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Physical Activity Dietary Calorie Restriction And Cancer Energy Balance And Cancer

Series Editor, Nathan A. Berger,

Anne McTiernan, Editor


1 Introduction ............................... 1

Anne McTiernan, Linda Nebeling, and Rachel Ballard-Barbash

2 Epidemiology of Overweight/Obesity and Cancer Risk ....... 5

Andrew G. Renehan

3 Epidemiology of Physical Activity and Cancer Risk . . . . . . . . . 25

Rebecca M. Speck, Kathryn H. Schmitz, I.-Min Lee,

and Anne McTiernan

4 Energetics and Cancer: Exploring a Road Less Traveled . . . . . . 55

Henry J. Thompson, Weiqin Jiang, and Zongjian Zhu

5 Calorie Restriction, Exercise, and Colon Cancer

Prevention: A Mechanistic Perspective . . . . . . . . . . . . . . . . 69

Connie J. Rogers, Lisa H. Colbert, Susan N. Perkins,

and Stephen D. Hursting

6 Mechanisms Linking Obesity to Cancer Risk . . . . . . . . . . . . 99

Ikuyo Imayama, Caitlin Mason, and Catherine Duggan

7 Mechanisms Underlying the Effects of Physical Activity

on Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

Andrew Rundle

8 Physical Activity, Weight Control, and Cancer Prognosis . . . . . . 165

Kathryn H. Schmitz, Melinda L. Irwin, and Rebecca M. Speck

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Octopamine enhances oxidative stress resistance through the fasting-responsive transcription factor DAF-16/FOXO in C. elegans.

Hoshikawa H, Uno M, Honjoh S, Nishida E.

Genes Cells. 2017 Jan 20. doi: 10.1111/gtc.12469. [Epub ahead of print]

PMID: 28105749



Dietary restriction regimens lead to enhanced stress resistance and extended life span in many species through the regulation of fasting and/or diet-responsive mechanisms. The fasting stimulus is perceived by sensory neurons and causes behavioral and metabolic adaptations. Octopamine (OA), one of the Caenorhabditis elegans neurotransmitters, is involved in behavioral adaptations, and its levels are increased under fasting conditions. However, it remains largely unknown how OA contributes to the fasting responses. In this study, we found that OA administration enhanced organismal resistance to oxidative stress. This enhanced resistance was suppressed by a mutation of the OA receptors, SER-3 and SER-6. Moreover, we found that OA administration promoted the nuclear translocation of DAF-16, the key transcription factor in fasting responses, and that the OA-induced enhancement of stress resistance required DAF-16. Altogether, our results suggest that OA signaling, which is triggered by the absence of food, shifts the organismal state to a more protective one to prepare for environmental stresses.


Potential Benefits and Harms of Intermittent Energy Restriction and Intermittent Fasting Amongst Obese, Overweight and Normal Weight Subjects-A Narrative Review of Human and Animal Evidence.

Harvie M, Howell A.

Behav Sci (Basel). 2017 Jan 19;7(1). pii: E4. doi: 10.3390/bs7010004. Review.

PMID: 28106818



Intermittent energy restriction (IER) has become popular as a means of weight control amongst people who are overweight and obese, and is also undertaken by normal weight people hoping spells of marked energy restriction will optimise their health. This review summarises randomised comparisons of intermittent and isoenergetic continuous energy restriction for weight loss to manage overweight and obesity. It also summarises the potential beneficial or adverse effects of IER on body composition, adipose stores and metabolic effects from human studies, including studies amongst normal weight subjects and relevant animal experimentation. Six small short term (<6 month) studies amongst overweight or obese individuals indicate that intermittent energy restriction is equal to continuous restriction for weight loss, with one study reporting greater reductions in body fat, and two studies reporting greater reductions in HOMA insulin resistance in response to IER, with no obvious evidence of harm. Studies amongst normal weight subjects and different animal models highlight the potential beneficial and adverse effects of intermittent compared to continuous energy restriction on ectopic and visceral fat stores, adipocyte size, insulin resistance, and metabolic flexibility. The longer term benefits or harms of IER amongst people who are overweight or obese, and particularly amongst normal weight subjects, is not known and is a priority for further investigation.


fasting; intermittent energy restriction; weight gain; weight loss


Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain.

Morabito MV, Ravussin Y, Mueller BR, Skowronski AA, Watanabe K, Foo KS, Lee SX, Lehmann A, Hjorth S, Zeltser LM, LeDuc CA, Leibel RL.

PLoS One. 2017 Jan 20;12(1):e0168226. doi: 10.1371/journal.pone.0168226.

PMID: 28107353




Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin. HFD attenuated leptin sensing throughout the brain, but weight loss did not restore central leptin signaling to control levels in several brain regions important in energy homeostasis, including the arcuate and dorsomedial hypothalamic nuclei. Effects of diet on leptin signaling varied by brain region, with results dependent on the method of weight loss (restriction of calories of HFD, ad lib intake of standard mouse chow). High fat diet attenuates leptin signaling throughout the brain, but some brain regions maintain their ability to sense leptin. Weight loss restores leptin sensing to some degree in most (but not all) brain regions, while other brain regions display hypersensitivity to leptin following weight loss. Normal leptin sensing was restored in several brain regions, with the pattern of restoration dependent on the method of weight loss.


Age-Dependent Neuroendocrine Signaling from Sensory Neurons Modulates the Effect of Dietary Restriction on Longevity of Caenorhabditis elegans.

Fletcher M, Kim DH.

PLoS Genet. 2017 Jan 20;13(1):e1006544. doi: 10.1371/journal.pgen.1006544. [Epub ahead of print]

PMID: 28107363




Dietary restriction extends lifespan in evolutionarily diverse animals. A role for the sensory nervous system in dietary restriction has been established in Drosophila and Caenorhabditis elegans, but little is known about how neuroendocrine signals influence the effects of dietary restriction on longevity. Here, we show that DAF-7/TGFβ, which is secreted from the C. elegans amphid, promotes lifespan extension in response to dietary restriction in C. elegans. DAF-7 produced by the ASI pair of sensory neurons acts on DAF-1/TGFβ receptors expressed on interneurons to inhibit the co-SMAD DAF-3. We find that increased activity of DAF-3 in the presence of diminished or deleted DAF-7 activity abrogates lifespan extension conferred by dietary restriction. We also observe that DAF-7 expression is dynamic during the lifespan of C. elegans, with a marked decrease in DAF-7 levels as animals age during adulthood. We show that this age-dependent diminished expression contributes to the reduced sensitivity of aging animals to the effects of dietary restriction. DAF-7 signaling is a pivotal regulator of metabolism and food-dependent behavior, and our studies establish a molecular link between the neuroendocrine physiology of C. elegans and the process by which dietary restriction can extend lifespan.


Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation.

Hasenour CM, Ridley DE, James FD, Hughey CC, Donahue EP, Viollet B, Foretz M, Young JD, Wasserman DH.

PLoS One. 2017 Jan 20;12(1):e0170382. doi: 10.1371/journal.pone.0170382.

PMID: 28107516




AMPK is an energy sensor that protects cellular energy state by attenuating anabolic and promoting catabolic processes. AMPK signaling is purported to regulate hepatic gluconeogenesis and substrate oxidation; coordination of these processes is vital during nutrient deprivation or pathogenic during overnutrition. Here we directly test hepatic AMPK function in regulating metabolic fluxes that converge to produce glucose and energy in vivo. Flux analysis was applied in mice with a liver-specific deletion of AMPK (L-KO) or floxed control littermates to assess rates of hepatic glucose producing and citric acid cycle (CAC) fluxes. Fluxes were assessed in short and long term fasted mice; the latter condition is a nutrient stressor that increases liver AMP/ATP. The flux circuit connecting anaplerosis with gluconeogenesis from the CAC was unaffected by hepatic AMPK deletion in short and long term fasting. Nevertheless, depletion of hepatic ATP was exacerbated in L-KO mice, corresponding to a relative elevation in citrate synthase flux and accumulation of branched-chain amino acid-related metabolites. L-KO mice also had a physiological reduction in flux from glycogen to G6P. These results demonstrate AMPK is unnecessary for maintaining gluconeogenic flux from the CAC yet is critical for stabilizing liver energy state during nutrient deprivation.

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Pleiotropic responses to methionine restriction.

Ables G, Johnson J.

Exp Gerontol. 2017 Jan 17. pii: S0531-5565(17)30045-1. doi: 10.1016/j.exger.2017.01.012. [Epub ahead of print]

PMID: 28108330



Methionine restriction (MR) extends lifespan across different species. The main responses of rodent models to MR are well-documented in adipose tissue (AT) and liver, which have reduced mass and improved insulin sensitivity, respectively. Recently, molecular mechanisms that improve healthspan have been identified in both organs during MR. In fat, MR induced a futile lipid cycle concomitant with beige AT accumulation, producing elevated energy expenditure. In liver, MR upregulated fibroblast growth factor 21 and improved glucose metabolism in aged mice and in response to a high-fat diet. Furthermore, MR also reduces mitochondrial oxidative stress in various organs such as liver, heart, kidneys, and brain. Other effects of MR have also been reported in such areas as cardiac function in response to hyperhomocysteinemia (HHcy), identification of molecular mechanisms in bone development, and enhanced epithelial tight junction. In addition, rodent models of cancer responded positively to MR, as has been reported in colon, prostate, and breast cancer studies. The beneficial effects of MR have also been documented in a number of invertebrate model organisms, including yeast, nematodes, and fruit flies. MR not only promotes extended longevity in these organisms, but in the case of yeast has also been shown to improve stress tolerance. In addition, expression analyses of yeast and Drosophila undergoing MR have identified multiple candidate mediators of the beneficial effects of MR in these models. In this review, we emphasize other in vivo effects of MR such as in cardiovascular function, bone development, epithelial tight junction, and cancer. We also discuss the effects of MR in invertebrates.


Methionine restriction; bone; cancer; cardiovascular; invertebrates; lifespan extension; yeast


Melatonin and sirtuins: a 'not-so unexpected' relationship.

Mayo JC, Sainz RM, González Menéndez P, Cepas V, Tan DX, Reiter RJ.

