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Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors.

He B, Hoang TK, Wang T, Ferris M, Taylor CM, Tian X, Luo M, Tran DQ, Zhou J, Tatevian N, Luo F, Molina JG, Blackburn MR, Gomez TH, Roos S, Rhoads JM, Liu Y.

J Exp Med. 2016 Dec 19. pii: jem.20160961. [Epub ahead of print]

PMID: 27994068



Regulatory T (T reg) cell deficiency causes lethal, CD4+ T cell-driven autoimmune diseases. Stem cell transplantation is used to treat these diseases, but this procedure is limited by the availability of a suitable donor. The intestinal microbiota drives host immune homeostasis by regulating the differentiation and expansion of T reg, Th1, and Th2 cells. It is currently unclear if T reg cell deficiency-mediated autoimmune disorders can be treated by targeting the enteric microbiota. Here, we demonstrate that Foxp3+ T reg cell deficiency results in gut microbial dysbiosis and autoimmunity over the lifespan of scurfy (SF) mouse. Remodeling microbiota with Lactobacillus reuteri prolonged survival and reduced multiorgan inflammation in SF mice. L. reuteri changed the metabolomic profile disrupted by T reg cell deficiency, and a major effect was to restore levels of the purine metabolite inosine. Feeding inosine itself prolonged life and inhibited multiorgan inflammation by reducing Th1/Th2 cells and their associated cytokines. Mechanistically, the inhibition of inosine on the differentiation of Th1 and Th2 cells in vitro depended on adenosine A2A receptors, which were also required for the efficacy of inosine and of L. reuteri in vivo. These results reveal that the microbiota-inosine-A2A receptor axis might represent a potential avenue for combatting autoimmune diseases mediated by T reg cell dysfunction.



Intermittent calorie restriction largely counteracts the adverse health effects of a moderate-fat diet in aging C57BL/6J mice.

Rusli F, Lute C, Boekschoten MV, van Dijk M, van Norren K, Menke AL, Müller M, Steegenga WT.

Mol Nutr Food Res. 2016 Dec 20. doi: 10.1002/mnfr.201600677. [Epub ahead of print]

PMID: 27995741




Calorie restriction (CR) has been shown to extend life- and health-span in model species. For most humans, a life-long CR diet is too arduous to adhere to. The aim of this study was to explore whether weekly intermittent CR can 1) provide long-term beneficial effects and 2) counteract diet-induced obesity in male aging mice.


In this study we have exposed C57Bl/6J mice for 24 months to an intermittent (INT) diet, alternating weekly between CR of a control diet and ad libitum moderate-fat (MF) feeding. This weekly intermittent CR significantly counteracted the adverse effects of the MF diet on mortality, body weight and liver health markers in male 24-month-old mice. Hepatic gene expression profiles of INT-exposed animals appeared much more comparable to CR than to MF-exposed mice. At 12 months of age, a subgroup of MF-exposed mice was transferred to the INT diet. Gene expression profiles in the liver of the 24-month-old diet switch mice were highly similar to the INT-exposed mice. However, a small subset of genes was consistently changed by the MF diet during the first phase of life.


Weekly intermittent CR largely, but not completely, reversed adverse effects caused by a MF diet. This article is protected by copyright. All rights reserved.


Aging; Intermittent calorie restriction; Liver; Moderate-fat diet; Obesity; Transcriptomics

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A randomized control trial for reduction of caloric and non-caloric sweetened beverages in young adults: effects in weight, body composition and blood pressure.

Vázquez-Durán M, Orea-Tejeda A, Castillo-Martínez L, Cano-García Á, Téllez-Olvera L, Keirns-Davis C.

Nutr Hosp. 2016 Nov 29;33(6):1372-1378. doi: 10.20960/nh.797.

PMID: 28000468




Recently has been documented that the consumption of sweetened non-caloric beverages has increased as an option to weight control, however randomized control trials have demonstrated a modest weight loss.


To evaluate the effect of reducing consumption of beverage with caloric and non-caloric sweeteners on weight, body composition and blood pressure in young Mexican adults.


In an experimental study 148 nursing students were randomly assigned to one of 3 groups: 1) no sweetened beverages were permitted, only plain water, tea or coffee without sugar; 2) consumption of beverages with non-caloric sweeteners was allowed; and 3) no restriction of sweetened beverages was imposed. All groups were given individualized isocaloric diets monitored by a 24-hour record of consumption and food frequency questionnaire and blood pressure, weight, waist circumference and body composition by tetrapolar bioelectric impedance were taken at the beginning of the study and three and six months later.


Differences between groups were found in body mass index at 3 months that decrease in group 1 and 2 and increase in group 3 (-1.75 vs.-0.61 vs.0.54% of change, p < 0.001). At six months there were also statistical differences in waist circumference (-4.07 vs.-1.23 vs. 0.62% of change, p < 0.001) and sugar consumption (-62.0 vs.-54.61 vs.11.08% of change, p < 0.001) in groups 1, 2 and 3 respectively.


The reduction in consumption of both caloric and non-caloric sweetened beverages contributes to significant body mass index loss and waist circumference.


