO1). In addition, these interventions resulted in lower odor-induced c-fos expression in areas of the olfactory bulb receiving projections from dorsal-zone OSNs than in areas receiving ventral-zone projections. Further, we observed substantial oxidative stress in NQO1-positive cells and apoptotic OSNs in the dorsal zone in Ex and CR animals. These results suggest that, in contrast to their positive effects in other organs, Ex and CR facilitate oxidative stress and negatively impact structure and function in dorsal-zone OSNs, probably in association with NQO1 bioactivation.

Circadian clock genes' overexpression in Drosophila alters diet impact on lifespan.
Solovev I, Shegoleva E, Fedintsev A, Shaposhnikov M, Moskalev A.
Biogerontology. 2018 Nov 24. doi: 10.1007/s10522-018-9784-2. [Epub ahead of print]
PMID: 30470951
Abstract
Diet restriction is one of the most accurately confirmed interventions which extend lifespan. Genes coding circadian core clock elements are known to be the key controllers of cell metabolism especially in aging aspect. The molecular mechanisms standing behind the phenomenon of diet-restriction-mediated life extension are connected to circadian clock either. Here we investigate the effects of protein-rich and low-protein diets on lifespan observed in fruit flies overexpressing core clock genes (cry, per, Clk, cyc and tim). The majority of core clock genes being upregulated in peripheral tissues (muscles and fat body) on protein-rich diet significantly decrease the lifespan of male fruit flies from 5 to 61%. Nevertheless, positive increments of median lifespan were observed in both sexes, males overexpressing cry in fat body lived 20% longer on poor diet. Overexpression of per also on poor medium resulted in life extension in female fruit flies. Diet restriction reduces mortality caused by overexpression of core clock genes. Cox-regression model revealed that diet restriction seriously decreases mortality risks of flies which overexpress core clock genes. The hazard ratios are lower for flies overexpressing clock genes in fat body relatively to muscle-specific overexpression. The present work suggests a phenomenological view of how two peripheral circadian oscillators modify effects of rich and poor diets on lifespan and hazard ratios.
KEYWORDS:
Aging; Circadian clock; Diet restriction; Drosophila melanogaster; Feeding assay; Lifespan

[AlPater]

Brain health: Low-protein, high-carb diet just as good as low-calorie diet
Published    Friday 23 November 2018 By Ana Sandoiu    
https://www.medicalnewstoday.com/articles/323772.php
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Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice.
Wahl D, Solon-Biet SM, Wang QP, Wali JA, Pulpitel T, Clark X, Raubenheimer D, Senior AM, Sinclair DA, Cooney GJ, de Cabo R, Cogger VC, Simpson SJ, Le Couteur DG.
Cell Rep. 2018 Nov 20;25(8):2234-2243.e6. doi: 10.1016/j.celrep.2018.10.070.
PMID: 30463018
Highlights
Calorie restriction (CR) and low-protein, high-carb (LPHC) diets improve health
Hippocampus RNA expression is positively influenced by CR and LPHC diets
Nutrient-sensing pathways are similarly influenced by CR and LPHC diets
CR and LPHC diets positively influence dendritic spines and cognitive function
Summary
Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.

[AlPater]

Treatment of malignant gliomas with ketogenic or caloric restricted diets: A systematic review of preclinical and early clinical studies.
Noorlag L, De Vos FY, Kok A, Broekman MLD, Seute T, Robe PA, Snijders TJ.
Clin Nutr. 2018 Nov 14. pii: S0261-5614(18)32519-6. doi: 10.1016/j.clnu.2018.10.024. [Epub ahead of print] Review.
PMID: 30473444
https://sci-hub.tw/10.1016/j.clnu.2018.10.024
Abstract
BACKGROUND & AIMS:
Patients with malignant gliomas have a poor prognosis. Diets that lower blood glucose, such as ketogenic or caloric restricted diets (KCRDs), are hypothesized to reduce tumor growth and improve survival. In this systematic review, we summarize preclinical and clinical data on KCRDs in gliomas.
METHODS:
We searched PubMed and Embase for preclinical and clinical studies on KCRDs in gliomas, and extracted data on surrogate and clinically relevant endpoints, in accordance with PRISMA statement. Quality assessment of clinical studies was performed with use of Cochrane Collaboration's tool. We performed Fisher's exact test to examine associations between surrogate and clinically relevant endpoints.
RESULTS:
We included 24 preclinical studies, seven clinical studies and one mixed study. Both preclinical and clinical studies were highly heterogeneous. Preclinically, KCRDs reduced tumor growth, but only a small majority of the in vivo studies found improved survival. These effects were stronger in groups with decreased blood glucose than in those with increased ketones, and also when other therapies were used concomitantly. Finally, KCRDs influence multiple molecular-biological pathways, including the PTEN/Akt/TSC2 and NF-kB pathway. In clinical studies, KCRDs seem to be safe and feasible in glioma patients. Clinical data were insufficient to draw conclusions regarding efficacy.
CONCLUSIONS:
KCRDs have positive effects on malignant gliomas in published preclinical studies. Preliminary clinical data suggest that KCRDs are safe and feasible. However, because of the paucity of clinical data, the efficacy of KCRDs for improving survival and quality of life of glioma patients remains to be proven in prospective studies.
KEYWORDS:
Caloric restriction; Glioblastoma; Glioma; Ketogenic diet; Short-term starvation; Targeted therapy

Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial.
Schübel R, Nattenmüller J, Sookthai D, Nonnenmacher T, Graf ME, Riedl L, Schlett CL, von Stackelberg O, Johnson T, Nabers D, Kirsten R, Kratz M, Kauczor HU, Ulrich CM, Kaaks R, Kühn T.
Am J Clin Nutr. 2018 Nov 1;108(5):933-945. doi: 10.1093/ajcn/nqy196.
PMID: 30475957
https://sci-hub.tw/10.1093/ajcn/nqy196
Abstract
BACKGROUND:
Although preliminary evidence suggests that intermittent calorie restriction (ICR) exerts stronger effects on metabolic parameters, which may link obesity and major chronic diseases, compared with continuous calorie restriction (CCR), there is a lack of well-powered intervention studies.
OBJECTIVE:
We conducted a randomized controlled trial to test whether ICR, operationalized as the "5:2 diet," has stronger effects on adipose tissue gene expression, anthropometric and body composition measures, and circulating metabolic biomarkers than CCR and a control regimen.
DESIGN:
One hundred and fifty overweight and obese nonsmokers [body mass index (kg/m2) ≥25 to <40, 50% women], aged 35-65 y, were randomly assigned to an ICR group (5 d without energy restriction and 2 d with 75% energy deficit, net weekly energy deficit ∼20%), a CCR group (daily energy deficit ∼20%), or a control group (no advice to restrict energy) and participated in a 12-wk intervention phase, a 12-wk maintenance phase, and a 26-wk follow-up phase.
RESULTS:
Loge relative weight change over the intervention phase was -7.1% ± 0.7% (mean ± SEM) with ICR, -5.2% ± 0.6% with CCR, and -3.3% ± 0.6% with the control regimen (Poverall < 0.001, PICR vs. CCR = 0.053). Despite slightly greater weight loss with ICR than with CCR, there were no significant differences between the groups in the expression of 82 preselected genes in adipose tissue implicated in pathways linking obesity to chronic diseases. At the final follow-up assessment (week 50), weight loss was -5.2% ± 1.2% with ICR, -4.9% ± 1.1% with CCR, and -1.7% ± 0.8% with the control regimen (Poverall = 0.01, PICR vs. CCR = 0.89). These effects were paralleled by proportional changes in visceral and subcutaneous adipose tissue volumes. There were no significant differences between ICR and CCR regarding various circulating metabolic biomarkers.
CONCLUSION:
Our results on the effects of the "5:2 diet" indicate that ICR may be equivalent but not superior to CCR for weight reduction and prevention of metabolic diseases.
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Intermittent calorie restriction-a more effective approach to weight loss?
Sundfør TM, Svendsen M, Tonstad S.
Am J Clin Nutr. 2018 Nov 1;108(5):909-910. doi: 10.1093/ajcn/nqy288. No abstract available.
PMID: 30475966
https://sci-hub.tw/10.1093/ajcn/nqy288