J Pineal Res. 2017 Jan 21. doi: 10.1111/jpi.12391. [Epub ahead of print]

PMID: 28109165



Epigenetic modifications, including methylation or acetylation as well as posttranscriptional modifications are mechanisms used by eukaryotic cells to increase the genome diversity in terms of differential gene expression and protein diversity. Among these modifying enzymes, sirtuins, a class III histone deacetylase (HDAC) enzymes are of particular importance. Sirtuins regulate the cell cycle, DNA repair, cell survival and apoptosis, thus having important roles in normal and cancer cells. Sirtuins can also regulate metabolic pathways by changing preference for glycolysis under aerobic conditions as well as glutaminolysis. These actions make sirtuins a major target in numerous physiological processes as well as in other contexts such as calorie restriction-induced antiaging, cancer or neurodegenerative disease. Interestingly melatonin, a nighttime-produced indole synthesized by pineal gland and many other organs, have important cytoprotective effects in many tissues including aging, neurodegerative diseases, immunomodulation and cancer. The pleiotropic actions of melatonin in different physiological and pathological conditions indicate that may be basic cellular targetd for the indole. Thus, much research has focused attention on the potential mechanisms of the indole in modulating expression and/or activity of sirtuins. Numerous findings report a rise in activity, especially on SIRT1, in a diversity of cells and animal models after melatonin treatment. This contrasts, however, with data reporting an inhibitory effect of melatonin on this sirtuin in some tumor cells. This review tabulates and discusses the recent findings relating melatonin with sirtuins, particularly SIRT1 and mitochondrial SIRT3, showing the apparent dichotomy with the differential actions documented in normal and in cancer cells. This article is protected by copyright.


SIRT1; SIRT3; aging; apoptosis post-translational modification; cancer; deacetylases; mitochondria

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[The below paper is not pdf-availed.]

Food Restriction Induces Synaptic Incorporation of Calcium-Permeable AMPA Receptors in Nucleus Accumbens.

Ouyang J, Carcea I, Schiavo JK, Jones KT, Rabinowitsch A, Kolaric R, de Vaca SC, Froemke RC, Carr KD.

Eur J Neurosci. 2017 Jan 23. doi: 10.1111/ejn.13528. [Epub ahead of print]

PMID: 28112453


Chronic food restriction potentiates behavioral and cellular responses to drugs of abuse and D-1 dopamine receptor agonists administered systemically or locally in the nucleus accumbens (NAc). However, the alterations in NAc synaptic transmission underlying these effects are incompletely understood. AMPA receptor trafficking is a major mechanism for regulating synaptic strength, and previous studies have shown that both sucrose and d-amphetamine rapidly alter the abundance of AMPA receptor subunits in the NAc postsynaptic density (PSD) in a manner that differs between food-restricted and ad libitum fed rats. The present study examined whether food restriction, in the absence of reward stimulus challenge, alters AMPAR subunit abundance in the NAc PSD. Food restriction was found to increase surface expression and, specifically, PSD abundance, of GluA1 but not GluA2, suggesting synaptic incorporation of GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs). Naspm, an antagonist of CP-AMPARs, decreased the amplitude of evoked EPSCs in Nac shell, and blocked the enhanced locomotor response to local microinjection of the D-1 receptor agonist, SKF-82958, in food-restricted, but not ad libitum fed, subjects. Although microinjection of the D-2 receptor agonist, quinpirole, also induced greater locomotor activation in food-restricted than ad libitum fed rats, this effect was not decreased by Naspm. Taken together, the present findings are consistent with synaptic incorporation of CP-AMPARs in D-1 receptor expressing medium spiny neurons in NAc as a mechanistic underpinning of the enhanced responsiveness of food-restricted rats to natural rewards and drugs of abuse. This article is protected by copyright. All rights reserved.


Addiction; Dieting; Neuroplasticity; Reward


Combination of Recreational Soccer and Caloric Restricted Diet Reduces Markers of Protein Catabolism and Cardiovascular Risk in Patients with Type 2 Diabetes.

Vieira de Sousa M, Fukui R, Krustrup P, Dagogo-Jack S, Rossi da Silva ME.

J Nutr Health Aging. 2017;21(2):180-186. doi: 10.1007/s12603-015-0708-4.

PMID: 28112773




Moderate calorie-restricted diets and exercise training prevent loss of lean mass and cardiovascular risk. Because adherence to routine exercise recommendation is generally poor, we utilized recreational soccer training as a novel therapeutic exercise intervention in type 2 diabetes (T2D) patients.


We compared the effects of acute and chronic soccer training plus calorie-restricted diet on protein catabolism and cardiovascular risk markers in T2D.


Fifty-one T2D patients (61.1±6.4 years, 29 females: 22 males) were randomly allocated to the soccer+diet-group (SDG) or to the diet-group (DG). The 40-min soccer sessions were held 3 times per week for 12 weeks.


Nineteen participants attended 100% of scheduled soccer sessions, and none suffered any injuries. The SDG group showed higher levels of growth hormone (GH), free fatty acids and ammonia compared with DG. After 12 weeks, insulin-like growth factor binding protein (IGFPB)-3 and glucose levels were lower in SDG, whereas insulin-like growth factor (IGF)-1/ IGFBP-3 ratio increased in both groups. After the last training session, an increase in IGF-1/IGFBP-3 and attenuation in ammonia levels were suggestive of lower muscle protein catabolism.


Recreational soccer training was popular and safe, and was associated with decreased plasma glucose and IGFBP-3 levels, decreased ammoniagenesis, and increased lipolytic activity and IGF-1/IGFBP-3 ratio, all indicative of attenuated catabolism.

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Effect of dietary macronutrients on aflatoxicosis: A mini review.

Nurul Adilah Z, Mohd Redzwan S.

J Sci Food Agric. 2017 Jan 23. doi: 10.1002/jsfa.8234. [Epub ahead of print] Review.

PMID: 28111762



Aflatoxin is a toxin produced by Aspergillus species of fungi. The main route of aflatoxin exposure is through the diet. Indeed, the long term aflatoxin exposure is linked to the development of hepatocellular carcinoma (HCC). Aflatoxin causes aflatoxicosis, which can be affected by several factors and it is prevalent in many developing Asian and African countries. This mini review discussed the effects of carbohydrates, fat and protein on aflatoxicosis based on findings from animal and human studies. It was found that high carbohydrate intake enhanced aflatoxicosis occurrence, while low ingestion of carbohydrate with caloric restriction slowed the symptoms associated with aflatoxicosis. Additionally, diets with low protein content worsened the symptoms related to HCC due to aflatoxin exposure. Nevertheless, a study reported that high protein diet favored detoxification of aflatoxin in vivo. There were also conflicting results on the influence of dietary fats as high ingestion of fat enhanced aflatoxicosis development as compared to the low fat diet. Moreover, the types of fat also play a significant role that influence aflatoxin toxicity. In regard to food safety, understanding the influence of macronutrients toward the progression of aflatoxicosis can improve the preventive measures to prevent humans and animals exposure to aflatoxin.


Aflatoxicosis; Carbohydrate; Fat; Macronutrients; Protein

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Contrasting effects of 5-HT<sub>3</sub> receptor stimulation of the nucleus accumbens or ventral tegmentum on food intake in the rat.

Pratt WE, Lin P, Pierce-Messick Z, Ilesanmi AO, Clissold KA.

Behav Brain Res. 2017 Jan 20. pii: S0166-4328(17)30122-5. doi: 10.1016/j.bbr.2017.01.031. [Epub ahead of print]

PMID: 28115218




Although serotonin (5-HT) signaling is known to regulate food intake and energy homeostasis, the roles of the 5-HT3 receptor in feeding processes has been elusive. 5-HT3 receptors are found throughout mesolimbic circuitry that promote feeding not only in response to hunger, but also to the palatable and rewarding properties of food. These experiments examined if stimulation or blockade of the 5-HT3 receptor of the nucleus accumbens (NAcc) or ventral tegmentum affected food intake in the rat in response to hunger or the presence of a palatable diet. Rats (N=6-9/group) received bilateral injections of the 5-HT3 agonist m-chlorophenylbiguanide hydrochloride (mCPBG; at 0.0, 10.0, or 20.0μg/0.5μl/side) or the 5-HT3 antagonist ondansetron hydrochloride (at 0.0, 1.0, 2.0, or 5.0μg/0.5μl/side) into either the NAcc or the ventral tegmentum. NAcc 5-HT3 receptor stimulation significantly increased 2-hr food intake in food-deprived animals offered rat chow and in a separate group of unrestricted rats offered a sweetened fat diet. In contrast to the feeding increase seen with NAcc treatments, stimulation of 5-HT3 receptors of the ventral tegmentum significantly reduced food and water intake in food-restricted animals; reductions of intake in non-restricted rats offered the palatable diet did not approach significance. Blockade of the 5-HT3 receptor had no effect on feeding in either brain region. These data support a functional role for serotonergic signaling in the mesolimbic pathway on motivated behavior, and demonstrate that 5-HT3 receptors differentially modulate food consumption in a region-dependent manner.


5-HT(3); Food intake; Motivation; Nucleus accumbens; Serotonin; Ventral tegmental area


Positive effects of intermittent fasting in ischemic stroke.

Fann DY, Ng GY, Poh L, Arumugam TV.

Exp Gerontol. 2017 Jan 20. pii: S0531-5565(16)30428-4. doi: 10.1016/j.exger.2017.01.014. [Epub ahead of print]

PMID: 28115234



Intermittent fasting (IF) is a dietary protocol where energy restriction is induced by alternate periods of ad libitum feeding and fasting. Prophylactic intermittent fasting has been shown to extend lifespan and attenuate the progress and severity of age-related diseases such as cardiovascular (e.g. stroke and myocardial infarction), neurodegenerative (e.g. Alzheimer's disease and Parkinson's disease) and cancerous diseases in animal models. Stroke is the second leading cause of death, and lifestyle risk factors such as obesity and physical inactivity have been associated with elevated risks of stroke in humans. Recent studies have shown that prophylactic IF may mitigate tissue damage and neurological deficit following ischemic stroke by a mechanism(s) involving suppression of excitotoxicity, oxidative stress, inflammation and cell death pathways in animal stroke models. This review summarizes data supporting the potential hormesis mechanisms of prophylactic IF in animal models, and with a focus on findings from animal studies of prophylactic IF in stroke in our laboratory.


Cell death; Dietary restriction; Infarct; Intermittent fasting; Ischemic stroke


Energy Metabolism and Ageing in the Mouse: A Mini-Review.

Azzu V, Valencak TG.

Gerontology. 2017 Jan 25. doi: 10.1159/000454924. [Epub ahead of print]

PMID: 28118636




The mouse has rapidly become the mammalian model organism of choice in ageing research due to its relatively short lifespan, the proximity of its genome and physiology to humans, and most importantly due to its genetic pliability and the availability of mutant strains. Mouse models have provided great insights into the ageing process, which in its broadest sense is the progressive decline of body functions over time. In this mini-review, we briefly cover the historical views on the link between ageing and metabolic rate, highlight genetically modified transgenic mouse models of extended lifespan, discuss endocrine pathways linked to senescence and ageing, and then examine pathways by which caloric restriction is postulated to result in longevity.

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[The below paper is pdf-availed.]

The methylation of nuclear and mitochondrial DNA in ageing phenotypes and longevity.

Bacalini MG, D'Aquila P, Marasco E, Nardini C, Montesanto A, Franceschi C, Passarino G, Garagnani P, Bellizzi D.

Mech Ageing Dev. 2017 Jan 20. pii: S0047-6374(16)30239-1. doi: 10.1016/j.mad.2017.01.006. [Epub ahead of print] Review.