Sweetened beverages. Caloric and non-caloric sweeteners. Body weight. Body composition. Blood pressure.

Edited by AlPater
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Dietary restriction and lifespan: Lessons from invertebrate models.

Kapahi P, Kaberlein M, Hansen M.

Ageing Res Rev. 2016 Dec 19. pii: S1568-1637(16)30288-4. doi: 10.1016/j.arr.2016.12.005. [Epub ahead of print] Review.

PMID: 28007498



Dietary restriction (DR) is the most robust environmental manipulation known to increase active and healthy lifespan in many species. Despite differences in the protocols and the way DR is carried out in different organisms, conserved relationships are emerging among multiple species. Elegant studies from numerous model organisms are further defining the importance of various nutrient-signaling pathways including mTOR (mechanistic target of rapamycin), insulin/IGF-1-like signaling and sirtuins in mediating the effects of DR. We here review current advances in our understanding of the molecular mechanisms altered by DR to promote lifespan in three major invertebrate models, the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster.


Yeast; autophagy; flies; metabolism; mitochondrial respiration; sirtuins; worms


[The beelow paper is not pdf-availed.]

Life history evolution, reproduction, and the origins of sex-dependent aging and longevity.

Brooks RC, Garratt MG.

Ann N Y Acad Sci. 2016 Dec 23. doi: 10.1111/nyas.13302. [Epub ahead of print]

PMID: 28009055


Males and females in many species differ in how they age and how long they live. These differences have motivated much research, concerning both their evolution and the underlying mechanisms that cause them. We review how differences in male and female life histories have evolved to shape patterns of aging and some of the mechanisms and pathways involved. We pay particular attention to three areas where considerable potential for synergy between mechanistic and evolutionary research exists: (1) the role of estrogens, androgens, the growth hormone/insulin-like growth factor 1 pathway, and the mechanistic target of rapamycin signaling pathway in sex-dependent growth and reproduction; (2) sexual conflict over mating rate and fertility, and how mate presence or mating can become an avenue for males and females to directly affect each other's life span; and (3) the link between dietary restriction and aging, and the emerging understanding that only the restriction of certain nutrients is involved and that this is linked to reproduction. We suggest that ideas about life histories, sex-dependent selection, and sexual conflict can inform and be informed by the ever more refined and complex understanding of the mechanisms that cause aging.


adaptation; aging; life span; senescence; sexual conflict; sexual selection

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[The below paper is not pdf-availed.]

Roles of Estrogen Receptor-Alpha In Mediating Lifespan: The Hypothalamic Deregulation Hypothesis.

Gouw AM, Efe G, Barakat R, Preecha A, Mehdizadeh M, Garan SA, Brooks GA.

Physiol Genomics. 2016 Dec 23:physiolgenomics.00073.2016. doi: 10.1152/physiolgenomics.00073.2016. [Epub ahead of print]

PMID: 28011880


In several species caloric restriction (CR) extends lifespan. In this paper we integrate data from studies on CR and other sources to articulate the Hypothalamic Deregulation Hypothesis by which Estrogen Receptor-alpha (ER-α) signaling in the hypothalamus and limbic system affects lifespan under the stress of CR in mammals. ER-α is one of two principal estrogen-binding receptors differentially expressed in the amygdala, hippocampus, and several key hypothalamic nuclei: the Arcuate nucleus (ARN), Preoptic Area (POA), Ventromedial nucleus (VMN), Antero Ventral Periventricular Nucleus (AVPV), Paraventricular nucleus (PVN), Supraoptic nucleus (SON), and Suprachiasmatic nucleus (SCN). Estradiol signaling via ER-α is essential in basal level functioning of reproductive cycle, sexually-receptive behaviors, physiological stress responses, as well as sleep cycle, and other non-sexual behaviors. When an organism is placed under a long-term CR, which introduces an external stress to this ER-α signaling, the reduction of ER-α expression is attenuated over time in the hypothalamus. This review paper seeks to characterize the downstream effects of ER-α in the hypothalamus and limbic system that affect normal endocrine functioning.


Estrogen receptor; HPG Axis; aging; hypothalamus; sexual dimorphism

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[Mesentery from the CRed mice being so much lighter relative to ad libitum fed or exercised mice informed me of something of which I was unaware.]

Age-related arterial immune cell infiltration in mice is attenuated by caloric restriction or voluntary exercise.

Trott DW, Henson GD, Ho MH, Allison SA, Lesniewski LA, Donato AJ.