Intermittent Fasting Improves Glucose Tolerance and Promotes Adipose Tissue Remodeling in Male Mice Fed a High Fat Diet.
Liu B, Page AJ, Hatzinikolas G, Chen M, Wittert GA, Heilbronn LK.
Endocrinology. 2018 Nov 21. doi: 10.1210/en.2018-00701. [Epub ahead of print]
PMID: 30476012
Abstract
Obesity is associated with increased macrophage and extracellular matrix accumulation in adipose tissue, which can be partially reversed following weight loss by daily caloric restriction. This study examined the effects of 8 weeks of intermittent fasting (IF, 24-hours fast on 3 non-consecutive days per week) in mice fed a chow or high-fat diet (HFD, 43% fat), on markers of adipose tissue inflammation and fibrosis. We found that IF decreased energy intake, body weight and fat cell size in HFD fed mice, and decreased fat mass and improved glucose tolerance in chow and HFD fed mice. IF decreased mRNA levels of macrophage markers (Lgals3, Itgax, Ccl2 and Ccl3) in inguinal and gonadal fat, and adipose tissue macrophages numbers in HFD fed mice only, and altered NLRP3-inflammasome pathway in both diet groups. IF increased mRNA levels of matrix metallopeptidase 9, which is involved in extracellular matrix degradation, and reduced mRNA levels of collagen 6 alpha-1 and tissue inhibitor of matrix metallopeptidase 1, and fibrosis in gonadal fat in HFD fed mice. In summary, our results show that intermittent fasting improved glucose tolerance in chow and high-fat diet fed mice, and ameliorated adipose tissue inflammation and fibrosis in high-fat diet fed mice.

[AlPater]

Does Calorie Restriction in Primates Increase Lifespan? Revisiting Studies on Macaques (Macaca mulatta) and Mouse Lemurs (Microcebus murinus).
Le Bourg E.
Bioessays. 2018 Oct;40(10):e1800111. doi: 10.1002/bies.201800111. Epub 2018 Aug 1. Review.
PMID: 30067295
Abstract
The effects of calorie restriction have now been studied in two non-human primates, the macaque Macaca mulatta and the mouse lemur Microcebus murinus. The study on lemurs and one of the two studies on macaques have reported a lifespan increase. In this review, I argue that these results are better explained by a lifespan decrease in the control group because of a bad diet and/or overfeeding, rather than by a real lifespan increase in calorie-restricted animals. If these results can be readily translated to humans, it would mean that no beneficial effect of calorie restriction on lifespan can be expected in normal-weight or lean people, but that overweight and/or obese people could benefit to some extent from a decrease in excessive food intake.
KEYWORDS:
calorie restriction; human beings; non-human primates
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Calorie Restriction off the Menu for the Time Being?….
Moore A.
Bioessays. 2018 Oct;40(10):e1800170. doi: 10.1002/bies.201800170. No abstract available.
PMID: 30246504
https://onlinelibrary.wiley.com/doi/epdf/10.1002/bies.201800170
If you're interested in living a healthy, long life, mere calorie restriction probably won't do much for you. But wait! Before you impulsively dash to the fridge to gobble up a whole pot of artificially sweetened yoghurt − with a freshly cleared conscience, and resolved simply to enjoy your remaining mortal days − it's more complicated than that. Sorry, but this is, after all, biology that we're talking about. Increasing, epidemiological and sociological evidence, and critical examination of calorie restriction experiments, are combining to give a more scientifically‐founded explanation for the “obesity epidemic” afflicting wealthy nations. Here's the bottom line: It's likely to be eating habits and the type of diet associated with them, not the calories per se, that threaten to curtail many people's lives short of their potential span. It's the way we eat and what we eat.
First to the way: humans face a serious risk to health in having food constantly available, increasingly advertised, and ever less associated with regular eating times. Basically this is a type of industrially encouraged ad libitum feeding regime.1 What's the connexion with calorie‐restriction studies? Having covered the risks of simplistically translating results from calorie restriction in animal models into personal eating habits in our previous issue,2 Le Bourg is back with a “Think again” article3 in this issue that basically forces us to examine the negative effects of ad libitum feeding. Herein is the reasoned claim that the seeming life extension effect of calorie restriction in laboratory animal studies is more likely to be due a lowered life expectancy in the ad libitum‐fed control groups. Animals in this setting escape the predation, natural accidents, and most of the disease burden that wild animals suffer; however, if Le Bourg is right, the control group can't profit as much from these advantages as the calorie‐restricted one, because ad libitum feeding is not healthy for them. These ad libitum fed diets at least contain foodstuffs that are species‐appropriate. In the human population, by contrast, that is highly questionable.
And so to the what. Industrialized wealthy nations are increasingly eating foodstuffs laced with refined carbohydrates and carbohydrates with high glycemic indexes (put crudely, that rapidly enter into the blood as monosaccharides, and hence have high insulin‐releasing potential). George Monbiot's analysis,1 drawing on published peer reviewed literature, claims that today's obesity‐prone populations are not eating more calories on average than their counterparts even in the 1970s; rather they are eating them in different forms, predominantly in more carbohydrate‐rich foods − a trend that is promoted by the food industry's strategic development and advertising of attractive foods. Put dysregulated eating habits together with unbalanced nutrition, and one has a metabolic energy economy that is forced to run out of synchrony with physiological circadian rhythms, and on a fuel that exhausts the insulin machinery. And mere exercise won't help you much in that situation either.4
It seems, therefore, that putting calorie restriction into practice in human populations has never been further from the realms of realism − and at least as much for practical, as scientific, reasons. If there are any potential benefits in humans, these might only be realized if we manage to get our diet and eating habits back into order. Performing calorie restriction on such a poor, carbohydrate‐rich, diet is a bit like saying to an obese person “If you cut down your consumption of fizzy orangeade, you'll live longer”, knowing that the fizzy drink is likely the major source of certain important vitamins in that person's diet…

Vitamin E supplementation and caloric restriction promotes regulation of insulin secretion and glycemic homeostasis by different mechanisms in rats.
Venturini PR, Thomazini BF, Oliveira CA, Alves AA, Camargo TF, Domingues CEC, Barbosa-Sampaio HCL, do Amaral MEC.
Biochem Cell Biol. 2018 Nov 27:1-9. doi: 10.1139/bcb-2018-0066. [Epub ahead of print]
PMID: 30481061
http://sci-hub.tw/http://www.nrcresearchpress.com/doi/10.1139/bcb-2018-0066
Abstract
Vitamin E and caloric restriction have antioxidant effects in mammals. The aim of this study was to evaluate effects of vitamin E supplementation and caloric restriction upon insulin secretion and glucose homeostasis in rats. Male Wistar rats were distributed among the following groups: C, control group fed ad libitum; R, food quantity reduction of 40%; CV, control group supplemented with vitamin E [30 mg·kg-1·day-1]; and RV, food-restricted group supplemented with vitamin E. The experiments ran for 21 days. Glucose tolerance and insulin sensitivity was higher in the CV, R, and RV groups. Insulin secretion stimulated with different glucose concentrations was lower in the R and RV groups, compared with C and CV. In the presence of glucose and secretagogues, insulin secretion was higher in the CV group and was lower in the R and RV groups. An increase in insulin receptor occurred in the fat pad and muscle tissue of groups CV, R, and RV. Levels of hepatic insulin receptor and phospho-Akt protein were higher in groups R and RV, compared with C and CV, while muscle phospho-Akt was increased in the CV group. There was a reduction in hepatic RNA levels of the hepatocyte growth factor gene and insulin degrading enzyme in the R group, and increased levels of insulin degrading enzyme in the CV and RV groups. Thus, vitamin E supplementation and caloric restriction modulate insulin secretion by different mechanisms to maintain glucose homeostasis.
KEYWORDS:
coussinet adipeux; fat pad; foie; gros intestin; ilots; islets; large intestine; liver; muscle

[AlPater]