PMID: 28115210


An increasing body of data is progressively indicating that the comprehension of the epigenetic landscape, actively integrated with the genetic elements, is crucial to delineate the molecular basis of the inter-individual complexity of ageing process. Indeed, it has emerged that DNA methylation changes occur during ageing, consisting mainly in a progressive process of genome demethylation, in a hypermethylation of gene-specific CpG dinucleotides, as well as in an inter-individual divergence of the epigenome due to stochastic events and environmental exposures throughout life, namely as epigenetic drift. Additionally, it has also come to light an implication of the mitochondrial genome in the regulation of the intracellular epigenetic landscape, as demonstrated by the being itself object of epigenetic modifications. An overview of DNA methylation changes occurring during ageing process at both nuclear and mitochondrial level will be described in this review, also taking into account the recent and promising data available on the 5-hydroxymethylcytosine.


ageing; ageing phenotypes; centenarians; epigenetic clock; epigenetic drift; longevity; mitochondrial DNA methylation; nuclear DNA methylation


Histone deacetylase 2 in the mouse hippocampus: attenuation of age-related increase by caloric restriction.

Chouliaras L, van den Hove DL, Kenis G, Draanen Mv, Hof PR, van Os J, Steinbusch HW, Schmitz C, Rutten BP.

Curr Alzheimer Res. 2013 Oct;10(8):868-76.

PMID: 24093534 Free PMC Article



Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction.

Chouliaras L, van den Hove DL, Kenis G, Keitel S, Hof PR, van Os J, Steinbusch HW, Schmitz C, Rutten BP.

Curr Alzheimer Res. 2012 Jun;9(5):536-44.

PMID: 22272625 Free PMC Article


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Caloric restriction improves health-related quality of life in healthy normal weight and overweight individuals.

Butsch WS, Stanford F.

Evid Based Med. 2016 Nov 23. pii: ebmed-2016-110526. doi: 10.1136/ebmed-2016-110526. [Epub ahead of print] No abstract available.

PMID: 27881466

Commentary on:

Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults: The CALERIE 2 Randomized Clinical Trial.

Martin CK, Bhapkar M, Pittas AG, Pieper CF, Das SK, Williamson DA, Scott T, Redman LM, Stein R, Gilhooly CH, Stewart T, Robinson L, Roberts SB; Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) Phase 2 Study Group..

JAMA Intern Med. 2016 Jun 1;176(6):743-52. doi: 10.1001/jamainternmed.2016.1189.

PMID: 27136347





Calorie restriction (CR) increases longevity in many species and reduces risk factors for chronic diseases. In humans, CR may improve health span, yet concerns remain about potential negative effects of CR.


To test the effect of CR on mood, quality of life (QOL), sleep, and sexual function in healthy nonobese adults.


A multisite randomized clinical trial (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 [CALERIE 2]) was conducted at 3 academic research institutions. Adult men and women (N = 220) with body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 22.0 to 28.0 were randomized to 2 years of 25% CR or an ad libitum (AL) control group in a 2:1 ratio favoring CR. Data were collected at baseline, 12 months, and 24 months and examined using intent-to-treat analysis. The study was conducted from January 22, 2007, to March 6, 2012. Data analysis was performed from July 18, 2012, to October 27, 2015.


Two years of 25% CR or AL.


Self-report questionnaires were administered to measure mood (Beck Depression Inventory-II [bDI-II], score range 0-63, higher scores indicating worse mood, and Profile of Mood States [POMS], with a total mood disturbance score range of -32 to 200 and higher scores indicating higher levels of the constructs measured), QOL (Rand 36-Item Short Form, score range 0-100, higher scores reflecting better QOL, and Perceived Stress Scale, score range 0-40, higher scores indicating higher levels of stress), sleep (Pittsburgh Sleep Quality Index [PSQI], total score range 0-21, higher scores reflecting worse sleep quality), and sexual function (Derogatis Interview for Sexual Function-Self-report, total score range 24-188, higher scores indicating better sexual functioning).


In all, 218 participants (152 women [69.7%]; mean [sD] age, 37.9 (7.2) years; mean [sD] BMI, 25.1 [1.6]) were included in the analyses. The CR and AL groups lost a mean (SE) of 7.6 (0.3) kg and 0.4 (0.5) kg, respectively, at month 24 (P < .001). Compared with the AL group, the CR group had significantly improved mood (BDI-II: between-group difference [bGD], -0.76; 95% CI, -1.41 to -0.11; effect size [ES], -0.35), reduced tension (POMS: BGD, -0.79; 95% CI, -1.38 to -0.19; ES, -0.39), and improved general health (BGD, 6.45; 95% CI, 3.93 to 8.98; ES, 0.75) and sexual drive and relationship (BGD, 1.06; 95% CI, 0.11 to 2.01; ES, 0.35) at month 24 as well as improved sleep duration at month 12 (BGD, -0.26; 95% CI, -0.49 to -0.02; ES, -0.32) (all P < .05). Greater percent weight loss in the CR group at month 24 was associated with increased vigor (Spearman correlation coefficient, ρ = -0.30) and less mood disturbance (ρ = 0.27) measured with the POMS, improved general health (ρ = -0.27) measured with the SF-36, and better sleep quality per the PSQI total score (ρ = 0.28) (all P < .01).


In nonobese adults, CR had some positive effects and no negative effects on health-related QOL.

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Differential effects of eating and drinking on wellbeing - An ecological ambulatory assessment study.

Strahler J, Nater UM.

Biol Psychol. 2017 Jan 21. pii: S0301-0511(17)30008-X. doi: 10.1016/j.biopsycho.2017.01.008. [Epub ahead of print]

PMID: 28119068





Various behaviors, such as physical activity and sleep, have been shown to have stress-reducing and beneficial effects on wellbeing. In contrast, the rewarding effects of eating and drinking have rarely been investigated, particularly using ecologically valid approaches, and little is known about mediating mechanisms on the biological level.


Seventy-seven healthy young adults completed items on eating and drinking as well as momentary wellbeing (measured by mood, energy, tension, stress and fatigue levels) on an iPod touch 5x/day for 4 consecutive days. With each entry, a saliva sample was collected for the later assessment of cortisol, alpha-amylase and salivary flow rate as markers of neuroendocrine and autonomic activity, respectively.


Hierarchical linear models showed better momentary wellbeing on various scales after the consumption of juice, coffee and alcohol. Having a snack predicted lower fatigue levels. In contrast, consuming high-fat food resulted in impaired wellbeing. With regard to affect-induced eating as well as biomarkers, only a few associations emerged as significant. However, autonomic activity partially mediated the alcohol-stress association.


These findings corroborate previous reports that dietary behaviors could have rewarding effects, but also challenge the assumption of a general mood-enhancing and stress-relieving effect of certain foods. Findings on biomarkers provide first insights into underlying biological mechanisms. Research on further assumed mechanisms (reward-associated brain networks) and moderators (hedonic overeating) is highly warranted. Moreover, implications for addiction research are discussed.


dietary behavior; electronic momentary assessment; emotional eating; hunger; restricted eating; salivary alpha-amylase; salivary cortisol; satiety; wellbeing


Low Cytochrome Oxidase 1 Links Mitochondrial Dysfunction to Atherosclerosis in Mice and Pigs.

Holvoet P, Vanhaverbeke M, Geeraert B, De Keyzer D, Hulsmans M, Janssens S.

PLoS One. 2017 Jan 25;12(1):e0170307. doi: 10.1371/journal.pone.0170307.

PMID: 28122051





Cytochrome oxidase IV complex regulates energy production in mitochondria. Therefore, we determined the relation of COX genes with atherosclerosis in mice and pigs.


First, we compared atherosclerosis in the aortic arch of age-matched (24 weeks) C57BL/6J control (n = 10), LDL-receptor deficient (n = 8), leptin-deficient ob/ob (n = 10), and double knock-out (lacking LDL-receptor and leptin) mice (n = 12). Low aortic mitochondria-encoded cytochrome oxidase 1 in obese diabetic double knock-out mice was associated with a larger plaque area and higher propensity of M1 macrophages and oxidized LDL. Caloric restriction increased mitochondria-encoded cytochrome oxidase 1 and reduced plaque area and oxidized LDL. This was associated with a reduction of titer of anti-oxidized LDL antibodies, a proxy of systemic oxidative stress. Low of mitochondria-encoded cytochrome oxidase 1 was related to low expression of peroxisome proliferative activated receptors α, δ, and γ and of peroxisome proliferative activated receptor, gamma, co-activator 1 alpha reflecting mitochondrial dysfunction. Caloric restriction increased them. To investigate if there was a diabetic/obesity requirement for mitochondria-encoded cytochrome oxidase 1 to be down-regulated, we then studied atherosclerosis in LAD of hypercholesterolemic pigs (n = 37). Pigs at the end of the study were divided in three groups based on increasing LAD plaque complexity according to Stary (Stary I: n = 12; Stary II: n = 13; Stary III: n = 12). Low mitochondria-encoded cytochrome oxidase 1 in isolated plaque macrophages was associated with more complex coronary plaques and oxidized LDL. Nucleus-encoded cytochrome oxidase 4I1 and cytochrome oxidase 10 did not correlate with plaque complexity and oxidative stress. In mice and pigs, MT-COI was inversely related to insulin resistance.


Low MT-COI is related to mitochondrial dysfunction, oxidative stress and atherosclerosis and plaque complexity.


Metformin: a metabolic modulator.

Pietrocola F, Kroemer G.

Oncotarget. 2017 Jan 22. doi: 10.18632/oncotarget.14794. [Epub ahead of print]

PMID: 28122334



Recent findings have shed new light on the mechanisms of action through which biguanides exert their anti-aging and cytostatic effects in Caenorhabditis elegans and human cell lines. The drop in energy charge resulting from the metformin mediated inhibition of mitochondrial activity affects the function of the nuclear pore complex, blocks mTOR signaling and enhances the expression of ACAD10. Whether the inhibition of this pathway is truly responsible for the anti-diabetic and cancer effects of the drug in mammals remains to be established.


AMPK; ATP; aging; autophagy; biguanides; caloric restriction; cancer therapy; mitochondria; rapamycin; type-2 diabetes

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Expression of adenosine 5'-monophosphate-Activated protein kinase (AMPK) in ovine testis (Ovis aries): In vivo regulation by nutritional state.

Taibi N, Dupont J, Bouguermouh Z, Froment P, Ramé C, Anane A, Amirat Z, Khammar F.