Exp Gerontol. 2016 Dec 21. pii: S0531-5565(16)30348-5. doi: 10.1016/j.exger.2016.12.016. [Epub ahead of print]

PMID: 28012941



Age-related arterial inflammation is associated with dysfunction of the arteries and increased risk for cardiovascular disease. To determine if aging increases arterial immune cell infiltration as well as the populations of immune cells principally involved, we tested the hypothesis that large elastic and resistance arteries in old mice would exhibit increased immune cell infiltration compared to young controls. Additionally, we hypothesized that vasoprotective lifestyle interventions such as life-long caloric restriction or 8weeks of voluntary wheel running would attenuate age-related arterial immune cell infiltration. The aorta and mesenteric vasculature with surrounding perivascular adipose was excised from young normal chow (YNC, 4-6months, n=10), old normal chow (ONC, 28-29months, n=11), old caloric restricted (OCR, 28-29months, n=9) and old voluntary running (OVR, 28-29months, n=5) mice and digested to a single cell suspension. The cells were then labeled with antibodies against CD45 (total leukocytes), CD3 (pan T cells), CD4 (T helper cells), CD8 (cytotoxic T cells), CD19 (B cells) CD11b and F4/80 (macrophages) and analyzed by flow cytometry. Total leukocytes, T cells (both CD4+ and CD8+ subsets), B cells and macrophages in both aorta and mesentery were all 5-6 fold greater in ONC compared to YNC. Age-related increases in T cell (both CD4+ and CD8+), B cell and macrophage infiltration in aorta were abolished in OCR mice. OVR mice exhibited 50% lower aortic T cell and normalized macrophage infiltration. B cell infiltration was not effected by VR. Age-related mesenteric CD8+ T cell and macrophage infiltration was normalized in OCR and OVR mice compared to young mice, whereas B cell infiltration was normalized by CR but not VR. Splenic CD4+ T cells from ONC mice exhibited a 3 fold increase in gene expression for the T helper (Th)1 transcription factor, Tbet, and a 4 fold increase in FoxP3, a T regulatory cell transcription factor, compared to YNC. Splenic B cells and mesenteric macrophages from old mice exhibited decreased proinflammatory cytokine gene expression regardless of treatment group. These results demonstrate that aging is associated with infiltration of immune cells around both the large-elastic and resistance arteries and that the vasoprotective lifestyle interventions, CR and VR, can ameliorate age-related arterial immune cell infiltration.


B cells; T cells; aorta; inflammation; macrophages; mesentery

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Circadian rhythms, time-restricted feeding, and healthy aging.

Manoogian EN, Panda S.

Ageing Res Rev. 2016 Dec 22. pii: S1568-1637(16)30301-4. doi: 10.1016/j.arr.2016.12.006. [Epub ahead of print] Review.

PMID: 28017879



Circadian rhythms optimize physiology and health by temporally coordinating cellular function, tissue function, and behavior. These endogenous rhythms dampen with age and thus compromise temporal coordination. Feeding-fasting patterns are an external cue that profoundly influence the robustness of daily biological rhythms. Erratic eating patterns can disrupt the temporal coordination of metabolism and physiology leading to chronic diseases that are also characteristic of aging. However, sustaining a robust feeding-fasting cycle, even without altering nutrition quality or quantity, can prevent or reverse these chronic diseases in experimental models. In humans, epidemiological studies have shown erratic eating patterns increase the risk of disease, whereas sustained feeding-fasting cycles, or prolonged overnight fasting, is correlated with protection from breast cancer. Therefore, optimizing the timing of external cues with defined eating patterns can sustain a robust circadian clock, which may prevent disease and improve prognosis.


aging; circadian rhythms; health; metabolism; time-restricted feeding


Calorie restriction prevents the development of insulin resistance and impaired lipid metabolism in gestational diabetes offspring.

Li T, Chen K, Liu G, Huang LP, Chen L, Wang QW, Hu CL, Hou LJ.

Pediatr Res. 2016 Dec 26. doi: 10.1038/pr.2016.273. [Epub ahead of print]

PMID: 28024145




Gestational diabetes mellitus (GDM) has long-lasting influence on offspring, which is associated with increased risks of insulin resistance, obesity and type II diabetes mellitus. Calorie restriction (CR) is one of the most common and available nutritional interventions to prevent obesity and diabetes. We are trying to explore the effect of CR on GDM offspring.MethodsThe streptozotocin was used to stimulate C57BL/6J mice to develop GDM, a number of metabolic characteristics and related protein expression were determined in GDM offspring that were fed ad-libitum or treated with calorie restriction.ResultsCR reduced body weight and glucose levels in GDM offspring. CR modulated the lipid metabolism by decreasing triglyceride and cholesterol levels in plasma. We also found that the effect of CR on insulin sensitivity may involve in signaling pathway through the regulations of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and protein kinase B (Akt).ConclusionGDM is a high risk factor for GDM offspring to develop insulin resistance, while CR could ameliorate this adverse outcome. Moreover, the specific decrease in PTEN activation and increase in Akt phosphorylation in livers of GDM offspring with CR improved insulin sensitivity and lipid metabolism.


Repeated restraint stress lowers the threshold for response to third ventricle CRF administration.

Harris RB.