Caloric restriction attenuates aging-induced cardiac insulin resistance in male Wistar rats through activation of PI3K/Akt pathway.
Granado M, Amor S, Martín-Carro B, Guerra-Menéndez L, Tejera-Muñoz A, González-Hedström D, Rubio C, Carrascosa JM, García-Villalón ÁL.
Nutr Metab Cardiovasc Dis. 2018 Sep 26. pii: S0939-4753(18)30275-8. doi: 10.1016/j.numecd.2018.09.005. [Epub ahead of print]
PMID: 30497927
http://sci-hub.tw/https://linkinghub.elsevier.com/retrieve/pii/S0939475318302758
Abstract
BACKGROUND AND AIM:
Caloric restriction (CR) improves insulin sensitivity and is one of the dietetic strategies most commonly used to enlarge life and to prevent aging-induced cardiovascular alterations. The aim of this study was to analyze the possible beneficial effects of caloric restriction (CR) preventing the aging-induced insulin resistance in the heart of male Wistar rats.
METHODS AND RESULTS:
Three experimental groups were used: 3 months old rats (3m), 24 months old rats (24m) and 24 months old rats subjected to 20% CR during their three last months of life (24m-CR). After sacrifice hearts were mounted in a perfusion system (Langendorff) and heart function in basal conditions and in response to accumulative doses of insulin (10-9-10-7 M), in the presence or absence of Wortmannin (10-6 M), was recorded. CR did not attenuate the aging-induced decrease in coronary artery vasodilation in response to insulin administration, but it prevented the aging-induced downregulation of cardiac contractility (dp/dt) through activation of the PI3K/Akt intracellular pathway. Insulin stimulated in a greater extent the PI3K/Akt pathway vs the activation of the MAPK pathway and increased the protein expression of IR, GLUT-4 and eNOS in the hearts of 3m and 24m-CR rats, but not in the hearts of 24m rats. Furthermore, CR prevented the aging induced increase in endothelin-1 protein expression in myocardial tissue.
CONCLUSION:
In conclusion CR partially improves cardiac insulin sensitivity and prevents the aging induced decrease in myocardial contractility in response to insulin administration through activation of PI3K/Akt pathway.
KEYWORDS:
Aging; Akt; Caloric restriction; Cardiovascular; Heart; Insulin; Langendorff; Rat

[AlPater]

Low calorie dieting increases cortisol.
Tomiyama AJ, Mann T, Vinas D, Hunger JM, Dejager J, Taylor SE.
Psychosom Med. 2010 May;72(4):357-64. doi: 10.1097/PSY.0b013e3181d9523c. Epub 2010 Apr 5.
PMID: 20368473 Free PMC Article
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895000/pdf/nihms198826.pdf
Abstract
OBJECTIVE:
To test the hypothesis that dieting, or the restriction of caloric intake, is ineffective because it increases chronic psychological stress and cortisol production--two factors that are known to cause weight gain; and to examine the respective roles of the two main behaviors that comprise dieting--monitoring one's caloric intake and restricting one's caloric intake--on psychological and biological stress indicators.
METHODS:
In a 2 (monitoring vs. not) x 2 (restricting vs. not) fully crossed, controlled experiment, 121 female participants were assigned randomly to one of four dietary interventions for 3 weeks. The monitoring + restricting condition tracked their caloric intake and restricted their caloric intake (1200 kcal/day); the monitoring only condition tracked their caloric intake but ate normally; the restricting only condition was provided 1200 kcal/day of food but did not track their calories, and the control group ate normally and did not track their intake. Before and after the interventions, participants completed measures of perceived stress and 2 days of diurnal saliva sampling to test for cortisol.
RESULTS:
Restricting calories increased the total output of cortisol, and monitoring calories increased perceived stress.
CONCLUSIONS:
Dieting may be deleterious to psychological well-being and biological functioning, and changes in clinical recommendations may be in order.
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Psychosom Med. 2010 Jul;72(6):598-9; author reply 599-600. doi: 10.1097/PSY.0b013e3181e9df06. Epub 2010 Jul 1.
Low-calorie dieting and dieters' cortisol levels: don't forget cortisone.
Remer T, Shi L.
PMID: 20595418 
https://sci-hub.tw/10.1097/PSY.0b013e3181e9df06

[AlPater]

Obs Rev Volume 19, Issue S1
Supplement: Targeting Lifestyle Energy Expenditure in Management of Obesity & Cardiometabolic Risks: from Biology to Built environment, 9th Fribourg Obesity Research Conference (FORC 2017), Held on October 19th 2017 at the Faculty of Science, University of Fribourg, Organised by Department of Medicine‐Physiology, University of Fribourg, Switzerland, In association with the Swiss Association for Study of Obesity, Guest Editor: Abdul G. Dulloo
Pages: 1-107
December 2018
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Regulation of intestinal growth in response to variations in energy supply and demand.
Nilaweera KN, Speakman JR.
Obes Rev. 2018 Dec;19 Suppl 1:61-72. doi: 10.1111/obr.12780. Review.
PMID: 30511508
https://sci-hub.tw/https://onlinelibrary.wiley.com/doi/abs/10.1111/obr.12780
Abstract
The growth of the intestine requires energy, which is known to be met by catabolism of ingested nutrients. Paradoxically, during whole body energy deficit including calorie restriction, the intestine grows in size. To understand how and why this happens, we reviewed data from several animal models of energetic challenge. These were bariatric surgery, cold exposure, lactation, dietary whey protein intake and calorie restriction. Notably, these challenges all reduced the adipose tissue mass, altered hypothalamic neuropeptide expression and increased intestinal size. Based on these data, we propose that the loss of energy in the adipose tissue promotes the growth of the intestine via a signalling mechanism involving the hypothalamus. We discuss possible candidates in this pathway including data showing a correlative change in intestinal (ileal) expression of the cyclin D1 gene with adipose tissue mass, adipose derived-hormone leptin and hypothalamic expression of leptin receptor and the pro-opiomelanocortin gene. The ability of the intestine to grow in size during depletion of energy stores provides a mechanism to maximize assimilation of ingested energy and in turn sustain critical functions of tissues important for survival.
KEYWORDS:
adipose tissue; hypothalamus; intestine
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Changes in physical activity over the lifespan: impact on body composition and sarcopenic obesity.
Westerterp KR.
Obes Rev. 2018 Dec;19 Suppl 1:8-13. doi: 10.1111/obr.12781. Review.
PMID: 30511504
https://sci-hub.tw/https://onlinelibrary.wiley.com/doi/abs/10.1111/obr.12781
Abstract
Physical activity and body composition show a typical pattern over the lifecycle. Fat-free mass and physical performance generally peak in early adulthood. Here, evidence for a relation between physical activity changes over the life span and the development of sarcopenic obesity is presented. Activity-induced energy expenditure increases with body size and physical activity during growth. The physical activity level, calculated by expressing total energy expenditure as a multiple of resting energy expenditure, gradually increases from early age to adulthood to decrease again in old age. Habitual physical activity has a significant effect on growth of fat-free mass during adolescence and thus on peak fat-free mass and physical performance in early adulthood. Older subjects have a lower fat-free mass and lower physical activity levels but there is no association, suggesting physical activity does not protect against loss of lean body mass at higher age. Prevention of sarcopenic obesity starts with a physically active lifestyle to develop a healthy peak fat-free mass and subsequent prevention of excess fat gain. The change from a physically active to a more sedentary routine in later life requires restriction of energy intake to maintain energy balance.
KEYWORDS:
Fat-free mass; fat-free mass index; physical activity level; sarcopenic obesity
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A systematic review of the separate and combined effects of energy restriction and exercise on fat-free mass in middle-aged and older adults: implications for sarcopenic obesity.
Weinheimer EM, Sands LP, Campbell WW.
Nutr Rev. 2010 Jul;68(7):375-88. doi: 10.1111/j.1753-4887.2010.00298.x. Review.
PMID: 20591106
https://sci-hub.tw/10.1111/j.1753-4887.2010.00298.x
Abstract
The systematic review presented here assessed the effects of energy restriction (ER) and exercise (EX) on fat-free mass (FFM) in overweight and obese middle-aged and older adults. PubMed was searched using the key words "weight loss or energy restriction" AND "skeletal muscle or body composition," with limitations set for "human" and "middle-aged and aged." Results from 52 studies are reported as the percentages of EX (mainly aerobic training), ER, or ER+EX groups that had a specified change in body weight and FFM, since insufficient data were available for a meta-analysis. The EX groups had modest body weight and FFM changes. Eighty-one percent and 39% of the ER and ER+EX groups, respectively, lost > or = 15% of body weight as FFM. These findings suggest that exercise is an effective tool to help men and postmenopausal women aged > or = 50 years, with a BMI greater than 25 kg/m(2) preserve FFM after moderate ER-induced weight loss, which is important for combating sarcopenic obesity.
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Rationale for novel intermittent dieting strategies to attenuate adaptive responses to energy restriction.
Sainsbury A, Wood RE, Seimon RV, Hills AP, King NA, Gibson AA, Byrne NM.
Obes Rev. 2018 Dec;19 Suppl 1:47-60. doi: 10.1111/obr.12787. Review.
PMID: 30511512
Abstract
Eating patterns involving intermittent energy restriction (IER) include 'intermittent fasting' where energy intake is severely restricted for several 'fasting' days per week, with 'refeeding' days (involving greater energy intake than during fasting days) at other times. Intermittent fasting does not improve weight loss compared to continuous energy restriction (CER), where energy intake is restricted every day. We hypothesize that weight loss from IER could be improved if refeeding phases involved restoration of energy balance (i.e. not ongoing energy restriction, as during intermittent fasting). There is some evidence in adults with overweight or obesity showing that maintenance of a lower weight may attenuate (completely or partially) some of the adaptive responses to energy restriction that oppose ongoing weight loss. Other studies show some adaptive responses persist unabated for years after weight loss. Only five randomized controlled trials in adults with overweight or obesity have compared CER with IER interventions that achieved energy balance (or absence of energy restriction) during refeeding phases. Two reported greater weight loss than CER, whereas three reported similar weight loss between interventions. While inconclusive, it is possible that achieving energy balance (i.e. avoiding energy restriction or energy excess) during refeeding phases may be important in realizing the potential of IER.
KEYWORDS:
Diet-reducing; intermittent energy restriction; intermittent fasting; obesity