Anim Reprod Sci. 2017 Jan 19. pii: S0378-4320(16)30332-3. doi: 10.1016/j.anireprosci.2017.01.003. [Epub ahead of print]

PMID: 28122665



In the present study, we identified AMPK and investigated its potential role in steroidogenesis in vivo in the ovine testis in response to variation in nutritional status (fed control vs. restricted). We performed immunoblotting to show that both active and non-active forms of AMPK exist in ovine testis and liver. In testis, we confirmed these results by immunohistochemistry. We found a correlation between ATP (Adenosine-Triphosphate) levels and the expression of AMPK in liver. Also, low and high caloric diets induce isoform-dependent AMPK expression, with an increase in α2, ß1ß2 and γ1 activity levels. Although the restricted group exhibited an increase in lipid balance, only the triglyceride and HC-VLDL (Cholesterol-Very low density lipoprotein) fractions showed significant differences between groups, suggesting an adaptive mechanism. Moreover, the relatively low rate of non-esterified fatty acid released into the circulation implies re-esterification to compensate for the physiological need. In the fed control group, AMPK activates the production of testosterone in Leydig cells; this is, in turn, associated with an increase in the expression of 3ß-HSD (3 beta hydroxy steroid deshydrogenase), p450scc (Cholesterol side-chain cleavage enzyme) and StAR (Steroidogenic acute regulatory protein) proteins induced by decreased MAPK ERK½ (Extracellular signal-regulated kinase -Mitogen-activated protein kinase) phosphorylation. In contrast, in the restricted group, testosterone secretion was reduced but intracellular cholesterol concentration was not. Furthermore, the combination of high levels of lipoproteins and emergence of the p38 MAP kinase pathway suggest the involvement of pro-inflammatory cytokines, as confirmed by transcriptional repression of the StAR protein. Taken together, these results suggest that AMPK expression is tissue dependent.


AMPK; Diet; Domestic ruminant; Signal transduction; Steroidogenesis



Is Apelin Gene Expression and Concentration Affected by Dietary Intakes? A Systematic Review.

Yuzbashian E, Zarkesh M, Asghari G, Hedayati M, Safarian M, Mirmiran P, Khalaj AR.

Crit Rev Food Sci Nutr. 2017 Jan 26:0. doi: 10.1080/10408398.2016.1262325. [Epub ahead of print]

PMID: 28125271




Overproduction of apelin in obesity could be one of the last protective defenses before type 2 diabetes develops.


To summarize the existing evidence on the association between dietary intake and apelin gene expression and concentration.


We systematically searched MEDLINE, EMBASE, and google scholar and hand-searched bibliographies, including peer-reviewed articles with English abstracts, without restriction in publication date, updated until 21 February 2016 that reported the association between dietary intake and apelin gene expression or concentration.


From a total of 1075 articles, we identified 12 relevant studies. There were 6 clinical trials in human and 6 studies in animals. Overall, two of three studies conducted in humans showed that calorie-restriction diet in obese subjects decreases apelin concentration. Five animal studies reported that higher intake of fatty acids and eicosapentaenoic acid (EPA) increased apelin expression and concentration. Given the paucity of data available, the heterogeneity of study designs used, and exposures tested, no quantitative meta-analysis was justified.


Based on human studies, hypocaloric diet can reduce apelin concentration in obese individuals. In addition, higher intakes of total fatty acids and EPA may increase apelin gene expression and concentration.


Fatty acids; adipose tissue; eicosapentaenoic acid; hypocaloric diet

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Calorie Restriction Attenuates Terminal Differentiation of Immune Cells.

White MJ, Beaver CM, Goodier MR, Bottomley C, Nielsen CM, Wolf AF, Boldrin L, Whitmore C, Morgan J, Pearce DJ, Riley EM.

Front Immunol. 2017 Jan 12;7:667. doi: 10.3389/fimmu.2016.00667.

PMID: 28127296



Immune senescence is a natural consequence of aging and may contribute to frailty and loss of homeostasis in later life. Calorie restriction increases healthy life-span in C57BL/6J (but not DBA/2J) mice, but whether this is related to preservation of immune function, and how it interacts with aging, is unclear. We compared phenotypic and functional characteristics of natural killer (NK) cells and T cells, across the lifespan, of calorie-restricted (CR) and control C57BL/6 and DBA/2 mice. Calorie restriction preserves a naïve T cell phenotype and an immature NK cell phenotype as mice age. The splenic T cell populations of CR mice had higher proportions of CD11a-CD44lo cells, lower expression of TRAIL, KLRG1, and CXCR3, and higher expression of CD127, compared to control mice. Similarly, splenic NK cells from CR mice had higher proportions of less differentiated CD11b-CD27+ cells and correspondingly lower proportions of highly differentiated CD11b+CD27-NK cells. Within each of these subsets, cells from CR mice had higher expression of CD127, CD25, TRAIL, NKG2A/C/E, and CXCR3 and lower expression of KLRG1 and Ly49 receptors compared to controls. The effects of calorie restriction on lymphoid cell populations in lung, liver, and lymph nodes were identical to those seen in the spleen, indicating that this is a system-wide effect. The impact of calorie restriction on NK cell and T cell maturation is much more profound than the effect of aging and, indeed, calorie restriction attenuates these age-associated changes. Importantly, the effects of calorie restriction on lymphocyte maturation were more marked in C57BL/6 than in DBA/2J mice indicating that delayed lymphocyte maturation correlates with extended lifespan. These findings have implications for understanding the interaction between nutritional status, immunity, and healthy lifespan in aging populations.


T cell; aging; calorie restriction; differentiation; maturation; natural killer cell

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The effect of preload/meal energy density on energy intake in a subsequent meal: A systematic review and meta-analysis.

Rouhani MH, Surkan PJ, Azadbakht L.

Eat Behav. 2017 Jan 3;26:6-15. doi: 10.1016/j.eatbeh.2016.12.011. [Epub ahead of print] Review.

PMID: 28131006





To conduct a systematic review and meta-analysis of the effects of preload/meal energy density on energy intake in a subsequent meal(s).


Multiple databases were searched for studies published through December 2016 on the effects of preload/meal energy density on energy intake in a subsequent meal(s). We extracted information on mean energy intake in a subsequent meal(s) and on variables that could contribute to between-subject heterogeneity.


Forty and Thirty nine eligible studies were identified for our systematic review and meta-analysis, respectively. The meta-analysis showed that preload/meal energy density did not affect energy intake in a subsequent meal(s) (95% CI:-21.21, 21.29). As heterogeneity was remarkable among studies, we stratified the studies by intervention type into "meal" or "preload" classifications. In the "preload" subgroup, studies used either fixed energy or fixed weight preloads. The results reveal that in comparison to a high energy-dense (HED) preload, consuming a low energy-dense (LED) preload with same weight resulted in higher energy intake in a subsequent meal (95% CI: 9.72, 56.19). On the other hand, decreased energy intake was observed after consuming an LED preload compared to after consumption of an HED preload with same energy content (95% CI: -138.71, -57.33). In the "meal" subgroup, studies were categorized by different subsequent meal (i.e., "afternoon or evening", "lunch" and "dinner or post-dinner"). Meta-analysis showed that an LED meal resulted in more energy intake only in afternoon or evening meals (95% CI: 14.82, 31.22).


In summary, the current analysis revealed that we can restrict the energy intake by consuming an LED preload. Moreover, consuming an LED preload could favorably affect preload+meal energy intake.


Energy density; Energy intake; Meta-analysis; Obesity; Systematic review

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Glycation inhibitors extend yeast chronological lifespan by reducing advanced glycation end products and by back regulation of proteins involved in mitochondrial respiration.

Kazi RS, Banarjee RM, Deshmukh AB, Patil GV, Jagadeeshaprasad MG, Kulkarni MJ.

J Proteomics. 2017 Jan 26. pii: S1874-3919(17)30028-3. doi: 10.1016/j.jprot.2017.01.015. [Epub ahead of print]

PMID: 28132874



Advanced Glycation End products (AGEs) are implicated in aging process.Thus, reducing AGEs by using glycation inhibitors may help in attenuating the aging process. In this study using Saccharomyces cerevisiae yeast system, we show that Aminoguanidine (AMG), a well-known glycation inhibitor, decreases the AGE modification of proteins in non-calorie restriction (NR) (2% glucose) and extends chronological lifespan (CLS) similar to that of calorie restriction (CR) condition (0.5% glucose).Proteomic analysis revealed that AMG back regulates the expression of differentially expressed proteins especially those involved in mitochondrial respiration in NR condition, suggesting that it switches metabolism from fermentation to respiration, mimicking CR.AMG induced back regulation of differentially expressed proteins could possibly due to its chemical effect or indirectly by glycation inhibition. To delineate this, Metformin (MET), a structural analog of AMG and a mild glycation inhibitor and Hydralazine (HYD), another potent glycation inhibitor but not structural analog of AMG were used. HYD was more effective than MET in mimicking AMG suggesting that glycation inhibition was responsible for restoration of differentially expressed proteins. Thus glycation inhibitors particularly AMG, HYD and MET extend yeast CLS by reducing AGEs, modulating the expression of proteins involved in mitochondrial respiration and possibly by scavenging glucose.


This study reports the role of glycation in aging process. In the non-caloric restriction condition, carbohydrates such as glucose promote protein glycation and reduce CLS. While, the inhibitors of glycation such as AMG, HYD, MET mimic the caloric restriction condition by back regulating deregulated proteins involved in mitochondrial respiration which could facilitate shift of metabolism from fermentation to respiration and extend yeast CLS. These findings suggest that glycation inhibitors can be potential molecules that can be used in management of aging.


Aging; Glucose; Glycation; Mass spectrometry; Proteomics


The Human Longevity Gene Homolog INDY and Interleukin-6 Interact in Hepatic Lipid Metabolism.

von Loeffelholz C, Lieske S, Neuschäfer-Rube F, Willmes DM, Raschzok N, Sauer IM, König J, Fromm M, Horn P, Chatzigeorgiou A, Pathe-Neuschäfer-Rube A, Jordan J, Pfeiffer AF, Mingrone G, Bornstein SR, Stroehle P, Harms C, Wunderlich FT, Helfand SL, Bernier M, de Cabo R, Shulman GI, Chavakis T, Püschel GP, Birkenfeld AL.

Hepatology. 2017 Jan 30. doi: 10.1002/hep.29089. [Epub ahead of print]

PMID: 28133767



Reduced expression of the Indy ('I am Not Dead, Yet') gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane associated citrate transporter expressed highly in the liver, protects mice from high-fat diet and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We aimed to study a possible role of mIndy in human hepatic fat metabolism. In obese, insulin resistant patients with NAFLD, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In non-human primates, a two year high fat, high sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription via the IL-6-receptor (IL-6R) and activation of the transcription factor Stat3 and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-Stat3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and non-human primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 via mINDY. Targeting human mINDY may have therapeutic potential in obese patients with NAFLD.


IL-6; Indy; Insulin Resistance; Liver; NAFLD


Caloric restriction in grouped rats: aggregate influence on behavioural and hormonal data.

Moneo M, Martín Zúñiga J, Morón I.