Horm Behav. 2016 Dec 22. pii: S0018-506X(16)30363-4. doi: 10.1016/j.yhbeh.2016.12.008. [Epub ahead of print]

PMID: 28017597



Rats and mice exposed to repeated stress or a single severe stress exhibit a sustained increase in energetic, endocrine and behavioral response to subsequent novel mild stress. This study tested whether the hyper-responsiveness was due to a lowered threshold of response to corticotropin releasing factor (CRF) or an exaggerated response to a standard dose of CRF. Male Sprague Dawley rats were subjected to 3h of restraint on each of 3 consecutive days (RRS) or were non-restrained Controls. RRS caused a temporary hypophagia, but a sustained reduction in body weight. Eight days after the end of restraint rats received increasing third ventricle doses of CRF (0-3.0μg). The lowest dose of CRF (0.25μg) increased corticosterone release in RRS, but not Control rats. Higher doses caused the same stimulation of corticosterone in the two groups of rats. Fifteen days after the end of restraint rats were food deprived during the light period and received increasing third ventricle doses of CRF at the start of the dark period. The lowest dose of CRF inhibited food intake during the first hour following infusion in RRS, but not Control rats. All other doses of CRF inhibited food intake to the same degree in both RRS and Control rats. The lowered threshold of response to central CRF is consistent with the chronic hyper-responsiveness to CRF and mild stress in RRS rats during the post-restraint period.


HPA axis; food intake; rats; stress-responsiveness


Deficiency of succinyl-CoA synthetase α subunit delays development, impairs locomotor activity and reduces survival under starvation in Drosophila.

Quan X, Sato-Miyata Y, Tsuda M, Muramatsu K, Asano T, Takeo S, Aigaki T.

Biochem Biophys Res Commun. 2016 Dec 22. pii: S0006-291X(16)32165-9. doi: 10.1016/j.bbrc.2016.12.105. [Epub ahead of print]

PMID: 28017724



Succinyl-CoA synthetase/ligase (SCS) is a mitochondrial enzyme that catalyzes the reversible process from succinyl-CoA to succinate and free coenzyme A in TCA cycle. SCS deficiencies are implicated in mitochondrial hepatoencephalomyopathy in humans. To investigate the impact of SCS deficiencies in Drosophila, we generated a null mutation in Scs alpha subunit (Scsα) using the CRISPR/Cas9 system, and characterized their phenotype. We found that the Drosophila SCS deficiency, designated ScsαKO, contained a high level of succinyl-CoA, a substrate for the enzyme, and altered levels of various metabolites in TCA cycle and glycolysis, indicating that the energy metabolism was impaired. Unlike SCSα deficiencies in humans, there was no reduction in lifespan, indicating that Scsα is not critical for viability in Drosophila. However, they showed developmental delays, locomotor activity defects, and reduced survival under starvation. We also found that glycogen breakdown occurred during development, suggesting that the mutant flies were unable to produce sufficient energy to promote normal growth. These results suggested that SCSα is essential for proper energy metabolism in Drosophila. The ScsαKO flies should be useful as a model to understand the physiological role of SCSα as well as the pathophysiology of SCSα deficiency.


Developmental delay; Energy metabolism; Glycogen breakdown; SCS deficiency; Succinyl-CoA synthetase α subunit

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Sirtuins and nonalcoholic fatty liver disease.

Nassir F, Ibdah JA.

World J Gastroenterol. 2016 Dec 14;22(46):10084-10092. doi: 10.3748/wjg.v22.i46.10084. Review.

PMID: 28028356



Mammalian sirtuins are seven members belonging to the silent information regulator 2 family, a group of Class III histone/protein deacetylases. Sirtuins (SIRT 1-7) have different subcellular localization and function and they regulate cellular protein function through various posttranslational modifications. SIRT1 and 3, the most studied sirtuins, use the product of cellular metabolism nicotinamide adenine dinucleotide as a cofactor to post-translationally deacetylate cellular proteins and consequently link the metabolic status of the cell to protein function. Sirtuins have been shown to play a key role in the development and rescue of various metabolic diseases including non-alcoholic fatty liver disease (NAFLD). NAFLD is currently the most chronic liver disease due mainly to high-calorie consumption and lower physical activity. No pharmacological approach is available to treat NAFLD, the current recommended treatment are lifestyle modification such as weight loss through calorie restriction and exercise. Recent studies have shown downregulation of sirtuins in human as well as animal models of NAFLD indicating an important role of sirtuins in the dynamic pathophysiology of NAFLD. In this review, we highlight the recent knowledge on sirtuins, their role in NAFLD and their unique potential role as novel therapeutic target for NAFLD treatment.


Non-alcoholic fatty liver disease; SIRT1; SIRT3; Sirtuins


[The below paper is not pdf-availed.]

Nutrition and Exercise in Sarcopenia.

Anton SD, Hida A, Mankowski R, Layne A, Solberg L, Mainous AG, Buford TW.

Curr Protein Pept Sci. 2016 Dec 27. [Epub ahead of print]

PMID: 28029078


Sarcopenia is a debilitating condition that involves loss of muscle mass and function, which affects virtually everyone as they age, and can lead to frailty and ultimately disability. In growing recognition of the importance of both muscle strength and muscle mass relative to body size in contributing to functional decline, recent definitions have now incorporated grip strength and a correction for body mass as part of the key criteria that define sarcopenia. With this new definition, a much larger population of older adults are now at risk of sarcopenia. In the present article, we reviewed the literature for studies which tested the effects of diet or exercise interventions on changes in lean mass and/or functional outcomes in individuals with either sarcopenia and/or frailty and identified 19 clinical trials. There were a few key findings. First, dietary interventions involving protein supplementation improved functional and/or strength outcomes in a few trials, however, other dietary approaches were less effective. Exercise interventions and combined diet and exercise interventions produced consistent improvements in lower body muscle strength but had less consistent effects on walking speed and grip strength. Lifestyle interventions not involving calorie restriction generally did not induce significant changes in body composition. There were a limited number of trials in which participants with sarcopenia were specifically targeted, and thus there is an important need for more research to determine the appropriate types of intervention approaches for the high risk population of sarcopenic older adults.


