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A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties.

Zaini MA, Müller C, Ackermann T, Reinshagen J, Kortman G, Pless O, Calkhoven CF.

Sci Rep. 2017 Feb 15;7:42603. doi: 10.1038/srep42603.

PMID: 28198412



An important part of the beneficial effects of calorie restriction (CR) on healthspan and lifespan is mediated through regulation of protein synthesis that is under control of the mechanistic target of rapamycin complex 1 (mTORC1). As one of its activities, mTORC1 stimulates translation into the metabolic transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) isoform Liver-specific Inhibitory Protein (LIP). Regulation of LIP expression strictly depends on a translation re-initiation event that requires a conserved cis-regulatory upstream open reading frame (uORF) in the C/EBPβ-mRNA. We showed before that suppression of LIP in mice, reflecting reduced mTORC1-signaling at the C/EBPβ level, results in CR-type of metabolic improvements. Hence, we aim to find possibilities to pharmacologically down-regulate LIP in order to induce CR-mimetic effects. We engineered a luciferase-based cellular reporter system that acts as a surrogate for C/EBPβ-mRNA translation, emulating uORF-dependent C/EBPβ-LIP expression under different translational conditions. By using the reporter system in a high-throughput screening (HTS) strategy we identified drugs that reduce LIP. The drug Adefovir Dipivoxil passed all counter assays and increases fatty acid β-oxidation in a hepatoma cell line in a LIP-dependent manner. Therefore, these drugs that suppress translation into LIP potentially exhibit CR-mimetic properties.


The Hunger Gains: Extreme Calorie-Restriction Diet Shows Anti-Aging Results

A new study shows five days of hunger a month may reduce risk factors for aging and age-related diseases

By Richard Conniff on February 16, 2017


The idea that organisms can live longer, healthier lives by sharply reducing their calorie intake is not exactly new. Laboratory research has repeatedly demonstrated the anti-aging value of calorie restriction, often called CR, in animals from nematodes to rats—with the implication that the same might be true for humans.

In practice though, permanently reducing calorie intake by 25 to 50 percent or more sounds to many like a way to extend life by making it not worth living. Researchers have also warned that what works for nematodes or rats may not work—and could even prove dangerous—in humans, by causing muscle or bone density loss, for example.

But now two new studies appear to move calorie restriction from the realm of wishful thinking to the brink of practical, and perhaps even tolerable, reality. Writing in Nature Communications, researchers at the University of Wisconsin–Madison and the National Institute on Aging reported last month chronic calorie restriction produces significant health benefits in rhesus monkeys—a primate with humanlike aging patterns—indicating “that CR mechanisms are likely translatable to human health.” The researchers describe one monkey they started on a 30 percent calorie restriction diet when he was 16 years old, late middle age for this type of animal. He is now 43, a longevity record for the species, according to the study, and the equivalent of a human living to 130.

In the second study, published this week in Science Translational Medicine, a research team led by gerontologist Valter Longo at the University of Southern California (U.S.C.) suggests it is possible to gain anti-aging benefits without signing up for a lifetime of hunger. Instead, a “fasting-mimicking diet,” practiced just five days a month for three months—and repeated at intervals as needed—is “safe, feasible and effective in reducing risk factors for aging and age-related diseases.”

Some researchers, however, still find the calorie-restriction argument unpersuasive. Leslie Robert, a biochemist and physician at the University of Paris who was not involved in the two new studies, says pharmaceutical approaches offer greater anti-aging potential than “inefficient and apparently harmful” diets. The important thing, adds Luigi Fontana, a longevity researcher at the Washington University School of Medicine in Saint Louis who also was not involved in the new work, is “if you’re doing a healthy diet, exercising, everything good, without doing anything extreme, without making life miserable by counting every single calorie.”

Rozalyn Anderson, a researcher in the Wisconsin study, does not necessarily disagree. “Life is difficult enough without engaging in some bonkers diet,” she says. “We really study this as a paradigm to understand aging. We’re not recommending people do it.” The combined results in the Nature Communications paper show aging is “malleable” in primates, she explains, and that “aging itself presents a reasonable target for intervention.” Whereas conventional medicine views aging as a fight against cancer, cardiovascular issues, neural degeneration and other diseases, she adds, calorie restriction “delays the aging and vulnerability. Instead of going after diseases one at a time, you go after the underlying vulnerability and tackle them all at once.”

Despite her reservations about recommending CR, Anderson praised the work of the research team in the Science Translational Medicine study for “pushing this forward for possible application in clinics.” In that study, test subjects followed a carefully designed 50 percent calorie restricted diet (totaling about 1,100 calories on the first day and 70 percent (about 700 calories) on the next four days, then ate whatever they wanted for the rest of the month.

Longo, the gerontologist at U.S.C., says the underlying theory of the on-again/off-again approach is that the regenerative effects of the regimen occur not so much from the fasting itself as from the recovery afterward. By contrast, long-term, uninterrupted calorie restriction can lead to the sort of negative effects seen in extreme conditions like anorexia.

The calorie-restricted diet in Longo’s study was 100 percent plant-based and featured vegetable soups, energy bars, energy drinks and a chip snack as well as mineral and vitamin supplements. It included nutrients designed to manipulate the expression of genes involved in aging-related processes, Longo explains. (Longo and U.S.C. are both owners of L-Nutra, the company that manufactures the diet. But he says he takes no salary or consulting fees from the company and has assigned his shares to a nonprofit organization established to support further research.)

Even the five-day-a-month calorie restriction regimen was apparently a struggle for some test subjects, resulting in a 25 percent dropout rate. But health benefits in the form of decreased body mass and better levels of glucose, triglycerides and cholesterol, along with other factors, showed up after the third month and persisted for at least three months—even after subjects had returned full-time to a normal diet. Notably, given concerns about other forms of calorie restriction, lean muscle mass remained unchanged.

The benefits were greater for people who were obese or otherwise unhealthy, Longo says. But those individuals might also need to repeat the five-day regimen as often as once a month to the point of recovery, he adds, whereas individuals who are already healthy and athletic might repeat it just twice a year.

Neither of the two new studies argues the benefits of CR necessarily add up to a longer life. Longevity in humans is still an unpredictable by-product of our myriad variations in individual biology, behavior and circumstance. The objective, according to researchers, is merely to make the healthy portion of our lives last longer.


Caloric restriction improves health and survival of rhesus monkeys.

Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM.

Nat Commun. 2017 Jan 17;8:14063. doi: 10.1038/ncomms14063.

PMID: 28094793 Free PMC Article



Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease


Science Translational Medicine 15 Feb 2017:

Vol. 9, Issue 377,

DOI: 10.1126/scitranslmed.aai8700


A periodic fasting diet improves markers of metabolic dysfunction, particularly in people already at risk.

Editor's Summary

Fasting: More than a fad

Mice that fast periodically are healthier, metabolically speaking. To explore whether fasting can help people as well, Wei et al. studied 71 people who either consumed a fasting-mimicking diet for 5 days each month for 3 months or maintained their normal diet for 3 months and then switched to the fasting schedule. The fasting-like diet reduced body weight and body fat, lowered blood pressure, and decreased the hormone IGF-1, which has been implicated in aging and disease. A post hoc analysis replicated these results and also showed that fasting decreased BMI, glucose, triglycerides, cholesterol, and C-reactive protein (a marker for inflammation). These effects were generally larger in the subjects who were at greater risk of disease at the start of the study. A larger study is needed to replicate these results, but they raise the possibility that fasting may be a practical road to a healthy metabolic system.


Calorie restriction or changes in dietary composition can enhance healthy aging, but the inability of most subjects to adhere to chronic and extreme diets, as well as potentially adverse effects, limits their application. We randomized 100 generally healthy participants from the United States into two study arms and tested the effects of a fasting-mimicking diet (FMD)—low in calories, sugars, and protein but high in unsaturated fats—on markers/risk factors associated with aging and age-related diseases. We compared subjects who followed 3 months of an unrestricted diet to subjects who consumed the FMD for 5 consecutive days per month for 3 months. Three FMD cycles reduced body weight, trunk, and total body fat; lowered blood pressure; and decreased insulin-like growth factor 1 (IGF-1). No serious adverse effects were reported. After 3 months, control diet subjects were crossed over to the FMD program, resulting in a total of 71 subjects completing three FMD cycles. A post hoc analysis of subjects from both FMD arms showed that body mass index, blood pressure, fasting glucose, IGF-1, triglycerides, total and low-density lipoprotein cholesterol, and C-reactive protein were more beneficially affected in participants at risk for disease than in subjects who were not at risk. Thus, cycles of a 5-day FMD are safe, feasible, and effective in reducing markers/risk factors for aging and age-related diseases. Larger studies in patients with diagnosed diseases or selected on the basis of risk factors are warranted to confirm the effect of the FMD on disease prevention and treatment.

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Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease.

Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, Groshen S, Mack WJ, Guen E, Di Biase S, Cohen P, Morgan TE, Dorff T, Hong K, Michalsen A, Laviano A, Longo VD.

Sci Transl Med. 2017 Feb 15;9(377). pii: eaai8700. doi: 10.1126/scitranslmed.aai8700.

PMID: 28202779



Calorie restriction or changes in dietary composition can enhance healthy aging, but the inability of most subjects to adhere to chronic and extreme diets, as well as potentially adverse effects, limits their application. We randomized 100 generally healthy participants from the United States into two study arms and tested the effects of a fasting-mimicking diet (FMD)-low in calories, sugars, and protein but high in unsaturated fats-on markers/risk factors associated with aging and age-related diseases. We compared subjects who followed 3 months of an unrestricted diet to subjects who consumed the FMD for 5 consecutive days per month for 3 months. Three FMD cycles reduced body weight, trunk, and total body fat; lowered blood pressure; and decreased insulin-like growth factor 1 (IGF-1). No serious adverse effects were reported. After 3 months, control diet subjects were crossed over to the FMD program, resulting in a total of 71 subjects completing three FMD cycles. A post hoc analysis of subjects from both FMD arms showed that body mass index, blood pressure, fasting glucose, IGF-1, triglycerides, total and low-density lipoprotein cholesterol, and C-reactive protein were more beneficially affected in participants at risk for disease than in subjects who were not at risk. Thus, cycles of a 5-day FMD are safe, feasible, and effective in reducing markers/risk factors for aging and age-related diseases. Larger studies in patients with diagnosed diseases or selected on the basis of risk factors are warranted to confirm the effect of the FMD on disease prevention and treatment.


Mild and Short-Term Caloric Restriction Prevents Obesity-Induced Cardiomyopathy in Young Zucker Rats without Changing in Metabolites and Fatty Acids Cardiac Profile.

Ruiz-Hurtado G, García-Prieto CF, Pulido-Olmo H, Velasco-Martín JP, Villa-Valverde P, Fernández-Valle ME, Boscá L, Fernández-Velasco M, Regadera J, Somoza B, Fernández-Alfonso MS.

Front Physiol. 2017 Feb 1;8:42. doi: 10.3389/fphys.2017.00042.

PMID: 28203206



Caloric restriction (CR) ameliorates cardiac dysfunction associated with obesity. However, most of the studies have been performed under severe CR (30-65% caloric intake decrease) for several months or even years in aged animals. Here, we investigated whether mild (20% food intake reduction) and short-term (2-weeks) CR prevented the obese cardiomyopathy phenotype and improved the metabolic profile of young (14 weeks of age) genetically obese Zucker fa/fa rats. Heart weight (HW) and HW/tibia length ratio was significantly lower in fa/fa rats after 2 weeks of CR than in counterparts fed ad libitum. Invasive pressure measurements showed that systolic blood pressure, maximal rate of positive left ventricle (LV) pressure, LV systolic pressure and LV end-diastolic pressure were all significantly higher in obese fa/fa rats than in lean counterparts, which were prevented by CR. Magnetic resonance imaging revealed that the increase in LV end-systolic volume, stroke volume and LV wall thickness observed in fa/fa rats was significantly lower in animals on CR diet. Histological analysis also revealed that CR blocked the significant increase in cardiomyocyte diameter in obese fa/fa rats. High resolution magic angle spinning magnetic resonance spectroscopy analysis of the LV revealed a global decrease in metabolites such as taurine, creatine and phosphocreatine, glutamate, glutamine and glutathione, in obese fa/fa rats, whereas lactate concentration was increased. By contrast, fatty acid concentrations in LV tissue were significantly elevated in obese fa/fa rats. CR failed to restore the LV metabolomic profile of obese fa/fa rats. In conclusion, mild and short-term CR prevented an obesity-induced cardiomyopathy phenotype in young obese fa/fa rats independently of the cardiac metabolic profile.


caloric restriction; hypertension; hypertrophy; metabolite profile; nuclear magnetic resonance; obesity-induced cardiomyopathy


Altered Activity of the Autonomous Nervous System as a Determinant of the Impaired β-Cell Secretory Response after Protein-Energy Restriction in the Rat.

Leon-Quinto T, Magnan C, Portha B.

Endocrinology. 1998 Aug 1;139(8):3382-3389. doi: 10.1210/endo.139.8.6149. No abstract available.

PMID: 28199634




Glucose-induced insulin secretion in vivo is known to be severely blunted in the rat as a consequence of protein-energy restriction starting early in life. We have recently reported in such malnourished rats (M rats) that the release of the counterregulatory hormones that defend against hypoglycemia was severely disturbed, and their plasma levels of epinephrine and norepinephrine were prominently increased. Knowing that the autonomic nervous system has the potential to play a major role in the control of insulin secretion in response to glucose in vivo, we therefore determined whether protein-energy restriction starting after weaning could alter sympathetic and/or parasympathetic nerve activities, and whether these changes could be responsible for the lack of response to glucose of their beta-cells in vivo. When tested in the basal postabsorptive state, the malnourished rats exhibited profound alterations of both parasympathetic and sympathetic nerve activities; the firing rates of the vagus nerve and the superior cervical ganglion were dramatically decreased and increased, respectively. Under the same conditions, insulin secretion in vivo in response to a glucose load (deltaI/deltaG) was severely decreased in M rats compared with that in control © rats. When evaluated after administration of acetylcholine, deltaI was amplified to the same extent in M rats as in C rats. After administration of the alpha2A-adrenergic agonist oxymetazoline, glucose-induced insulin release in M rats was not significantly affected, whereas it was sharply decreased in C rats. Finally, administration of yohimbine, an alpha2-adrenergic antagonist, partially restored the lack of reactivity of the beta-cells to glucose in the M rats, as deltaI/deltaG was amplified by 6-fold in the M group and by 3.3-fold in the C group. We conclude that protein-energy restriction starting early in life in rats brings about changes in the overall activity of the autonomic nervous system that, in turn, are responsible at least in part for the acquisition/maintenance of decreased beta-cell reactivity to glucose in vivo.

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Nutrients in Energy and One-Carbon Metabolism: Learning from Metformin Users.

Luciano-Mateo F, Hernández-Aguilera A, Cabre N, Camps J, Fernández-Arroyo S, Lopez-Miranda J, Menendez JA, Joven J.

Nutrients. 2017 Feb 10;9(2). pii: E121. doi: 10.3390/nu9020121. Review.

PMID: 28208582



Metabolic vulnerability is associated with age-related diseases and concomitant co-morbidities, which include obesity, diabetes, atherosclerosis and cancer. Most of the health problems we face today come from excessive intake of nutrients and drugs mimicking dietary effects and dietary restriction are the most successful manipulations targeting age-related pathways. Phenotypic heterogeneity and individual response to metabolic stressors are closely related food intake. Understanding the complexity of the relationship between dietary provision and metabolic consequences in the long term might provide clinical strategies to improve healthspan. New aspects of metformin activity provide a link to many of the overlapping factors, especially the way in which organismal bioenergetics remodel one-carbon metabolism. Metformin not only inhibits mitochondrial complex 1, modulating the metabolic response to nutrient intake, but also alters one-carbon metabolic pathways. Here, we discuss findings on the mechanism(s) of action of metformin with the potential for therapeutic interpretations.


diabetes mellitus; energy intake; epigenetics; folic acid; food source; food-drug interactions; obesity; vitamins B

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[The below paper is pdf-availed.]

Insulin/insulin-like growth factor-1 signalling (IIS) based regulation of lifespan across species.

Mathew R, Pal Bhadra M, Bhadra U.

Biogerontology. 2017 Jan 18. doi: 10.1007/s10522-016-9670-8. [Epub ahead of print] Review.

PMID: 28101820


An organism's well-being is facilitated by numerous molecular and biochemical pathways that ensure homeostasis within cells and tissues. Aging causes a gradual let-down in the maintenance of homeostasis due to various endogenous and environmental challenges, leading to amassing of damages, functional deterioration of different tissues and vulnerability to ailments. Nutrient sensing pathways that maintain glucose homeostasis in body are involved in regulation of aging. Insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) pathway was the first nutrient sensing pathway discovered to affect the aging process. This pathway is highly conserved and the most studied among different organisms. Epigenetic machineries that include DNA and histone modifying enzymes and various non-coding RNAs have been identified as important contributors to nutrition-related longevity and aging control. In this report, we present the homology and differences in IIS pathway of various organisms including worm, fly, rodent and human. We also discuss how epigenome remodelling, chromatin based strategies, small and long non-coding RNA are involved to regulate multiple steps of aging or age-related insulin homeostasis. Enhanced study of the role of IIS pathway and epigenetic mechanisms that regulate aging may facilitate progressive prevention and treatment of human age-related diseases.


DNA methylation; FOXO; Histone modification; Insulin signalling; Longevity; Non-coding RNA

Concluding remarks

Although evolutionarily conserved, IIS pathway is

more complicated in higher organisms. IIS pathway

controls life expectancy in many organisms, but

despite recent research, its molecular mechanisms

remain largely unknown. Disruption of IIS pathway in

worm or fly causes significant increase in lifespan but

it does not do so in higher animals as mammals have

different receptors for insulin and IGFs with distinct

pathways and diverse functions. Mammals have

insulin/IGF-1 receptors in many organs whereas lower

organisms have this signalling mainly through nervous

system. IIS pathway in humans is responsible for

approximately 5% of lifespan, but the kinds of

dramatic increases seen from IIS in worms and flies

are unlikely from similar manipulations in humans. On

a molecular level, human longevity is mysterious.

Further research is needed to throw light on the distinct

molecular mechanisms of human longevity and their

evolutionary trends. FOXO transcriptional factors

play a crucial and diversified role in the IIS pathway.

Activation of FOXO under low IIS activity leads to

diverse effects on various tissues to aid in lifespan

increase. Studies on FOXO in both lower and higher

organisms open broader avenues for the investigation

of lifespan extension. Interaction between diet and

nutrient-sensing pathways plays a vital role in affecting

organism physiology and health.

DR has attracted much attention as it extends lifespan

and prevents or postpones a number of age-related

diseases without causing irreversible developmental or

reproductive flaws. DR increases lifespan by reducing

IIS. DR also increases lifespan by stimulation of

sirtuins, some of which in turn act through IIS.

Exploration of DR coupled with IIS pathway and

sirtuins holds a promising future for organism longevity.

Additionally, we show epigenomic and non-coding

RNA-mediated manipulation of aging. DNA methylation

and histone modifications are known to influence

aging. Recent research shows their role in aging through

IIS. Regulatory RNA-based epigenomics appears to be

a novel understanding of aging regulatory pathway.

Non-coding RNA induced epigenetic instability during

lifespan forms an integral driver of the aging process.

Among non-coding RNAs, the role of miRNAs in aging

has been most widely researched. Components of IIS

pathway are involved in miRNA-mediated regulation of

aging in C. elegans. However, with both beneficial and

antagonising roles of miRNAs on the lifespan of C.

elegans, it opens a whole new arena of research both in

lower and developed organisms. LncRNAs show

diverse roles in regulating lifespan and age-related

diseases. Their involvement in aging through IIS

pathway is yet to be established. We suggest the

importance of different regulatory non-coding RNAs in

the pursuit of various factors for healthy aging.

Despite recent progress, a complete mapping of the

insulin signalling pathway, role of DR in relation to

IIS and the multiple roles of regulatory RNAs

including microRNAs and lncRNAs that impact aging

through nutrient sensing pathway is still elusive. It will

be of great interest to further explore the association

between epigenetic and non-epigenetic factors that

influence the lifespan of an organism. This will help in

the advancement of strategies to reverse different

aging mechanisms in humans.


[The below paper is pdf-availed.]

Effect of Food Deprivation or Short-term Western Diet Feeding on BDNF Protein Expression in the Hypothalamic Arcuate, Paraventricular, and Ventromedial Nuclei.

Gilland KE, Fox EA.

Am J Physiol Regul Integr Comp Physiol. 2017 Feb 15:ajpregu.00256.2016. doi: 10.1152/ajpregu.00256.2016. [Epub ahead of print]

PMID: 28202438


Mutations in the brain-derived neurotrophic factor (BDNF) gene are associated with human obesity and BDNF has potent inhibitory effects on eating and body weight. Little is known about the effects of energy-balance manipulations on BDNF protein in the hypothalamus, though this brain region is critical for regulation of feeding and body weight and has high levels of BDNF. Here we investigated the effects of negative and positive energy status on BDNF protein levels in the arcuate (ARC), paraventricular (PVN), and ventromedial (VMH) hypothalamic nuclei, and the ectorhinal cortex. To achieve this, mice were food deprived for forty-eight hours or fed a western diet (WD), a restricted amount of WD, or chow for six hours, forty-eight hours, one week, or three weeks. BDNF protein levels were estimated as the number of neurons in each brain region that exhibited BDNF-like immunoreactivity (LIR). Food deprivation decreased BDNF protein (and mRNA) expression in the ARC compared with fed mice (32%). In contrast, one week of WD consumption increased BDNF protein expression in the VMH as compared with chow or restricted WD feeding (40%), and unexpectedly, increased BDNF protein in the ectorhinal cortex (20%). Furthermore, of the diet conditions and durations tested, only one week of WD consumption was associated with both hyperphagia and excess weight, suggesting effects of one or both contributed to the changes in BDNF levels. The decrease in ARC BDNF may support increased feeding in food-deprived mice, whereas, the increase in the VMH may moderate overeating in WD fed mice.


BDNF; Obesity; food intake


A global characterization of the translational and transcriptional programs induced by methionine restriction through ribosome profiling and RNA-seq.