[AlPater]

Drosophila Gut-A Nexus Between Dietary Restriction and Lifespan.
Lian T, Wu Q, Hodge BA, Wilson KA, Yu G, Yang M.
Int J Mol Sci. 2018 Nov 29;19(12). pii: E3810. doi: 10.3390/ijms19123810. Review.
PMID: 30501099
https://www.mdpi.com/1422-0067/19/12/3810/htm
Abstract
Aging is often defined as the accumulation of damage at the molecular and cellular levels which, over time, results in marked physiological impairments throughout the organism. Dietary restriction (DR) has been recognized as one of the strongest lifespan extending therapies observed in a wide array of organisms. Recent studies aimed at elucidating how DR promotes healthy aging have demonstrated a vital role of the digestive tract in mediating the beneficial effects of DR. Here, we review how dietary restriction influences gut metabolic homeostasis and immune function. Our discussion is focused on studies of the Drosophila digestive tract, where we describe in detail the potential mechanisms in which DR enhances maintenance of the intestinal epithelial barrier, up-regulates lipid metabolic processes, and improves the ability of the gut to deal with damage or stress. We also examine evidence of a tissue-tissue crosstalk between gut and neighboring organs including brain and fat body. Taken together, we argue that the Drosophila gut plays a critical role in DR-mediated lifespan extension.
KEYWORDS:
Drosophila; aging; dietary restriction; gut; intestinal epithelia barrier

[AlPater]

Healthy aging and the Mediterranean diet
ROZALYN ANDERSON 
DECEMBER 3RD 2018
https://blog.oup.com/2018/12/healthy-aging-mediterranean-diet/
In this Q&A, Rozalyn Anderson, PhD and Co-Editor in Chief of the biological sciences section of The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, sits down with Luigi Fontana, PhD, and Mediterranean Diet expert.
Dr. Luigi Fontana is well-known for his research focused primarily on healthy aging and longevity. His interest in this field began years ago in his native country, Italy, when he was practicing clinician in internal medicine. At that time in the late 1990s, the emphasis was primarily on diagnosis and treatment, not preventative care. Dr. Fontana was interested in following a different path. While working on his PhD in nutrition and metabolism, he reached out to international leaders in basic research focused on nutrition and health including Dr. Rick Weindruch, a leader in caloric restriction, and Dr. John Holloszy, an expert in exercise and health studies. For nearly 20 years since, Dr. Fontana has been engaged in aging and nutrition research at the Washington University School of Medicine. He has maintained research programs in the US and in Italy and has written extensively on nutrition and health. His newest adventure began in the summer of 2018 when he moved to Australia to work on a new initiative in health and aging at the University of Sydney.
Rozalyn Anderson: How would you describe your perspective in aging research?
Luigi Fontana: My emphasis is more toward nutrition and exercise than drug discovery. The goal is to identify the molecular determinants of aging and use that information to design diets, lifestyle strategies, and preventative interventions to ensure prolonged health into old age.
 RA: So one of the areas you are best known for is your work with people on the caloric restriction diet, what is the latest there?
LF: It’s really amazing. We are now seeing people from the Caloric Restriction Society reach their 70s and 80s in robust health. Many of them at this age are active, prescription free, and still without complications of age-associated diseases and disorders. The diet is really delivering on the promise of healthy aging.
RA: What do you see as the next steps?
LF: We really need to know the framework of how diet influences aging and health. We need biomarkers of health and of risk for age-related conditions. With these tools, we can really appreciate the impact of nutrition on disease risk and figure out what works to promote healthy aging. At this stage, we are looking for alternate ways to enhance health. For example, it is possible to choose a diet that promotes health such as the Mediterranean Diet without actually doing full-blown caloric restriction.
RA: So what are we talking about when we talk about the Mediterranean Diet?
LF: A key feature of this health-promoting diet is that it is largely plant-based. The emphasis is on local fruit and vegetables, whole grains, beans, and nuts – with protein sources from grains, legumes, and fish, rather than red meat. A glass of wine taken with food is not unusual. Traditionally the diet is also associated with extra-virgin olive oil but there is a caveat here; in times gone by individuals on this kind of diet has an active lifestyle with physically demanding tasks being a routine day to day occurrence. The amount of food eaten must be matched to energy demands on the body, especially with the modern sedentary lifestyle, otherwise, the benefits may not be as strong.
RA: How did you first learn about this diet?
LF: When I was a child, I lived in a small town in the Dolomites close to Lake Garda. My mother became interested in what was known then as the macrobiotic diet, which basically has many commonalities with the Mediterranean Diet. We had a small garden and grew our own vegetables. You could say I have had a healthy diet since the very beginning.
RA: There are a number of different diets out there, how do we know what will work?
LF: There is really great support for health benefits of the Mediterranean diet, from epidemiology studies of large populations that are basically observational studies to randomized clinical trials that are strictly regulated studies. All the evidence suggests improvements in health from cognition, to cardiovascular disease, diabetes, and even cancer. Keep in mind though that for any diet to really be beneficial it has to be balanced with lifestyle and physical activity.
RA: So how will we get to eventually seeing this work in clinical practice?
LF: The current clinical paradigm waits until you are sick and then begins treating the condition. I really believe that the future of healthcare is going to be preventative medicine where the focus is on strategies to maintain health. To get there, basic research will be super important. This is the driving force to develop ideas and then we can test these ideas in human studies. Translatability is key but without basic science, we would have no leads to follow, it’s hard to see how any advances in human aging biology could be made without this foundational work.

Differential Metabolic Responses to Adipose Atrophy Associated with Cancer Cachexia and Caloric Restriction in Rats and the Effect of Rikkunshito in Cancer Cachexia.
Sudo Y, Otsuka H, Miyakawa R, Goto A, Kashiwase Y, Terawaki K, Miyano K, Hirao Y, Taki K, Tagawa R, Kobayashi M, Okita N, Uezono Y, Higami Y.
Int J Mol Sci. 2018 Dec 3;19(12). pii: E3852. doi: 10.3390/ijms19123852.
PMID: 30513935
https://www.mdpi.com/1422-0067/19/12/3852/htm
Abstract
Despite the similar phenotypes, including weight loss, reduction of food intake, and lower adiposity, associated with caloric restriction (CR) and cancer cachexia (CC), CC is a progressive wasting syndrome, while mild CR improves whole body metabolism. In the present study, we compared adipose metabolic changes in a novel rat model of CC, mild CR (70% of the food intake of control rats, which is similar to the food consumption of CC rats), and severe CR (30% of the food intake of controls). We show that CC and severe CR are associated with much smaller adipocytes with significantly lower mitochondrial DNA content; but, that mild CR is not. CC and both mild and severe CR similarly upregulated proteins involved in lipolysis. CC also downregulated proteins involved in fatty acid biosynthesis, but mild CR upregulated these. These findings suggest that CC might impair de novo fatty acid biosynthesis and reduce mitochondrial biogenesis, similar to severe CR. We also found that rikkunshito, a traditional Japanese herbal medicine, does not ameliorate the enhanced lipolysis and mitochondrial impairment, but rather, rescues de novo fatty acid biosynthesis, suggesting that rikkunshito administration might have partially similar effects to mild CR.
KEYWORDS:
caloric restriction; cancer cachexia; rikkunshito; sterol regulatory element-binding transcription factor 1c