Serum concentrations and gene expression of sirtuin 1 in healthy and slightly overweight subjects after caloric restriction or resveratrol supplementation: A randomized trial.

Mansur AP, Roggerio A, Goes MF, Avakian SD, Leal DP, Maranhão RC, Strunz CM.

Int J Cardiol. 2016 Oct 27. pii: S0167-5273(16)33139-4. doi: 10.1016/j.ijcard.2016.10.058. [Epub ahead of print]

PMID: 28029409




Sirtuin 1 (Sirt1) plays an important role in vascular biology, and influences aspects of age-dependent atherosclerosis. In animals, the sirtuin system is strongly influenced by resveratrol and caloric restriction, but its expression in humans is controversial. This study investigated the effects of resveratrol and caloric restriction on Sirt1 serum concentrations and vascular biomarkers in a healthy human population.


Forty-eight healthy participants (24 women) aged 55-65years were randomized to either 30days of resveratrol administration (500mg/day) or caloric restriction (1000cal/day). Blood was collected at baseline and day 30. Laboratory data analyzed were triglycerides, total cholesterol, HDL, VLDL, LDL, apolipoprotein A1, apolipoprotein B, lipoprotein (a), non-esterified fatty acids (NEFA), glucose, insulin, oxidative stress, C-reactive protein, and Sirt1. Expression of the Sirt1 gene was analyzed using real-time PCR. Caloric restriction diminished the abdominal circumference and improved the lipid profile, but not resveratrol intervention. Resveratrol and caloric restriction increased serum concentrations of Sirt1, from 1.06±0.71 to 5.75±2.98ng/mL; p<0.0001, and from 1.65±1.81 to 5.80±2.23ng/mL; p<0.0001, respectively. Sirt1 increased in women and men in both interventions. On the other hand expression of Sirt1 mRNA was not different after caloric restriction and resveratrol treatment.


Caloric restriction and resveratrol significantly increased plasma concentrations of Sirt1. The long-term impact of these interventions on atherosclerosis should be assessed.


Caloric restriction; Gene expression; Human population; Resveratrol; Sirtuin 1


Effect of Ramadan fasting on fatigue, mood, sleepiness, and health-related quality of life of healthy young men in summer time in Germany: A prospective controlled study.

Nugraha B, Ghashang SK, Hamdan I, Gutenbrunner C.

Appetite. 2016 Dec 24. pii: S0195-6663(16)30983-7. doi: 10.1016/j.appet.2016.12.030. [Epub ahead of print]

PMID: 28027907



Muslims around the world fast during the lunar month of Ramadan. The month consists of 29 or 30 days, which vary in length depending on geographic location and the time of year. During this month, Muslims abstain from food, drink, smoking, and sex from dawn until sunset. In 2015, Ramadan fell during the summer. As a result, Muslims in Germany fasted 19 h a day. Previous research has shown associations between fasting and mood enhancement. This study aimed to determine the effect of fasting on young, healthy males who fasted in Germany during Ramadan 2015. In particular, this study examined the impact of fasting on mood, fatigue, and health-related Quality of Life (QoL). This study had 2 groups: fasting group (FG; n = 25), and non-fasting group (NFG; n = 25). In FG, participants were assessed at four different points: one week before Ramadan (T1), mid Ramadan (T2), the last days of Ramadan (T3), and one week after Ramadan (T4). In NFG, participants were assessed only at T1 and T3. The results revealed that there were no significant differences between the participants in the FG and the NFG at T1 or T3 for any of the outcomes. However, participants in the FG demonstrated significant improvement from T2 to T4 in fatigue (visual analogue scale p < 0.01; fatigue severity scale:p < 0.01), mood (Beck's Depression Index-II; ANOVA; p < 0.05), and sleepiness during day time (Epworth Sleepiness Scale: ANOVA; p < 0.01). Participants in the FG also experienced significant loss of body weight (ANOVA; p < 0.001), body mass index (ANOVA; p < 0.001), skeletal muscle mass (ANOVA; p < 0.01) and fat free mass (ANOVA; p < 0.01). Findings demonstrate that Ramadan fasting did not significantly influence mood, fatigue and QoL, when compared to NFG. Even, it gives benefit to fasting group with regard to these parameters.


Fasting; Fatigue; Mood; Quality of life; Ramadan

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Here’s why your plans to lose weight this year could be doomed

Robert Ferris


Your own gut might be undermining your New Year's resolution to lose weight.

Bacteria in the human digestive tract, sometimes referred to as "microbiomes," "microbiota," or "gut bacteria," are an increasingly popular subject among scientists. It has been linked to everything from food allergies, to neurodegenerative disease, to obesity and weight loss.

Now, research suggests microbiota can even hamper efforts to lose weight in the early days of a new diet.