Zou K, Ouyang Q, Li H, Zheng J.

BMC Genomics. 2017 Feb 17;18(1):189. doi: 10.1186/s12864-017-3483-2.

PMID: 28212626




Among twenty amino acids, methionine has a special role as it is coded by the translation initiation codon and methionyl-tRNAi (Met-tRNAi) is required for the assembly of the translation initiation complex. Thus methionine may play a special role in global gene regulation. Methionine has also been known to play important roles in cell growth, development, cancer, and aging. In this work, we characterize the translational and transcriptional programs induced by methionine restriction (MetR) and investigate the potential mechanisms through which methionine regulates gene expression, using the budding yeast S. cerevisiae as the model organism.


Using ribosomal profiling and RNA-seq, we observed a broad spectrum of gene expression changes in response to MetR and identified hundreds of genes whose transcript level and/or translational efficiency changed significantly. These genes show clear functional themes, suggesting that cell slows down its growth and cell cycle progression and increases its stress resistance and maintenance in response to MetR. Interestingly, under MetR cell also decreases glycolysis and increases respiration, and increased respiration was linked to lifespan extension caused by caloric restriction. Analysis of genes whose translational efficiency changed significantly under MetR revealed different modes of translational regulation: 1) Ribosome loading patterns in the 5'UTR and coding regions of genes with increased translational efficiency suggested mechanisms both similar and different from that for the translational regulation of Gcn4 under general amino acid starvation condition; 2) Genes with decreased translational efficiency showed strong enrichment of lysine, glutamine, and glutamate codons, supporting the model that methionine can regulate translation by controlling tRNA thiolation.


MetR induced a broad spectrum of gene expression changes at both the transcriptional and translational levels, with clear functional themes indicative of the physiological state of the cell under MetR. Different modes of translational regulation were induced by MetR, including the regulation of the ribosome loading at 5'UTR and regulation by tRNA thiolation. Since MetR extends the lifespan of many species, the list of genes we identified in this study can be good candidates for studying the mechanisms of lifespan extension.


[The below paper is pdf-availed.]

Calorie Restriction Promotes Cardiolipin Biosynthesis and Distribution Between Mitochondrial Membranes.

Luévano-Martínez LA, Forni MF, Peloggia J, Watanabe IS, Kowaltowski AJ.

Mech Ageing Dev. 2017 Feb 14. pii: S0047-6374(16)30226-3. doi: 10.1016/j.mad.2017.02.004. [Epub ahead of print]

PMID: 28213011


Calorie restriction (CR) has been amply demonstrated to modify mitochondrial function. However, little is known regarding the effects of this dietary regimen on mitochondrial membranes. We isolated phospholipids from rat liver mitochondria from animals on CR or ad libitum diets and found that mitochondria from ad libitum animals present an increased content of lipoperoxides and the content of cardiolipin. Cardiolipin is the main anionic phospholipid present in mitochondrial membranes, and plays a key role in mitochondrial function, signaling and stress response. Expression levels of the enzymes involved in cardiolipin biosynthesis and remodeling were quantified and found to be upregulated in CR animals. Interestingly, when mitochondrial membranes were fractionated, the outer membrane presented a higher content of cardiolipin, indicating a redistribution of this phospholipid mediated by a phospholipid scramblase in CR. This change is associated with Drp1-mediated mitochondrial fragmentation and autophagy. Overall, we find that CR promotes extensive mitochondrial membrane remodeling, decreasing oxidatively damaged lipids, and increasing cardiolipin levels and redistributing cardiolipin. These changes in membrane properties are consistent with and may be causative of changes in mitochondrial morphology, function and turnover previously found to occur in CR.


Calorie restriction; cardiolipin; membrane; mitochondria; phospholipid

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"Is there an optimal diet for weight management and metabolic health?"

Thom G, Lean M.

Gastroenterology. 2017 Feb 15. pii: S0016-5085(17)30158-0. doi: 10.1053/j.gastro.2017.01.056. [Epub ahead of print]

PMID: 28214525



Individuals can lose body weight and improve health status on a wide range of energy (calorie) restricted dietary interventions. In this paper, we have reviewed the effectiveness of the most commonly utilized diets, including low-fat, low-carbohydrate and Mediterranean approaches in addition to commercial slimming programmes, meal replacements and newly-popularized intermittent fasting diets. We also consider the role of artificial sweeteners in weight management. Low-fat diets tend to improve LDL-cholesterol most, whilst lower-carbohydrate diets may preferentially improve triglycerides and HDL-cholesterol, however differences between diets are marginal. Weight loss improves almost all obesity related co-morbidities and metabolic markers, regardless of the macronutrient composition of the diet, but individuals do vary in preferences and ability to adhere to different diets. Optimizing adherence is the most important factor for weight loss success, and this is enhanced by regular professional contact and supportive behavioral change programs. Maintaining weight losses in the long-term remains the biggest challenge, and is undermined by an 'obesogenic' environment and biological adaptations that accompany weight loss.


diet; obesity; sweeteners; type 2 diabetes; weight-loss

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[The below paper is not pdf-availed.]

Comparative effects of energy restriction and resveratrol intake on glycemic control improvement.

Milton-Laskibar I, Aguirre L, Macarulla MT, Etxeberria U, Milagro FI, Martínez JA, Contreras J, Portillo MP.

Biofactors. 2017 Feb 20. doi: 10.1002/biof.1347. [Epub ahead of print]

PMID: 28218490


Resveratrol (RSV) has been proposed as an energy restriction mimetic. This study aimed to compare the effects of RSV and energy restriction on insulin resistance induced by an obesogenic diet. Any additive effect of both treatments was also analyzed. Rats were fed a high-fat high-sucrose diet for 6 weeks. They were then distributed in four experimental groups which were either fed a standard control diet ©, or treated with RSV (30 mg/kg/d), or submitted to energy restriction (R, 15%), or treated with RSV and submitted to energy restriction (RR). A glucose tolerance test was performed, and serum glucose, insulin, fructosamine, adiponectin, and leptin concentrations determined. Muscle triacylglycerol content and protein expression of insulin receptor (IRβ), protein kinase B (Akt), Akt substrate of 160 kDa (AS160) and glucose transporter 4 (GLUT-4) were measured. In RSV rats, fructosamine concentrations were reduced, HOMA-IR remained unchanged, but glucose tolerance was improved, without changes in phosphorylation of IRβ, Akt, and AS160 or in GLUT-4 protein expression. Rats under energy restriction showed an improvement in all the markers related to glycemic control, as well as increased phosphorylation of AS160 and protein expression of GLUT-4. In rats from RR group the results were similar to R group, with the exception of IRβ and Akt phosphorylation, which were increased. In conclusion, mild energy restriction is more efficient than intake of RSV within a standard balanced diet, and acts by means of a different mechanism from that of RSV. No additive effects between RSV and energy restriction were observed.


energy restriction; glycemic control; high-fat high-sucrose diet; rat; resveratrol


Nutrition, metabolism, and targeting aging in nonhuman primates.

Balasubramanian P, Mattison JA, Anderson RM.

Ageing Res Rev. 2017 Feb 17. pii: S1568-1637(17)30034-X. doi: 10.1016/j.arr.2017.02.002. [Epub ahead of print] Review.



This short review focuses on the importance of nonhuman primate nutrition and aging studies and makes the case that a targeted expansion of the use of this highly translatable model would be advantageous to the biology of aging field. First, we describe the high degree of similarity of the model in terms of aging phenotypes including incidence and prevalence of common human age-related diseases. Second, we discuss the importance of the nonhuman primate nutrition and aging studies and the extent to which the outcomes of two ongoing long-term studies of caloric restriction are congruent with short-term equivalent studies in humans. Third, we showcase a number of pharmacological agents previously employed in nonhuman primate studies that display some potential as caloric restriction mimetics. Finally, we present nonhuman primates as an important model for translation of mechanisms of delayed aging identified in studies of shorter-lived animals. Proof of efficacy and safety of candidate longevity agents in nonhuman primates would be a cost-effective means to bring these exciting new avenues a step closer to clinical application.


Aging; caloric restriction; mimetics; nonhuman primates; nutrition; translational research


Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects.

Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, Onken B, Coleman-Hulbert AL, Dumas KJ, Guo S, Johnson E, Bhaumik D, Xue J, Crist AB, Presley MP, Harinath G, Sedore CA, Chamoli M, Kamat S, Chen MK, Angeli S, Chang C, Willis JH, Edgar D, Royal MA, Chao EA, Patel S, Garrett T, Ibanez-Ventoso C, Hope J, Kish JL, Guo M, Lithgow GJ, Driscoll M, Phillips PC.

Nat Commun. 2017 Feb 21;8:14256. doi: 10.1038/ncomms14256.

PMID: 28220799



Limiting the debilitating consequences of ageing is a major medical challenge of our time. Robust pharmacological interventions that promote healthy ageing across diverse genetic backgrounds may engage conserved longevity pathways. Here we report results from the Caenorhabditis Intervention Testing Program in assessing longevity variation across 22 Caenorhabditis strains spanning 3 species, using multiple replicates collected across three independent laboratories. Reproducibility between test sites is high, whereas individual trial reproducibility is relatively low. Of ten pro-longevity chemicals tested, six significantly extend lifespan in at least one strain. Three reported dietary restriction mimetics are mainly effective across C. elegans strains, indicating species and strain-specific responses. In contrast, the amyloid dye ThioflavinT is both potent and robust across the strains. Our results highlight promising pharmacological leads and demonstrate the importance of assessing lifespans of discrete cohorts across repeat studies to capture biological variation in the search for reproducible ageing interventions.

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[The below paper is pdf-availed.]

Dietary restriction reduces blood lipids and ameliorates liver function of mice with hyperlipidemia.

Gao HT, Cheng WZ, Xu Q, Shao LX.

J Huazhong Univ Sci Technolog Med Sci. 2017 Feb;37(1):79-86. doi: 10.1007/s11596-017-1698-8.

PMID: 28224418


Dietary restriction (DR) can delay senescence, prolong lifespan of mammals and improve their learning-memory activity. The purpose of the study was to explore the effects of DR on hypolipidemic action and liver function of mice with hyperlipidemia. To investigate these effects, hyperlipidemia mouse models were established with high-fat diet (HFD) (34% of energy), then randomly divided into HFD group, DR30% group and DR50% group. Mice in DR30% and DR50% group were respectively supplied with HFD as much as about 70% and 50% of the consumption of HFD in the mice of HFD group. Rats in control group were fed routinely. After DR for 5 weeks, the average body weight, liver weight, liver index, serum lipids and glucose levels in both DR groups decreased significantly as compared with the HFD group (P<0.05 or P<0.01), so did alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) levels and the ratio of LDL-C/HDL-C in the DR50% group (P<0.05 or P<0.01). Histopathology examination of liver tissues further proved ameliorative effect of DR on liver function. Western blotting showed that DR significantly increased the expression of silent mating type information regulation 2 homolog 1 (SIRT1) in liver and adipose, while notably decreased the expression of peroxisome proliferators-activated receptors-gamma (PPARγ) in adipose (P<0.05 or P<0.01). The increase of SIRT1 and decrease of PPARγ may be a mechanism by which DR reduces blood lipids and ameliorates liver function.


PPARγ; SIRT1; dietary restriction; high-fat diet; hyperlipidemia; hypolipidemic action; liver function


Caloric restriction reduces the systemic progression of mouse AApoAII amyloidosis.

Li L, Sawashita J, Ding X, Yang M, Xu Z, Miyahara H, Mori M, Higuchi K.

PLoS One. 2017 Feb 22;12(2):e0172402. doi: 10.1371/journal.pone.0172402.

PMID: 28225824




In mouse senile amyloidosis, apolipoprotein (Apo) A-II is deposited extracellularly in many organs in the form of amyloid fibrils (AApoAII). Reduction of caloric intake, known as caloric restriction (CR), slows the progress of senescence and age-related disorders in mice. In this study, we intravenously injected 1 μg of isolated AApoAII fibrils into R1.P1-Apoa2c mice to induce experimental amyloidosis and investigated the effects of CR for the next 16 weeks. In the CR group, AApoAII amyloid deposits in the liver, tongue, small intestine and skin were significantly reduced compared to those of the ad libitum feeding group. CR treatment led to obvious reduction in body weight, improvement in glucose metabolism and reduction in the plasma concentration of ApoA-II. Our molecular biological analyses of the liver suggested that CR treatment might improve the symptoms of inflammation, the unfolded protein response induced by amyloid deposits and oxidative stress. Furthermore, we suggest that CR treatment might improve mitochondrial functions via the sirtuin 1-peroxisome proliferator-activated receptor γ coactivator 1α (SIRT1-PGC-1α) pathway. We suggest that CR is a promising approach for treating the onset and/or progression of amyloidosis, especially for systemic amyloidosis such as senile AApoAII amyloidosis. Our analysis of CR treatment for amyloidosis should provide useful information for determining the cause of amyloidosis and developing effective preventive treatments.



Chang JJ, Bena J, Kannan S, Kim J, Burguera B, Kashyap SR.

Endocr Pract. 2017 Feb 22. doi: 10.4158/EP161383.OR. [Epub ahead of print]

PMID: 28225305




Weight loss maintenance following very-low-calorie meal plans is poorly studied. This report describes weight loss efficacy and predictors of weight loss maintenance of a ketogenic, very-low-calorie meal plan (protein-sparing modified fast, PSMF) in people with obesity.


127 consecutive adults in the PSMF meal plan (27.2 ±19.5 weeks) and 48 adults on a conventional, hypocaloric meal plan (23.6 ±20.8 weeks) were retrospectively studied for percent weight change from baseline to end of intervention and at 6, 12, and 24 months post-intervention. Baseline factors were analyzed for correlations with weight loss maintenance.


At end of intervention, weight loss from baseline was greater for the PSMF group compared to the conventional intervention group (-12.4% vs. -2.6%, p<0.001) but was similar between groups by 12 months post-intervention. PSMF subjects who attended follow-up visits to receive instruction on gradual and limited carbohydrate refeeding after ketosis saw significant weight loss at the end of PSMF compared to those who did not follow up to receive instruction (-17.5% vs. -8.0%, p<0.001) and maintained greater weight loss through 12 months post-PSMF (-9.8% vs. -1.5%, p<0.001). Higher baseline BMI correlated with less weight loss at 12 months post-PSMF (p=0.035).


PSMF results in effective short-term weight loss of more than 5% from baseline weight. Follow-up for limited carbohydrate refeeding instruction is important for weight loss maintenance up to two years after initial weight loss.


diabetes; ketogenic meal plan; obesity; very low calorie meal plan; weight loss maintenance

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Calorically restricted diets decrease PCSK9 in overweight adolescents.

Levenson AE, Milliren CE, Biddinger SB, Ebbeling CB, Feldman HA, Ludwig DS, de Ferranti SD.

Nutr Metab Cardiovasc Dis. 2017 Jan 3. pii: S0939-4753(16)30356-8. doi: 10.1016/j.numecd.2016.12.010. [Epub ahead of print]

PMID: 28228332




Nutritional therapy is the first line approach to treatment of hyperlipidemia in childhood. Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of plasma cholesterol levels and a target of novel lipid-lowering pharmacotherapies. We examined the effects of an intensive nutritional intervention on PCSK9 levels in overweight adolescents with cardiovascular disease (CVD) risk factors.


Twenty seven obese and overweight adolescents with CVD risk factors were assigned to either a low fat or low glycemic load diet. During an 8-week "Intensive Phase," assigned meals were delivered to the home, and all participants received weekly in-person home nutrition counseling and phone calls. The subjects then underwent a 4-month "Maintenance Phase" without food provision and with no in-person contact. Anthropometric measurements, laboratory data, and serum PCSK9 protein levels were measured at baseline, 8 weeks, and 6 months. PCSK9 decreased by 16.5% at 8 weeks (201.2 ± 56.3 vs 165.6 ± 58.4 ng/mL; p < 0.001); PCSK9 levels returned to baseline levels at 6 months, after the Maintenance Phase. Change in PCSK9 was associated with change in fasting insulin, HOMA-IR, and AUC insulin, independent of weight loss.


PCSK9 decreased in youth participating in an intensive dietary intervention. Change in HOMA-IR was associated with change in PCSK9, independent of weight loss, suggesting an important relationship with insulin sensitivity. ClinicalTrials.gov Identifier: NCT01080339.


Adolescents; Dyslipidemia; Nutritional Therapy; Obesity; PCSK9


[The below paper is pdf-availed and the fibers were about 40% smaller and more numerous.]

Reduced skeletal muscle fiber size following caloric restriction is associated with calpain-mediated proteolysis and attenuation of IGF-1 signaling.

Lu Y, Bradley JS, McCoski SR, Gonzalez JM, Ealy AD, Johnson SE.

Am J Physiol Regul Integr Comp Physiol. 2017 Feb 22:ajpregu.00400.2016. doi: 10.1152/ajpregu.00400.2016. [Epub ahead of print]

PMID: 28228415


Caloric restriction decreases skeletal muscle mass in mammals, principally due to a reduction in fiber size. The effect of suboptimal nutrient intake on skeletal muscle metabolic properties in neonatal calves was examined. The longissimus muscle (LM) was collected after 8 wks consuming a control (CON) or caloric restricted (CR) diet and muscle fiber size, gene expression and metabolic signal transduction activity was measured. Results revealed that CR animals had smaller (P < 0.05) LM fiber cross-sectional area than CON, as expected. Western blot analysis detected equivalent amounts of PGC1α-1 but reduced (P < 0.05) amounts of the splice-variant, PGC1α-4 in CR LM. Expression of IGF-1, a PGC1α-4 target gene, was 40% less (P < 0.05) in CR than CON. Downstream mediators of autocrine IGF-1 signaling also are attenuated in CR by comparison to CON. The amount of phosphorylated AKT1 was less (P < 0.05) in CR than CON. The ratio of p4EBP1T37/46:total 4EBP1, a downstream mediator of AKT1, did not differ between CON and CR. By contrast, protein lysates from CR LM contained less (P < 0.05) total GSK3β and phosphorylated GSK3β than CON LM, suggesting blunted protein synthesis. Smaller CR LM fiber size associates with increased (P < 0.05) CAPN1 activity coupled with lower (P < 0.05) expression of calpastatin, the endogenous inhibitor of CAPN1. Atrogin-1 and MuRF expression and autophagy components were unaffected by CR. Thus, CR suppresses the hypertrophic PGC1α-4/IGF-1/AKT1 pathway while promoting activation of the calpain system.


CAPN1; IGF-I; PGC1a; caloric restriction; skeletal muscle


Hepatic iron storage is related to body adiposity and hepatic inflammation.

Park CY, Chung J, Koo KO, Kim MS, Han SN.

Nutr Metab (Lond). 2017 Feb 13;14:14. doi: 10.1186/s12986-017-0169-3.

PMID: 28228829




Obesity has been reported to be associated with iron deficiency. However, few studies have investigated iron status in low adiposity. To investigate whether body adiposity was associated with altered hepatic iron status, we compared liver iron levels and markers involved in inflammation and iron absorption in obese, control, and mildly calorie restricted mice.


Seven week old C57BL/6 mice were fed control (10% kcal fat, Control) or high fat (60% kcal fat, HFD) diets, or reduced amount of control diet to achieve 15% calorie restriction (CR) for 16 weeks. Hepatic non-heme iron content and ferritin protein level, and hematocrit and hemoglobin levels were determined to assess iron status. Hepatic expression of Mcp-1 and Tnf-α were measured as hepatic inflammatory markers. Hepatic hepcidin (Hamp) and Bmp6, and duodenal Dmt1, Dcyt1b, hephaestin (Heph) and ferroportin mRNA levels were measured as factors involved in regulation of iron absorption.


Hepatic non-heme iron and ferritin protein levels were significantly higher in the CR group compared with the Control group, and significantly lower in the HFD group. These two iron status markers showed significantly negative correlations with the amount of white adipose tissue (r = -0.689 for hepatic non-heme iron and r = -0.740 for ferritin). Hepatic Mcp-1 and Tnf-α mRNA levels were significantly lower in the CR compared with the HFD (74 and 47% lower) and showed significantly negative correlations with hepatic non-heme iron levels (Mcp-1: r = -0.557, P < 0.05; Tnf-α: r = -0.464, P < 0.05). Hepatic Hamp mRNA levels were lower in the HFD and higher in the CR groups compared with the Control group, which could be a response to maintain iron homeostasis. Duodenal Dcyt1b mRNA levels were higher in the CR group compared with the HFD group and duodenal Heph mRNA levels were higher in the CR group than the Control group.


We showed that body adiposity was inversely correlated with liver iron status. Low inflammation levels in hepatic milieu and enhanced expression of duodenal oxidoreductases induced by calorie restriction could have contributed to higher iron status.


Body adiposity; Duodenal iron transporter; Hepatic non-heme iron; Hepcidin; Iron absorption; Mild calorie restriction


Antioxidant response is a protective mechanism against nutrient deprivation in C. elegans.

Tao J, Wu QY, Ma YC, Chen YL, Zou CG.

Sci Rep. 2017 Feb 23;7:43547. doi: 10.1038/srep43547.

PMID: 28230214



Animals often experience periods of nutrient deprivation; however, the molecular mechanisms by which animals survive starvation remain largely unknown. In the nematode Caenorhabditis elegans, the nuclear receptor DAF-12 acts as a dietary and environmental sensor to orchestrate diverse aspects of development, metabolism, and reproduction. Recently, we have reported that DAF-12 together with co-repressor DIN-1S is required for starvation tolerance by promoting fat mobilization. In this report, we found that genetic inactivation of the DAF-12 signaling promoted the production of reactive oxygen species (ROS) during starvation. ROS mediated systemic necrosis, thereby inducing organismal death. The DAF-12/DIN-1S complex up-regulated the expression of antioxidant genes during starvation. The antioxidant enzyme GST-4 in turn suppressed ROS formation, thereby conferring worm survival. Our findings highlight the importance of antioxidant response in starvation tolerance and provide a novel insight into multiple organisms survive and adapt to periods of nutrient deprivation.


How Can Diet Affect the Accumulation of Advanced Glycation End-Products in the Human Body?

Guilbaud A, Niquet-Leridon C, Boulanger E, Tessier FJ.

Foods. 2016 Dec 6;5(4). pii: E84. doi: 10.3390/foods5040084. Review.