Lab Anim. 2017 Jan 1:23677216686805. doi: 10.1177/0023677216686805. [Epub ahead of print]

PMID: 28134018




The majority of studies in short- and middle-term caloric restriction (CR) have been primarily focused on physiological parameters, improvements in aging, modulation of oxidative stress, and long-term negative effects on cognitive functions. However, single-housing associated with CR may pose many logistical problems. Thus, it is necessary to study the effects of CR under conditions in which animals are group-housed. The aims of this study were to (i) observe the possible differences in the proportion of the weights and social behaviour under ad libitum and CR (at 70%) conditions; (ii) examine the eventual inequalities in the proportion of the weights and social behaviour (the time spent eating under the feeder as an indicator of dominance and empathy, and the number of 'pushes' as an indicator of aggressiveness) in sibling and non-sibling rats under CR conditions; and (iii) compare the concentrations of corticosterone (stress biomarker) in serum under ad libitum and CR conditions. The results indicated the effectiveness of CR in different groups independent of the relationship between the rats. No extreme changes in weight were observed in the CR rats. Behavioural observations also indicated the differences in the total time spent under the feeder and in the number of pushes (higher in both cases for the sibling rats). However, no significant differences in corticosterone levels were observed. Our results suggest the viability of group-housing rats during long periods of CR maintenance.


advanced social behaviour; aggregate rats; caloric restriction; corticosterone; eating behaviour; grouped rats; relationship behaviour

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Functional evidence that the nucleus of the hippocampal commissure shows an earlier activation from a stressor than the paraventricular nucleus: Implication of an additional structural component of the avian hypothalamo-pituitary-adrenal axis.

Nagarajan G, Kang SW, Kuenzel WJ.

Neurosci Lett. 2017 Jan 27. pii: S0304-3940(17)30092-7. doi: 10.1016/j.neulet.2017.01.064. [Epub ahead of print]

PMID: 28137650



Despite extensive data addressing the regulation of the hypothalamo-pituitary-adrenal (HPA) axis in vertebrates, the neuroendocrine regulation of stress in birds remains incomplete. The paraventricular nucleus (PVN) contains the key neuropeptides, corticotropin releasing hormone (CRH) and arginine vasotocin (AVT), containing neurons. However, another population of CRH neurons was recently identified in a septal nucleus called the nucleus of the hippocampal commissure (NHpC). Therefore, the current study investigated changes in gene expression of CRH and/or AVT in the PVN and NHpC, as well as changes in plasma corticosterone concentrations following a stressor, food deprivation. In the NHpC, a rapid increase in CRH mRNA levels was observed as early as 2hr, while relative CRH mRNA expression in the PVN increased thereafter from 4 to 12hr of food deprivation. On the other hand, relative mRNA levels of AVT in the PVN were not observed until 8hr and significantly increased at 12 and 24hr following food deprivation. Furthermore, at the level of the anterior pituitary, relative expression of proopiomelanocortin transcripts followed gene expression patterns of CRH and AVT in the brain. In the absence of food, the pattern of plasma CORT showed an initial rise at 2hr and a fourfold increase was measured at 4hr that was sustained through 24hr. Taken together, results from this study suggest that (1) CRH neurons in the NHpC appear to be the first responsive neurons to stress stimuli compared to those in the PVN, (2) CRH is predominant functional in the early phase of stress while AVT is involved in the later phase of the stress period and (3) in birds, CRH neurons in the NHpC appears to be part of the classical HPA axis.


corticosterone; corticotropin releasing hormone; food deprivation; hypothalamus; septum; vasotocin


The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice.

Green CL, Mitchell SE, Derous D, Wang Y, Chen L, Han JJ, Promislow DE, Lusseau D, Douglas A, Speakman JR.

Aging Cell. 2017 Jan 31. doi: 10.1111/acel.12570. [Epub ahead of print]

PMID: 28139067




Calorie restriction (CR) remains the most robust intervention to extend lifespan and improve health span. Using a global mass spectrometry-based metabolomic approach, we identified 193 metabolites that were significantly differentially expressed (SDE) in the livers of C57BL/6 mice, fed graded levels of CR (10, 20, 30 and 40% CR) compared to mice fed ad libitum for 12 h a day. The differential expression of metabolites also varied with the different feeding groups. Pathway analysis revealed that graded CR had an impact on carnitine synthesis and the carnitine shuttle pathway, sphingosine-1-phosphate (S1P) signalling and methionine metabolism. S1P, sphingomyelin and L-carnitine were negatively correlated with body mass, leptin, insulin-like growth factor- 1 (IGF-1) and major urinary proteins (MUPs). In addition, metabolites which showed a graded effect, such as ceramide, S1P, taurocholic acid and L-carnitine, responded in the opposite direction to previously observed age-related changes. We suggest that the modulation of this set of metabolites may improve liver processes involved in energy release from fatty acids. S1P also negatively correlated with catalase activity and body temperature, and positively correlated with food anticipatory activity. Injecting mice with S1P or an S1P receptor 1 agonist did not precipitate changes in body temperature, physical activity or food intake suggesting that these correlations were not causal relationships.


Metabolomics; aging; bile acid; calorie restriction; carnitine; sphingolipid


[The below paper is pdf-availed.]

New insights into the mechanisms of the ketogenic diet.

Boison D.

Curr Opin Neurol. 2017 Jan 30. doi: 10.1097/WCO.0000000000000432. [Epub ahead of print]

PMID: 28141738



High-fat, low-carbohydrate ketogenic diets have been used for almost a century for the treatment of epilepsy. Used traditionally for the treatment of refractory pediatric epilepsies, in recent years the use of ketogenic diets has experienced a revival to include the treatment of adulthood epilepsies as well as conditions ranging from autism to chronic pain and cancer. Despite the ability of ketogenic diet therapy to suppress seizures refractory to antiepileptic drugs and reports of lasting seizure freedom, the underlying mechanisms are poorly understood. This review explores new insights into mechanisms mobilized by ketogenic diet therapies.


Ketogenic diets act through a combination of mechanisms, which are linked to the effects of ketones and glucose restriction, and to interactions with receptors, channels, and metabolic enzymes. Decanoic acid, a component of medium-chain triclycerides, contributes to seizure control through direct α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition, whereas drugs targeting lactate dehydrogenase reduce seizures through inhibition of a metabolic pathway. Ketogenic diet therapy also affects DNA methylation, a novel epigenetic mechanism of the diet.


Ketogenic diet therapy combines several beneficial mechanisms that provide broad benefits for the treatment of epilepsy with the potential to not only suppress seizures but also to modify the course of the epilepsy.


Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence.

Choi IY, Lee C, Longo VD.

Mol Cell Endocrinol. 2017 Jan 27. pii: S0303-7207(17)30055-2. doi: 10.1016/j.mce.2017.01.042. [Epub ahead of print]

PMID: 28137612



Complex and coordinated signals are necessary to initiate and sustain the activation, proliferation, and differentiation of lymphocytes. These signals, which are known to determine T-cell fate and function, also depend on the metabolic state of the organism. Recent studies indicate that both the type and levels of nutrients can influence the generation, survival and function of lymphocytes and therefore can affect several autoimmune diseases. Here, we review the dysregulation of lymphocytes during autoimmunity and aging, the mechanisms associated with loss of immune function, and how fasting mimicking diets and other dietary interventions affect autoimmunity and immunosenescence.


Aging; Autoimmune diseases; Fasting; Fasting mimicking diet; Immunology; Metabolism

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Alleviation of senescence and epithelial-mesenchymal transition in aging kidney by short-term caloric restriction and caloric restriction mimetics via modulation of AMPK/mTOR signaling.

Dong D, Cai GY, Ning YC, Wang JC, Lv Y, Hong Q, Cui SY, Fu B, Guo YN, Chen XM.

Oncotarget. 2016 Jan 28. doi: 10.18632/oncotarget.14884. [Epub ahead of print]

PMID: 28147330



Renal fibrosis contributes to declining renal function in the elderly. What is unclear however, is whether epithelial-mesenchymal transition (EMT) contributes to this age-related renal fibrosis. Here, we analyzed indicators of EMT during kidney aging and investigated the protective effects and mechanisms of short-term regimens of caloric restriction (CR) or caloric restriction mimetics (CRMs), including resveratrol and metformin. High glucose was used to induce premature senescence and EMT in human primary proximal tubular cells (PTCs) in vitro. To test the role of AMPK-mTOR signaling, siRNA was used to deplete AMPK. Cellular senescence and AMPK-mTOR signaling markers associated with EMT were detected. CR or CRMs treatment alleviated age-related EMT in aging kidneys, which was accompanied by activation of AMPK-mTOR signaling. High glucose induced premature senescence and EMT in PTCs in vitro, which was accompanied by down-regulation of AMPK/mTOR signaling. CRMs alleviated high glucose-induced senescence and EMT via stimulation of AMPK/mTOR signaling. Activation of AMPK/mTOR signaling protected PTCs from high glucose-induced EMT and cellular senescence. Short-term regimens of CR and CRMs alleviated age-related EMT via AMPK-mTOR signaling, suggesting a potential approach to reducing renal fibrosis during aging.


AMPK/mTOR signaling; Gerotarget; caloric restriction mimetics; epithelial-mesenchymal transition; senescence; short-term caloric restriction

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Exploring the power of yeast to model aging and age-related neurodegenerative disorders.

Oliveira AV, Vilaça R, Santos CN, Costa V, Menezes R.

Biogerontology. 2016 Nov 1. [Epub ahead of print] Review.

PMID: 27804052



Aging is a multifactorial process determined by molecular, cellular and systemic factors and it is well established that advancing age is a leading risk factor for several neurodegenerative diseases. In fact, the close association of aging and neurodegenerative disorders has placed aging as the greatest social and economic challenge of the 21st century, and age-related diseases have also become a key priority for countries worldwide. The growing need to better understand both aging and neurodegenerative processes has led to the development of simple eukaryotic models amenable for mechanistic studies. Saccharomyces cerevisiae has proven to be an unprecedented experimental model to study the fundamental aspects of aging and to decipher the intricacies of neurodegenerative disorders greatly because the molecular mechanisms underlying these processes are evolutionarily conserved from yeast to human. Moreover, yeast offers several methodological advantages allowing a rapid and relatively easy way of establishing gene-protein-function associations. Here we review different aging theories, common cellular pathways driving aging and neurodegenerative diseases and discuss the major contributions of yeast to the state-of-art knowledge in both research fields.


Aging; Alzheimer’s disease; Calorie restriction; Neurodegenerative diseases; Parkinson’s disease; Yeast models

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PPAR mRNA Levels Are Modified by Dietary n-3 Fatty Acid Restriction and Energy Restriction in the Brain and Liver of Growing Rats.

Picklo MJ Sr, Johnson L, Idso J.

J Nutr. 2016 Dec 7. pii: jn237107. [Epub ahead of print]

PMID: 27927977




Without dietary sources of n-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs), α-linolenic acid (ALA; 18:3n-3) is the precursor for docosahexaenoic acid (DHA; 22:6n-3). It is not known how energy restriction (ER) affects ALA conversion to DHA.