Effects of intermittent versus continuous energy restriction for weight loss on diet quality and eating behavior. A randomized trial.
Sundfør TM, Tonstad S, Svendsen M.
Eur J Clin Nutr. 2018 Dec 4. doi: 10.1038/s41430-018-0370-0. [Epub ahead of print]
PMID: 30514879
Abstract
BACKGROUND/OBJECTIVES:
Weight loss diets affect food choices and control of eating. We evaluated the effects of intermittent energy restriction (IER) vs. continuous energy restriction (CER) on nutritional composition and eating behavior.
SUBJECT/METHODS:
Individuals with BMI 30-45 kg/m2, abdominal obesity and ≥1 additional metabolic syndrome component were randomized to IER vs. CER with similar energy restriction. Of 112 participants, 98 completed weighed dietary records and the Three Factor Eating Questionnaire at baseline and three months. In statistical analysis, changes were adjusted for baseline values.
RESULTS:
Weight loss, energy intake, and macronutrient composition were similar in the IER and CER groups. The CER group reported a greater increase in fruit and berries (45 g/day [95% CI 21, 71] vs. 2 g/day [-28, 33]; p = 0.047) and vegetables (135 g/day [91, 179] vs. 65 g/day [35, 96]; p = 0.010) than the IER group. Fiber intake increased in the CER compared to the IER group (1.0 g/MJ/day [0.8, 1.2] vs. 0.2 [0.0, 0.4]; p < 0.001). Sugar intake was reduced in the CER compared to the IER group (-2.2E% [-3.2, -2.2] vs. -0.1E% [-1.2, 1.0]; p = 0.007). Intakes of folate, potassium, and magnesium decreased more in the IER than the CER group, while vitamin C increased more in the CER group (all p-values <0.014). Both diets improved eating behavior scores, but cognitive restraint increased more in the CER than the IER group (34 [30, 39] vs. 17 [12, 22]; p = 0.013).
CONCLUSIONS:
Men and women with obesity had more favorable changes in nutritional composition and eating behavior with CER than IER.

[AlPater]

Role of the variant in adiponectin gene rs266729 on weight loss and cardiovascular risk factors after a hypocaloric diet with the Mediterranean pattern.
de Luis DA, Primo D, Izaola O, Gomez Hoyos E, Lopez Gomez JJ, Ortola A, Aller R.
Nutrition. 2018 Aug 23;60:1-5. doi: 10.1016/j.nut.2018.08.018. [Epub ahead of print]
PMID: 30508762
https://sci-hub.tw/10.1016/j.nut.2018.08.018
Abstract
OBJECTIVES:
The role of ADIPOQ gene variants on weight loss after a dietary intervention remain unclear. The aim of this study was to analyze the effects of rs266729 of the ADIPOQ gene on cardiovascular risk factors and adiposity parameters after adherence to a Mediterranean-type hypocaloric diet.
METHOD:
Eighty-three obese patients were studied before and after 12 wk on a Mediterranean-type hypocaloric diet. Anthropometric parameters and biochemical profiles were measured. The variant of ADIPOQ gene rs266729 was assessed at basal time by polymerase chain reaction at real time.
RESULTS:
Two genotype groups were realized (CC versus CG + GG). The final genotype distribution was 48 patients CC (57.8%), 30 patients CG (36.2%) and 5 patients GG (6%). After dietary intervention with a moderate calorie restriction and in both genotypes, body mass index (BMI), weight, fat mass, systolic blood pressure, and waist circumference decreased. After dietary intervention and in non-G allele carriers (CC versus CG+ GG), glucose (δ: -6.2 ± 1.1 versus -2.9 ± 1.2 mg/dL; P = 0.02), total cholesterol (δ:-15.2 ± 3.1 versus -3.4 ± 2 mg/dL; P = 0.02), low-density lipoprotein cholesterol (δ, -14.9 ± 3.1 versus -4.9 ± 1.2 mg/dL; P = 0.01), insulin levels (δ, -4± 0.6 versus 0.7 ± 0.3 UI/L;P = 0.01), homeostasis model assessment for insulin resistance (δ, -1.6 ± 0.4 versus -0.2 ± 0.4 units; P = 0.01), and adiponectin (δ, -10.4 ± 3.1 versus -1.3 ± 1.0 ng/dL; P = 0.01) improved.
CONCLUSION:
After weight loss, the CC genotype of ADIPOQ gene variant (rs266729) is associated with increases in adiponectin levels and decreases of low-density lipoprotein cholesterol, insulin and homeostasis model assessment for insulin resistance after weight loss.
KEYWORDS:
Adipokines; Adiponectin gene; Cardiovascular risk factors; Hypocaloric diet; rs266729

[AlPater]

mTOR, glycotoxins and the parallel universe.
Green AS.
Aging (Albany NY). 2018 Dec 12. doi: 10.18632/aging.101720. [Epub ahead of print] No abstract available.
PMID: 30540565
KEYWORDS:
advance glycation end products; aging; food restriction; rapamycin
https://www.aging-us.com/article/101720/text

Adipose tissue is less responsive to food restriction anti-inflammatory effects than liver, muscle, and brain in mice.
Antunes MM, de Almeida-Souza CB, Godoy G, Crisma AR, Masi LN, Curi R, Bazotte RB.
Braz J Med Biol Res. 2018 Dec 10;52(1):e8150. doi: 10.1590/1414-431X20188150.
PMID: 30539971
Abstract
High caloric intake promotes chronic inflammation, insulin resistance, and chronic diseases such as type-2 diabetes, which may be prevented by food restriction (FR). The effect of FR on expression of pro-inflammatory and anti-inflammatory genes in adipose tissue, liver, muscle, and brain was compared. Male Swiss mice were submitted to FR (FR group) or had free access to food (control group) during 56 days. The liver, gastrocnemius muscle, brain, and epididymal white adipose tissue (WAT) were collected for analysis of gene expressions. FR attenuated inflammation in the liver, brain, and gastrocnemius muscle but did not markedly change inflammatory gene expression in epididymal WAT. We concluded that adipose tissue was less responsive to FR in terms of gene expression of pro-inflammatory and anti-inflammatory genes.

Caloric restriction rescues yeast cells from alpha-synuclein toxicity through autophagic control of proteostasis.
Sampaio-Marques B, Pereira H, Santos AR, Teixeira A, Ludovico P.
Aging (Albany NY). 2018 Dec 7. doi: 10.18632/aging.101675. [Epub ahead of print]
PMID: 30530923
Abstract
α-Synuclein (SNCA) is a presynaptic protein that is associated with the pathophysiology of synucleinopathies, including Parkinson's disease. SNCA is a naturally aggregation-prone protein, which may be degraded by the ubiquitin-proteasome system (UPS) and by lysosomal degradation pathways. Besides being a target of the proteolytic systems, SNCA can also alter the function of these pathways further, contributing to the progression of neurodegeneration. Deterioration of UPS and autophagy activities with aging further aggravates this toxic cycle. Caloric restriction (CR) is still the most effective non-genetic intervention promoting lifespan extension. It is known that CR-mediated lifespan extension is linked to the regulation of proteolytic systems, but the mechanisms underlying CR rescue of SNCA toxicity remain poorly understood. This study shows that CR balances UPS and autophagy activities during aging. CR enhances UPS activity, reversing the decline of the UPS activity promoted by SNCA, and keeps autophagy at homeostatic levels. Maintenance of autophagy at homeostatic levels appears to be relevant for UPS activity and for the mechanism underlying rescue of cells from SNCA-mediated toxicity by CR.
KEYWORDS:
aging; alpha-synuclein; autophagy; caloric restriction; ubiquitin-proteasome system

Effects of caloric restriction on neuropathic pain, peripheral nerve degeneration and inflammation in normometabolic and autophagy defective prediabetic Ambra1 mice.
Coccurello R, Nazio F, Rossi C, De Angelis F, Vacca V, Giacovazzo G, Procacci P, Magnaghi V, Ciavardelli D, Marinelli S.
PLoS One. 2018 Dec 10;13(12):e0208596. doi: 10.1371/journal.pone.0208596. eCollection 2018.
PMID: 30532260
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208596
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0208596&type=printable
Abstract
There is a growing interest on the role of autophagy in diabetes pathophysiology, where development of neuropathy is one of the most frequent comorbidities. We have previously demonstrated that neuropathic pain after nerve damage is exacerbated in autophagy-defective heterozygous Ambra1 mice. Here, we show the existence of a prediabetic state in Ambra1 mice, characterized by hyperglycemia, intolerance to glucose and insulin resistance. Thus, we further investigate the hypothesis that prediabetes may account for the exacerbation of allodynia and chronic pain and that counteracting the autophagy deficit may relieve the neuropathic condition. We took advantage from caloric restriction (CR) able to exert a double action: a powerful increase of autophagy and a control on the metabolic status. We found that CR ameliorates neuropathy throughout anti-inflammatory and metabolic mechanisms both in Ambra1 and in WT animals subjected to nerve injury. Moreover, we discovered that nerve lesion represents, per se, a metabolic stressor and CR reinstates glucose homeostasis, insulin resistance, incomplete fatty acid oxidation and energy metabolism. As autophagy inducer, CR promotes and anticipates Schwann cell autophagy via AMP-activated protein kinase (AMPK) that facilitates remyelination in peripheral nerve. In summary, we provide new evidence for the role of autophagy in glucose metabolism and identify in energy depletion by dietary restriction a therapeutic approach in the fight against neuropathic pain.