PMID: 28231179



The accumulation of advanced glycation end products (AGEs) is associated with the complications of diabetes, kidney disease, metabolic disorders and degenerative diseases. It is recognized that the pool of glycation products found in the human body comes not only from an endogenous formation, but also from a dietary exposure to exogenous AGEs. In recent years, the development of pharmacologically-active ingredients aimed at inhibiting endogenous glycation has not been successful. Since the accumulation of AGEs in the human body appears to be progressive throughout life, an early preventive action against glycation could be effective through dietary adjustments or supplementation with purified micronutrients. The present article provides an overview of current dietary strategies tested either in vitro, in vivo or both to reduce the endogenous formation of AGEs and to limit exposure to food AGEs.


Maillard; advanced glycation end products; ageing; calorie restriction; carboxymethyllysine; diabetes; fructose; glycation; probiotics; vitamins

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Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes.

Cheng CW, Villani V, Buono R, Wei M, Kumar S, Yilmaz OH, Cohen P, Sneddon JB, Perin L, Longo VD.

Cell. 2017 Feb 23;168(5):775-788.e12. doi: 10.1016/j.cell.2017.01.040.

PMID: 28235195




Stem-cell-based therapies can potentially reverse organ dysfunction and diseases, but the removal of impaired tissue and activation of a program leading to organ regeneration pose major challenges. In mice, a 4-day fasting mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing β cells, resembling that observed during pancreatic development. FMD cycles restore insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production. The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition. These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models.


Making a splash with splicing.

Branicky R, Hekimi S.

Cell Res. 2017 Feb 24. doi: 10.1038/cr.2017.24. [Epub ahead of print]

PMID: 28233771



Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans.

Heintz C, Doktor TK, Lanjuin A, Escoubas CC, Zhang Y, Weir HJ, Dutta S, Silva-García CG, Bruun GH, Morantte I, Hoxhaj G, Manning BD, Andresen BS, Mair WB.

Nature. 2017 Jan 5;541(7635):102-106. doi: 10.1038/nature20789. Epub 2016 Dec 5.

PMID: 27919065



Nutritional status dependent endocannabinoid signalling regulates the integration of rat visceral information.

Khlaifia A, Matias I, Cota D, Tell F.

J Physiol. 2017 Feb 24. doi: 10.1113/JP273484. [Epub ahead of print]

PMID: 28233325



Communication form the viscera to the brain is essential to set physiological homoeostatic parameters but also to drive more complex behaviours such as mood, memory and emotional states. Here we investigated the impact of the nutritional status on long-term changes in excitatory synaptic transmission in the nucleus tractus solitarius (NTS), a neural hub integrating visceral signals. These excitatory synapses exhibit a CB1 endocannabinoid (eCB) induced long-term depression (LTD) triggered by vagal fibre stimulation. Since eCB signalling is known to be an important component of homoeostatic regulation of the body and is regulated during various stressful conditions, we tested the hypothesis that food deprivation alters eCB signalling in central visceral afferent fibres. Food deprivation prevents eCB-LTD induction due to the absence of eCB signalling. This loss was reverted by blockade of ghrelin receptors. Activation of the cellular fuel sensor AMP-activated protein kinase or inhibition of the mechanistic target of rapamycin pathway abolished eCB-LTD in free-fed rats. Signals associated with energy surfeit, such as short-term refeeding restore eCB-LTD induction, which in turn requires activation of cholecystokinin receptors and the extracellular signal-regulated kinase pathway. These data suggest a tight link between eCB-LTD in the NTS and the nutritional status and shed light on the key role of eCB in the integration of visceral information.


The effects of reduced dietary protein level on amino acid transporters and mTOR signaling pathway in pigs.

Wang D, Wan X, Peng J, Xiong Q, Niu H, Li H, Chai J, Jiang S.

Biochem Biophys Res Commun. 2017 Feb 20. pii: S0006-291X(17)30375-3. doi: 10.1016/j.bbrc.2017.02.084. [Epub ahead of print]

PMID: 28235480



Amino acid transporter plays an important role in regulating mTOR signaling pathway. This study investigated the effects of reduced dietary protein levels on amino acid transporters and mTOR signaling pathway. A total of 54 weaning pigs were randomly allocated into a 3 × 3 factorial design, followed by slaughtering the pigs separately after 10-, 25- and 45-day feeding, with 18 pigs from each feeding period divided into three subgroups for treatment with three different protein-level diets: 20% crude protein (CP) diet (normal recommended, high protein, HP), 17% CP diet (medium protein, MP) and 14% CP diet (low protein, LP). The results indicated that reduced dietary protein level decreased the weight of longissimus dorsi. Additionally, quantitative PCR chip analysis showed that mRNA expression of amino acid transporters SLC38A2, SLC1A7, SLC7A1, SLC7A5, SLC16A10 and SLC3A2 in the LP group were significantly (P < 0.05) higher than those in the MP or HP group, and the phosphorylation of mTOR and S6K1 decreased in the LP group after 25-day feeding. Furthermore, the vitro experimental results further confirmed that the mRNA levels for SLC7A1, SLC7A5, SLC3A2, SLC38A2 and SLC36A1 were increased and the phosphorylation of mTOR and S6K1 was decreased when the concentration of amino acids in C2C12 myoblasts was reduced. All these results indicated that the LP diet induced a high expression of amino acid transporters and the inhibition of the mTOR activity, which resulting in restriction on protein synthesis and longissimus dorsi growth.


Amino acids transporter; Longissimus dorsi weight; Quantitative PCR chip; Reduced dietary protein; mTOR signaling pathway


Different types of dietary advice for women with gestational diabetes mellitus.

Han S, Middleton P, Shepherd E, Van Ryswyk E, Crowther CA.

Cochrane Database Syst Rev. 2017 Feb 25;2:CD009275. doi: 10.1002/14651858.CD009275.pub3. [Epub ahead of print] Review.

PMID: 28236296




Dietary advice is the main strategy for managing gestational diabetes mellitus (GDM). It remains unclear what type of advice is best.


To assess the effects of different types of dietary advice for women with GDM for improving health outcomes for women and babies.


We searched Cochrane Pregnancy and Childbirth's Trials Register (8 March 2016), PSANZ's Trials Registry (22 March 2016) and reference lists of retrieved studies.


Randomised controlled trials comparing the effects of different types of dietary advice for women with GDM.


Two authors independently assessed study eligibility, risk of bias, and extracted data. Evidence quality for two comparisons was assessed using GRADE, for primary outcomes for the mother: hypertensive disorders of pregnancy; caesarean section; type 2 diabetes mellitus; and child: large-for-gestational age; perinatal mortality; neonatal mortality or morbidity composite; neurosensory disability; secondary outcomes for the mother: induction of labour; perineal trauma; postnatal depression; postnatal weight retention or return to pre-pregnancy weight; and child: hypoglycaemia; childhood/adulthood adiposity; childhood/adulthood type 2 diabetes mellitus.


In this update, we included 19 trials randomising 1398 women with GDM, at an overall unclear to moderate risk of bias (10 comparisons). For outcomes assessed using GRADE, downgrading was based on study limitations, imprecision and inconsistency. Where no findings are reported below for primary outcomes or pre-specified GRADE outcomes, no data were provided by included trials. Primary outcomes Low-moderate glycaemic index (GI) versus moderate-high GI diet (four trials): no clear differences observed for: large-for-gestational age (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.22 to 2.34; two trials, 89 infants; low-quality evidence); severe hypertension or pre-eclampsia (RR 1.02, 95% CI 0.07 to 15.86; one trial, 95 women; very low-quality evidence); eclampsia (RR 0.34, 95% CI 0.01 to 8.14; one trial, 83 women; very low-quality evidence) or caesarean section (RR 0.66, 95% CI 0.29 to 1.47; one trial, 63 women; low-quality evidence). Energy-restricted versus no energy-restricted diet (three trials): no clear differences seen for: large-for-gestational age (RR 1.17, 95% CI 0.65 to 2.12; one trial, 123 infants; low-quality evidence); perinatal mortality (no events; two trials, 423 infants; low-quality evidence); pre-eclampsia (RR 1.00, 95% CI 0.51 to 1.97; one trial, 117 women; low-quality evidence); or caesarean section (RR 1.12, 95% CI 0.80 to 1.56; two trials, 420 women; low-quality evidence). DASH (Dietary Approaches to Stop Hypertension) diet versus control diet (three trials): no clear differences observed for: pre-eclampsia (RR 1.00, 95% CI 0.31 to 3.26; three trials, 136 women); however there were fewer caesarean sections in the DASH diet group (RR 0.53, 95% CI 0.37 to 0.76; two trials, 86 women). Low-carbohydrate versus high-carbohydrate diet (two trials): no clear differences seen for: large-for-gestational age (RR 0.51, 95% CI 0.13 to 1.95; one trial, 149 infants); perinatal mortality (RR 3.00, 95% CI 0.12 to 72.49; one trial, 150 infants); maternal hypertension (RR 0.40, 95% CI 0.13 to 1.22; one trial, 150 women); or caesarean section (RR 1.29, 95% CI 0.84 to 1.99; two trials, 179 women). High unsaturated fat versus low unsaturated fat diet (two trials): no clear differences observed for: large-for-gestational age (RR 0.54, 95% CI 0.21 to 1.37; one trial, 27 infants); pre-eclampsia (no cases; one trial, 27 women); hypertension in pregnancy (RR 0.54, 95% CI 0.06 to 5.26; one trial, 27 women); caesarean section (RR 1.08, 95% CI 0.07 to 15.50; one trial, 27 women); diabetes at one to two weeks (RR 2.00, 95% CI 0.45 to 8.94; one trial, 24 women) or four to 13 months postpartum (RR 1.00, 95% CI 0.10 to 9.61; one trial, six women). Low-GI versus high-fibre moderate-GI diet (one trial): no clear differences seen for: large-for-gestational age (RR 2.87, 95% CI 0.61 to 13.50; 92 infants); caesarean section (RR 1.91, 95% CI 0.91 to 4.03; 92 women); or type 2 diabetes at three months postpartum (RR 0.76, 95% CI 0.11 to 5.01; 58 women). Diet recommendation plus diet-related behavioural advice versus diet recommendation only (one trial): no clear differences observed for: large-for-gestational age (RR 0.73, 95% CI 0.25 to 2.14; 99 infants); or caesarean section (RR 0.78, 95% CI 0.38 to 1.62; 99 women). Soy protein-enriched versus no soy protein diet (one trial): no clear differences seen for: pre-eclampsia (RR 2.00, 95% CI 0.19 to 21.03; 68 women); or caesarean section (RR 1.00, 95% CI 0.57 to 1.77; 68 women). High-fibre versus standard-fibre diet (one trial): no primary outcomes reported. Ethnic-specific versus standard healthy diet (one trial): no clear differences observed for: large-for-gestational age (RR 0.14, 95% CI 0.01 to 2.45; 20 infants); neonatal composite adverse outcome (no events; 20 infants); gestational hypertension (RR 0.33, 95% CI 0.02 to 7.32; 20 women); or caesarean birth (RR 1.20, 95% CI 0.54 to 2.67; 20 women). Secondary outcomes For secondary outcomes assessed using GRADE no differences were observed: between a low-moderate and moderate-high GI diet for induction of labour (RR 0.88, 95% CI 0.33 to 2.34; one trial, 63 women; low-quality evidence); or an energy-restricted and no energy-restricted diet for induction of labour (RR 1.02, 95% CI 0.68 to 1.53; one trial, 114 women, low-quality evidence) and neonatal hypoglycaemia (average RR 1.06, 95% CI 0.48 to 2.32; two trials, 408 infants; very low-quality evidence).Few other clear differences were observed for reported outcomes. Longer-term health outcomes and health services use and costs were largely not reported.


Evidence from 19 trials assessing different types of dietary advice for women with GDM suggests no clear differences for primary outcomes and secondary outcomes assessed using GRADE, except for a possible reduction in caesarean section for women receiving a DASH diet compared with a control diet. Few differences were observed for secondary outcomes.Current evidence is limited by the small number of trials in each comparison, small sample sizes, and variable methodological quality. More evidence is needed to assess the effects of different types of dietary advice for women with GDM. Future trials should be adequately powered to evaluate short- and long-term outcomes.


Amylin Acts in the Lateral Dorsal Tegmental Nucleus to Regulate Energy Balance Through Gamma-Aminobutyric Acid Signaling.

Reiner DJ, Mietlicki-Baase EG, Olivos DR, McGrath LE, Zimmer DJ, Koch-Laskowski K, Krawczyk J, Turner CA, Noble EE, Hahn JD, Schmidt HD, Kanoski SE, Hayes MR.

Biol Psychiatry. 2017 Jan 10. pii: S0006-3223(17)30007-0. doi: 10.1016/j.biopsych.2016.12.028. [Epub ahead of print]

PMID: 28237459




The pancreatic- and brain-derived hormone amylin promotes negative energy balance and is receiving increasing attention as a promising obesity therapeutic. However, the neurobiological substrates mediating amylin's effects are not fully characterized. We postulated that amylin acts in the lateral dorsal tegmental nucleus (LDTg), an understudied neural processing hub for reward and homeostatic feeding signals.


We used immunohistochemical and quantitative polymerase chain reaction analyses to examine expression of the amylin receptor complex in rat LDTg tissue. Behavioral experiments were performed to examine the mechanisms underlying the hypophagic effects of amylin receptor activation in the LDTg.


Immunohistochemical and quantitative polymerase chain reaction analyses show expression of the amylin receptor complex in the LDTg. Activation of LDTg amylin receptors by the agonist salmon calcitonin dose-dependently reduces body weight, food intake, and motivated feeding behaviors. Acute pharmacological studies and longer-term adeno-associated viral knockdown experiments indicate that LDTg amylin receptor signaling is physiologically and potentially preclinically relevant for energy balance control. Finally, immunohistochemical data indicate that LDTg amylin receptors are expressed on gamma-aminobutyric acidergic neurons, and behavioral results suggest that local gamma-aminobutyric acid receptor signaling mediates the hypophagia after LDTg amylin receptor activation.


These findings identify the LDTg as a novel nucleus with therapeutic potential in mediating amylin's effects on energy balance through gamma-aminobutyric acid receptor signaling.


Calcitonin; Food intake; IAPP; Motivated behavior; Obesity; Reward

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Metabolically distinct weight loss by 10,12 CLA and caloric restriction highlight the importance of subcutaneous white adipose tissue for glucose homeostasis in mice.

den Hartigh LJ, Wang S, Goodspeed L, Wietecha T, Houston B, Omer M, Ogimoto K, Subramanian S, Gowda GA, O'Brien KD, Kaiyala KJ, Morton GJ, Chait A.

PLoS One. 2017 Feb 28;12(2):e0172912. doi: 10.1371/journal.pone.0172912.

PMID: 28245284





Widely used as a weight loss supplement, trans-10,cis-12 conjugated linoleic acid (10,12 CLA) promotes fat loss in obese mice and humans, but has also been associated with insulin resistance.


We therefore sought to directly compare weight loss by 10,12 CLA versus caloric restriction (CR, 15-25%), an acceptable healthy method of weight loss, to determine how 10,12 CLA-mediated weight loss fails to improve glucose metabolism.


Obese mice with characteristics of human metabolic syndrome were either supplemented with 10,12 CLA or subjected to CR to promote weight loss. Metabolic endpoints such as energy expenditure, glucose and insulin tolerance testing, and trunk fat distribution were measured.


By design, 10,12 CLA and CR caused equivalent weight loss, with greater fat loss by 10,12 CLA accompanied by increased energy expenditure, reduced respiratory quotient, increased fat oxidation, accumulation of alternatively activated macrophages, and browning of subcutaneous white adipose tissue (WAT). Moreover, 10,12 CLA-supplemented mice better defended their body temperature against a cold challenge. However, 10,12 CLA concurrently induced the detrimental loss of subcutaneous WAT without reducing visceral WAT, promoted reduced plasma and WAT adipokine levels, worsened hepatic steatosis, and failed to improve glucose metabolism. Obese mice undergoing CR were protected from subcutaneous-specific fat loss, had improved hepatic steatosis, and subsequently showed the expected improvements in WAT adipokines, glucose metabolism and WAT inflammation.


These results suggest that 10,12 CLA mediates the preferential loss of subcutaneous fat that likely contributes to hepatic steatosis and maintained insulin resistance, despite significant weight loss and WAT browning in mice. Collectively, we have shown that weight loss due to 10,12 CLA supplementation or CR results in dramatically different metabolic phenotypes, with the latter promoting a healthier form of weight loss.


Ketone Body Infusion With 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study.

Gormsen LC, Svart M, Thomsen HH, Søndergaard E, Vendelbo MH, Christensen N, Tolbod LP, Harms HJ, Nielsen R, Wiggers H, Jessen N, Hansen J, Bøtker HE, Møller N.

J Am Heart Assoc. 2017 Feb 27;6(3). pii: e005066. doi: 10.1161/JAHA.116.005066.

PMID: 28242634




High levels of ketone bodies are associated with improved survival as observed with regular exercise, caloric restriction, and-most recently-treatment with sodium-glucose linked transporter 2 inhibitor antidiabetic drugs. In heart failure, indices of ketone body metabolism are upregulated, which may improve energy efficiency and increase blood flow in skeletal muscle and the kidneys. Nevertheless, it is uncertain how ketone bodies affect myocardial glucose uptake and blood flow in humans. Our study was therefore designed to test whether ketone body administration in humans reduces myocardial glucose uptake (MGU) and increases myocardial blood flow.


Eight healthy subjects, median aged 60 were randomly studied twice: (1) During 390 minutes infusion of Na-3-hydroxybutyrate (KETONE) or (2) during 390 minutes infusion of saline (SALINE), together with a concomitant low-dose hyperinsulinemic-euglycemic clamp to inhibit endogenous ketogenesis. Myocardial blood flow was measured by 15O-H2O positron emission tomography/computed tomography, myocardial fatty acid metabolism by 11C-palmitate positron emission tomography/computed tomography and MGU by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Similar euglycemia, hyperinsulinemia, and suppressed free fatty acids levels were recorded on both study days; Na-3-hydroxybutyrate infusion increased circulating Na-3-hydroxybutyrate levels from zero to 3.8±0.5 mmol/L. MGU was halved by hyperketonemia (MGU [nmol/g per minute]: 304±97 [sALINE] versus 156±62 [KETONE], P<0.01), whereas no effects were observed on palmitate uptake oxidation or esterification. Hyperketonemia increased heart rate by ≈25% and myocardial blood flow by 75%.


Ketone bodies displace MGU and increase myocardial blood flow in healthy humans; these novel observations suggest that ketone bodies are important cardiac fuels and vasodilators, which may have therapeutic potentials.


11C‐palmitate; 18F‐fluorodeoxyglucose; cardiac metabolism; hyperketonemia; myocardial glucose uptake; myocardial perfusion; nuclear medicine; positron emission tomography/computed tomography


ZRF1 is a novel S6 kinase substrate that drives the senescence programme.

Barilari M, Bonfils G, Treins C, Koka V, De Villeneuve D, Fabrega S, Pende M.

EMBO J. 2017 Feb 27. pii: e201694966. doi: 10.15252/embj.201694966. [Epub ahead of print]

PMID: 28242756




The inactivation of S6 kinases mimics several aspects of caloric restriction, including small body size, increased insulin sensitivity and longevity. However, the impact of S6 kinase activity on cellular senescence remains to be established. Here, we show that the constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) by tuberous sclerosis complex (TSC) mutations induces a premature senescence programme in fibroblasts that relies on S6 kinases. To determine novel molecular targets linking S6 kinase activation to the control of senescence, we set up a chemical genetic screen, leading to the identification of the nuclear epigenetic factor ZRF1 (also known as DNAJC2, MIDA1, Mpp11). S6 kinases phosphorylate ZRF1 on Ser47 in cultured cells and in mammalian tissues in vivo Knock-down of ZRF1 or expression of a phosphorylation mutant is sufficient to blunt the S6 kinase-dependent senescence programme. This is traced by a sharp alteration in p16 levels, the cell cycle inhibitor and a master regulator of senescence. Our findings reveal a mechanism by which nutrient sensing pathways impact on cell senescence through the activation of mTORC1-S6 kinases and the phosphorylation of ZRF1.


S6 kinase; ZRF1; mTOR; senescence; tuberous sclerosis complex


Impact of carbohydrate restriction in the context of obesity on prostate tumor growth in the Hi-Myc transgenic mouse model.

Allott EH, Macias E, Sanders S, Knudsen BS, Thomas GV, Hursting SD, Freedland SJ.

Prostate Cancer Prostatic Dis. 2017 Feb 28. doi: 10.1038/pcan.2016.73. [Epub ahead of print]

PMID: 28244492




Previously, we showed that carbohydrate restriction with calorie restriction slowed tumor growth in xenograft mouse prostate cancer models. Herein, we examined the impact of carbohydrate restriction without calorie restriction on tumor development within the context of diet-induced obesity in the Hi-Myc transgenic mouse model of prostate cancer.


Mice were randomized at 5 weeks of age to ad libitum western diet (WD; 40% fat, 42% carbohydrate; n=39) or ad libitum no carbohydrate ketogenic diet (NCKD; 82% fat, 1% carbohydrate; n=44). At age 3 or 6 months, mice were killed, prostates weighed and prostate histology, proliferation, apoptosis and macrophage infiltration evaluated by hematoxylin and eosin, Ki67, TUNEL and F4/80 staining, respectively. Body composition was assessed by DEXA, serum cytokines measured using multiplex, and Akt/mTOR signaling assessed by Western.


Caloric intake was higher in the NCKD group, resulting in elevated body weights at 6 months of age, relative to the WD group (45 g vs 38g; P=0.008). Despite elevated body weights, serum monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-1α levels were lower in NCKD versus WD mice (P=0.046 and P=0.118, respectively), and macrophage infiltration was reduced in prostates of NCKD versus WD mice (P=0.028). Relative Akt phosphorylation and phospho-S6 ribosomal protein levels were reduced in prostates of NCKD versus WD mice. However, while mice randomized to NCKD had smaller prostates after adjustment for body weight at 3 and 6 months (P=0.004 and P=0.002, respectively), NCKD mice had higher rates of adenocarcinoma at 6 months compared to WD mice (100 vs 80%, P=0.04).