A team of researchers from several institutions in the United States and Italy took fecal samples from two groups of people who had been eating two different diets for an extended period of time. One group had been on a standard American diet, while the other stuck to a restrictive diet that emphasizes optimizing nutrients per calorie. These are often called Calorie Restriction with Optimal Nutrition (CRON) diets.

The scientists deposited gut bacteria from these fecal samples into the digestive tracts of specially bred germ-free mice. Being germ-free, the mice were able to act as blank bacterial canvases for the human microbiota, taking on the same bacterial communities. Some of the mice ended up with bacteria from people long on the standard American diet; others got the the bacteria from the calorie restriction dieters.

The mice were then placed on a plant-based, low-calorie diet that resembled the one the CRON dieters had already been on. The mice with the bacteria from the CRON eaters responded better to the diet.

"In our study, Americans consuming unrestricted diets maintained less diverse fecal microbiota than those of individuals adhering to plant-rich diet with restricted caloric intake," the researchers wrote in their study.

This suggests that sticking with a veggie-heavy diet for a longer period of time may give dieters a leg up over those who attempt to achieve rapid results.

The findings were published this week in Cell Host & Microbe, a peer-reviewed research journal.

Other evidence from previous studies has shown that practitioners of Western-style diets tend to have less bacterial diversity than those on traditional diets, but that lack of diversity may be remedied in part by changing their eating habits.

In the most recent study, the research team took another step that revealed a further insight: they placed the mice from both groups together. Once in the same living space, the mice began exchanging microbes, and the guts of the SAD mice began to resemble the calorie-restrictive mice.

The way they do this is rather disgusting — mice have a habit of eating feces, which helps them obtain certain nutrients, such as vitamin B12. But the result does suggest that long term diet changes, taking certain probiotics, or other treatments could influence the composition of gut bacteria.

Evidence has shown that people tend to quit on their New Year's resolutions, and have a hard time sticking to diets. There are, of course, likely countless reasons why these plans fail. But this research suggests part of the problem may be biological.

Even among bacteria, old habits die hard.


Prior Dietary Practices and Connections to a Human Gut Microbial Metacommunity Alter Responses to Diet Interventions

Nicholas W. Griffin, Philip P. Ahern, Jiye Cheng, Andrew C. Heath, Olga Ilkayeva, Christopher B. Newgard, Luigi Fontana, Jeffrey I. Gordon

Cell Host & Microbe In Press DOI: http://dx.doi.org/10.1016/j.chom.2016.12.006Published online: December 29, 2016



In brief

Ensuring that gut microbiota respond consistently to dietary interventions is critical for nutritional therapy. Griffin et al. find that dietary practices alter the human gut microbiota. The magnitude of microbiota responses to diet interventions varies among individuals. Dispersal of diet-responsive bacterial taxa between hosts enhances subsequent responses to diet interventions.


•Dietary practices can alter bacterial diversity in the human gut microbiota

•Microbiota responses to diets vary in strength across individuals

•Promoting bacterial dispersal between host microbiota enhances responses to diets

•Metacommunity dynamics have implications for effective nutritional interventions


Ensuring that gut microbiota respond consistently to prescribed dietary interventions, irrespective of prior dietary practices (DPs), is critical for effective nutritional therapy. To address this, we identified DP-associated gut bacterial taxa in individuals either practicing chronic calorie restriction with adequate nutrition (CRON) or without dietary restrictions (AMER). When transplanted into gnotobiotic mice, AMER and CRON microbiota responded predictably to CRON and AMER diets but with variable response strengths. An individual’s microbiota is connected to other individuals’ communities (“metacommunity”) by microbial exchange. Sequentially cohousing AMER-colonized mice with two different groups of CRON-colonized mice simulated metacommunity effects, resulting in enhanced responses to a CRON diet intervention and changes in several metabolic features in AMER animals. This response was driven by an influx of CRON DP-associated taxa. Certain DPs may impair responses to dietary interventions, necessitating the introduction of diet-responsive bacterial lineages present in other individuals and identified using the strategies described.

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In Search of Rationality in Human Longevity and Immortality.

Bhar GC.

Mens Sana Monogr. 2016 Jan-Dec;14(1):187-213. doi: 10.4103/0973-1229.193083. Review.

PMID: 28031631



The human body is machine-like, but self-moving, self-regulating, and self-adjusting, governed by willpower and intelligence. Aging of the body is basically a maintenance problem and so it could perhaps be postponed by thorough and frequent maintenance. Aging brings on a cascade of ills and health problems leading to deterioration of physical, mental, emotional, and social dimensions of life. This paper deals with solution of the problem philosophically in the light of Indian scriptures without entering into traditional bioethical issues. With a meaningful reason for existence, life can be extended. Examining the scientific perspectives on aging, some common manipulations for its extension are discussed. These are calorie restriction, vitamin and antioxidant treatment, exercise and hormonal interventions, etc. Finally, the question of longevity is explored through pursuance of eternal value-based activity and spirituality in the tradition of Indian heritage.


Accumulation of damage; Aging; Gene-evolved mechanism; Human evolution; Indian philosophical perspectives; Life span; Longevity; Manipulation of aging; Psychosocial and spiritual dimensions of aging; Spirituality; Unselfish love


Intermittent energy restriction in type 2 diabetes: A short discussion of medication management.