Common polymorphism in the cannabinoid receptor gene type 2 (CB2R) rs3123554 are associated with metabolic changes after two different hypocaloric diets with different dietary fatty profiles.
Aller R, Primo D, Izaola O, de Luis DA.
Clin Nutr. 2018 Nov 30. pii: S0261-5614(18)32546-9. doi: 10.1016/j.clnu.2018.11.013. [Epub ahead of print]
PMID: 30528951
Abstract
BACKGROUND:
The role of CB2R gene variants on weight loss after a dietary intervention has been investigated in few studies.
OBJECTIVE:
We evaluate the effect of this genetic variant (rs3123554) of CB2R gene on cardiovascular risk factors and weight loss secondary to high monounsaturated fat vs a high polyunsaturated fat hypocaloric diets.
DESIGN:
A Caucasian population of 362 obese patients was enrolled. Patients were randomly allocated during 3 months to one of two diets (Diet P high polyunsaturated (PUFAs) fat hypocaloric diet vs, Diet M high monounsaturated (MUFAs) fat hypocaloric diet).
RESULTS:
In both genotype groups (GG vs GA+AA), body weight, body mass index (BMI), fat mass, waist circumference and systolic blood pressure decreased after diet P and M. Body weight, BMI, fat mass and waist circumference were higher in A allele carriers than non A allele carriers. The improvement of these parameters was higher in non A allele carriers than A allele carriers. In non A allele carriers with both diets, the decrease of total cholesterol, LDL-cholesterol, insulin and HOMA-IR was higher than A allele carriers after both diets. After diet P, triglyceride levels decrease in non A allele carriers.
CONCLUSION:
Our data suggest that carriers of the minor allele of rs3123554 variant of CB2R gene lose less body weight during to different hypocaloric diets with different fatty acid. Moreover, non A-allele carriers showed a better response of LDL-cholesterol, HOMA-IR and insulin levels than A-carriers with both hypocaloric diets.
KEYWORDS:
Cannabinoid receptor gene type 2; Hypocaloric diet; Lipid profile; Obesity; rs3123554

DECEMBER 10, 2018 BY PORTSMOUTH DAILY TIMES
High carb diet makes mice live longer
https://www.portsmouth-dailytimes.com/opinion/33551/high-carb-diet-makes-mice-live-longer
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Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice.
Wahl D, Solon-Biet SM, Wang QP, Wali JA, Pulpitel T, Clark X, Raubenheimer D, Senior AM, Sinclair DA, Cooney GJ, de Cabo R, Cogger VC, Simpson SJ, Le Couteur DG.
Cell Rep. 2018 Nov 20;25(8):2234-2243.e6. doi: 10.1016/j.celrep.2018.10.070.
PMID: 30463018 Free Article
https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31674-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124718316747%3Fshowall%3Dtrue
Abstract
Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.
KEYWORDS:
brain aging; calorie restriction; cardiometabolic health; cognitive function; hippocampus; protein restriction

[AlPater]

Modulation of senoinflammation by calorie restriction based on biochemical and Omics big data analysis.
Bang E, Lee B, Noh SG, Kim DH, Jung HJ, Ha S, Yu BP, Chung HY.
BMB Rep. 2018 Dec 14. pii: 4456. [Epub ahead of print]
PMID: 30545444
Abstract
Aging is a complex and progressive process characterized by physiological and functional decline with time that increases susceptibility to diseases. Aged-related functional change is accompanied by a low-grade, unresolved chronic inflammation as a major underlying mechanism. In order to explain aging in the context of chronic inflammation, a new integrative concept on age-related chronic inflammation is necessary that encompasses much broader and wider characteristics of cells, tissues, organs, systems, and interactions between immune and non-immune cells, metabolic and non-metabolic organs. We have previously proposed a novel concept of senescent (seno)-inflammation and provided its frameworks. This review summarizes senoinflammation concept and additionally elaborates modulation of senoinflammation by calorie restriction (CR). Based on aging and CR studies and systems-biological analysis of Omics big data, we observed that senescence associated secretory phenotype (SASP) primarily composed of cytokines and chemokines was notably upregulated during aging whereas CR suppressed them. This result further strengthens the novel concept of senoinflammation in aging process. Collectively, such evidence of senoinflammation and modulatory role of CR provide insights into aging mechanism and potential interventions, thereby promoting healthy longevity.

[AlPater]