Despite higher caloric intake and elevated body weights, carbohydrate restriction lowered serum MCP-1 levels, reduced prostate macrophage infiltration, reduced prostate weight, but failed to slow adenocarcinoma development. Together, these data suggest that although carbohydrate restriction within the context of obesity may reduce obesity-associated systemic inflammation and perhaps slow tumor growth, it is not sufficient to counteract obesity-associated tumor development.


Suppressed sympathetic outflow to skeletal muscle, muscle thermogenesis, and activity energy expenditure with calorie restriction.

Almundarij TI, Gavini CK, Novak CM.

Physiol Rep. 2017 Feb;5(4). pii: e13171. doi: 10.14814/phy2.13171.

PMID: 28242830




During weight loss, adaptive thermogenesis occurs where energy expenditure (EE) is suppressed beyond that predicted for the smaller body size. Here, we investigated the contributions of resting and nonresting EE to the reduced total EE seen after 3 weeks of 50% calorie restriction (CR) in rats, focusing on activity-associated EE, muscle thermogenesis, and sympathetic outflow. Prolonged food restriction resulted in a 42% reduction in daily EE, through a 40% decrease in resting EE, and a 48% decline in nonresting EE These decreases in EE were significant even when the reductions in body weight and lean mass were taken into account. Along with a decreased caloric need for low-to-moderate-intensity treadmill activity with 50% CR, baseline and activity-related muscle thermogenesis were also suppressed, though the ability to increase muscle thermogenesis above baseline levels was not compromised. When sympathetic drive was measured by assessing norepinephrine turnover (NETO), 50% CR was found to decrease NETO in three of the four muscle groups examined, whereas elevated NETO was found in white adipose tissue of food-restricted rats. Central activation of melanocortin 4 receptors in the ventromedial hypothalamus stimulated this pathway, enhancing activity EE; this was not compromised by 50% CR These data suggest that suppressed activity EE contributes to adaptive thermogenesis during energy restriction. This may stem from decreased sympathetic drive to skeletal muscle, increasing locomotor efficiency and reducing skeletal muscle thermogenesis. The capacity to increase activity EE in response to central stimuli is retained, however, presenting a potential target for preventing weight regain.


melanocortin 4 receptor (MC4R); nonexercise activity thermogenesis (NEAT); norepinephrine turnover (NETO); sympathetic nervous system (SNS); ventromedial hypothalamus (VMH)


Modified lingguizhugan decoction incorporated with dietary restriction and exercise ameliorates hyperglycemia, hyperlipidemia and hypertension in a rat model of the metabolic syndrome.

Yao L, Wei J, Shi S, Guo K, Wang X, Wang Q, Chen D, Li W.

BMC Complement Altern Med. 2017 Feb 28;17(1):132. doi: 10.1186/s12906-017-1557-y.

PMID: 28241808





Modified Lingguizhugan Decoction (MLD) came from famous Chinese medicine Linggui Zhugan Decoction. The MLD is used for the treatment of metabolic syndrome in the clinical setting. Our study focuses on the comprehensive treatment of MLD incorporated with dietary restriction and exercise in a rat model of the metabolic syndrome (MS).


Rats were divided into five groups: control group (Cont), high-fat diet group (HFD), high-fat diet incorporated with dietary restriction group (HFD-DR), exercise incorporated with dietary restriction group (HFD-DR-Ex) and MLD incorporated with dietary restriction and exercise group (HFD-DR-Ex-MLD). Treatments were conducted for 1 week after feeding high-fat diet for 12 weeks. The effects of treatments on high fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance in rats of MS were examined. In addition, the tumor necrosis factor-α (TNF-α), leptin and protein kinase B (PKB) in rats serum and liver were also examined by enzyme-linked immunosorbent assay (ELISA).


After a week's intervention by dietary restriction, dietary restriction incorporated with exercise or MLD, compared with HFD rats, the relative weight of liver and fat, levels of triglyceride, total cholesterol, low-density lipoprotein, free fatty acid, aspartate aminotransferase, glutamic-pyruvic transaminase and alkaline phosphatase, insulin, were significantly decreased (p < 0.05 or 0.01). This treatment also inhibited abnormal increases of TNF-α, leptin and PKB in serum and liver.


MLD incorporated with dietary restriction and exercise treatment exhibit effects in alleviating high-fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance, which are possibly due to the down-regulation of TNF-α, leptin and PKB.


Dietary restriction; Exercise; High-fat diet; Metabolic syndrome; Modified lingguizhugan decoction


Unraveling the metabolic health benefits of fasting related to religious beliefs: A narrative review.

Persynaki A, Karras S, Pichard C.

Nutrition. 2017 Mar;35:14-20. doi: 10.1016/j.nut.2016.10.005. Review.

PMID: 28241983



Periodic fasting, under a religious aspect, has been adopted by humans for centuries as a crucial pathway of spiritual purification. Caloric restriction, with or without exclusion of certain types of food, is often a key component. Fasting varies significantly among different populations according to cultural habits and local climate conditions. Religious fasting in terms of patterns (continuous versus intermittent) and duration can vary from 1 to 200 d; thus, the positive and negative impact on health can be considerable. Advantages of religious fasting are claimed by many but have been explored mainly by a limited number of studies conducted in Buddhist, Christian, or Muslim populations. These trials indicate that religious fasting has beneficial effects on body weight and glycemia, cardiometabolic risk markers, and oxidative stress parameters. Animals exposed to a diet mimicking fasting have demonstrated weight loss as well as lowered plasma levels of glucose, triacylglycerols, and insulin growth factor-1, although lean body mass remained stable. Diabetic mice on repeated intermittent fasting had less insulin resistance that mice fed ad libitum. The long-term significance of such changes on global health remains to be explored. This review summarizes the data available with regard to benefits of fasting followed for religious reasons on human health, body anthropometry, and cardio-metabolic risk markers; aims to bridge the current knowledge gap on available evidence and suggests considerations for the future research agenda. Future studies should explore every type of religious fasting, as well as their consequences in subpopulations such as children, pregnant women, and the elderly, or patients with chronic metabolic diseases.


Alternate day fasting; Health benefits; Intermittent fasting; Religious fasting; Side-effects


Short fasting does not protect perfused ex vivo rat liver against ischemia-reperfusion. On the importance of a minimal cell energy charge.

Papegay B, Stadler M, Nuyens V, Kruys V, Boogaerts JG, Vamecq J.

Nutrition. 2017 Mar;35:21-27. doi: 10.1016/j.nut.2016.10.008.

PMID: 28241986




Dietary restriction or reduced food intake was supported to protect against renal and hepatic ischemic injury. In this vein, short fasting was recently shown to protect in situ rat liver against ischemia-reperfusion. Here, perfused ex vivo instead of in situ livers were exposed to ischemia-reperfusion to study the impact of disconnecting liver from extrahepatic supply in energetic substrates on the protection given by short-term fasting.


Perfused ex vivo livers using short (18 h) fasted compared with fed rats were submitted to ischemia-reperfusion and studied for release of cytolysis markers in the perfusate. Energetic stores are differently available in time and cell energetic charges (ratio of adenosine triphosphate plus half of the adenosine diphosphate concentrations to the sum of adenosine triphosphate + adenosine diphosphate + adenosine monophosphate concentrations), adenosine phosphates, and glycogen, which were further measured at different time points in livers.


Short fasting versus feeding failed to protect perfused ex vivo rat livers against ischemia/reperfusion, increasing the release of cytolysis markers (potassium, cytochrome c, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) in the perfusate during reoxygenation phase. Toxicity of short fasting versus feeding was associated with lower glycogen and energetic charges in livers and lower lactate levels in the perfusate.


High energetic charge, intracellular content in glycogen, and glycolytic activity may protect liver against ischemia/reperfusion injury. This work does not question how much the protective role previously demonstrated in the literature for dietary restriction and short fasting. In fact, it suggests that exceeding the energy charge threshold value of 0.3 might trigger the effectiveness of this protective role.


Ex vivo perfused liver; Feeding; In situ perfused liver; Short fasting


Time-restricted feeding on weekdays restricts weight gain: A study using rat models of high-fat diet-induced obesity.

Olsen MK, Choi MH, Kulseng B, Zhao CM, Chen D.

Physiol Behav. 2017 Feb 24. pii: S0031-9384(16)30917-9. doi: 10.1016/j.physbeh.2017.02.032. [Epub ahead of print]

PMID: 28242469




A recent study reported that a special weekly scheduled time-restricted feeding regimen (TRF), i.e., no food consumption for 15h during the light (inactive) phase per day for 5 weekdays, attenuated the outcome of diverse nutritional challenges in response to high fat diet in mice. In the present study, we wanted to further test whether this TRF could restrict body weight gain in both juvenile and adult animals when fed a high-fat diet. Fifty male Sprague-Dawley rats at ages from 5 to 27weeks were used. First, we found that freely fed rats with 60% fat diet gained weight significantly, which was associated with more calorie intake (particularly during light phase) than those fed standard food (7% fat). Secondly, we found that TRF restricted high-fat diet-induced weight gain in both groups of juvenile rats (5 and 13weeks of age) compared to freely fed rats with high-fat diet, despite the same levels of 24h-calorie intake during either weekdays or the weekend. Thirdly, we found that TRF did not restrict high fat diet-induce weight gain in adult rats (27weeks of age). Thus, we suggest that this special TRF regimen could be further tested in humans (particularly young adults) for the purpose of obesity prevention.


Body weight; Circadian rhythm; Feeding behavior; Food intake; Obesity

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UCP2 expression is associated with weight loss after hypocaloric diet intervention.

Cortes-Oliveira C, Nicoletti CF, de Souza Pinhel MA, de Oliveira BA, Quinhoneiro DC, Noronha NY, Marchini JS, da Silva Júnior WA, Júnior WS, Nonino CB.

Eur J Clin Nutr. 2016 Oct 19. doi: 10.1038/ejcn.2016.185. [Epub ahead of print]

PMID: 27759071




Although energy restriction contributes to weight loss, it may also reduce energy expenditure, limiting the success of weight loss in the long term. Studies have described how genetics contributes to the development of obesity, and uncoupling proteins 1 and 2 (UCP1 and UCP2) and beta-3-adrenoceptor (ADRB3) have been implicated in the metabolic pathways that culminate in this condition. This study aimed to evaluate how the UCP1, UCP2 and ADRB3 genes influence weight loss in severely obese women submitted to hypocaloric dietary intervention.


This longitudinal study included 21 women divided into two groups: Group 1 (Dietary intervention (G1)) consisted of 11 individuals with severe obesity (body mass index (BMI) ⩾40 kg/m2), selected for dietary intervention and Group 2 (Control (G2)) consisted of 10 normal-weight women (BMI between 18.5 and 24.9 kg/m2). Evaluation included weight (kg), height (m), waist circumference (cm), body composition, resting metabolic rate (RMR, kcal) and abdominal subcutaneous adipose tissue collection. The dietary intervention required that G1 patients remained hospitalized in the university hospital for 6 weeks receiving a hypocaloric diet (1200 kcal per day). The statistical analyses included t-test for paired samples, Spearman correlation and multivariate linear regressions, with the level of significance set at P<0.05.


Weight (155.0±31.4-146.5±27.8 kg), BMI (58.5±10.5-55.3±9.2 kg/m2), fat-free mass (65.4±8.6-63.1±7.1 kg), fat mass (89.5±23.0-83.4±21.0 kg) and RMR (2511.6±386.1-2324.0±416.4 kcal per day) decreased significantly after dietary intervention. Multiple regression analyses showed that UCP2 expression contributed to weight loss after dietary intervention (P=0.05).


UCP2 expression is associated with weight loss after hypocaloric diet intervention.


Less-than-expected weight loss in normal-weight women undergoing caloric restriction and exercise is accompanied by preservation of fat-free mass and metabolic adaptations.

Koehler K, De Souza MJ, Williams NI.

Eur J Clin Nutr. 2016 Oct 26. doi: 10.1038/ejcn.2016.203. [Epub ahead of print]

PMID: 27782114




Normal-weight women frequently restrict their caloric intake and exercise, but little is known about the effects on body weight, body composition and metabolic adaptations in this population.


We conducted a secondary analysis of data from a randomized controlled trial in sedentary normal-weight women. Women were assigned to a severe energy deficit (SEV: -1062±80 kcal per day; n=9), a moderate energy deficit (MOD: -633±71 kcal per day; n=7) or energy balance (BAL; n=9) while exercising five times per week for 3 months. Outcome variables included changes in body weight, body composition, resting metabolic rate (RMR) and metabolic hormones associated with energy conservation.


Weight loss occurred in SEV (-3.7±0.9 kg, P<0.001) and MOD (-2.7±0.8 kg; P=0.003), but weight loss was significantly less than predicted (SEV: -11.1±1.0 kg; MOD: -6.5±1.1 kg; both P<0.001 vs actual). Fat mass declined in SEV (P<0.001) and MOD (P=0.006), whereas fat-free mass remained unchanged in all groups (P>0.33). RMR decreased by -6±2% in MOD (P=0.020). In SEV, RMR did not change on a group level (P=0.66), but participants whose RMR declined lost more weight (P=0.020) and had a higher baseline RMR (P=0.026) than those whose RMR did not decrease. Characteristic changes in leptin (P=0.003), tri-iodothyronine (P=0.013), insulin-like growth factor-1 (P=0.016) and ghrelin (P=0.049) occurred only in SEV. The energy deficit and adaptive changes in RMR explained 54% of the observed weight loss.


In normal-weight women, caloric restriction and exercise resulted in less-than-predicted weight loss. In contrast to previous literature, weight loss consisted almost exclusively of fat mass, whereas fat-free mass was preserved.

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High rates of diabetes reversal in newly diagnosed Asian Indian young adults with type 2 diabetes mellitus with intensive lifestyle therapy.

Sarathi V, Kolly A, Chaithanya HB, Dwarakanath CS.

J Nat Sci Biol Med. 2017 Jan-Jun;8(1):60-63. doi: 10.4103/0976-9668.198343.

PMID: 28250676




There are variable reports on the reversibility of type 2 diabetes mellitus (type 2 DM) with higher rates among younger patients with short duration of diabetes. Hence, we studied the reversibility of diabetes among young adults with newly diagnosed type 2 DM.


This prospective study included 32 patients with newly diagnosed type 2 DM. All type 2 DM patients were initially treated with intensive lifestyle therapy (ILT) (low-calorie diet [1500 kcal/day] and brisk walking for 1 h/day]). Four patients who with HbA1C <9.0% were treated with ILT alone. Except for three patients with concomitant infections who were treated with insulin, remaining 25 patients with HbA1C ≥9.0% were treated with metformin (1000-2000 g) in addition to ILT. When fasting plasma glucose was <126 mg/dl or HbA1C was <6.5% antidiabetic drug dose was reduced or stopped. The patients were followed for a minimum period of 2 years.


Reversal/remission rates at 3 months, 1 year, and 2 years were 24 (75%), 24 (75%), and 22 (68.75%), respectively. Seventeen (53.1%) patients achieved complete reversal and seven (21.9%) patients achieved partial reversal at 3 months. Rates of complete and partial remission at 1 year were 50% and 25% and at 2 years were 46.9% and 21.9%, respectively.


Young adults with newly diagnosed type 2 DM have high rates of diabetes reversal and should receive ILT to achieve reversal of diabetes.


Intensive lifestyle therapy; remission; reversal; type 2 diabetes


Strain-specific differences of the effects of stress on memory in Lymnaea.

Hughes E, Shymansky T, Swinton E, Lukowiak KS, Swinton C, Sunada H, Protheroe A, Phillips I, Lukowiak K.

J Exp Biol. 2017 Mar 1;220(Pt 5):891-899. doi: 10.1242/jeb.149161.

PMID: 28250177



Stress alters the ability to form, recall and maintain memory according to the Yerkes-Dodson/Hebb (YDH) law. The effects of environmentally relevant stressors, such as low environmental calcium and crowding, on learning and memory have previously been described in a laboratory-reared 'average' strain of Lymnaea stagnalis (i.e. the Dutch strain) as well as two strains of freshly collected L. stagnalis with enhanced memory formation abilities (i.e. 'smart' snails). Here, we use L. stagnalis to study the effects of other environmentally relevant stressors on memory formation in two other strains of freshly collected snails, one 'smart' and one 'average'. The stressors we examined are thermal, resource restriction combined with food odour, predator detection and, for the first time, tissue injury (shell damage). We show that the same stressor has significantly different effects on memory formation depending on whether snails are 'smart' or 'average'. Specifically, our data suggest that a stressor or a combination of stressors act to enhance memory in 'average' snails but obstruct memory formation in 'smart' snails. These results are consistent with the YDH law and our hypothesis that 'smart' snails are more easily stressed than 'average' snails.


Average; Environmentally relevant stressors; Learning and memory; Lymnaea; Smart; Strain-specific learning abilities


Metabolism: Calorie restriction for healthy ageing.

Fernández-Ruiz I.

Nat Rev Cardiol. 2017 Mar 2. doi: 10.1038/nrcardio.2017.26. [Epub ahead of print] No abstract available.

PMID: 28250449



One-year calorie restriction impacts gut microbial composition but not its metabolic performance in obese adolescents.

Ruiz A, Cerdó T, Jáuregui R, Pieper DH, Marcos A, Clemente A, García F, Margolles A, Ferrer M, Campoy C, Suárez A.

Environ Microbiol. 2017 Mar 2. doi: 10.1111/1462-2920.13713. [Epub ahead of print]

PMID: 28251782



Recent evidence has disclosed a connection between gut microbial glycosidase activity and adiposity in obese. Here, we measured microbial α-glucosidase and β-galactosidase activities and sorted fluorescently labeled β-galactosidase containing (βGAL) microorganisms in faecal samples of eight lean and thirteen obese adolescents that followed a controlled calorie restriction program during one year. β-galactosidase is a highly distributed functional trait, mainly expressed by members of Blautia, Bacteroides, Alcaligenes, Acinetobacter and Propionibacterium. Only long-term calorie restriction induced clear changes in the microbiota of obese adolescents. Long-term calorie restriction induced significant shifts in total and βGAL gut microbiota, reducing the Firmicutes:Bacteroidetes ratio and enhancing the growth of beneficial microorganisms such as Bacteroides, Roseburia, Faecalibacterium and Clostridium XIVa. Moreover, the structure and composition of βGAL community in obese after long-term calorie restriction was highly similar to that of lean adolescents. However, despite this high compositional similarity, microbial metabolic performance was different, split in two metabolic states at a body mass index value of 25. Our study shows that calorie restriction is a strong environmental force reshaping gut microbiota though its metabolic performance is linked to host's adiposity, suggesting that functional redundancy and metabolic plasticity are fundamental properties of gut microbial ecosystem.


Diet affects arctic ground squirrel gut microbial metatranscriptome independent of community structure.

Hatton JJ, Stevenson TJ, Buck CL, Duddleston KN.

Environ Microbiol. 2017 Mar 2. doi: 10.1111/1462-2920.13712. [Epub ahead of print]

PMID: 28251799



We examined the effect of diet on pre-hibernation fattening and the gut microbiota of captive arctic ground squirrels (Urocitellus parryii). We measured body composition across time and gut microbiota density, diversity, and function prior to and after five-weeks on control, high-fat, low-fat (18%, 40%, and 10% energy from fat, respectively), or restricted calorie (50% of control) diets. Squirrels fattened at the same rate and to the same degree on all diets. Additionally, we found no differences in gut microbiota diversity or short chain fatty acid production across time or with diet. Analysis of the gut microbial transcriptome indicated differences in community function among diet groups, but not across time, and revealed shifts in the relative contribution of function at a taxonomic level. Our results demonstrate that pre-hibernation fattening of arctic ground squirrels is robust to changes in diet and is accomplished by more than increased food intake. Although our analyses did not uncover a definitive link between host fattening and the gut microbiota, and suggest the squirrels may possess a gut microbial community structure that is unresponsive to dietary changes, studies manipulating diet earlier in the active season may yet uncover a relationship between host diet, fattening and gut microbiota.


Alkylresorcinols activate SIRT1 and delay ageing in Drosophila melanogaster.

Kayashima Y, Katayanagi Y, Tanaka K, Fukutomi R, Hiramoto S, Imai S.

Sci Rep. 2017 Mar 2;7:43679. doi: 10.1038/srep43679.

PMID: 28252007



Sirtuins are enzymes that catalyze NAD+ dependent protein deacetylation. The natural polyphenolic compound resveratrol received renewed interest when recent findings implicated resveratrol as a potent SIRT1 activator capable of mimicking the effects of calorie restriction. However, resveratrol directly interacts with fluorophore-containing peptide substrates. It was demonstrated that the SIRT1 activation of resveratrol is affected by the amino acid composition of the substrate. Resveratrol did increase the enzyme activity in cases in which hydrophobic amino acids are at the +1 position to the acetylated lysine in the substrate. Alkylresorcinols (ARs) are compounds that belong to the family of phenolic lipids, and they are found in numerous biological species. Here we show that the natural activators ARs increased the Vmax of recombinant SIRT1 for NAD+ and peptide substrate, and that ARs decreased acetylated histone in human monocyte cells by stimulating SIRT1-dependent deacetylation of substrates. ARs also extended the lifespan of Drosophila melanogaster, which was shown to be dependent on functional Sir2. Our results demonstrated that ARs are natural catalytic activators for sirtuin.


Moderate dietary protein restriction alters the composition of gut microbiota and improves ileal barrier function in adult pig model.

Fan P, Liu P, Song P, Chen X, Ma X.

Sci Rep. 2017 Mar 2;7:43412. doi: 10.1038/srep43412.