Carter S, Clifton PM, Keogh JB.

World J Diabetes. 2016 Dec 15;7(20):627-630. doi: 10.4239/wjd.v7.i20.627.

PMID: 28031781




To discuss type 2 diabetes mellitus (T2DM) medication changes required during the popular 5:2 intermittent energy restriction (IER) diet.


A search was conducted in MEDLINE, EMBASE, AMED, CINAHL and Cochrane library for original research articles investigating the use of very low calorie diets (VLCD) in people with T2DM. The search terms used included "VLCD" or "very low energy diet" or "very low energy restriction" or "IER" or "intermittent fasting" or "calorie restriction" or "diabetes mellitus type 2" and "type 2 diabetes". Reference lists of selected articles were also screened for relevant publications. Only research articles written in English, which also included an explanation of medication changes were included. A recent pilot trial using the 5:2 IER method, conducted by our research group, will also be summarized.


A total of 8 studies were found that investigated the use of VLCD in T2DM and discussed medication management. Overall these studies indicate that the use of a VLCD for people with T2DM usually require the cessation of medication to prevent hypoglycemia. Therefore, the 5:2 IER method will also require medication changes, but as seen in our pilot trial, may not require total cessation of medication, rather a cessation on the 2 IER days only.


Guidelines outlined here can be used in the initial stages of a 2-d IER diet, but extensive blood glucose monitoring is still required to make the necessary individual reductions to medications in response to weight loss.


Caloric restriction; Diabetes complication; Diabetes mellitus/therapy; Fasting; Intermittent energy restriction; Medication management; Obesity; Type 2 diabetes mellitus; Very low calorie diet


DNA base excision repair and nucleotide excision repair synergistically contribute to survival of stationary-phase cells of the fission yeast Schizosaccharomyces pombe.

Senoo T, Kawano S, Ikeda S.

Cell Biol Int. 2016 Dec 29. doi: 10.1002/cbin.10722. [Epub ahead of print]

PMID: 28032397



Defects of genome maintenance may causally contribute to aging. In general, base excision repair (BER) is involved in the repair of subtle base lesions and AP sites, and bulky helix-distorting lesions are restored by nucleotide excision repair (NER). Here, we measured the chronological lifespan (CLS) of BER- and NER-deficient mutants of the fission yeast Schizosaccharomyces pombe, and observed the aging process of cells. The CLS of the nth1 (gene for DNA glycosylase/AP lyase) mutant and the rad16 (a homolog of human XPF) mutant were slightly shorter than that of the wild-type (WT) strain. However, survival of the nth1Δ rad16Δ double mutant was significantly reduced after entry into the stationary phase. Deletion of rad16 in an AP endonuclease mutant apn2Δ also accelerated chronological aging. These results indicate that BER and NER synergistically contribute to genome maintenance in non-dividing cells. Reactive oxygen species (ROS) accumulated in cells during the stationary phase, and nth1Δ rad16Δ cells produced more ROS than WT cells. High mutation frequencies and nuclear DNA fragmentation were observed in nth1Δ rad16Δ stationary-phase cells concurrent with apoptotic-like cell death. Calorie restriction significantly reduced the level of ROS in the stationary phase and extended the CLS of nth1Δ rad16Δ cells. Therefore, ROS production critically affects the survival of the DNA repair mutant during chronological aging.


DNA repair; Schizosaccharomyces pombe; chronological lifespan; oxidative DNA damage; reactive oxygen species

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[Nutrient deprivation means three days of not feeding the mice.]

Emerging roles for histone deacetylases in age-related muscle atrophy.

Walsh ME, Van Remmen H.

Nutr Healthy Aging. 2016 Oct 27;4(1):17-30. doi: 10.3233/NHA-160005. Review.

PMID: 28035339



BACKGROUND: Skeletal muscle atrophy during aging, a process known as sarcopenia, is associated with muscle weakness, frailty, and the loss of independence in older adults. The mechanisms contributing to sarcopenia are not totally understood, but muscle fiber loss due to apoptosis, reduced stimulation of anabolic pathways, activation of catabolic pathways, denervation, and altered metabolism have been observed in muscle from old rodents and humans. OBJECTIVE: Recently, histone deacetylases (HDACs) have been implicated in muscle atrophy and dysfunction due to denervation, muscular dystrophy, and disuse, and HDACs play key roles in regulating metabolism in skeletal muscle. In this review, we will discuss the role of HDACs in muscle atrophy and the potential of HDAC inhibitors for the treatment of sarcopenia. CONCLUSIONS: Several HDAC isoforms are potential targets for intervention in sarcopenia. Inhibition of HDAC1 prevents muscle atrophy due to nutrient deprivation. HDAC3 regulates metabolism in skeletal muscle and may inhibit oxidative metabolism during aging. HDAC4 and HDAC5 have been implicated in muscle atrophy due to denervation, a process implicated in sarcopenia. HDAC inhibitors are already in use in the clinic, and there is promise in targeting HDACs for the treatment of sarcopenia.