We tested the hypothesis that ER reduces n-3 LCPUFA concentrations in tissues of growing rats fed diets replete with and deficient in ALA.


Male Sprague-Dawley rats (23 d old) were provided AIN93G diets (4 wk) made with soybean oil (SO; ALA sufficient) or corn oil (CO; ALA deficient) providing 16% of energy as fat. For each dietary oil, ER rats were individually pair-fed 75% of another rat's ad libitum (AL) intake. Fatty acid (FA) concentrations in brain regions, liver, and plasma were analyzed. Expression of peroxisome proliferator-activated receptors (PPARs), uncoupling proteins (UCPs), and mitochondrial DNA was analyzed in the brain and liver.


AL rats consuming CO had a 65% lower concentration of n-3 docosapentaenoic acid (22:5n-3) and a 10% lower DHA concentration in the cerebral cortex and cerebellum than did the SO-AL group. ER did not alter cerebral n-3 LCPUFA status. Liver n-3 LCPUFA concentrations were reduced in rats fed CO compared with SO. ER reduced hepatic linoleic acid (18:2n-6), ALA, and arachidonic acid (20:4n-6) regardless of oil. ER and n-3 FA deficiency had independent effects on the mRNA levels of Pparα, Pparβ/δ, and Pparγ in the liver, cerebral cortex, and cerebellum. ER reduced Ucp3 mRNA by nearly 50% in the cerebral cortex, cerebellum, and liver, and Ucp5 mRNA was 30% lower in the cerebellum of rats receiving the CO diet.


Small perturbations in PUFA concentration and ER modify the mRNA levels of Ppar and Ucp in the juvenile rat brain. More research is needed to identify the long-term physiologic and behavioral impacts of ER and PUFA restriction in the juvenile brain.


PPAR; brain; energy restriction; uncoupling proteins; α-linolenic acid

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miRNAs in human subcutaneous adipose tissue: Effects of weight loss induced by hypocaloric diet and exercise.

Kristensen MM, Davidsen PK, Vigelsø A, Hansen CN, Jensen LJ, Jessen N, Bruun JM, Dela F, Helge JW.

Obesity (Silver Spring). 2017 Feb 3. doi: 10.1002/oby.21765. [Epub ahead of print]

PMID: 28158925




Obesity is central in the development of insulin resistance. However, the underlying mechanisms still need elucidation. Dysregulated microRNAs (miRNAs; post-transcriptional regulators) in adipose tissue may present an important link.


The miRNA expression in subcutaneous adipose tissue from 19 individuals with severe obesity (10 women and 9 men) before and after a 15-week weight loss intervention was studied using genome-wide microarray analysis. The microarray results were validated with RT-qPCR, and pathway enrichment analysis of in silico predicted targets was performed to elucidate the biological consequences of the miRNA dysregulation. Lastly, the messenger RNA (mRNA) and/or protein expression of multiple predicted targets as well as several proteins involved in lipolysis were investigated.


The intervention led to upregulation of miR-29a-3p and miR-29a-5p and downregulation of miR-20b-5p. The mRNA and protein expression of predicted targets was not significantly affected by the intervention. However, negative correlations between miR-20b-5p and the protein levels of its predicted target, acyl-CoA synthetase long-chain family member 1, were observed. Several other miRNA-target relationships correlated negatively, indicating possible miRNA regulation, including miR-29a-3p and lipoprotein lipase mRNA levels. Proteins involved in lipolysis were not affected by the intervention.


Weight loss influenced several miRNAs, some of which were negatively correlated with predicted targets. These dysregulated miRNAs may affect adipocytokine signaling and forkhead box protein O signaling.


Aging and caloric restriction impact adipose tissue, adiponectin, and circulating lipids.

Miller KN, Burhans MS, Clark JP, Howell PR, Polewski MA, DeMuth TM, Eliceiri KW, Lindstrom MJ, Ntambi JM, Anderson RM.

Aging Cell. 2017 Feb 3. doi: 10.1111/acel.12575. [Epub ahead of print]

PMID: 28156058




Adipose tissue expansion has been associated with system-wide metabolic dysfunction and increased vulnerability to diabetes, cancer, and cardiovascular disease. A reduction in adiposity is a hallmark of caloric restriction (CR), an intervention that extends longevity and delays the onset of these same age-related conditions. Despite these parallels, the role of adipose tissue in coordinating the metabolism of aging is poorly defined. Here, we show that adipose tissue metabolism and secretory profiles change with age and are responsive to CR. We conducted a cross-sectional study of CR in adult, late-middle-aged, and advanced-aged mice. Adiposity and the relationship between adiposity and circulating levels of the adipose-derived peptide hormone adiponectin were age-sensitive. CR impacted adiposity but only levels of the high molecular weight isoform of adiponectin responded to CR. Activators of metabolism including PGC-1a, SIRT1, and NAMPT were differentially expressed with CR in adipose tissues. Although age had a significant impact on NAD metabolism, as detected by biochemical assay and multiphoton imaging, the impact of CR was subtle and related to differences in reliance on oxidative metabolism. The impact of age on circulating lipids was limited to composition of circulating phospholipids. In contrast, the impact of CR was detected in all lipid classes regardless of age, suggesting a profound difference in lipid metabolism. These data demonstrate that aspects of adipose tissue metabolism are life phase specific and that CR is associated with a distinct metabolic state, suggesting that adipose tissue signaling presents a suitable target for interventions to delay aging.


NAD metabolism; adiponectin; adipose tissue; aging; caloric restriction; fatty acids


Effects of calorie restriction on the lifespan and healthspan of POLG mitochondrial mutator mice.

Someya S, Kujoth GC, Kim MJ, Hacker TA, Vermulst M, Weindruch R, Prolla TA.

PLoS One. 2017 Feb 3;12(2):e0171159. doi: 10.1371/journal.pone.0171159.

PMID: 28158260



Mitochondrial DNA (mtDNA) mutations are thought to have a causative role in age-related pathologies. We have shown previously that mitochondrial mutator mice (PolgD257A/D257A), harboring a proofreading-deficient version of the mtDNA polymerase gamma (POLG), accumulate mtDNA mutations in multiple tissues and display several features of accelerated aging. Calorie restriction (CR) is known to delay the onset of age-related diseases and to extend the lifespan of a variety of species, including rodents. In the current study we investigated the effects of CR on the lifespan and healthspan of mitochondrial mutator mice. Long-term CR did not increase the median or maximum lifespan of PolgD257A/D257A mice. Furthermore, CR did not reduce mtDNA deletions in the heart and muscle, accelerated sarcopenia, testicular atrophy, nor improve the alterations in cardiac parameters that are present in aged mitochondrial mutator mice. Therefore, our findings suggest that accumulation of mtDNA mutations may interfere with the beneficial action of CR in aging retardation.

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Effects of very-low-calorie diet on body composition, metabolic state, and genes expression: a randomized double-blind placebo-controlled trial.

Merra G, Gratteri S, De Lorenzo A, Barrucco S, Perrone MA, Avolio E, Bernardini S, Marchetti M, Di Renzo L.

Eur Rev Med Pharmacol Sci. 2017 Jan;21(2):329-345.

PMID: 28165552




Very low-calorie diets (VLCDs, < 800 kcal day-1) and Ketogenic diet (KD) are generally used as part of integrated intervention, medical monitoring and a program of lifestyle modification, to improve a multitude of clinical states. The effect of three different very low calories KD (VLCKD), with (VLCKD1) or without (VLCKD2,3) synthetic amino acid replacement of the 50% protein intake, were analyzed after weight loss.


The clinical study used a cross-over randomized double-blind placebo-controlled trial. Obese subjects, who were eligible for the study, were randomly ® divided into three groups: one intervention group (IG) and two control groups (CG1 and CG2). We comprehensively analyzed body composition, serum metabolites, superoxide dismutase (SOD1), nuclear factor kappa-light-chain-enhancer of activated B cells (NfKB), Chemokine (C-C Motif) Ligand 2 (CCL2) gene expression.


After VLDKDs a significant decreased in BMI was observed. TBF (kg) significantly decrease after VLCKD1 and VLCKD3. After VLCKD2, a reduction of waist circumference (p = 0.02), FM L2-L5 (p < 0.05) was observed. After VLCKD1 reduction of IMAT (p = 0.00), LDL-C (p = 0.00) and HDL-C (p = 0.00) were observed. No significant changes of GH, ESR, and fibrinogen were highlighted. CRP (p = 0.02) reduced significantly after VLCKD3. Significant modulation of SOD1 expression (p = 0.009), CRP and decrease of glucose levels (p = 0.03) were obtained after VLCKD3.


This is the first study that analyzes comprehensively body composition, metabolic profile, and inflammation and oxidative stress genes expression after VLCKD. Our results show the efficacy of VLCKD with synthetic aminoacidic protein replacement, for the reduction of cardiovascular risk, without the development of sarcopenia and activation of inflammatory and oxidative processes.


Food Restriction Affects Inflammatory Response and Nutritional State in Tuco-tucos (Ctenomys talarum).

Merlo JL, Cutrera AP, Zenuto RR.

J Exp Zool A Ecol Genet Physiol. 2017 Feb 5. doi: 10.1002/jez.2060. [Epub ahead of print]

PMID: 28164466



Insufficient or unbalanced food intake typically has a negative impact on immune responses. The understanding of this effect is, however, hampered by the effect that food has on general condition, which, in turn, affects immunity, and the interaction among general condition, immunocompetence, and concurrent infections. The goal of this study was to determine the effects of food restriction and methionine supplementation on immunity in tuco-tucos (Ctenomys talarum). Effects of diet manipulations on nutritional state, inflammatory response to phytohemagglutinin (PHA), and other immune parameters (bacterial killing capacity, natural antibodies, and leukocyte profile) were evaluated. Health and stress parameters and endoparasite loads were assessed to understand more deeply potential effects of treatments on immune status. Individuals under food restriction presented an altered nutritional state as well as increased stress levels (higher N: L ratios) compared with individuals fed ad libitum, and a marked reduction in the inflammatory response to PHA. Supplementation with methionine did not affect any of the parameters analyzed. Endoparasite loads were not affected by treatments. Our results support the idea that food insufficiency can modulate the individual's immune responsiveness through the lack of adequate essential nutrients, metabolic fuel and energetic reserves, or by a detrimental effect of the stress caused by nutrient limitation. We show that the response to PHA previously reported as nonenergetically costly for C. talarum, implies a nutritional cost; an opposite pattern to that previously found for the adaptive antibody response to sheep red blood cells in the same species.

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Caloric restriction and IGF-I administration promote rabbit fecundity: Possible interrelationships and mechanisms of action.

Sirotkin AV, Florkovičová IK, Švarcová OØ, Rafay J, Laurincik J, Harrath AH.

Theriogenology. 2017 Mar 1;90:252-259. doi: 10.1016/j.theriogenology.2016.12.017.