PMID: 28252026



This study was conducted to investigate impacts of dietary protein levels on gut bacterial community and gut barrier. The intestinal microbiota of finishing pigs, fed with 16%, 13% and 10% crude protein (CP) in diets, respectively, were investigated using Illumina MiSeq sequencing. The ileal bacterial richness tended to decrease when the dietary protein concentration reduced from 16% to 10%. The proportion of Clostridium_sensu_stricto_1 in ileum significantly decreased, whereas Escherichia-Shigella increased with reduction of protein concentration. In colon, the proportion of Clostridium_sensu_stricto_1 and Turicibacter increased, while the proportion of RC9_gut_group significantly decreased with the dietary protein reduction. Notably, the proportion of Peptostreptococcaceae was higher in both ileum and colon of 13% CP group. As for metabolites, the intestinal concentrations of SCFAs and biogenic amines decreased with the dietary protein reduction. The 10% CP dietary treatment damaged ileal mucosal morphology, and decreased the expression of biomarks of intestinal cells (Lgr5 and Bmi1), whereas the expression of tight junction proteins (occludin and claudin) in 13% CP group were higher than the other two groups. In conclusion, moderate dietary protein restriction (13% CP) could alter the bacterial community and metabolites, promote colonization of beneficial bacteria in both ileum and colon, and improve gut barrier function.


Case Study: The Effect of 32 Weeks of Figure-Contest Preparation on a Self-Proclaimed Drug-free Female's Lean Body and Bone Mass.

Petrizzo J, DiMenna FJ, Martins K, Wygand J, Otto RM.

Int J Sport Nutr Exerc Metab. 2017 Mar 2:1-21. doi: 10.1123/ijsnem.2016-0313. [Epub ahead of print]

PMID: 28253030



To achieve the criterion appearance prior to competing in a physique competition, athletes undergo preparatory regimens involving high-volume intense resistance and aerobic exercise with hypocaloric energy intake. As the popularity of "drug-free" competition increases, more athletes are facing this challenge without the recuperative advantage provided by performance-enhancing drugs. Consequently, the likelihood of loss of lean body and/or bone mass is increased. The purpose of this investigation was to monitor changes in body composition for a 29-year-old self-proclaimed drug-free female figure competitor during a 32-week preparatory regimen comprising high-volume resistance and aerobic exercise with hypocaloric energy intake. We used dual-energy x-ray absorptiometry (DXA) to evaluate regional fat and bone mineral density. During the initial 22 weeks, the subject reduced energy intake and engaged in resistance (4-5 sessions/week) and aerobic (3 sessions/week) training. During the final 10 weeks, the subject increased exercise frequency to 6 (resistance) and 4 (aerobic) sessions/week while ingesting 1130-1380 kcal/day. During this 10-week period, she consumed a high quantity of protein (~55% of energy intake) and nutritional supplements. During the 32 weeks, body mass and fat mass decreased by 12% and 55%, respectively. Conversely, lean body mass increased by 1.5%, an amount that exceeded the coefficient of variation associated with DXA-derived measurement. Total bone mineral density was unchanged throughout. In summary, in preparation for a figure competition, a self-proclaimed drug-free female achieved the low body-fat percentage required for success in competition without losing lean mass or bone density by following a 32-week preparatory exercise and nutritional regimen.


Figure Competition; High-intensity Exercise; Hypocaloric Diet

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Regulation of 11β-hydroxysteroid dehydrogenase type 1 following caloric restriction and re-feeding is species dependent.

Loerz C, Staab-Weijnitz C, Huebbe P, Giller K, Metges C, Rimbach G, Maser E.

Chem Biol Interact. 2017 Feb 27. pii: S0009-2797(17)30217-X. doi: 10.1016/j.cbi.2017.02.018. [Epub ahead of print]

PMID: 28254522



Evidence in the current literature suggests that expression and activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a key regulatory enzyme in glucocorticoid metabolism, is elevated in the liver and reduced in visceral adipose tissue and skeletal muscle following caloric restriction (CR). In order to investigate the influence of CR on 11β-HSD1 in more detail, we assessed expression and activity of 11β-HSD1 in several tissues in two independent CR and re-feeding animal models. Levels and activity of 11β-HSD1 after CR and re-feeding were measured [mouse liver and pig liver, pig visceral adipose tissue and pig skeletal muscle] using semi-quantitative RT-PCR, Western Blot analysis, and HPLC. After CR, no significant difference on mRNA levels was detected in mouse liver. But 11β-HSD1 mRNA expression was upregulated after subsequent re-feeding. In contrast, 11β-HSD1 protein expression after CR was significantly up-regulated, while no difference was detected after re-feeding. Interestingly, upregulation of protein after CR (1.4-fold) was lower than the increase in enzymatic activity (2.6-fold). Furthermore, while no difference was observed in protein levels after two weeks re-feeding, 11β-HSD1 activity increased 2.5-fold. In pig tissues neither 11β-HSD1 mRNA levels, protein expression or enzyme activity were influenced after CR and re-feeding. Overall, the results demonstrate species-dependent differences in regulation of 11β-HSD1 following CR and suggest the presence of an additional regulation step for 11β-HSD1 activity in mouse liver.


Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction.

Fujii N, Narita T, Okita N, Kobayashi M, Furuta Y, Chujo Y, Sakai M, Yamada A, Takeda K, Konishi T, Sudo Y, Shimokawa I, Higami Y.

Aging Cell. 2017 Mar 3. doi: 10.1111/acel.12576. [Epub ahead of print]

PMID: 28256090



Caloric restriction (CR) can delay onset of several age-related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissue (WAT). In studies using genetically modified mice with extended lifespans, WAT characteristics influenced mammalian lifespans. However, molecular mechanisms underlying CR-associated metabolic remodeling of WAT remain unclear. Sterol regulatory element-binding protein-1c (Srebp-1c), a master transcription factor of fatty acid (FA) biosynthesis, is responsible for the pathogenesis of fatty liver (steatosis). Our study showed that, under CR conditions, Srebp-1c enhanced mitochondrial biogenesis via increased expression of peroxisome proliferator-activated receptor gamma coactivator-1α (Pgc-1α) and upregulated expression of proteins involved in FA biosynthesis within WAT. However, via Srebp-1c, most of these CR-associated metabolic alterations were not observed in other tissues, including the liver. Moreover, our data indicated that Srebp-1c may be an important factor both for CR-associated suppression of oxidative stress, through increased synthesis of glutathione in WAT, and for the prolongevity action of CR. Our results strongly suggested that Srebp-1c, the primary FA biosynthesis-promoting transcriptional factor implicated in fatty liver disease, is also the food shortage-responsive factor in WAT. This indicated that Srebp-1c is a key regulator of metabolic remodeling leading to the beneficial effects of CR.


caloric restriction (CR); mitochondria biogenesis; oxidative stress; peroxisome proliferator-activated receptor gamma coactivator-1α (Pgc-1α); sterol regulatory element binding protein-1c (Srebp-1c); white adipose tissue (WAT)


Matching Meals to Body Clocks-Impact on Weight and Glucose Metabolism.

Hutchison AT, Wittert GA, Heilbronn LK.

Nutrients. 2017 Mar 2;9(3). pii: E222. doi: 10.3390/nu9030222. Review.

PMID: 28257081



The prevalence of type 2 diabetes continues to rise worldwide and is reaching pandemic proportions. The notion that this is due to obesity, resulting from excessive energy consumption and reduced physical activity, is overly simplistic. Circadian de-synchrony, which occurs when physiological processes are at odds with timing imposed by internal clocks, also promotes obesity and impairs glucose tolerance in mouse models, and is a feature of modern human lifestyles. The purpose of this review is to highlight what is known about glucose metabolism in animal and human models of circadian de-synchrony and examine the evidence as to whether shifts in meal timing contribute to impairments in glucose metabolism, gut hormone secretion and the risk of type 2 diabetes. Lastly, we examine whether restricting food intake to discrete time periods, will prevent or reverse abnormalities in glucose metabolism with the view to improving metabolic health in shift workers and in those more generally at risk of chronic diseases such as type 2 diabetes and cardiovascular disease.


chronic disease risk; circadian rhythm; glucose metabolism; time-restricted feeding; type 2 diabetes

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Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor

by Jessica Coppens, Eduard Bentea, Jacqueline A. Bayliss, Thomas Demuyser, Laura Walrave, Giulia Albertini, Joeri Van Liefferinge, Lauren Deneyer, Najat Aourz, Ann Van Eeckhaut, Jeanelle Portelli, Zane B. Andrews, Ann Massie, Dimitri De Bundel and Ilse Smolders

Int. J. Mol. Sci. 2017, 18(3), 558; doi:10.3390/ijms18030558 (registering DOI)

Received: 21 December 2016 / Revised: 14 February 2017 / Accepted: 20 February 2017 / Published: 4 March 2017



Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT) and knockout (KO) mice were maintained on an ad libitum (AL) diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect.

Keywords: Parkinson’s disease; caloric restriction; lactacystin; ghrelin receptor


the Trumpet

The Thin Evidence of Counting Calories

March 5, 2017 • From theTrumpet.com

It’s not the quantity that counts.


If you’re one of 45 million Americans planning a low-calorie, quick-fix diet to solve your weight or health problem, take some advice: Don’t. Many doctors, nutritionists and food marketers actively promote restrictive eating, but there are good reasons to take a different approach.

According to Scientific American, the source of your calories is more important than just how many you eat. In fact, what makes us fat is not necessarily just a calorie imbalance but also a hormonal divergence, with the prime suspect being the quality of the foods we consume.

A Faulty Beginning

In 1921, Lulu Hunt Peters wrote the first American blockbuster diet book, Diet and Health, With Key to the Calories. Since then, restricting calories has been the main form of “dieting.” Peters wrote, “A person can eat what they like—candy, pie, cake, fat meat, butter, cream—but they need to count calories!”

Seventy years later, not much had changed. The American Journal of Medicine said that between 1980 and 1990, Americans were consuming 4 percent fewer calories and 11 percent less fats than before, and fat-free food consumption rose from 19 percent to 76 percent. Yet over the same decade, obesity in America rose a bewildering 31 percent.

Now we are over 90 years on, and the long-held notion of calorie restriction still hovers at a dismal 95 percent long-term failure rate; often, it proves harmful. Yet people continue to count their calories—and eat “low calorie” pre-packaged pies, cakes and so on as they do.

A Hormonal Issue?

Calories are important factors in weight loss and weight maintenance. But food quality is more important. More and more experts are seeing that it is better to consume quality food than to reduce calories. Unfortunately in America, convenience food is found in every nook and cranny. The average American now consumes 2,481 calories a day, about 23 percent more than in 1970.

As a person becomes conscious of weight gain, he often cuts back on calories. Instead of reaching for healthier, more natural foods, many turn to more processed, low-calorie options, with unexpected results. They do not stop to realize that a given calorie’s worth of salmon, olive oil, white rice or boxed cereal each has a different effect in the body. Whole foods inhibit appetite and promote energy, while processed foods promote hunger and energy storage.

Dr. David Ludwig, author of Always Hungry, writes that we have to think about obesity in terms of what makes us overeat: “When you’re gaining weight, something has triggered your fat cells to store too much energy, which doesn’t leave enough for the rest of the body. That ‘something’ is often the hormone insulin.”

While generally there is no one whole-food nutrient to blame for insulin trouble and weight gain, Ludwig correctly singles out refined grains, starches and sugars (found in many low-calorie foods) as the principal drivers. When your body’s insulin response is out of control, cutting back further on calories can actually make the problem worse. The excess insulin secretion causes cells to retain fat rather than using it to fuel the body. As few as 10 or 20 calories stored as excess fat each day can lead to obesity over decades.

Some experts still insist that all grains are problematic, but this is not true if they are complex and unprocessed. It’s the hyper-processed, overly stimulating foods with their intense taste and textures that are unhealthy and create food addictions. They also put the brakes on satiating hormonal signals, slow down your metabolism, cause thyroid hormones to drop and cortisol levels to rise, and activate fat-storage enzymes. The end result: excess body fat storage.

Journal Your Way to Health

Our bodies are complex and intricate creations. Since we must store nutrients continually in the body, we also have to eat a balanced, nutritious daily diet. Depriving the body of healthy food—or much food at all—in order to lose weight is the worst thing to do.

Natural foods, which have the highest nutritional content, do not need nutrition labels because they are often the lowest in calories anyway. But even natural meat and dairy foods that have higher calorie counts will nourish your body when consumed with the proper balance. To make sure you eat enough natural foods, you have to understand your eating habits. The easiest way to do so is not to relentlessly track every calorie based on its packaging and labels, but to instead keep a simple daily food journal. Note what you eat and how much, as well as perhaps when and why. This can be as simple as leaving a notepad out near the kitchen or in a kitchen drawer and jotting down, 3 cups spaghetti, 2 cups broccoli, 1 glass water.

The Creator of the human body also designed the food that fuels it. Humanly manufactured and mass-produced products simply are not proper fuel. God’s principle in eating, as with many other aspects of life, is always BALANCE. Whether you have a weight or health problem, you don’t need to restrict your calories. You can undo decades of unbalanced and excessive eating by sticking to a wide variety of high-quality, fresh, natural, unprocessed foods. As you adjust your expectations and your taste buds to this type of eating, you will find it to be free of unpleasant side effects, filling, easily sustained and much tastier!

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Uncouplers of Oxidation and Phosphorylation as Antiaging Compounds.

Knorre DA, Severin FF.

Biochemistry (Mosc). 2016 Dec;81(12):1438-1444. doi: 10.1134/S0006297916120051. Review.

PMID: 28259121



Food restriction causes a set of physiological changes that reduce the rate of aging. At the level of an organism, these changes are initiated by a hormonal response, which in turn activates certain intracellular signaling cascades. As a result, cells increase their antioxidant capacities and decrease the risk of cancerous transformation. A number of small molecule compounds activating these signaling cascades have been described. One could expect that direct pharmacological activation of the signaling can produce a stronger antiaging effect than that achieved by the indirect hormonal stimulation. Data from the literature point to the opposite. Possibly, a problem with pharmacological activators is that they cause generation of mitochondrial reactive oxygen species. Indeed, hyperpolarized mitochondria are known to induce oxidative stress. Such hyperpolarization could happen because of artificial activation of cellular response to caloric restriction in the absence of energy deficit. At the same time, energy deficit seems likely to be a natural consequence of the shortage of nutrients. Thus, there is a possibility that combining the pharmacological activators with compounds that decrease mitochondrial transmembrane potential, uncouplers, could be a powerful antiaging strategy.

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Concentration-dependent linkage of dietary methionine restriction to the components of its metabolic phenotype.

Forney LA, Wanders D, Stone KP, Pierse A, Gettys TW.

Obesity (Silver Spring). 2017 Mar 6. doi: 10.1002/oby.21806. [Epub ahead of print]

PMID: 28261952




Restricting dietary methionine to 0.17% produces a series of physiological responses through coordinated transcriptional effects in liver and adipose tissue. The goal of the present work was to determine the threshold concentrations above and below 0.17% at which the beneficial responses to 0.17% dietary methionine are preserved.


Diets were formulated to restrict methionine to different degrees, followed by evaluation of the transcriptional and physiological responses to the different diets.


Restriction of dietary methionine to 0.25%, but not 0.34%, was partially effective in reproducing the metabolic phenotype produced by restriction of methionine to 0.17%, while restriction of methionine to 0.12% reproduced the responses produced by restriction to 0.17% but failed to support growth and caused excessive weight loss. Restriction beyond 0.12% initiated responses characteristic of essential amino acid deprivation including food aversion and rapid weight loss.


Restriction of dietary methionine to levels above 0.25% was without effect, while restriction to levels below 0.12% produced responses characteristic of essential amino acid deprivation. In addition, although restriction of dietary methionine to 0.12% did not evoke essential amino acid deprivation responses, it provided insufficient methionine to support growth. The ideal range of dietary methionine restriction was from 0.17% to 0.25%.


Dietary restriction protects against diethylnitrosamine-induced hepatocellular tumorigenesis by restoring the disturbed gene expression profile.

Duan T, Sun W, Zhang M, Ge J, He Y, Zhang J, Zheng Y, Yang W, Shen HM, Yang J, Zhu X, Yu P.

Sci Rep. 2017 Mar 6;7:43745. doi: 10.1038/srep43745.

PMID: 28262799



Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent malignancies, worse still, there are very limited therapeutic measures with poor clinical outcomes. Dietary restriction (DR) has been known to inhibit spontaneous and induced tumors in several species, but the mechanisms are little known. In the current study, by using a diethylnitrosamine (DEN)-induced HCC mice model, we found that DR significantly reduced the hepatic tumor number and size, delayed tumor development, suppressed proliferation and promoted apoptosis. Further transcriptome sequencing of liver tissues from the DEN and the DEN accompanied with DR (DEN+DR) mice showed that DEN induced profound changes in the gene expression profile, especially in cancer-related pathways while DR treatment reversed most of the disturbed gene expression induced by DEN. Finally, transcription factor enrichment analysis uncovered the transcription factor specificity protein 1 (SP1) probably functioned as the main regulator of gene changes, orchestrating the protective effects of DR on DEN induced HCC. Taken together, by the first comprehensive transcriptome analysis, we elucidate that DR protects aginst DEN-induced HCC by restoring the disturbed gene expression profile, which holds the promise to provide effective molecular targets for cancer therapies.


Meal pattern alterations associated with intermittent fasting for weight loss are normalized after high-fat diet re-feeding.

Gotthardt JD, Bello NT.

Physiol Behav. 2017 Mar 2. pii: S0031-9384(16)31081-2. doi: 10.1016/j.physbeh.2017.02.046. [Epub ahead of print]

PMID: 28263771



Alternate day, intermittent fasting (IMF) can be an effective weight loss strategy. However, the effects of IMF on eating behaviors are not well characterized. We investigated the acute and residual effects of IMF for weight loss on meal patterns in adult obese male C57BL/6 mice. After 8weeks of ad libitum high-fat diet to induce diet-induced obesity (DIO), mice were either continued on ad libitum high-fat diet (HFD) or placed on one of 5 diet strategies for weight loss: IMF of high-fat diet (IMF-HFD), pair-fed to IMF-HFD group (PF-HFD), ad libitum low-fat diet (LFD), IMF of low-fat diet (IMF-LFD), or pair-fed to IMF-LFD group (PF-LFD). After the 4-week diet period, all groups were refed the high-fat diet for 6weeks. By the end of the diet period, all 5 groups had lost weight compared with HFD group, but after 6weeks of HFD re-feeding all groups had similar body weights. On (Day 2) of the diet period, IMF-HFD had greater first meal size and faster eating rate compared with HFD. Also, first meal duration was greater in LFD and IMF-LFD compared with HFD. At the end of the diet period (Day 28), the intermittent fasting groups (IMF-HFD and IMF-LFD) had greater first meal sizes and faster first meal eating rate compared with their respective ad libitum fed groups on similar diets (HFD and LFD). Also, average meal duration was longer on Day 28 in the low-fat diet groups (LFD and IMF-LFD) compared with high-fat diet groups (HFD and IMF-HFD). After 6weeks of HFD re-feeding (Day 70), there were no differences in meal patterns in groups that had previously experienced intermittent fasting compared with ad libitum fed groups. These findings suggest that meal patterns are only transiently altered during alternate day intermittent fasting for weight loss in obese male mice.


Body fat; Caloric restriction; Dieting; Feeding; Glucose homeostasis; Intermittent fasting; Meal patterns


Effect of orlistat on periostin, adiponectin, inflammatory markers and ultrasound grades of fatty liver in obese NAFLD patients.

Ali Khan R, Kapur P, Jain A, Farah F, Bhandari U.

Ther Clin Risk Manag. 2017 Feb 20;13:139-149. doi: 10.2147/TCRM.S124621.

PMID: 28260907



Orlistat is recommended in the treatment of obesity, which is an independent risk factor for nonalcoholic fatty liver disease (NAFLD). The reported findings of orlistat in NAFLD are divisive. Recently, periostin is identified as an important regulatory molecule in the pathogenesis of obesity-induced fatty liver. Therefore, this study aimed to evaluate the potential effects of orlistat in the treatment of NAFLD. A 16-week prospective observational study was conducted, with obese NAFLD patient (n=77) receiving orlistat (120 mg capsules, three times a day) with hypocaloric diet or hypocaloric diet only. Grades of fatty liver were determined using ultrasound (US) echogenicity of liver; serum levels of periostin, adiponectin, tumor necrosis factor (TNF)-α and interleukin-6 were determined using ELISA kits at 0 and 16 weeks. Correlations of US grades of fatty liver with these biomarkers were also determined. Orlistat significantly reversed the US grades of fatty liver (P=0.016), decreased serum levels of periostin (P=0.030) and TNF-α (P=0.040), and increased serum adiponectin levels (P<0.001) when compared with hypocaloric diet only. Serum interleukin-6 levels were not found to be significantly different in both groups after the treatment. In the orlistat group, the degree of reduction in grades of fatty liver was found to be positively correlated with the changes in serum levels of periostin (rs=0.306, P=0.041) and adiponectin (rs=0.314, P=0.036), whereas the associations were insignificant with the change in serum levels of TNF-α (rs=0.053, P=0.729). Mild gastrointestinal side effects (20%) were reported in the orlistat group. In conclusion, orlistat is effective in the treatment of NAFLD patients without fibrosis. This study demonstrated a positive association between the reduction of fatty infiltration in the liver and the changes in serum levels of periostin and adiponectin in obese NAFLD patients.


NAFLD; obesity; orlistat; periostin; ultrasound grades of fatty liver

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Liver metabolic changes induced by conjugated linoleic acid in calorie-restricted rats.

Moraes C, Oliveira CA, Amaral ME, Landini GA, Catisti R.

Arch Endocrinol Metab. 2017 Jan-Feb;61(1):45-53. doi: 10.1590/2359-3997000000186.

PMID: 28273203




Complexes like conjugated linoleic acid (CLA) reduce the percentage of body fat by increasing energy expenditure, fat oxidation, or both. The aim of this study was to verify if CLA is able to mimic caloric restriction (CR), and determine the effects of CLA on liver metabolic profile of young adult male Wistar rats.


We divided 36 animals into the following groups: 1) Control; 2) CLA (1% of daily food intake, 21 days, orogastric intubation); 3) Restr (fed 60% of the diet offered to controls); and 4) CLA Restr. Liver tissues were processed for biochemical and molecular or mitochondrial isolation (differential centrifugation) and blood samples were collected for biochemical analyses.


Treatment of the animals for 21 days with 1% CLA alone or combined with CR increased liver weight and respiration rates of liver mitochondria suggesting significant mitochondrial uncoupling. We observed a decrease in adipose tissue leading to insulin resistance, hyperinsulinemia, and hepatic steatosis due to increased liver cholesterol and triacylglycerol levels, but no significant effects on body mass. The expression of hepatic cellular connexins (43 and 26) was significantly higher in the CLA group compared with the Control or Restr groups.