Nutritional strategies for psoriasis: current scientific evidence in clinical trials.
Zuccotti E, Oliveri M, Girometta C, Ratto D, Di Iorio C, Occhinegro A, Rossi P.
Eur Rev Med Pharmacol Sci. 2018 Dec;22(23):8537-8551. doi: 10.26355/eurrev_201812_16554.
PMID: 30556896
Abstract
OBJECTIVE:
Several nutritional strategies for the management of psoriasis are promising. Even if recent data support that nutrition may play a pivotal role in prevention and co-treatment and despite patient's concerns regarding the best nutritional habits, the consensus regarding the nutritional strategies to be adopted lacks in clinical settings. In this manuscript, the effects of several nutritional strategies for psoriasis patients such as hypocaloric diet, vitamin D, fish oil, selenium, and zinc supplementation were systematically reviewed. Randomized controlled trials (RCTs) on beneficial botanical oral supplements were also included in the analysis.
MATERIALS AND METHODS:
For each topic, a search was conducted in MEDLINE electronic databases for articles published in English between January 1, 1990 and September 2018. Two independent reviewers assessed and extracted the data. Only controlled clinical trials were selected.
RESULTS:
The evidence regarding the current nutritional strategies for psoriasis patients were summarized and translated into a global, comprehensible recommendation.
CONCLUSIONS:
Weight loss combined with a healthy lifestyle was shown to be very beneficial for patients with moderate to severe disease with a significant reduction of the Psoriasis Area and Severity Index (PASI) score. Currently, oral vitamin D supplementation for prevention or treatment of psoriasis in adults with normal vitamin D levels is not recommended; however, psoriasis patients with a deficit in plasma vitamin D levels are advised to complement with oral supplements to prevent psoriasis-related comorbidities. Instead of zinc, selenium, and omega 3 supplements have been proven beneficial for psoriasis patients. Among botanical species, Dunaliella bardawil (D. bardawil), Tripterygium wilfordii (T. wilfordii), Azadirachta indica (A. indica), Curcuma longa (C. longa), and HESA-A are the most beneficial. In conclusion, a close cooperation between nutritionists and dermatologists may be useful for the management of psoriasis.
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Long-term effects of weight reduction on the severity of psoriasis in a cohort derived from a randomized trial: a prospective observational follow-up study.
Jensen P, Christensen R, Zachariae C, Geiker NR, Schaadt BK, Stender S, Hansen PR, Astrup A, Skov L.
Am J Clin Nutr. 2016 Aug;104(2):259-65. doi: 10.3945/ajcn.115.125849. Epub 2016 Jun 22.
PMID: 27334236
https://watermark.silverchair.com/ajcn125849.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAkkwggJFBgkqhkiG9w0BBwagggI2MIICMgIBADCCAisGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMeCuaTlI7dhyJdj24AgEQgIIB_EzrYkdtGh2OPYRSDqyu04gGHGVKSty29gkAd_ssygO8siK3R9LH9lWDuUgEz481JLo_vbCn0re5G4vcFqZHyh0cLpaYTzc-7TPrLzEA9g_XJhFLM2JhljLuGRxPtaBQ46rG9sQrAT5xOvpxt52jBgb-CiUaW_y-ECQtN0aaHak25Ew6wuTC1aRjlGqZR2eR_DcdncYHsSOhMwXA0jQ10piuUGa9ITH7snWP_0xRdzqdRkM7HYNDNceor6g42Kq7icYl3i8peuWpEMzCCvCCn0MUNRkwEEuuLMy0LSHnA0_6HUUXNoFpdRqhafb-DnJBNmiv6RQZM9rkdXpNxI5uw70CkaWmtQXyl9etGUnIUR9Hto1JGW98AXoH8wxHezHP3x83cRlGvfpOWTPONZAjTqbMp9eCGgqMQ2ufRffDFi7Lc94bu1hNQf-GAN9sOUa8YQRK-fkeSHwBTWZ8nK-HtWdGv3bUJX-ZbEGBBSq481_GDibZCwA58nT--q8R1wiSMnBVKj6Jf5lnovU75wRq7iCNP9qNQJ4JKbna_ImPMKja_AcNQdEozPvq5EjaAKDfSe8qqUSpqMIrvS2wnxRYfueMIGz0C7RStk9af9a3Ul23NvOl06icKETprjwo9UQP1YkO20woe_dRZhY3mapmTbyy0ZqGk3Gb_6aDeo0
Abstract
BACKGROUND:
Weight reduction may reduce the severity of psoriasis, but little is known about the long-term effects.
OBJECTIVE:
We aimed to investigate long-term effects of weight reduction in psoriasis.
DESIGN:
We previously conducted a randomized trial (n = 60) involving patients with psoriasis who were allocated to a control group or a low-energy diet (LED) group. Here we followed the participants for an additional 48-wk period. In total, 56 patients with psoriasis [mean ± SD body mass index (in kg/m(2)): 34.4 ± 5.3] underwent a 64-wk weight-loss program consisting of an initial 16-wk randomized phase with an LED for 8 wk and 8 wk of normal food intake combined with 2 LED products/d, followed by a 48-wk period of weight maintenance with the latter diet. After the randomization phase, the control group received the same 8 + 8-wk LED intervention, and all patients were then followed for 48 wk while on the weight-loss maintenance diet. The main outcome was the Psoriasis Area and Severity Index (PASI), and secondary outcome was the Dermatology Life Quality Index (DLQI).
RESULTS:
For the present study, 56 patients were eligible, 38 agreed to participate, and 32 completed. After the 16-wk LED-only period, the mean weight loss was -15.0 kg (95% CI: -16.6, -13.4 kg), and PASI and DLQI were reduced by -2.3 (95% CI: -3.1, -1.5) and -2.3 (95% CI: -3.2, -1.4), respectively. At week 64, the mean weight loss compared with baseline was -10.1 kg (95% CI: -12.0, -8.1 kg), and PASI and DLQI were maintained at -2.9 (95% CI: -3.9, -1.9) and -1.9 (95% CI: -3.0, -0.9), respectively.
CONCLUSION:
Long-term weight loss in patients with psoriasis has long-lasting positive effects on the severity of psoriasis. This trial was registered at clinicaltrials.gov as NCT01137188.
KEYWORDS:
inflammation; long-term weight maintenance; obesity; psoriasis; weight reduction
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Am J Clin Nutr. 2016 Aug;104(2):241-2. doi: 10.3945/ajcn.116.139444. Epub 2016 Jul 13.
Lifestyle intervention in psoriasis: a new avenue for treatment?
Fleming P
PMID: 27413133 DOI: 10.3945/ajcn.116.139444
https://watermark.silverchair.com/ajcn139444.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAkkwggJFBgkqhkiG9w0BBwagggI2MIICMgIBADCCAisGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMU6gErCj1_-qEBJy0AgEQgIIB_MEkNNXtT0mLnAbqkUUBuSWYXQM0kejY36r7HXKp5S8IFLqRcUnXyH_31Kh0OR4TGdLX2HSTHCze9EmlHL16sap3pgckllc42Oz8b1SYWYMPoR2p4wAx5m0xFHOFYIX4n8gE3viwMIB0hqMxfE1oDbNZtXZdcJ0OdrNz7jxNtxpIG8r3QhNSc_eypdJ5S15BZfBRSu7OgeMIQBRDOOPkAEXruxhZDSYrVBTb-4oGGqfEICpPOXgEWbMv3Llf7ZKmCyaZKbFx_GjPr4Yr6GQv7omZEmOs6XRBjx5G4gqO_GQSa5R0wt2cfhDdyr3ltWSKjE7-g_z379ggemNgtEqDNzuSQbBTgErfE18Ja82b-8rSRfha1hiOe_noAMo-5Kt7mZbsBbXqT6_xuzAGOGQzrv8o9A3qdWBD24sUM9oJCnNQBf3UJ0-5FZ71MKhI215_A2eyphhxqKcVFO1iINvrOQTIK8liSQjtDKQj9B_OyBCHDxzhLXNZBwc1rxylWaJS6KOw7SqVKffjc6DuFJXhyKLw0O_Boic8P5eWEZp-T0hHla1tHWKf2lbpfEA7vlbvXYkJf_2f1cMtXOJN7naFCg3N3aMMvrjicNecXgJcUee0m6TLuqIMse5qdm0VkG1_L-_WcS3dQCXausNe3mmCEZi8q5roEKFHVPtaJTo

[AlPater]

NMJ maintenance and repair in aging.
Taetzsch T, Valdez G.
Curr Opin Physiol. 2018 Aug;4:57-64. doi: 10.1016/j.cophys.2018.05.007. Epub 2018 Jun 11.
PMID: 30560223
Abstract
As the final output of the somatic nervous system, the neuromuscular junction (NMJ) is essential for all voluntary movements. The NMJ is also necessary for connected cells to function and survive. Because of this central role, much effort has been devoted to understanding the effects of aging, diseases, and injuries on the NMJ. These efforts have revealed a close relationship between aberrant changes at NMJs and its three cellular components - the presynaptic site on motor axons, the postsynaptic region on muscle fibers and perisynaptic Schwann cells. Here, we review the morphological and molecular changes associated with aging NMJs in rodents and humans. We also provide an overview of factors with potential roles in maintaining and repairing adult and aged NMJs.
KEYWORDS:
FGFBP1; LRP4; NMJ; aging; caloric restriction; cholinergic transmission; exercise; injury; regeneration; sarcopenia; synaptic cleft; z-agrin
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Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.
Valdez G, Tapia JC, Kang H, Clemenson GD Jr, Gage FH, Lichtman JW, Sanes JR.
Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14863-8. doi: 10.1073/pnas.1002220107. Epub 2010 Aug 2.
PMID: 20679195 Free PMC Article
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930485/pdf/pnas.201002220.pdf
Abstract
The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes.

Calorie restriction enhances adult mouse lung stem cells function and reverses several aging-induced changes.
Hegab AE, Ozaki M, Meligy FY, Nishino M, Kagawa S, Ishii M, Betsuyaku T.
J Tissue Eng Regen Med. 2018 Dec 18. doi: 10.1002/term.2792. [Epub ahead of print]
PMID: 30562419
http://sci-hub.tw/https://onlinelibrary.wiley.com/doi/abs/10.1002/term.2792
Abstract
Aging is associated with decreased lung function and an increased incidence of lung infections. Several studies have suggested that long-term calorie restriction (CR) promotes health and longevity and results in the reduced risk of several diseases. The effect of CR is thought to be through improving the function of tissue stem cells. Stem cell function is known to decline with aging. In this study, we examined the effects of aging on lung epithelial and stem cells, and the effect of CR on young and old lungs. We found that aging results in a decrease in tracheal basal stem cells. CR induced an increase in basal stem cells in both young and old mice. In addition, aging induced lung inflammation, and CR tended to reduce baseline lung inflammatory cell infiltration in young mice, and significantly reduced aging-induced lung inflammation. Furthermore, aging reduced the number and function of mitochondria in lung and increased level of mitochondrial ROS. CR increased the number and function of mitochondria both in young and old mice. Moreover, aging reduced lung stem cell colony forming efficiency (CFE), and CR increased the CFE in both young and old mice. Finally, CR improved epithelial cell survival in injured lungs of young mice. In conclusion, aging causes several structural and functional changes/impairments in lung epithelial cells. CR induces several potentially beneficial changes in lung epithelial cells, even when it is initiated at an older age, including reversal of some aging-induced changes.
KEYWORDS:
Aging; calorie restriction; colony formation assay; lung injury; lung stem cells; mitochondria

[AlPater]