PMID: 28166977



The aim of these in vivo and in vitro studies was to examine the influence of caloric restriction (CR), and the administration of insulin-like growth factor (IGF-I), on rabbit fecundity and to understand the interrelationships between CR and IGF-I, as well as the endocrine and intracellular mechanisms of their effects. Female rabbits were subjected to 50% CR, injections of IGF-I (20 μg/animal/day) and a combination of the two for 10 d before and 2 d after ovulation induced by 25 IU PMSG and 0.25 IU hCG. On the day of ovulation blood samples were collected and analyzed IGF-I, leptin, progesterone (P4) and estradiol (E2) concentrations by RIA. Some animals from each group were killed in their periovulatory period and weighed, as were their ovaries. Granulosa cells isolated from ovaries of does subjected or not to CR were cultured for 2 d with and without IGF-I (100 ng/mL). Accumulation of markers of cell proliferation (PCNA and cyclin B1), apoptosis (bax), MAP/ERK1,2 kinase (MAPK), protein kinase A (PKA) and IGF-I were evaluated by immunocytochemistry. In addition, E2 release by cells isolated from ovaries of animals subjected or not to CR and cultured with and without IGF-I (1, 10, 100, 1000 or 10000 ng/mL) was assessed by RIA. The remaining animals were kept until parturition, when the number of pups was recorded. CR did not affect animal and ovarian weight, but significantly increased the number of pups per litter and plasma levels of IGF-I and decreased plasma leptin and P4, but not E2 concentration. Injections of IGF-I did not influence body and ovarian weights, but increased the number of pups per litter and plasma IGF-I and leptin concentration and reduced plasma E2 but not P4 level. IGF-I administration did not modify the main effects of CR, although it prevented the CR-induced decrease in plasma P4 level. CR reduced accumulation of PCNA, bax, promoted accumulation of cyclin B1 but not of MAPK, PKA or IGF-I within ovarian granulosa cells. Addition of IGF-I to culture medium reduced accumulation of bax, MAPK, and IGF-I and promoted PKA accumulation and E2 release. CR promoted the stimulatory effect of IGF-I on E2 output. Thus, CR can increase rabbit fecundity, probably via changes in IGF-I, leptin and steroid hormones released, which in turn can affect ovarian cell cycle, apoptosis, and response to IGF-I. Furthermore, they demonstrate the stimulatory influence of IGF-I on rabbit fecundity, which was associated with changes in plasma leptin, E2 and ovarian cell apoptosis, PKA, MAPK, IGF-I and E2 release. The promotion of IGF-I output by CR and the ability of IGF-I to mimic/replace but not to modify CR effects on fecundity, plasma IGF-I, and ovarian cell apoptosis suggest that IGF can mediate the action of CR on these reproductive indexes. In contrast, differences in the action of CR and IGF-I on other hormones, ovarian cell proliferation, protein kinases and IGF-I suggest that CR action on these indexes is not mediated by IGF-I. We thus demonstrate that both CR and IGF-I administration can increase rabbit fecundity, and that their effects can be mediated by changes in reproductive hormones, ovarian cell proliferation, apoptosis, and the response of ovarian cells to IGF-I.


Apoptosis; Food restriction; Hormones; IGF-I; Ovary; Proliferation; Rabbit


Effect of a high protein diet and/or resistance exercise on the preservation of fat free mass during weight loss in overweight and obese older adults: a randomized controlled trial.

Verreijen AM, Engberink MF, Memelink RG, van der Plas SE, Visser M, Weijs PJ.

Nutr J. 2017 Feb 6;16(1):10. doi: 10.1186/s12937-017-0229-6.

PMID: 28166780




Intentional weight loss in obese older adults is a risk factor for accelerated muscle mass loss. We investigated whether a high protein diet and/or resistance exercise preserves fat free mass (FFM) during weight loss in overweight and obese older adults.


We included 100 overweight and obese adults (55-80 year) in a randomized controlled trial (RCT) with a 2 × 2 factorial design and intention-to-treat analysis. During a 10-week weight loss program all subjects followed a hypocaloric diet. Subjects were randomly allocated to either a high protein (1.3 g/kg body weight) or normal protein diet (0.8 g/kg), with or without a resistance exercise program 3 times/week. FFM was assessed by air displacement plethysmography.


At baseline, mean (±SD) BMI was 32 ± 4 kg/m2. During intervention, protein intake was 1.13 ± 0.35 g/kg in the high protein groups vs. 0.98 ± 0.29 in the normal protein groups, which reflects a 16.3 ± 5.2 g/d higher protein intake in the high protein groups. Both high protein diet and exercise did not significantly affect change in body weight, FFM and fat mass (FM). No significant protein*exercise interaction effect was observed for FFM. However, within-group analysis showed that high protein in combination with exercise significantly increased FFM (+0.6 ± 1.3 kg, p = 0.011).


A high protein diet, though lower than targeted, did not significantly affect changes in FFM during modest weight loss in older overweight and obese adults. There was no significant interaction between the high protein diet and resistance exercise for change in FFM. However, only the group with the combined intervention of high protein diet and resistance exercise significantly increased in FFM.


Fat free mass; High protein diet; Obesity; Older adults; Resistance exercise; Weight loss

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Physiology: An atypical switch for metabolism and ageing.

Selman C, Withers DJ.

Nature. 2017 Feb 8. doi: 10.1038/nature21500. [Epub ahead of print] No abstract available.

PMID: 28178230


The enzyme S6K1 phosphorylates the enzyme glutamyl-prolyl tRNA synthetase to modulate metabolic activity and lifespan, revealing an atypical role for this synthetase as a target of a key metabolic signalling pathway.



Osborne TB, Mendel LB, Ferry EL.

Science. 1917 Mar 23;45(1160):294-5. No abstract available.

PMID: 17760202



4 Thomas B. Osborne, Lafayette B. Mendel, and With the cooperation of Edna L. Ferry and Alfred J. Wakeman


J. Biol. Chem. 1915 23: 439-455




Osborne TB, Mendel LB, Ferry EL.

Science. 1917 Mar 23;45(1160):294-5. No abstract available.

PMID: 17760202





Thomas B. Osborne, Lafayette B. Mendel

Am. J. Physiol., March 1, 1916 : 16-20





J. Biol. Chem. 1926, 69:661-673.





3. EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice.

Arif A, Terenzi F, Potdar AA, Jia J, Sacks J, China A, Halawani D, Vasu K, Li X, Brown JM, Chen J, Kozma SC, Thomas G, Fox PL.

Nature. 2017 Feb 8. doi: 10.1038/nature21380. [Epub ahead of print]

PMID: 28178239



Metabolic pathways that contribute to adiposity and ageing are activated by the mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) axis. However, known mTORC1-S6K1 targets do not account for observed loss-of-function phenotypes, suggesting that there are additional downstream effectors of this pathway. Here we identify glutamyl-prolyl-tRNA synthetase (EPRS) as an mTORC1-S6K1 target that contributes to adiposity and ageing. Phosphorylation of EPRS at Ser999 by mTORC1-S6K1 induces its release from the aminoacyl tRNA multisynthetase complex, which is required for execution of noncanonical functions of EPRS beyond protein synthesis. To investigate the physiological function of EPRS phosphorylation, we generated Eprs knock-in mice bearing phospho-deficient Ser999-to-Ala (S999A) and phospho-mimetic (S999D) mutations. Homozygous S999A mice exhibited low body weight, reduced adipose tissue mass, and increased lifespan, similar to S6K1-deficient mice and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent. Substitution of the EprsS999D allele in S6K1-deficient mice normalized body mass and adiposity, indicating that EPRS phosphorylation mediates S6K1-dependent metabolic responses. In adipocytes, insulin stimulated S6K1-dependent EPRS phosphorylation and release from the multisynthetase complex. Interaction screening revealed that phospho-EPRS binds SLC27A1 (that is, fatty acid transport protein 1, FATP1), inducing its translocation to the plasma membrane and long-chain fatty acid uptake. Thus, EPRS and FATP1 are terminal mTORC1-S6K1 axis effectors that are critical for metabolic phenotypes.

Edited by AlPater
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Intermittent feeding alters sensitivity to changes in reward value.

Parkes SL, Furlong TM, Black AD, Balleine BW.

Appetite. 2017 Feb 8. pii: S0195-6663(16)30831-5. doi: 10.1016/j.appet.2017.02.009. [Epub ahead of print]

PMID: 28189750



The influence of binge-like feeding schedules on subsequent food-related behavior is not well understood. We investigated the effect of repeated cycles of restriction and refeeding on two food-related behaviors; goal-directed responding for a palatable food reward and sensory-specific satiety. Hungry rats were trained to perform two instrumental actions for two distinct food rewards and were then subjected to repeated cycles of restricted and unrestricted access to their maintenance chow for 30-days or were maintained on food restriction. Goal-directed control was then assessed using specific satiety-induced outcome devaluation. Rats were given 1 hour access to one of the instrumental rewards and were then immediately given a choice between the two actions. Rats maintained on food restriction responded more for the valued than the devalued reward. However, rats with a history of restriction and refeeding failed to show selective devaluation. Importantly, all rats showed sensory-specific satiety when offered a choice between the two foods, indicating that pre-feeding selectively reduced the value of the pre-fed food. By contrast, sensory-specific satiety was not observed in rats with a history of cyclic feeding when the foods were offered sequentially. These results indicate that, similar to calorically dense diets, intermittent feeding patterns can impair the performance of goal-directed actions as well as the ability to reject a pre-fed food when it is offered alone.


Goal-directed action; Habit; Instrumental conditioning; Outcome devaluation; Rat; Sensory-specific satiety

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Ghrelin-Reactive Immunoglobulins in Conditions of Altered Appetite and Energy Balance.

Fetissov SO, Lucas N, Legrand R.

Front Endocrinol (Lausanne). 2017 Jan 27;8:10. doi: 10.3389/fendo.2017.00010. Review.

PMID: 28191004



Part of circulating ghrelin is bound to immunoglobulins (Ig) protecting it from degradation and preserving its functional activity. This review summarizes the data on ghrelin- and desacyl-ghrelin-reactive IgG in conditions of altered appetite and energy balance. Plasma levels and affinity kinetics of such IgG were compared in patients with obesity and anorexia nervosa (AN) and in animal models of obesity including ob/ob mice, high-fat diet-induced obese mice, and obese Zucker rats as well as in mice after chronic food restriction and activity-based anorexia and in rats with methotrexate-induced anorexia. We show that plasmatic IgG in both obese humans and animals are characterized by increased affinity for ghrelin. In contrast, patients with AN and anorectic rodents all show lower affinity of ghrelin- and desacyl-ghrelin-reactive IgG, respectively, the changes which were not observed in non-anorectic, chronically starved mice. We also show that affinity of ghrelin-reactive IgG correlate with plasma levels of ghrelin. These data point to common mechanisms underlying modifications of affinity kinetics properties of ghrelin-reactive IgG during chronic alterations of energy balance in humans and rodents and support a functional role of such autoantibodies in ghrelin-mediated regulation of appetite.


anorexia; autoantibodies; desacyl-ghrelin; ghrelin; obesity


Obesity diabetes and the role of bile acids in metabolism.