CLA does not seem to be a safe compound to induce mass loss because it upregulates the mRNA expression of connexins and induces hepatic mitochondrial changes and lipids disorders.


Matching Dietary Amino Acid Balance to the In Silico-Translated Exome Optimizes Growth and Reproduction without Cost to Lifespan.

Piper MD, Soultoukis GA, Blanc E, Mesaros A, Herbert SL, Juricic P, He X, Atanassov I, Salmonowicz H, Yang M, Simpson SJ, Ribeiro C, Partridge L.

Cell Metab. 2017 Mar 7;25(3):610-621. doi: 10.1016/j.cmet.2017.02.005.

PMID: 28273481




Balancing the quantity and quality of dietary protein relative to other nutrients is a key determinant of evolutionary fitness. A theoretical framework for defining a balanced diet would both reduce the enormous workload to optimize diets empirically and represent a breakthrough toward tailoring diets to the needs of consumers. Here, we report a simple and powerful in silico technique that uses the genome information of an organism to define its dietary amino acid requirements. We show for the fruit fly Drosophila melanogaster that such "exome-matched" diets are more satiating, enhance growth, and increase reproduction relative to non-matched diets. Thus, early life fitness traits can be enhanced at low levels of dietary amino acids that do not impose a cost to lifespan. Exome matching also enhanced mouse growth, indicating that it can be applied to other organisms whose genome sequence is known.


Drosophila; amino acids; diet balance; dietary restriction; fitness; growth; lifespan; mouse; reproduction; trade-off

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Effects of a 72 hours fasting on brain metabolism in healthy women studied in vivo with magnetic resonance spectroscopic imaging.

Ding XQ, Maudsley AA, Schweiger U, Schmitz B, Lichtinghagen R, Bleich S, Lanfermann H, Kahl KG.

J Cereb Blood Flow Metab. 2017 Jan 1:271678X17697721. doi: 10.1177/0271678X17697721. [Epub ahead of print]

PMID: 28273723



Adaptive response of human brain to stress plays a key role in maintaining health. Knowledge about how stress affects neurometabolism may help to understand adaptive stress responses, and distinguish maladaptation in neuropsychiatric disorders. In this study, neurometabolic responses to fasting stress in healthy women were investigated. Fifteen healthy females were examined for mood and cognition and using whole-brain MR spectroscopic imaging before and immediately after a 72-h fasting. Results were compared to 15 age-matched healthy females who did not taken part in fasting (non-fasting). Maps of the distributions in the brain of N-acetylaspartate (NAA), total choline (tCho), total creatine (tCr), glutamine/glutamate (Glx), and myo-Inositol (mI) were derived. Metabolite concentrations of each brain lobe and cerebellum measured before fasting were compared to those of post-fasting and non-fasting by repeated-measures ANOVA. After fasting, mood scores significantly increased. Glx decreased in all nine brain regions, tCho in eight, NAA in four and tCr in one, with Glx having the greatest change and the frontal lobes being the most affected brain region. In conclusion, fasting directly influences neurometabolism, and the adaptive brain response to maintain energy homeostasis under food deprivation in healthy women is associated with metabolite-selective and region-dependent changes of metabolite contents.


Brain imaging; MR metabolite; MR spectroscopy; energy metabolism; glutamate; molecular imaging


Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor.

Coppens J, Bentea E, Bayliss JA, Demuyser T, Walrave L, Albertini G, Van Liefferinge J, Deneyer L, Aourz N, Van Eeckhaut A, Portelli J, Andrews ZB, Massie A, De Bundel D, Smolders I.

Int J Mol Sci. 2017 Mar 4;18(3). pii: E558. doi: 10.3390/ijms18030558.

PMID: 28273852



Parkinson's disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT) and knockout (KO) mice were maintained on an ad libitum (AL) diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect.


Parkinson’s disease; caloric restriction; ghrelin receptor; lactacystin


Dietary protein, aging and nutritional geometry.

Simpson SJ, Couteur DG, Raubenheimer D, Solon-Biet SM, Cooney GJ, Cogger VC, Fontana L.

Ageing Res Rev. 2017 Mar 5. pii: S1568-1637(17)30046-6. doi: 10.1016/j.arr.2017.03.001. [Epub ahead of print] Review.

PMID: 28274839



Nearly a century of research has shown that nutritional interventions can delay aging and age- related diseases in many animal models and possibly humans. The most robust and widely studied intervention is caloric restriction, while protein restriction and restriction of various amino acids (methionine, tryptophan) have also been shown to delay aging. However, there is still debate over whether the major impact on aging is secondary to caloric intake, protein intake or specific amino acids. Nutritional geometry provides new perspectives on the relationship between nutrition and aging by focusing on calories, macronutrients and their interactions across a landscape of diets, and taking into account compensatory feeding in ad libitum-fed experiments. Nutritional geometry is a state-space modelling approach that explores how animals respond to and balance changes in nutrient availability. Such studies in insects and mice have shown that low protein, high carbohydrate diets are associated with longest lifespan in ad libitum fed animals suggesting that the interaction between macronutrients may be as important as their total intake.


Calorie restriction; aging; lifespan; low protein high carbohydrate; methionine restriction; protein restriction


Rats do not eat alone in public: Food-deprived rats socialize rather than competing for baits.

Weiss O, Dorfman A, Ram T, Zadicario P, Eilam D.

PLoS One. 2017 Mar 9;12(3):e0173302. doi: 10.1371/journal.pone.0173302.

PMID: 28278246




Limited resources result in competition among social animals. Nevertheless, social animals also have innate preferences for cooperative behavior. In the present study, 12 dyads of food-deprived rats were tested in four successive trials, and then re-tested as eight triads of food-deprived rats that were unfamiliar to each other. We found that the food-deprived dyads or triads of rats did not compete for the food available to them at regular spatially-marked locations that they had previously learnt. Rather, these rats traveled together to collect the baits. One rat, or two rats in some triads, lead (ran ahead) to collect most of the baits, but "leaders" differed across trials so that, on average, each rat ultimately collected similar amounts of baits. Regardless of which rat collected the baits, the rats traveled together with no substantial difference among them in terms of their total activity. We suggest that rats, which are a social species that has been found to display reciprocity, have evolved to travel and forage together and to share limited resources. Consequently, they displayed a sort of 'peace economy' that on average resulted in equal access to the baits across trials. For social animals, this type of dynamics is more relaxed, tolerant, and effective in the management of conflicts. Rather than competing for the limited available food, the food-deprived rats socialized and coexisted peacefully.

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[The below paper is pdf-availed.]

Ecological Momentary Assessment of Dietary Lapses Across Behavioral Weight Loss Treatment: Characteristics, Predictors, and Relationships with Weight Change.

Forman EM, Schumacher LM, Crosby R, Manasse SM, Goldstein SP, Butryn ML, Wyckoff EP, Graham Thomas J.

Ann Behav Med. 2017 Mar 9. doi: 10.1007/s12160-017-9897-x. [Epub ahead of print]

PMID: 28281136



Adherence to dietary prescriptions is critical for successful weight loss and weight loss maintenance. However, research on specific instances of inadherence (lapses) is limited, and findings regarding the frequency, nature, and causes of lapses are mixed. Additionally, no studies have examined lapses over the course of a weight loss program.


In the context of a reduced calorie diet prescribed as part of a behavioral treatment, we aimed to characterize lapse occurrence, examine lapse frequency across treatment, examine predictors of lapses, and assess the relationship between lapses and weight loss.


Adults (n = 189) enrolled in a 12-month behavioral weight loss program completed ecological momentary assessment (EMA) at baseline, mid-treatment, and end of treatment. At each EMA survey, participants indicated whether a lapse had occurred, and responded to questions assessing situational, environmental, and affective states.


Lapse frequency showed a curvilinear relationship over time, such that frequency first decreased and then increased. Lapse frequency at baseline was negatively associated with early and overall weight loss. Lapses most often occurred at home, in the evenings, on the weekends, and entailed eating a forbidden food. Greater overall levels of assessed affective and environmental triggers predicted lapses, and greater momentary hunger and deprivation, and the presence of palatable food, also prospectively predicted lapses.


In addition to characterizing lapse frequency, the current study identified prospective predictors of lapses across treatment. These findings support the importance of lapses to weight control and provide insight for potential targets of intervention to prevent lapse occurrence.


Adherence; Behavioral weight loss; Dietary lapses; EMA; Ecological momentary assessment; Overweight

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Neurogenic Effects of Ghrelin on the Hippocampus.

Kim C, Kim S, Park S.

Int J Mol Sci. 2017 Mar 8;18(3). pii: E588. doi: 10.3390/ijms18030588. Review.

PMID: 28282857



Mammalian neurogenesis continues throughout adulthood in the subventricular zone of the lateral ventricle and in the subgranular zone of the dentate gyrus in the hippocampus. It is well known that hippocampal neurogenesis is essential in mediating hippocampus-dependent learning and memory. Ghrelin, a peptide hormone mainly synthesized in the stomach, has been shown to play a major role in the regulation of energy metabolism. A plethora of evidence indicates that ghrelin can also exert important effects on neurogenesis in the hippocampus of the adult brain. The aim of this review is to discuss the current role of ghrelin on the in vivo and in vitro regulation of neurogenesis in the adult hippocampus. We will also discuss the possible role of ghrelin in dietary restriction-induced hippocampal neurogenesis and the link between ghrelin-induced hippocampal neurogenesis and cognitive functions.


ghrelin; hippocampus; learning; memory; neurogenesis


[i could not find the below paper's full texts.]

Hyper- and hypo- nutrition studies of the hepatic transcriptome and epigenome suggest that PPARα regulates anaerobic glycolysis.

Soltis AR, Motola S, Vernia S, Ng CW, Kennedy NJ, Dalin S, Matthews BJ, Davis RJ, Fraenkel E.

Sci Rep. 2017 Dec;7(1):174. doi: 10.1038/s41598-017-00267-9.

PMID: 28282965


Diet plays a crucial role in shaping human health and disease. Diets promoting obesity and insulin resistance can lead to severe metabolic diseases, while calorie-restricted (CR) diets can improve health and extend lifespan. In this work, we fed mice either a chow diet (CD), a 16 week high-fat diet (HFD), or a CR diet to compare and contrast the effects of these diets on mouse liver biology. We collected transcriptomic and epigenomic datasets from these mice using RNA-Seq and DNase-Seq. We found that both CR and HFD induce extensive transcriptional changes, in some cases altering the same genes in the same direction. We used our epigenomic data to infer transcriptional regulatory proteins bound near these genes that likely influence their expression levels. In particular, we found evidence for critical roles played by PPARα and RXRα. We used ChIP-Seq to profile the binding locations for these factors in HFD and CR livers. We found extensive binding of PPARα near genes involved in glycolysis/gluconeogenesis and uncovered a role for this factor in regulating anaerobic glycolysis. Overall, we generated extensive transcriptional and epigenomic datasets from livers of mice fed these diets and uncovered new functions and gene targets for PPARα.

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Dietary Restriction reduces hippocampal neurogenesis and granule cell neuron density without affecting the density of mossy fibers.

Staples MC, Fannon-Pavlich MJ, Mysore KK, Dutta RR, Ongjoco AT, Quach LW, Kharidia KM, Somkuwar SS, Mandyam CD.

Brain Res. 2017 Mar 8. pii: S0006-8993(17)30098-7. doi: 10.1016/j.brainres.2017.02.028. [Epub ahead of print]

PMID: 28284897



The hippocampal formation undergoes significant morphological and functional changes after prolonged caloric and dietary restriction (DR). In this study we tested whether prolonged DR results in deleterious alterations in hippocampal neurogenesis, density of granule cell neurons and mossy fibers, all of which support plasticity in the dentate gyrus. Young adult animals either experienced free access to food (control condition), or every-other-day feeding regimen (DR condition) for 3 months. The number of Ki-67 cells and 28-day old 5-bromo-2'-deoxyuridine (BrdU) cells were quantified in the dorsal and ventral dentate gyrus to determine the effect of DR on cellular proliferation and survival of neural progenitor cells in the anatomically defined regions of the dentate gyrus. The density of granule cell neurons and synaptoporin were also quantified to determine the effect of DR on granule cell neurons and mossy fiber projections in the dentate gyrus. Our results show that DR increases cellular proliferation and concurrently reduces survival of newly born neurons in the ventral dentate gyrus without effecting the number of cells in the dorsal dentate gyrus. DR reduced density of granule cell neurons in the dorsal dentate gyrus. These alterations in the number of granule cell neurons did not affect mossy fiber density in DR animals, which was visualized as no differences in synaptoporin expression. Our findings demonstrate that granule cell neurons in the dentate gyrus are vulnerable to chronic DR and that the reorganization of granule cells in the dentate gyrus subregions is not producing concomitant alterations in dentate gyrus neuronal circuitry with this type of dietary restriction.


BrdU; Dentate gyrus; Food restriction; Ki-67; Neurogenesis; Synaptoporin

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  • 4 weeks later...

Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: a 2-y randomized controlled trial of calorie restriction in nonobese humans.

Das SK, Roberts SB, Bhapkar MV, Villareal DT, Fontana L, Martin CK, Racette SB, Fuss PJ, Kraus WE, Wong WW, Saltzman E, Pieper CF, Fielding RA, Schwartz AV, Ravussin E, Redman LM; CALERIE-2 Study Group..

Am J Clin Nutr. 2017 Feb 22. pii: ajcn137232. doi: 10.3945/ajcn.116.137232. [Epub ahead of print]

PMID: 28228420



Background: Calorie restriction (CR) retards aging and increases longevity in many animal models. However, it is unclear whether CR can be implemented in humans without adverse effects on body composition.Objective: We evaluated the effect of a 2-y CR regimen on body composition including the influence of sex and body mass index (BMI; in kg/m2) among participants enrolled in CALERIE-2 (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), a multicenter, randomized controlled trial.Design: Participants were 218 nonobese (BMI: 21.9-28.0) adults aged 21-51 y who were randomly assigned to 25% CR (CR, n = 143) or ad libitum control (AL, n = 75) in a 2:1 ratio. Measures at baseline and 12 and 24 mo included body weight, waist circumference, fat mass (FM), fat-free mass (FFM), and appendicular mass by dual-energy X-ray absorptiometry; activity-related energy expenditure (AREE) by doubly labeled water; and dietary protein intake by self-report. Values are expressed as means ± SDs.Results: The CR group achieved 11.9% ± 0.7% CR over 2-y and had significant decreases in weight (-7.6 ± 0.3 compared with 0.4 ± 0.5 kg), waist circumference (-6.2 ± 0.4 compared with 0.9 ± 0.5 cm), FM (-5.4 ± 0.3 compared with 0.5 ± 0.4 kg), and FFM (-2.0 ± 0.2 compared with -0.0 ± 0.2 kg) at 24 mo relative to the AL group (all between-group P < 0.001). Moreover, FFM as a percentage of body weight at 24 mo was higher, and percentage of FM was lower in the CR group than in the AL. AREE, but not protein intake, predicted preservation of FFM during CR (P < 0.01). Men in the CR group lost significantly more trunk fat (P = 0.03) and FFM expressed as a percentage of weight loss (P < 0.001) than women in the CR group.Conclusions: Two years of CR had broadly favorable effects on both whole-body and regional adiposity that could facilitate health span in humans. The decrements in FFM were commensurate with the reduced body mass; although men in the CR group lost more FFM than the women did, the percentage of FFM in the men in the CR group was higher than at baseline.


body composition; calorie restriction; humans; long-term; nonobese


Persistence of weight loss and acquired behaviors 2 y after stopping a 2-y calorie restriction intervention.

Marlatt KL, Redman LM, Burton JH, Martin CK, Ravussin E.

Am J Clin Nutr. 2017 Mar 8. pii: ajcn146837. doi: 10.3945/ajcn.116.146837. [Epub ahead of print]

PMID: 28275127



Background: Calorie restriction (CR) influences aging processes and extends average and maximal life spans. The CALERIE 2 (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy Phase 2) study was the first randomized clinical trial to examine the metabolic and psychological effects of CR in nonobese humans.Objective: We conducted a 2-y follow-up study of adults who underwent 2 y of CR or ad libitum (control) consumption and determined whether weight loss and acquired behaviors persisted after the study ended when participants determined their own lifestyle behaviors.Design: In this prospective, longitudinal study, we assessed differences in weight, body composition, psychological function, and energy expenditure in 39 nonobese [body mass index (in kg/m2): 22-28] men and women (25% CR: n = 24; control: n = 15) 12 and 24 mo after they completed the CALERIE 2 study at Pennington Biomedical.Results: Of 39 participants who were in the follow-up study, 29 subjects (CR: n = 18; control: n = 11) completed all visits at follow-up months 12 and 24. After the CR intervention, a mean ± SEM weight loss of 9.0 ± 0.6 kg was observed in the CR group, in which only 54% of the weight was regained 2 y later. Despite such a regain, weight, the percentage of body fat, and fat mass remained significantly reduced from baseline throughout follow-up and remained significantly less than in the control group (P < 0.05). At follow-up, the CR group retained higher degrees of dietary restraint and avoidance of certain foods.Conclusion: After a 2-y intensive CR intervention, ∼50% of CR-induced weight loss was maintained 2 y later, which was probably the result of lasting effects on acquired behaviors and dietary restraint.


CALERIE study; calorie restriction; diet; energy expenditure; metabolic adaptation; mood; quality of life; weight loss

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Some of the papers that caught my fancy and some free-full-texts via non-Sci-Hub sources are provided with full-text URLs.


Effect of diet-induced weight loss on lipoprotein(a) levels in obese individuals with and without type 2 diabetes.

Berk KA, Yahya R, Verhoeven AJ, Touw J, Leijten FP, van Rossum EF, Wester VL, Lips MA, Pijl H, Timman R, Erhart G, Kronenberg F, Roeters van Lennep JE, Sijbrands EJ, Mulder MT.

Diabetologia. 2017 Apr 6. doi: 10.1007/s00125-017-4246-y. [Epub ahead of print]

PMID: 28386638



Elevated levels of lipoprotein(a) [Lp(a)] are an independent risk factor for cardiovascular disease (CVD), particularly in individuals with type 2 diabetes. Although weight loss improves conventional risk factors for CVD in type 2 diabetes, the effects on Lp(a) are unknown and may influence the long-term outcome of CVD after diet-induced weight loss. The aim of this clinical study was to determine the effect of diet-induced weight loss on Lp(a) levels in obese individuals with type 2 diabetes.


Plasma Lp(a) levels were determined by immunoturbidimetry in plasma obtained before and after 3-4 months of an energy-restricted diet in four independent study cohorts. The primary cohort consisted of 131 predominantly obese patients with type 2 diabetes (cohort 1), all participants of the Prevention Of Weight Regain in diabetes type 2 (POWER) trial. The secondary cohorts consisted of 30 obese patients with type 2 diabetes (cohort 2), 37 obese individuals without type 2 diabetes (cohort 3) and 26 obese individuals without type 2 diabetes who underwent bariatric surgery (cohort 4).


In the primary cohort, the energy-restricted diet resulted in a weight loss of 9.9% (95% CI 8.9, 10.8) and improved conventional CVD risk factors such as LDL-cholesterol levels. Lp(a) levels increased by 14.8 nmol/l (95% CI 10.2, 20.6). In univariate analysis, the change in Lp(a) correlated with baseline Lp(a) levels (r = 0.38, p < 0.001) and change in LDL-cholesterol (r = 0.19, p = 0.033). In cohorts 2 and 3, the weight loss of 8.5% (95% CI 6.5, 10.6) and 6.5% (95% CI 5.7, 7.2) was accompanied by a median increase in Lp(a) of 13.5 nmol/l (95% CI 2.3, 30.0) and 11.9 nmol/l (95% CI 5.7, 19.0), respectively (all p < 0.05). When cohorts 1-3 were combined, the diet-induced increase in Lp(a) correlated with weight loss (r = 0.178, p = 0.012). In cohort 4, no significant change in Lp(a) was found (-7.0 nmol/l; 95% CI -18.8, 5.3) despite considerable weight loss (14.0%; 95% CI 12.2, 15.7).


Diet-induced weight loss was accompanied by an increase in Lp(a) levels in obese individuals with and without type 2 diabetes while conventional CVD risk factors for CVD improved. This increase in Lp(a) levels may potentially antagonise the beneficial cardiometabolic effects of diet-induced weight reduction.


Apolipoprotein(a); Bariatric surgery; Diet; Lipoprotein(a); Obesity; Type 2 diabetes; Weight loss


A Randomized, Double-Blind, Placebo-Controlled Trial to Determine the Effectiveness and Safety of a Thermogenic Supplement in Addition to an Energy-Restricted Diet in Apparently Healthy Females.

Kendall KL, Hyde PN, Fairman CM, Hollaway KM, Mumford PW, Haun CT, Mobley B, Kephart WC, Tribby AC, Kimber D, Moon JR, Beck DT, Roberts MD, Young KC.

J Diet Suppl. 2017 Apr 7:1-14. doi: 10.1080/19390211.2017.1304484. [Epub ahead of print]

PMID: 28388294


The increasing interest in weight loss has seen a concurrent rise in the supplemental use of thermogenics to aid weight loss efforts. To date, the effectiveness and safety of supplemental proprietary blend thermogenics, in conjunction with high-protein energy-restricted diets have not been thoroughly evaluated. The purpose of this study was to investigate the efficacy of a low-calorie, high-protein diet with and without the concomitant use of a thermogenic supplement on body weight and body composition in apparently healthy females. Subjects were divided into three groups, Bizzy Diet+FitMiss Burn (BURN, N = 12), Bizzy Diet+Placebo (PLA, N = 13), and Control (CON, N = 14), and underwent two testing sessions separated by approximately 3 weeks. Resting blood pressure (BP), resting heart rate (RHR), clinical safety markers, body weight (BW), and body composition were assessed during each testing session. Repeated measures analysis of variance (ANOVA) revealed a significant effect for time relative to BW, total body fat mass (FM), leg FM, and trunk FM. Post hoc analysis revealed that the BURN and PLA groups experienced significant decreases in both BW and total body FM compared to CON (p <.05). There were no significant interactions for BP, RHR, or clinical safety markers over the course of the study. The Bizzy Diet, both with and without the addition of FitMiss Burn thermogenic, appears to be safe for short-term use and may lead to greater improvement in body composition and BW in an apparently healthy female population.


body composition; body fat; nutrition; supplementation; weight loss


[EXPRESS] AMP-activated kinase and the endogenous endocannabinoid system might contribute to antinociceptive effects of prolonged moderate caloric restriction in mice.