Calorie restriction reprograms diurnal rhythms in protein translation to regulate metabolism.
Makwana K, Gosai N, Poe A, Kondratov RV.
FASEB J. 2018 Dec 19:fj201802167R. doi: 10.1096/fj.201802167R. [Epub ahead of print]
PMID: 30566374
https://sci-hub.tw/10.1096/fj.201802167R
Abstract
Calorie restriction (CR) delays aging and affects the circadian clocks by reprogramming circadian rhythms in gene expression. To expand on the circadian mechanisms in CR, we assayed rhythms in the protein translation by analyzing polysome-associated mRNAs in the liver of mice fed ad libitum (AL) and CR diets. Global comparison of the diets revealed that <1% of transcripts were differentially abundant in the polysomes. In contrast, the large differential, up to 10%, was detected when CR and AL diets were compared at individual times throughout the day. Most transcripts that were rhythmic under AL lost their rhythms, and many new transcripts gained rhythms under CR. Only a small fraction of transcripts, including the circadian clock genes, were rhythmic under both diets. Thus, CR strongly reprograms translation. CR affected translation of enzymes regulating long-chain acetyl-coenzyme A (Acyl-CoA) metabolism. The expression of the Acyl-CoA thioesterase (ACOT) family was induced upon CR, leading to the increased transcriptional activity of peroxisome proliferator-activated receptor α, the transcriptional factor regulated by the ACOT products. We propose that the differential translation induced by CR leads to a temporal partition and reprogramming of metabolic processes and provides a link between CR, lipid metabolism, and the circadian clock.
KEYWORDS:
ACOTs; lipid metabolism; mRNA-sequencing

[AlPater]

Effects of Intermittent Versus Continuous Energy Intakes on Insulin Sensitivity and Metabolic Risk in Women with Overweight.
Hutchison AT, Liu B, Wood RE, Vincent AD, Thompson CH, O'Callaghan NJ, Wittert GA, Heilbronn LK.
Obesity (Silver Spring). 2019 Jan;27(1):50-58. doi: 10.1002/oby.22345.
PMID: 30569640
https://sci-hub.tw/10.1002/oby.22345
Abstract
OBJECTIVE:
This study aimed to compare intermittent fasting (IF) versus continuous energy intakes at 100% or 70% of calculated energy requirements on insulin sensitivity, cardiometabolic risk, body weight, and composition.
METHODS:
Women with overweight (n = 88; 50 ± 1 years, BMI 32.3 ± 0.5 kg/m2 ) were randomized to one of four diets (IF70, IF100, dietary restriction [DR70], or control) in a 2:2:2:1 ratio for 8 weeks. IF groups fasted for 24 hours after breakfast on three nonconsecutive days per week. All foods were provided and diets matched for macronutrient composition (35% fat, 15% protein, 50% carbohydrate). Insulin sensitivity by hyperinsulinemic-euglycemic clamp, weight, body composition, and plasma markers were assessed following a "fed" day (12-hour fast) and a 24-hour fast (IF only).
RESULTS:
IF70 displayed greater reductions in weight, fat mass, total- and low-density lipoprotein cholesterol, and nonesterified fatty acids compared with DR70 and IF100 (all P ≤ 0.05). IF100 lost more weight and fat than control. However, fasting insulin was increased. There were no group differences in insulin sensitivity by clamp; however, a 24-hour fast transiently reduced insulin sensitivity.
CONCLUSIONS:
When prescribed at matched energy restriction, IF reduced weight and fat mass and improved total and low-density lipoprotein cholesterol more than DR. IF prescribed in energy balance did not improve health compared with other groups, despite modest weight loss.

[AlPater]

Interplay between Nutrition and Hearing Loss: State of Art.
Puga AM, Pajares MA, Varela-Moreiras G, Partearroyo T.
Nutrients. 2018 Dec 24;11(1). pii: E35. doi: 10.3390/nu11010035. Review.
PMID: 30586880
https://www.mdpi.com/2072-6643/11/1/35/htm
Abstract
Hearing loss has been recently ranked as the fifth leading cause of years lived with disability, ahead of many other chronic diseases such as diabetes, dementia, or chronic obstructive pulmonary disease. Moreover, according to the World Health Organization, moderate-to-profound hearing loss affects about 466 million people worldwide. Its incidence varies in each population segment, affecting approximately 10% of children and increasing to 30% of the population over 65 years. However, hearing loss receives still very limited research funding and public awareness. This sensory impairment is caused by genetic and environmental factors, and among the latter, the nutritional status has acquired relevance due its association to hearing loss detected in recent epidemiological studies. Several experimental models have proved that the onset and progression of hearing loss are closely linked to the availability of nutrients and their metabolism. Here, we have reviewed studies focused on nutrient effects on auditory function. These studies support the potential of nutritional therapy for the protection against hearing loss progression, which is especially relevant to the aging process and related quality of life.
KEYWORDS:
antioxidants; auditory function; caloric restriction; carbohydrates; lipids; minerals; noise induced hearing loss; presbycusis; proteins; vitamins

Infrequent Feeding of Restricted Amounts of Food Induces Stress and Adipose Tissue Inflammation, Contributing to Impaired Glucose Metabolism.
Lee YS, Lee C, Jun HS.
Int J Med Sci. 2018 Nov 5;15(14):1667-1675. doi: 10.7150/ijms.28503. eCollection 2018.
PMID: 30588190
http://www.medsci.org/v15p1667.pdf
Abstract
Food restriction has been recommended as an effective strategy for body weight loss. However, food restriction can alter biological rhythms and leads to physiological stress. However, relatively little is known about the physiological impact of different methods of food restriction. Therefore, we investigated whether different schedules of restricted food intake induce physiological stress and then contribute to glucose metabolism disorder. C57BL/6 mice were fed a high fat diet (60% fat) for 8 weeks and then randomly divided into three groups: the control group was continuously fed the high fat diet; the two food restriction groups were fed 50% of food consumed by the control mice with one group (FR1) being fed the full amount once a day and the other group (FR2) being fed the same total amount as FR1 twice a day for 3 days. We found increased body weight loss, the serum triglyceride levels, the expression of lipolysis-related genes, and serum corticosterone levels in the FR1 group compared with the FR2 group. The immune cell population infiltrating the adipose tissue and the expression of monocyte chemoattractant protein (MCP-1) and toll-like receptor (TLR-4) mRNA were increased in the FR1 group compared with the control. To determine whether long-term dietary manipulation is associated with metabolic disorders, mice were fed a restricted diet for 3 days alternating with an unrestricted diet for the following 4 days and this was repeated for 8 weeks. The alternating FR1 group showed impaired glucose tolerance compared with the alternating FR2 group. These results indicate that infrequent feeding of restricted amounts of food could induce stress hormones, lipolysis, adipose tissue immune cell infiltration and inflammation, which in turn may promote glucose metabolism disorder.
KEYWORDS:
Food restriction; body weight; glucose metabolism; infrequent feeding; stress

Alteration in gut microbiota caused by time-restricted feeding alleviate hepatic ischaemia reperfusion injury in mice.
Ren J, Hu D, Mao Y, Yang H, Liao W, Xu W, Ge P, Zhang H, Sang X, Lu X, Zhong S.
J Cell Mol Med. 2018 Dec 26. doi: 10.1111/jcmm.14069. [Epub ahead of print]
PMID: 30588757
https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.14069
Abstract
Time-restricted feeding (TRF), that is, no caloric intake for 14-16 hours each day leads to favourable nutritional outcomes. This study is the first to investigate TRF through a surgical perspective verifying its efficacy against liver ischaemia reperfusion (I/R) injury. We randomly assigned 100 10-week-old wild-type male C57BL/6 mice into two feeding regimens: TRF and ad libitum access to food. Main outcomes were evaluated at 6, 12 and 24 hours post-I/R surgery after 12 weeks of intervention. TRF group demonstrated minor liver injury via histological study; lower serum levels of liver enzymes, glucose and lipids; higher concentrations of free fatty acid and β-hydroxybutyrate; decreased oxidative stress and inflammatory biomarkers; as well as less severe cell apoptosis and proliferation. Further exploration indicated better gut microenvironment and intestinal epithelial tight junction function. TRF employed its positive influence on a wide spectrum of biochemical pathways and ultimately revealed protective effect against hepatic I/R injury possibly through adjusting the gut microbiota. The results referred to a strong indication of adopting better feeding pattern for surgical patients.
KEYWORDS:
gut microbiome; hepatic ischaemia reperfusion injury; time-restricted feeding