Tomkin GH, Owens D.

J Transl Int Med. 2016 Jun 1;4(2):73-80. doi: 10.1515/jtim-2016-0018.

PMID: 28191525




Bile acids have many activities over and above their primary function in aiding absorption of fat and fat soluble vitamins. Bile acids are synthesized from cholesterol, and thus are involved in cholesterol homeostasis. Bile acids stimulate glucagon-like peptide 1 (GLP1) production in the distal small bowel and colon, stimulating insulin secretion, and therefore, are involved in carbohydrate and fat metabolism. Bile acids through their insulin sensitising effect play a part in insulin resistance and type 2 diabetes. Bile acid metabolism is altered in obesity and diabetes. Both dietary restriction and weight loss due to bariatric surgery, alter the lipid carbohydrate and bile acid metabolism. Recent research suggests that the forkhead transcription factor FOXO is a central regulator of bile, lipid, and carbohydrate metabolism, but conflicting studies mean that our understanding of the complexity is not yet complete.


FOXO; acids; bariatric surgery; bile; diabetes; obesity


Metabolic gatekeeper function of B-lymphoid transcription factors.

Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H, Cosgun KN, Hurtz C, Shojaee S, Cazzaniga V, Schjerven H, Ernst T, Hochhaus A, Kornblau SM, Konopleva M, Pufall MA, Cazzaniga G, Liu GJ, Milne TA, Koeffler HP, Ross TS, Sánchez-García I, Borkhardt A, Yamamoto KR, Dickins RA, Graeber TG, Müschen M.

Nature. 2017 Feb 13:1-5. doi: 10.1038/nature21076. [Epub ahead of print]

PMID: 28192788



B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.

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The effects of graded levels of calorie restriction:VIII. impact of short term calorie and protein restriction on basal metabolic rate in the C57BL/6 mouse.

Mitchell SE, Tang Z, Kerbois C, Delville C, Derous D, Green CL, Wang Y, Han JJ, Chen L, Douglas A, Lusseau D, Promislow DE, Speakman JR.

Oncotarget. 2017 Feb 11. doi: 10.18632/oncotarget.15294. [Epub ahead of print]

PMID: 28193912



Under calorie restriction (CR) animals need to lower energy demands. Whether this involves a reduction in cellular metabolism is an issue of contention. We exposed C57BL/6 mice to graded CR for 3 months, measured BMR and dissected out 20 body compartments. From a separate age-matched group (n=57), we built 7 predictive models for BMR. Unadjusted BMR declined with severity of restriction. Comparison of measured and predicted BMR from the simple models suggested suppression occurred. The extent of 'suppression' was greater with increased CR severity. However, when models based on individual organ sizes as predictors were used, the discrepancy between the prediction and the observed BMR disappeared. This suggested 'metabolic suppression' was an artefact of not having a detailed enough model to predict the expected changes in metabolism. Our data have wide implications because they indicate that inferred 'metabolic' impacts of genetic and other manipulations may reflect effects on organ morphology.


Gerotarget; calorie restriction; dietary restriction; metabolic rate; metabolic suppression; protein restriction


Iron-restricted pair-feeding affects renal damage in rats with chronic kidney disease.

Naito Y, Senchi A, Sawada H, Oboshi M, Horimatsu T, Okuno K, Yasumura S, Ishihara M, Masuyama T.

PLoS One. 2017 Feb 14;12(2):e0172157. doi: 10.1371/journal.pone.0172157.

PMID: 28196143





We have previously shown that dietary iron restriction prevents the development of renal damage in a rat model of chronic kidney disease (CKD). However, iron deficiency is associated with appetite loss. In addition, calorie restriction is reported to prevent the development of end-stage renal pathology in CKD rats. Thus, the beneficial effect of iron restriction on renal damage may depend on calorie restriction. Here, we investigate the effect of pair-feeding iron restriction on renal damage in a rat model of CKD.


First, to determine the amount of food intake, Sprague-Dawley (SD) rats were randomly given an ad libitum normal diet or an iron-restricted diet, and the food intake was measured. Second, CKD was induced by a 5/6 nephrectomy in SD rats, and CKD rats were given either a pair-feeding normal or iron-restricted diet.


Food intake was reduced in the iron-restricted diet group compared to the normal diet group of SD rats for 16 weeks (mean food intake; normal diet group and iron-restricted diet group: 25 and 20 g/day, respectively). Based on the initial experiments, CKD rats received either a pair-feeding normal or iron-restricted diet (20 g/day) for 16 weeks. Importantly, pair-feeding iron restriction prevented the development of proteinuria, glomerulosclerosis, and tubulointerstitial damage in CKD rats. Interestingly, pair-feeding iron restriction attenuated renal expression of nuclear mineralocorticoid receptor in CKD rats.


Pair-feeding iron restriction affected renal damage in a rat model of CKD.



How eating less can slow the aging process



There's a multi-billion-dollar industry devoted to products that fight signs of aging, but moisturizers only go skin deep. Aging occurs deeper -- at a cellular level -- and scientists have found that eating less can slow this cellular process.

Recent research published in Molecular & Cellular Proteomics offers one glimpse into how cutting calories impacts aging inside a cell. The researchers found that when ribosomes -- the cell's protein makers -- slow down, the aging process slows too. The decreased speed lowers production but gives ribosomes extra time to repair themselves.

"The ribosome is a very complex machine, sort of like your car, and it periodically needs maintenance to replace the parts that wear out the fastest," said Brigham Young University biochemistry professor and senior author John Price. "When tires wear out, you don't throw the whole car away and buy new ones. It's cheaper to replace the tires."

So what causes ribosome production to slow down in the first place? At least for mice: reduced calorie consumption.

Price and his fellow researchers observed two groups of mice. One group had unlimited access to food while the other was restricted to consume 35 percent fewer calories, though still receiving all the necessary nutrients for survival.

"When you restrict calorie consumption, there's almost a linear increase in lifespan," Price said. "We inferred that the restriction caused real biochemical changes that slowed down the rate of aging."

Price's team isn't the first to make the connection between cut calories and lifespan, but they were the first to show that general protein synthesis slows down and to recognize the ribosome's role in facilitating those youth-extending biochemical changes.

"The calorie-restricted mice are more energetic and suffered fewer diseases," Price said. "And it's not just that they're living longer, but because they're better at maintaining their bodies, they're younger for longer as well."

Ribosomes, like cars, are expensive and important -- they use 10-20 percent of the cell's total energy to build all the proteins necessary for the cell to operate. Because of this, it's impractical to destroy an entire ribosome when it starts to malfunction. But repairing individual parts of the ribosome on a regular basis enables ribosomes to continue producing high-quality proteins for longer than they would otherwise. This top-quality production in turn keeps cells and the entire body functioning well.

Despite this study's observed connection between consuming fewer calories and improved lifespan, Price assured that people shouldn't start counting calories and expect to stay forever young. Calorie restriction has not been tested in humans as an anti-aging strategy, and the essential message is understanding the importance of taking care of our bodies.

"Food isn't just material to be burned -- it's a signal that tells our body and cells how to respond," Price said. "We're getting down to the mechanisms of aging, which may help us make more educated decisions about what we eat."


Mechanisms of In Vivo Ribosome Maintenance Change in Response to Nutrient Signals.

Mathis AD, Naylor BC, Carson RH, Evans E, Harwell J, Knecht J, Hexem E, Peelor FF 3rd, Miller BF, Hamilton KL, Transtrum MK, Bikman BT, Price JC.

Mol Cell Proteomics. 2017 Feb;16(2):243-254. doi: 10.1074/mcp.M116.063255.

PMID: 27932527




Control of protein homeostasis is fundamental to the health and longevity of all organisms. Because the rate of protein synthesis by ribosomes is a central control point in this process, regulation, and maintenance of ribosome function could have amplified importance in the overall regulatory circuit. Indeed, ribosomal defects are commonly associated with loss of protein homeostasis, aging, and disease (1-4), whereas improved protein homeostasis, implying optimal ribosomal function, is associated with disease resistance and increased lifespan (5-7). To maintain a high-quality ribosome population within the cell, dysfunctional ribosomes are targeted for autophagic degradation. It is not known if complete degradation is the only mechanism for eukaryotic ribosome maintenance or if they might also be repaired by replacement of defective components. We used stable-isotope feeding and protein mass spectrometry to measure the kinetics of turnover of ribosomal RNA (rRNA) and 71 ribosomal proteins (r-proteins) in mice. The results indicate that exchange of individual proteins and whole ribosome degradation both contribute to ribosome maintenance in vivo In general, peripheral r-proteins and those with more direct roles in peptide-bond formation are replaced multiple times during the lifespan of the assembled structure, presumably by exchange with a free cytoplasmic pool, whereas the majority of r-proteins are stably incorporated for the lifetime of the ribosome. Dietary signals impact the rates of both new ribosome assembly and component exchange. Signal-specific modulation of ribosomal repair and degradation could provide a mechanistic link in the frequently observed associations among diminished rates of protein synthesis, increased autophagy, and greater longevity (5, 6, 8, 9).

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SZT2 dictates GATOR control of mTORC1 signalling

Min Peng, Na Yin & Ming O. Li

Nature (2017) doi:10.1038/nature21378

Received 14 October 2015 Accepted 22 December 2016 Published online 15 February 2017



Mechanistic target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes1, 2, 3, 4. The evolutionarily conserved GATOR complex regulates mTORC1 signalling through Rag GTPases, and GATOR1 displays GTPase activating protein (GAP) activity for RAGA and RAGB (RAGA/B) and GATOR2 has been proposed to be an inhibitor of GATOR15, 6. Furthermore, the metazoan-specific SESN proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RAGA/B, and interact with GATOR2 with unknown effects7, 8, 9. Here we show that SZT2 (seizure threshold 2), a metazoan-specific protein mutated in epilepsy10, 11, 12, 13, recruits a fraction of mammalian GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex with an essential role in GATOR- and SESN-dependent nutrient sensing and mTORC1 regulation. The interaction of SZT2 with GATOR1 and GATOR2 was synergistic, and an intact SOG complex was required for its localization at the lysosome. SZT2 deficiency resulted in constitutive mTORC1 signalling in cells under nutrient-deprived conditions and neonatal lethality in mice, which was associated with failure to inactivate mTORC1 during fasting. Hyperactivation of mTORC1 in SZT2-deficient cells could be partially corrected by overexpression of the GATOR1 component DEPDC5, and by the lysosome-targeted GATOR2 component WDR59 or lysosome-targeted SESN2. These findings demonstrate that SZT2 has a central role in dictating GATOR-dependent nutrient sensing by promoting lysosomal localization of SOG, and reveal an unexpected function of lysosome-located GATOR2 in suppressing mTORC1 signalling through SESN recruitment.

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