King-Himmelreich TS, Möser CV, Wolters MC, Schmetzer J, Möller M, Schreiber Y, Ferreirós N, Geisslinger G, Niederberger E.

Mol Pain. 2017 Jan;13:1744806917703111. doi: 10.1177/1744806917703111. No abstract available.

PMID: 28381108



Effect of temperature and food restriction on immune function in striped hamsters (<i>Cricetulus barabensis</i>).

Xu DL, Hu XK, Tian YF.

J Exp Biol. 2017 Apr 5. pii: jeb.153601. doi: 10.1242/jeb.153601. [Epub ahead of print]

PMID: 28381582


Small mammals in the temperate area face seasonal fluctuations of temperature and food availability, both of which may influence their immune responses being critical to the survival. In the present study, we tested the hypothesis that low temperature and food restriction would suppress immune function in striped hamsters (Cricetulus barabensis). Thirty-seven adult male hamsters were randomly assigned into the warm (23±1°C) and the cold (5±1°C) groups, which were further divided into the fed and the food restricted groups, respectively. Body mass was not affected by cold stress, food restriction or the interactions of cold stress × food restriction. Cold stress decreased total body fat mass, hematological parameters including white blood cells (WBC), lymphocytes (LYMP) and neutrophilic granulocytes (GRAN), and immunoglobin (Ig) M titers after 5 days of injecting keyhole limpet haemocyanin (KLH). However, cold temperature increased bacterial killing capacity indicative of innate immunity and did not affect the masses of thymus and spleen, intermediate granulocytes (MID), phytohaemagglutinin (PHA) response and the levels of blood glucose, serum leptin. Corticosterone concentration was affected significantly by the interaction of cold stress × food restriction but not by cold stress or food restriction. Food restriction reduced thymus mass, but other immunological parameters including body fat mass, spleen mass, hematological parameters, innate immunity, PHA response, the titres of IgM and IgG, and the levels of blood glucose, serum leptin were all not affected by food restriction or the interaction of cold stress × food restriction. Innate immunity was positively correlated with leptin levels, whereas no significant correlations were observed among the levels of blood glucose, serum leptin, corticosterone and all the detected immune parameters. Our results showed that cold stress suppressed humoral immunity but enhanced innate immunity and did not affect cellular immunity in striped hamsters. Most immunological indices were not influenced by food restriction. Blood glucose, leptin and corticosterone could not interpret the changes of innate, cellular and humoral immunity upon cold stress or food restriction in striped hamsters.


Cellular immunity; Cold; Food restriction; Humoral immunity; Innate immunity; Striped hamster (Cricetulus barabensis)


Using DNA Methylation Profiling to Evaluate Biological Age and Longevity Interventions.

Petkovich DA, Podolskiy DI, Lobanov AV, Lee SG, Miller RA, Gladyshev VN.

Cell Metab. 2017 Apr 4;25(4):954-960.e6. doi: 10.1016/j.cmet.2017.03.016.

PMID: 28380383


The DNA methylation levels of certain CpG sites are thought to reflect the pace of human aging. Here, we developed a robust predictor of mouse biological age based on 90 CpG sites derived from partial blood DNA methylation profiles. The resulting clock correctly determines the age of mouse cohorts, detects the longevity effects of calorie restriction and gene knockouts, and reports rejuvenation of fibroblast-derived iPSCs. The data show that mammalian DNA methylomes are characterized by CpG sites that may represent the organism's biological age. They are scattered across the genome, they are distinct in human and mouse, and their methylation gradually changes with age. The clock derived from these sites represents a biomarker of aging and can be used to determine the biological age of organisms and evaluate interventions that alter the rate of aging.


Direct and correlated responses to selection in two lines of rabbits selected for feed efficiency under ad libitum and restricted feeding: III. Digestion and excretion of nitrogen and minerals.

Gidenne T, Fortun-Lamothe L, Bannelier C, Molette C, Gilbert H, Chemit ML, Segura M, Benitez F, Richard F, Garreau H, Drouilhet L.

J Anim Sci. 2017 Mar;95(3):1301-1312. doi: 10.2527/jas.2016.1192.

PMID: 28380512


Two rabbit lines have been created to result in better feed efficiency: the ConsoResidual line was selected for a lower residual feed intake under ad libitum feeding, and the ADGrestrict line was selected for higher ADG under restricted feeding (-20% of ad libitum). The present study aimed to analyze the digestion and excretion of N and minerals from 29 to 63 d of age of these 2 lines compared with an unselected control line (G0) under 2 feeding levels (ad libitum or restricted). The ADGrestrict line had greater digestibility compared with G0 (+1.3% for OM and N; < 0.05), and the ConsoResidual line had intermediate values. There was no genetic line effect on the digestibility of N and P and on minerals concentrations (P, Zn, and Cu) in the feces and in the urine. The N balance was improved for the 2 selected lines (+5%; < 0.05), leading to a reduced N output through the feces (0.06 g/d compared with G0; < 0.001) and the urine (-0.07 g/d; < 0.05) and to an improved N retention ratio (+3% compared with G0). Over the whole fattening period (d 29-63), significant differences were observed among lines only when fed ad libitum, with 13% greater DM fecal output and 5% greater N fecal output for G0. The N excretion in urine was 2 g less in the 2 selected lines, leading to a reduction of total N release of 4.4 g (compared with G0). The P excretion in feces (12 g) or urine (0.1 g) did not differ among the 3 lines. Over the whole fattening period and for ad libitum-fed rabbits, the 5% improvement in feed efficiency ( < 0.01) for the 2 selected lines corresponded to 400 g less feed intake (-8%) and to 20 g less N intake. The fecal excretion of the ADGrestrict and ConsoResidual lines were reduced by 200 g DM ( < 0.01), corresponding to 417 g fresh matter and 5 g of N. The excretion in minerals (P, Zn, and Cu) was not affected by the line. The feeding level strongly reduced the fecal and urine outputs (-50 and -60%, respectively; < 0.001). Higher digestibility coefficients ( < 0.001) were found in restricted-fed rabbits for OM (+6%), N (+8%), and P (+11%). The N balance was substantially improved by the restriction, with 40% less total (feces + urine) N excretion ( < 0.001). The P balance was improved by the restriction (0.469 vs. 0.360). Over the fattening period, the P fecal output was 37% less (-6 g) with 24% less feed intake and the Zn and Cu outputs were reduced by 27 (-130 mg) and 29% (-30 mg), respectively.


The influence of different calorie restriction protocols on serum pro-inflammatory cytokines, adipokines and IGF-I levels in female C57BL6 mice: short term and long term diet effects.

Dogan S, Ray A, Cleary MP.

Meta Gene. 2017 Jun;12:22-32. doi: 10.1016/j.mgene.2016.12.013. Epub 2017 Jan 3.

PMID: 28373962



Calorie restriction (CR) is an effective intervention to prevent chronic diseases including cancer. Although many factors, i.e., sex hormones, IGF-I and mTOR have been studied in response to CR, the molecular mechanisms of CR remain to be identified. Our objective was to determine the short and long-term effects of different CR protocols on pro-inflammatory cytokines. Our hypothesis was that Intermittent CR (ICR) would result in greater inhibition of pro-inflammatory serum cytokines compared to Chronic CR (CCR) as we previously found ICR to be more protective in the prevention of mammary tumor development. From ten weeks of age female C57BL6 mice were maintained on either ad libitum (AL) fed, ICR or CCR protocols (overall CR of ~75% of AL) for up to 74 weeks of age. Blood samples were collected for measurements of serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), adiponectin, leptin, IGF-I and insulin at specified ages. For ICR mice samples were collected following 3 weeks of restriction (ICR-R) and after one week of refeeding (ICR-RF). In general, both modes of CR significantly reduced serum IL-6, TNF-α, IGF-I and leptin levels compared to AL with IL-6 levels 24 and 3.5 fold and TNF-α levels t 11 and 1.5 fold lower in ICR and CCR groups, respectively at study termination. There was a trend for adiponectin and insulin to be highest in ICR-RF mice. Body weights were positively correlated with IL-6, TNF-α, insulin and leptin but negatively correlated with adiponectin-to-leptin ratio. Moreover, there was a positive correlation between IL-6 and TNF-α. Beneficial effects of ICR may function through pro-inflammatory cytokine pathways.


Cytokines; IGF-I; adipokines; calorie restriction; female; inflammation; wild-type mice


Energy balance modulation impacts epigenetic reprogramming, ERα and ERβ expression and mammary tumor development in MMTV-neu transgenic mice.

Rossi EL, Dunlap SM, Bowers LW, Khatib SA, Doerstling SS, Smith LA, Sharma MA, Holley D, Brown PH, Estecio MR, Kusewitt DF, deGraffenried LA, Bultman SJ, Hursting SD.

Cancer Res. 2017 Apr 3. pii: canres.2795.2016. doi: 10.1158/0008-5472.CAN-16-2795. [Epub ahead of print]

PMID: 28373182


The association between obesity and breast cancer risk and prognosis is well established in ER-positive disease but less clear in HER2-positive disease. Here, we report preclinical evidence suggesting weight maintenance through calorie restriction may limit risk of HER2-positive breast cancer. In female MMTV-HER2/neu transgenic mice, we found that ERα and ERβ expression, mammary tumorigenesis and survival are energy balance-dependent in association with epigenetic reprogramming. Mice were randomized to receive a calorie restriction (CR), overweight (OW)-inducing, or diet-induced obesity (DIO) regimen (n = 27/group). Subsets of mice (n = 4/group/time point) were euthanized after 1, 3 and 5 months to characterize diet-dependent metabolic, transcriptional, and epigenetic perturbations. Remaining mice were followed up to 22 months. Relative to the OW and DIO regimens, CR decreased body weight, adiposity, and serum metabolic hormones as expected, and also elicited an increase in mammary ERα and ERβ expression. Increased DNA methylation accompanied this pattern, particularly at CpG dinucleotides located within binding or flanking regions for the transcriptional regulator CCCTC-binding factor (CTCF) of ESR1 and ESR2, consistent with sustained transcriptional activation of ERα and ERβ. Mammary expression of the DNA methylation enzyme DNMT1 was stable in CR mice but increased over time in OW and DIO mice, suggesting CR obviates epigenetic alterations concurrent with chronic excess energy intake. In the survival study, CR elicited a significant suppression in spontaneous mammary tumorigenesis. Overall, our findings suggest a mechanistic rationale to prevent or reverse excess body weight as a strategy to reduce HER2-positive breast cancer risk.


Caloric restriction extends yeast chronological lifespan by optimizing the Snf1 (AMPK) signaling pathway.

Wierman MB, Maqani N, Strickler E, Li M, Smith JS.

Mol Cell Biol. 2017 Apr 3. pii: MCB.00562-16. doi: 10.1128/MCB.00562-16. [Epub ahead of print]

PMID: 28373292


AMP-activated protein kinase (AMPK) and the homologous yeast SNF1 complex, are key regulators of energy metabolism that counteract nutrient deficiency and ATP depletion by phosphorylating multiple enzymes and transcription factors that maintain energetic homeostasis. AMPK/SNF1 also promotes longevity in several model organisms, including yeast. Here we investigate the role of yeast SNF1 in mediating the extension of chronological lifespan (CLS) by caloric restriction (CR). We find that SNF1 activity is required throughout the log to stationary phase transition (diauxic shift) for effective CLS extension. CR expands the period of maximal SNF1 activation beyond the diauxic shift, as indicated by Sak1-dependent T210 phosphorylation of the Snf1 catalytic α-subunit. A concomitant increase in ADP is consistent with SNF1 activation by ADP in vivo Downstream of SNF1, the Cat8 and Adr1 transcription factors are required for full CR-induced CLS extension, implicating alternative carbon source utilization for acetyl-CoA production and gluconeogenesis. Indeed, CR increased acetyl-CoA levels during the diauxic shift, along with expression of both acetyl-CoA synthetase genes, ACS1 and ACS2 We conclude that CR maximizes Snf1 activity throughout and beyond diauxic shift, thus optimizing the coordination of nucleocytosolic acetyl-CoA production with massive reorganization of the transcriptome and respiratory metabolism.


Effects of almond consumption on the post-lunch dip and long-term cognitive function in energy-restricted overweight and obese adults.

Dhillon J, Tan SY, Mattes RD.

Br J Nutr. 2017 Feb;117(3):395-402. doi: 10.1017/S0007114516004463. Epub 2017 Feb 10.

PMID: 28183366



The post-lunch dip in cognition is a well-established phenomenon of decreased alertness, memory and vigilance after lunch consumption. Lunch composition reportedly influences the post-lunch dip. Moreover, dieting is associated with cognitive function impairments. The negative effects of dieting have been reversed with nut-supplemented diets. The aims of this study were to (1) evaluate the acute effect of an almond-enriched high-fat lunch or high-carbohydrate lunch on the post-lunch decline in cognitive function, and (2) evaluate the effects of chronic almond consumption as part of an energy-restricted diet on the memory and attention domains of cognitive function. In total, eighty-six overweight and obese adults were randomised to consume either an almond-enriched diet (AED) or a nut-free control diet (NFD) over a 12-week weight loss intervention. Participants were also randomised to receive either an almond-enriched high-fat lunch (A-HFL) (>55 % energy from fat, almonds contributing 70-75 % energy) or a high-carbohydrate lunch (HCL) (>85 % energy from carbohydrates) at the beginning and end of the weight loss intervention. Memory and attention performance indices decreased after lunch consumption (P<0·001). The A-HFL group ameliorated the decline in memory scores by 57·7 % compared with the HCL group (P=0·004). Both lunch groups had similar declines in attention. Moreover, memory and attention performance indices increased after the 12-week intervention period (P<0·05) with no difference between the AED and NFD groups. In conclusion, almond consumption at a midday meal can reduce the post-lunch dip in memory. However, long-term almond consumption may not further improve cognitive function outcomes in a weight loss intervention.


A-HFL almond-enriched high-fat lunch group; AED almond-enriched diet; CP concentration performance; HCL high-carbohydrate lunch group; NFD nut-free diet; TN quantitative performance; TNE qualitative performance; VLR verbal list recognition; Almonds; Cognitive function; Energy restriction; Nuts; Post-lunch dip


Ketone bodies mimic the life span extending properties of caloric restriction.

Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT.

IUBMB Life. 2017 Apr 3. doi: 10.1002/iub.1627. [Epub ahead of print] Review.

PMID: 28371201


The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3 ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders.


Caenorhabditis elegans; FOXO3a; NADPH; aging; ketone bodies; lifespan; reactive oxygen species


Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions.

Cole JJ, Robertson NA, Rather MI, Thomson JP, McBryan T, Sproul D, Wang T, Brock C, Clark W, Ideker T, Meehan RR, Miller RA, Brown-Borg HM, Adams PD.

Genome Biol. 2017 Mar 28;18(1):58. doi: 10.1186/s13059-017-1185-3.

PMID: 28351383 Free Article





Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging "clock", a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restriction and rapamycin.


In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice.


Age-associated hypo- and hypermethylation events occur at distinct regulatory features of the genome. Distinct longevity-promoting interventions, specifically genetic, dietary and drug interventions, suppress some age-associated methylation changes, consistent with the idea that these interventions exert their beneficial effects, in part, by modulation of the epigenome. This study is a foundation to understand the epigenetic contribution to healthy aging and longevity and the molecular basis of the DNA methylation clock.


Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism.

Hahn O, Grönke S, Stubbs TM, Ficz G, Hendrich O, Krueger F, Andrews S, Zhang Q, Wakelam MJ, Beyer A, Reik W, Partridge L.

Genome Biol. 2017 Mar 28;18(1):56. doi: 10.1186/s13059-017-1187-1.

PMID: 28351387 Free Article





Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time.


Here, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age.


Our results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile.


Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment.

Wang T, Tsui B, Kreisberg JF, Robertson NA, Gross AM, Yu MK, Carter H, Brown-Borg HM, Adams PD, Ideker T.

Genome Biol. 2017 Mar 28;18(1):57. doi: 10.1186/s13059-017-1186-2.

PMID: 28351423 Free Article





Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans.


We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls.


This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.


Aging; DNA methylation; Epigenetic aging; Epigenomics


Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging.

Ruetenik AL, Ocampo A, Ruan K, Zhu Y, Li C, Zhai RG, Barrientos A.

Microb Cell. 2016 Jul 26;3(8):338-351. doi: 10.15698/mic2016.08.518.

PMID: 28357370




Defects in mitochondrial biogenesis and function are common in many neurodegenerative disorders, including Huntington's disease (HD). We have previously shown that in yeast models of HD, enhancement of mitochondrial biogenesis through overexpression of Hap4, the catalytic subunit of the transcriptional complex that regulates mitochondrial gene expression, alleviates the growth arrest induced by expanded polyglutamine (polyQ) tract peptides in rapidly dividing cells. However, the mechanism through which HAP4 overexpression exerts this protection remains unclear. Furthermore, it remains unexplored whether HAP4 overexpression and increased respiratory function during growth can also protect against polyQ-induced toxicity during yeast chronological lifespan. Here, we show that in yeast, mitochondrial respiration and oxidative phosphorylation (OXPHOS) are essential for protection against the polyQ-induced growth defect by HAP4 overexpression. In addition, we show that not only increased HAP4 levels, but also alternative interventions, including calorie restriction, that result in enhanced mitochondrial biogenesis confer protection against polyQ toxicity during stationary phase. The data obtained in yeast models guided experiments in a fly model of HD, where we show that enhancement of mitochondrial biogenesis can also protect against neurodegeneration and behavioral deficits. Our results suggest that therapeutic interventions aiming at the enhancement of mitochondrial respiration and OXPHOS could reduce polyQ toxicity and delay disease onset.


Drosophila model; Saccharomyces cerevisiae; caloric restriction; mitochondrial OXPHOS; mitochondrial biogenesis; mitochondrial respiration; polyglutamine toxicity; yeast chronological life span


Autophagy extends lifespan via vacuolar acidification.

Ruckenstuhl C, Netzberger C, Entfellner I, Carmona-Gutierrez D, Kickenweiz T, Stekovic S, Gleixner C, Schmid C, Klug L, Hajnal I, Sorgo AG, Eisenberg T, Büttner S, Marin O G, Koziel R, Magnes C, Sinner F, Pieber TR, Jansen-Dürr P, Fröhlich KU, Kroemer G, Madeo F.

Microb Cell. 2014 May 5;1(5):160-162. doi: 10.15698/mic2014.05.147.

PMID: 28357240




Methionine restriction (MetR) is one of the rare regimes that prolongs lifespan across species barriers. Using a yeast model, we recently demonstrated that this lifespan extension is promoted by autophagy, which in turn requires vacuolar acidification. Our study is the first to place autophagy as one of the major players required for MetR-mediated longevity. In addition, our work identifies vacuolar acidification as a key downstream element of autophagy induction under MetR, and possibly after rapamycin treatment. Unlike other amino acids, methionine plays pleiotropic roles in many metabolism-relevant pathways. For instance, methionine (i) is the N-terminal amino acid of every newly translated protein; (ii) acts as the central donor of methyl groups through S-adenosyl methionine (SAM) during methylation reactions of proteins, DNA or RNA; and (iii) provides the sulfhydryl groups for FeS-cluster formation and redox detoxification via transsulfuration to cysteine. Intriguingly, MetR causes lifespan extension, both in yeast and in rodents. We could show that in Saccharomyces cerevisiae, chronological lifespan (CLS) is increased in two specific methionine-auxotrophic strains (namely Δmet2 and Δmet15).


acidification; autophagy; chronological lifespan; dietary restriction; longevity; lysosome; methionine restriction; vacuole

Comment on

Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification. [PLoS Genet. 2014]


Ramadan model of intermittent fasting for 28 d had no major effect on body composition, glucose metabolism, or cognitive functions in healthy lean men.

Harder-Lauridsen NM, Rosenberg A, Benatti FB, Damm JA, Thomsen C, Mortensen EL, Pedersen BK, Krogh-Madsen R.

Nutrition. 2017 May;37:92-103. doi: 10.1016/j.nut.2016.12.015. Epub 2016 Dec 28.

PMID: 28359370



There has been a parallel increase in the incidence of obesity and diabetes as well as the number of daily meals. However, evidence is lacking regarding the role of intermittent fasting. The aim of this study was to determine the effects of a Ramadan model of intermittent fasting (RIF; 14 h of daytime abstinence from food and drinking) for 28 d on body composition, glucose metabolism, and cognitive function.


Ten healthy, lean men were included in a nonrandomized, crossover, intervention study. Testing was performed before a control period of 28 d, as well as before and after 28 d of RIF. Whole-body dual-energy x-ray absorptiometry, magnetic resonance imaging of the abdomen, fitness test, oral glucose tolerance test, and cognitive function tests were performed. As secondary outcome, the participants' physical activity and 72-h glycemic responses were monitored 6 d within each of the periods. Dietary intake, appetite, and mood questionnaires also were assessed.


Comparing Δ differences from testing days; body mass index changes from the control period (Δ mean: 0.2 kg/m2, 95% confidence interval [CI], -2 to 0.5) and the RIF period (Δ mean: -0.3 kg/m2, 95% CI, -0.6 to -0.1) were significantly different (P < 0.05). Secondary outcomes within the RIF period showed an increased area under curve (AUC) for hunger accompanied by a reduced AUC for satiety (both, P < 0.05), less mean steps per day (P < 0.05), and less positive feelings in the afternoon (P < 0.01) compared with the control period. No changes were observed in any of the other evaluated parameters.


Free-living participants were able to comply with 14 h of daily daytime abstinence from food and drinking for 28 d with only a minor effect on body mass index and without any effects on body composition, glucose metabolism, and cognitive function.


Body composition; Clinical; Cognitive performance; Energy restriction; Glucose; Glucose tolerance test; Insulin; Intermittent fasting; Lean; Meal frequency; Metabolism; Mood; Ramadan; Satiety


Caloric restriction minimizes aging effects on the femoral medial condyle.

Fontinele RG, Krause Neto W, Gama EF, Brito Mari R, de Souza RR, Conrado A, Mochizuki L, Kfoury Junior JR.

Aging Male. 2017 Mar 23:1-7. doi: 10.1080/13685538.2017.1301418. [Epub ahead of print]

PMID: 28332902


This study aimed to analyze the effects of caloric restriction on aged femoral articular cartilage of Wistar rats. Three groups of eight animals each were considered: young (YC) and old (OC) control groups fed with a normal diet and old caloric restriction group (OCR) composed of 18-month-old animals fed with a 31% less caloric diet from 6-months of age. Articular cartilage was studied through morphometry and immunohistochemistry. Body mass was 12% less in the OCR group than in the OC group. The articular cartilage from OC rats show thinner medial condyles, fewer chondrocytes, smaller chondrocytes nuclear volume and, in both condyles, a predominance of collagen type II and less collagen density compared to both YC and OCR groups (p < .001). In contrast, OCR articular cartilage show thicker medial condyles, larger chondrocytes nuclear volume and increased collagen density compared to OC group (p < 0.001). We concluded that caloric restriction minimizes the effects of aging on medial condyles of the femoral articular cartilage.


Morphometry; Wistar rats; articular cartilage; hipocaloric nutrition


Effects of the Mediterranean Diet before and after Weight Loss on Eating Behavioral Traits in Men with Metabolic Syndrome.

Carbonneau É, Royer MM, Richard C, Couture P, Desroches S, Lemieux S, Lamarche B.

Nutrients. 2017 Mar 19;9(3). pii: E305. doi: 10.3390/nu9030305.

PMID: 28335489 Free Article



The objective of this study was to investigate the impact of the Mediterranean diet (MedDiet) consumed before and after weight loss on eating behavioral traits as measured by the Three-Factor Eating Questionnaire (TFEQ) in men with metabolic syndrome (MetS). In this fixed sequence study, 19 men with MetS (National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria), aged between 24 and 62 years, first consumed a five-week standardized North American control diet followed by a five-week MedDiet, both under weight-maintaining controlled-feeding conditions. This was followed by a 20-week caloric restriction weight loss period in free-living conditions, without specific recommendations towards adhering to the principles of the MedDiet. Participants were finally subjected to a final five-week MedDiet phase under isoenergetic controlled-feeding conditions. The MedDiet before weight loss had no impact on eating behavioral traits. Body weight reduction by caloric restriction (-10.2% of initial weight) was associated with increased cognitive restraint (p < 0.0001) and with reduced disinhibition (p = 0.02) and susceptibility to hunger (p = 0.01). Feeding the MedDiet for five weeks under isoenergetic conditions after the weight loss phase had no further impact on eating behavioral traits. Results of this controlled-feeding study suggest that consumption of the MedDiet per se has no effect on eating behavioral traits as measured by TFEQ, unless it is combined with significant weight loss.


Mediterranean diet; Three-Factor Eating Questionnaire; cognitive restraint; disinhibition; metabolic syndrome; susceptibility to hunger; weight loss


Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-analysis.

Elgebaly A, Radwan IA, AboElnas MM, Ibrahim HH, Eltoomy MF, Atta AA, Mesalam HA, Sayed AA, Othman AA.

J Gastrointestin Liver Dis. 2017 Mar;26(1):59-67. doi: 10.15403/jgld.2014.1121.261.ely. Review.

PMID: 28338115 Free Article




Resveratrol is a potential treatment option for management of non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant properties, and calorie restriction-like effects. We aimed to synthesise evidence from published randomized clinical trials (RCTs) about the efficacy of resveratrol in the management of NAFLD.


A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central was conducted using relevant keywords. Records were screened for eligible studies and data were extracted and synthesized using Review Manager Version 5.3 for windows. Subgroup analysis and sensitivity analysis were conducted.


Four RCTs (n=158 patients) were included in the final analysis. The overall effect estimates did not favor resveratrol group in terms of: serum ALT (MD -2.89, 95%CI [-15.66, 9.88], p=0.66), serum AST (MD -3.59, 95%CI [-13.82, 6.63], p=0.49), weight (MD -0.18, 95%CI [-0.92, 0.55], p=0.63), BMI (MD -0.10, 95 %CI [-0.43, 0.24], p=0.57), blood glucose level (MD -0.27, 95%CI [-0.55, 0.01], p=0.05), insulin level (MD -0.12, 95%CI [-0.69, 0.46], p=0.69), triglyceride level (MD 0.04, 95%CI [-0.45, 0.53], p=0.87), and LDL level (MD 0.21, 95%CI [-0.41, 0.83], p=0.51). Pooled studies were heterogeneous.


Current evidence is insufficient to support the efficacy of resveratrol in the management of NAFLD. Resveratrol does not attenuate the degree of liver fibrosis or show a significant decrease in any of its parameters.


Time restricted feeding for prevention and treatment of cardiometabolic disorders.

Melkani GC, Panda S.

J Physiol. 2017 Mar 10. doi: 10.1113/JP273094. [Epub ahead of print]

PMID: 28295377


The soaring prevalence of obesity and diabetes is associated with an increase in comorbidities, including elevated risk for cardiovascular diseases (CVD). CVDs continue to be among the leading causes of death and disability in the United States. While increased nutrition intake from an energy dense diet is known to disrupt metabolic homeostasis and contributes to the disease risk, circadian rhythm disruption is emerging as a new risk factor for CVD. Circadian rhythms coordinate cardiovascular health via temporal control of organismal metabolism and physiology. Thus, interventions that improve circadian rhythms are prospective entry points to mitigate cardiometabolic disease risk. Although light is a strong modulator of neural circadian clock, time of food intake is emerging as a dominant agent that affects circadian clocks in metabolic organs. We discovered that imposing a time-restricted feeding (TRF) regimen in which all caloric intakes occur within a consistent ≤12 h every day exerts many cardiometabolic benefits. TRF prevents excessive body weight gain, improves sleep, and attenuates age- and diet- induced deterioration in cardiac performance. Using an integrative approach that combines Drosophila melanogaster (fruit fly) genetics with transcriptome analyses it was found that the beneficial effects of TRF are mediated by circadian clock, ATP dependent TCP/TRiC/CCT chaperonin and mitochondrial-ETC components. Parallel studies in rodents have shown TRF reduces cardiometabolic disease risks by maintaining metabolic homeostasis. As modern humans continue to live under extended periods of wakefulness and ingestion events, daily eating pattern offers a new potential target for lifestyle intervention to reduce CVD risk.


The effect of CART on pituitary hormones release from cultured pituitary cells harvested from fasted and fed ad libitum male rats.

Chmielowska M, Baranowska B, Wolinska-Witort E, Martynska L, Kalisz M, Litwiniuk A, Bik W.

Peptides. 2017 Mar 11;91:20-25. doi: 10.1016/j.peptides.2017.03.003. [Epub ahead of print]

PMID: 28300671


Cocaine and Amphetamine-Regulated Transcript (CART) is widely expressed in the central nervous system and in several endocrine organs. CART is an important factor in the regulation of energy homeostasis. The aim of the study was to assess the role of CART in physiological response of pituitary cells in a course of starvation. The pituitary cells harvested from starved and fed ad libitum male rats were cultured for 48h and treated with: 0.1nM, 1nM, 10nM or 100nM doses of CART. The medium was collected after 60min and stored at -70°C until samples were further assayed for: LH, FSH, PRL, GH, TSH and ACTH. We revealed that in cultures of pituitary cells collected from fasted rats the basal levels of the examined hormones were reduced. Incubation of pituitary cells of non-starved rats with any dose of CART reduced the concentration of LH and TSH, while the levels of the other hormones were decreased after administration only specific doses of CART. In cells of fasted rats no change in the concentration of gonadotrophins was observed. The PRL level was increased only in the 1nM dose of CART, while the 10nM and 100nM CART doses markedly enhanced GH and TSH. Moreover, administration of 1nM, 10nM and 100nM of CART to cultured cells of fasted rats resulted in a significant rise of the ACTH. Our results indicate that CART can directly affect the physiological release of PRL, ACTH, TSH and GH in pituitary cells of starved animals. Moreover, CART did not alter the LH and FSH suppression level, which is correlated with food deprivation. This data stays in contrast with the already proposed role of CART as an anorexigenic hypothalamic factor.


CART; Pituitary hormones; Starvation


Exploring the role of locomotor sensitization in the circadian food entrainment pathway.

Opiol H, de Zavalia N, Delorme T, Solis P, Rutherford S, Shalev U, Amir S.

PLoS One. 2017 Mar 16;12(3):e0174113. doi: 10.1371/journal.pone.0174113. eCollection 2017 Mar 16.

PMID: 28301599 Free Article



Food entrainment is the internal mechanism whereby the phase and period of circadian clock genes comes under the control of daily scheduled food availability. Food entrainment allows the body to efficiently realign the internal timing of behavioral and physiological functions such that they anticipate food intake. Food entrainment can occur with or without caloric restriction, as seen with daily schedules of restricted feeding (RF) or restricted treat (RT) that restrict food or treat intake to a single feeding time. However, the extent of clock gene control is more pronounced with caloric restriction, highlighting the role of energy balance in regulating clock genes. Recent studies have implicated dopamine (DA) to be involved in food entrainment and caloric restriction is known to affect dopaminergic pathways to enhance locomotor activity. Since food entrainment results in the development of a distinct behavioral component, called food anticipatory activity (FAA), we examined the role of locomotor sensitization (LS) in food entrainment by 1) observing whether amphetamine (AMPH) sensitization results in enhanced locomotor output of FAA and 2) measuring LS of circadian and non-circadian feeding paradigms to an acute injection of AMPH (AMPH cross-sensitization). Unexpectedly, AMPH sensitization did not show enhancement of FAA. On the contrary, LS did develop with sufficient exposure to RF. LS was present after 2 weeks of RF, but not after 1, 3 or 7 days into RF. When food was returned and rats regain their original body weight at 10-15 days post-RF, LS remained present. LS did not develop to RT, nor to feedings of a non-circadian schedule, e.g. variable restricted feeding (VRF) or variable RT (VRT). Further, when RF was timed to the dark period, LS was observed only when tested at night; RF timed to the light period resulted in LS that was present during day and night. Taken together our results show that LS develops with food entrainment to RF, an effect that is dependent on the chronicity and circadian phase of RF but independent of body weight. Given that LS involves reorganization of DA-regulated motor circuitry, our work provides indirect support for the role of DA in the food entrainment pathway of RF. The findings also suggest differences in neuronal pathways involved in LS from AMPH sensitization and LS from RF.


Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation.

Estrela GR, Wasinski F, Batista RO, Hiyane MI, Felizardo RJ, Cunha F, de Almeida DC, Malheiros DM, Câmara NO, Barros CC, Bader M, Araujo RC.

Front Physiol. 2017 Mar 2;8:116. doi: 10.3389/fphys.2017.00116. eCollection 2017 Mar 2.

PMID: 28303105 Free PMC Article




The antineoplastic drug cisplatin promotes renal injury, which limits its use. Protocols that reduce renal cisplatin toxicity will allow higher doses to be used in cisplatin treatment. Here, we compare physical exercise and caloric restriction (CR) as protocols to reduce cisplatin renal injury in mice. Male C57BL/6 were divided into four groups: Control, cisplatin, exercise + cisplatin, and 30% CR + cisplatin. Animals were injected with a single dose of cisplatin (20 mg/kg i.p.) and sacrificed 96 h after injection. Quantitative real time PCR, histological analyses, immunohistochemistry, and biochemical measurements were performed to investigate renal injury, necrosis, apoptosis, and inflammatory mechanisms. Both protocols protected against cisplatin renal injury, but CR was more effective in reducing uraemia and renal necrosis. The CR + Cisplatin group exhibited reduced serum IL-1β and TNF-α levels. No differences were noted in the renal mRNA expression of cytokines. Both interventions reduced apoptosis, but only the CR + Cisplatin group decreased TNFR2 protein expression. PPAR-α was activated in mice after CR. An antagonist of PPAR-α blocked the protective effect of CR. Both interventions attenuated the nephrotoxicity caused by cisplatin injection, but CR + Cisplatin showed a better response by modulating TNFR2. Moreover, part of the CR benefit depends on PPAR-α activation.


PPAR-alpha; caloric restriction; cisplatin nephrotoxicity; exercise; inflammation


Nutrient Sensing and the Oxidative Stress Response.

Luo H, Chiang HH, Louw M, Susanto A, Chen D.

Trends Endocrinol Metab. 2017 Mar 14. pii: S1043-2760(17)30025-5. doi: 10.1016/j.tem.2017.02.008. [Epub ahead of print] Review.

PMID: 28314502


The simplicity and effectiveness of calorie restriction (CR) in lifespan and healthspan extension have fascinated generations searching for the Fountain of Youth. CR reduces levels of oxidative stress and damage, which have been postulated in the free radical theory of aging as a major cause of aging and diseases of aging. This reduction has long been viewed as a result of passive slowing of metabolism. Recent advances in nutrient sensing have provided molecular insights into the oxidative stress response and suggest that CR triggers an active defense program involving a cascade of molecular regulators to reduce oxidative stress. Physiological studies have provided strong support for oxidative stress in the development of aging-associated conditions and diseases but have also revealed the surprising requirement for oxidative stress to support normal physiological functions and, in some contexts, even slow aging and prevent the progression of cancer. Deciphering the molecular mechanisms and physiological implications of the oxidative stress response during CR will increase our understanding of the basic biology of aging and pave the way for the design of CR mimetics to improve healthspan.


Repeated Sprints in Fasted State Impair Reaction Time Performance.

Cherif A, Meeusen R, Farooq A, Briki W, Fenneni MA, Chamari K, Roelands B.

J Am Coll Nutr. 2017 Mar 20:1-8. doi: 10.1080/07315724.2016.1256795. [Epub ahead of print]

PMID: 28318450



The aim of this study was to assess the effects of 3-day Islamic intermittent fasting (3d-IF) on cognitive performance and serum levels of neurotrophic factors (brain-derived neurotrophic factor [bDNF] and vascular endothelial growth factor [VEGF]) before and after repeated sprints.


Twenty-one physically active male Muslims (29.8 ± 5.9 years, exercising 4 ± 1.5 times/week) were randomly assigned to one of 2 experimental sessions: the control or nonfasting session (CS) or the fasting session (FS). These 2 sessions occurred 7 days apart in a counterbalanced crossover design. In both conditions, the test was performed at the same time of day, approximately 1 hour before sunset. In the FS, the test occurred on the third day of the 3d-IF and involved the participants' performance of the following: (a) two series of 5 maximal 5-second sprints and (b) 2 cognitive tasks: One Touch Stockings (OTS) and reaction time (simple and complex RTI).


In both conditions, the participants' reaction times during the RTI test were similar at the pre- and mid-exercise points, but postexercise, simple and complex reaction times were higher in FS compared to CS (p = 0.045, effect size [ES] = 0.21 and p = 0.006, ES = 0.41, respectively). However, OTS performance and serum levels of neurotrophic factors were not influenced by the 3d-IF.


Simple and complex reaction times during the RTI test were negatively affected by the 3d-IF after 2 bouts of intensive repeated sprints.


Dietary restriction; anaerobic exercise; brain; cognitive task; memory


Calorie restriction breaks an epigenetic barrier to longevity.

Molina-Serrano D, Kirmizis A.

Cell Cycle. 2017 Mar 20:1-2. doi: 10.1080/15384101.2017.1304745. [Epub ahead of print] No abstract available.

PMID: 28319441



3. Loss of Nat4 and its associated histone H4 N-terminal acetylation mediates calorie restriction-induced longevity.

Molina-Serrano D, Schiza V, Demosthenous C, Stavrou E, Oppelt J, Kyriakou D, Liu W, Zisser G, Bergler H, Dang W, Kirmizis A.

EMBO Rep. 2016 Dec;17(12):1829-1843. Epub 2016 Oct 31.

PMID: 27799288 Free PMC Article




Changes in histone modifications are an attractive model through which environmental signals, such as diet, could be integrated in the cell for regulating its lifespan. However, evidence linking dietary interventions with specific alterations in histone modifications that subsequently affect lifespan remains elusive. We show here that deletion of histone N-alpha-terminal acetyltransferase Nat4 and loss of its associated H4 N-terminal acetylation (N-acH4) extend yeast replicative lifespan. Notably, nat4Δ-induced longevity is epistatic to the effects of calorie restriction (CR). Consistent with this, (i) Nat4 expression is downregulated and the levels of N-acH4 within chromatin are reduced upon CR, (ii) constitutive expression of Nat4 and maintenance of N-acH4 levels reduces the extension of lifespan mediated by CR, and (iii) transcriptome analysis indicates that nat4Δ largely mimics the effects of CR, especially in the induction of stress-response genes. We further show that nicotinamidase Pnc1, which is typically upregulated under CR, is required for nat4Δ-mediated longevity. Collectively, these findings establish histone N-acH4 as a regulator of cellular lifespan that links CR to increased stress resistance and longevity.


Nat4; Pnc1; calorie restriction; histone N‐terminal acetylation; lifespan

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Selected life-extending interventions reduce arterial CXCL10 and macrophage colony-stimulating factor in aged mouse arteries.

Trott DW, Lesniewski LA, Donato AJ.

Cytokine. 2017 Apr 5;96:102-106. doi: 10.1016/j.cyto.2017.03.008. [Epub ahead of print]

PMID: 28390264


Cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Aging is the most predictive risk factor for CVD and is associated with arterial inflammation which contributes to increased CVD risk. Although age-related arterial inflammation has been described in both humans and animals, only a limited number of inflammatory mediators, cytokines and chemokines have been identified. In this investigation we sought to determine whether lifespan extending interventions, including crowded litter early life nutrient deprivation (CL), traditional lifelong caloric restriction (CR) and lifelong Rapamycin treatment (Rap) would attenuate age-related arterial inflammation using multi analyte profiling. Aortas from Young (4-6months), Old (22months), Old CL, Old CR and Old Rap mice were homogenized and cytokine concentrations were assessed using Luminex Multi Analyte Profiling. Chemokines involved in immune cell recruitment, such as CCL2, CXCL9, CXCL10, GMCSF and MCSF, were increased in Old vs. Young (p<0.05). The age-related increase of CXCL10 was prevented by CR (p<0.05 vs. Old). MSCF concentrations were lower in aortas of Rap treated mice (p<0.05 vs. Old). Interleukins (IL), IL-1α, IL-1β and IL-10, were also greater in Old vs. Young mice (p<0.05). These data demonstrate selected lifespan extending interventions can prevent or limit age-related increases in selected aortic chemokines.


Aorta; Caloric restriction; Chemokine; Cytokine; Interleukin; Rapamycin

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[The first below paper is not pdf-availed.]

Effects of a 6-month caloric restriction induced-weight loss program in obese postmenopausal women with and without the metabolic syndrome: a MONET study.

Ghachem A, Prud'homme D, Rabasa-Lhoret R, Brochu M.

Menopause. 2017 Apr 10. doi: 10.1097/GME.0000000000000862. [Epub ahead of print]

PMID: 28399005



To compare the effects of a caloric restriction (CR) on body composition, lipid profile, and glucose homeostasis in obese postmenopausal women with and without metabolic syndrome (MetS).


Secondary analyses were performed on 73 inactive obese postmenopausal women (age 57.7 ± 4.8 years; body mass index 32.4 ± 4.6 kg/m) who participated in the 6-month CR arm of a study of the Montreal-Ottawa New Emerging Team. The harmonized MetS definition was used to categorize participants with MetS (n = 20, 27.39%) and without MetS (n = 53, 72.61%). Variables of interest were: body composition (dual-energy X-ray absorptiometry), body fat distribution (computed tomography scan), glucose homeostasis at fasting state and during a euglycemic/hyperinsulinemic clamp, fasting lipids, and resting blood pressure.


By design, the MetS group had a worse cardiometabolic profile, whereas both groups were comparable for age. Fifty-five participants out of 73 displayed no change in MetS status after the intervention. Twelve participants out of 20 (or 60.0%) in the MetS group had no more MetS after weight loss (P = NS), whereas 6 participants out of 53 (or 11.3%) in the other group developed the MetS after the intervention (P = NS). Overall, indices of body composition and body fat distribution improved significantly and similarly in both groups (P between 0.03 and 0.0001). Furthermore, with the exception of triglyceride levels and triglycerides/high-density lipoprotein cholesterol ratio, which decrease significantly more in the MetS group (P ≤ 0.05), no difference was observed between groups for the other variables of the cardiometabolic profile.


Despite no overall significant effects on MetS, heteregeneous results were obtained in response to weight loss in the present study, with some improving the MetS, whereas other displaying deteriorations. Further studies are needed to identify factors and phenotypes associated with positive and negative cardiometabolic responses to CR intervention.


Caloric Restriction and Healthy Life Span: Frail Phenotype of Nonhuman Primates in the Wisconsin National Primate Research Center Caloric Restriction Study.

Yamada Y, Kemnitz JW, Weindruch R, Anderson RM, Schoeller DA, Colman RJ.

J Gerontol A Biol Sci Med Sci. 2017 Apr 8. doi: 10.1093/gerona/glx059. [Epub ahead of print]

PMID: 28398464



Calorie restriction without malnutrition increases longevity and delays the onset of age-associated disorders in multiple species. Recently, greater emphasis has been placed on healthy life span and preventing frailty than on longevity. Here, we show the beneficial effect of long-term calorie restriction on frailty in later life in a nonhuman primate. Frail phenotypes were evaluated using metabolic and physical activity data and defined using the Fried index. Shrinking was defined as unintentional weight loss of greater than 5% of body weight. Weakness was indicated by decline in high intensity spontaneous physical activity. Poor endurance or exhaustion was indicated by a reduction in energy efficiency of movements. Slowness was indicated by physical activity counts in the morning. Low physical activity level was measured by total energy expenditure using doubly labeled water divided by sleeping metabolic rate. Weakness, poor endurance, slowness, and low physical activity level were significantly higher in control compared with calorie restriction (p < .05) as was total incidence of frailty (p < .001). In conclusion, we established a novel set of measurable criteria of frailty in nonhuman primates, and using these criteria, showed that calorie restriction reduces the incidence of frailty and increases healthy life span in nonhuman primates.


Caloric restriction; Frailty; Monkey

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