Aging; epigenetics; histone deacetylases; sarcopenia


HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy.

Beharry AW, Sandesara PB, Roberts BM, Ferreira LF, Senf SM, Judge AR.

J Cell Sci. 2014 Apr 1;127(Pt 7):1441-53. doi: 10.1242/jcs.136390.

PMID: 24463822 Free PMC Article



The Forkhead box O (FoxO) transcription factors are activated, and necessary for the muscle atrophy, in several pathophysiological conditions, including muscle disuse and cancer cachexia. However, the mechanisms that lead to FoxO activation are not well defined. Recent data from our laboratory and others indicate that the activity of FoxO is repressed under basal conditions via reversible lysine acetylation, which becomes compromised during catabolic conditions. Therefore, we aimed to determine how histone deacetylase (HDAC) proteins contribute to activation of FoxO and induction of the muscle atrophy program. Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate that class I HDACs are key regulators of FoxO and the muscle-atrophy program during both nutrient deprivation and skeletal muscle disuse. Furthermore, we demonstrate, through the use of wild-type and dominant-negative HDAC1 expression plasmids, that HDAC1 is sufficient to activate FoxO and induce muscle fiber atrophy in vivo and is necessary for the atrophy of muscle fibers that is associated with muscle disuse. The ability of HDAC1 to cause muscle atrophy required its deacetylase activity and was linked to the induction of several atrophy genes by HDAC1, including atrogin-1, which required deacetylation of FoxO3a. Moreover, pharmacological inhibition of class I HDACs during muscle disuse, using MS-275, significantly attenuated both disuse muscle fiber atrophy and contractile dysfunction. Together, these data solidify the importance of class I HDACs in the muscle atrophy program and indicate that class I HDAC inhibitors are feasible countermeasures to impede muscle atrophy and weakness.

KEY WORDS: Histone deacetylase, Acetylation, Deacetylation, Muscle disuse, Nutrient deprivation, FoxO


Targeting glucose metabolism for healthy aging.

Brewer RA, Gibbs VK, Smith DL Jr.

Nutr Healthy Aging. 2016 Oct 27;4(1):31-46. doi: 10.3233/NHA-160007. Review.

PMID: 28035340




Advancing age is the greatest single risk factor for numerous chronic diseases. Thus, the ability to target the aging process can facilitate improved healthspan and potentially lifespan. Lack of adequate glucoregulatory control remains a recurrent theme accompanying aging and chronic disease, while numerous longevity interventions result in maintenance of glucoregulatory control. In this review, we propose targeting glucose metabolism to enhance regulatory control as a means to ameliorate the aging process. We highlight that calorie restriction improves glucoregulatory control and extends both lifespan and healthspan in model organisms, but we also indicate more practical interventions (i.e., calorie restriction mimetics) are desirable for clinical application in humans. Of the calorie restriction mimetics being investigated, we focus on the type 2 diabetes drug acarbose, an α-glucosidase inhibitor that when taken with a meal, results in reduced enzymatic degradation and absorption of glucose from complex carbohydrates. We discuss alternatives to acarbose that yield similar physiologic effects and describe dietary sources (e.g., sweet potatoes, legumes, and berries) of bioactive compounds with α-glucosidase inhibitory activity. We indicate future research should include exploration of how non-caloric compounds like α-glucosidase inhibitors modify macronutrient metabolism prior to disease onset, which may guide nutritional/lifestyle interventions to support health and reduce age-related disease risk.


Glucose; aging; calorie restriction; diabetes; disease; glucosidase inhibitor; insulin


Stage dependent nutritional regulation of transgenerational longevity.

Roussou IG, Savakis C, Tavernarakis N, Metaxakis A.

Nutr Healthy Aging. 2016 Oct 27;4(1):47-54. doi: 10.3233/NHA-160012.

PMID: 28035341




BACKGROUND: Statistical analyses in human populations have associated limited food availability during development with increased longevity of next generations. In support, recent findings in Caenorhabditis elegans revealed nutritional effects on transgenerational longevity. OBJECTIVES: In this study we tested the effect of nutrition on longevity of future generations in Drosophila and whether this is sex-specific. METHODS: We reared male larvae and adults of Drosophila under different food conditions and performed lifespan analyses in F2 generation. RESULTS: Grandsons of males which experienced starvation through larval stages were long-lived and grandsons of well fed larvae were short lived, in two Drosophila strains. In one strain, the nutritional effect on transgenerational longevity was transmitted through male line. Interestingly, we find that dietary restriction in adult males is the main nutritional condition affecting lifespan of grandsons. CONCLUSIONS: Our findings suggest that nutritional regulation of transgenerational longevity is evolutionarily conserved and developmental stage - dependent in Drosophila.


Aging; dietary restriction; drosophila; epigenetic regulation; lifespan; longevity; starvation; transgenerational inheritance


Variation of lifespan in multiple strains, and effects of dietary restriction and BmFoxO on lifespan in silkworm, Bombyx mori.

Song J, Tang D, Li Z, Tong X, Zhang J, Han M, Hu H, Lu C, Dai F.

Oncotarget. 2016 Dec 26. doi: 10.18632/oncotarget.14235. [Epub ahead of print]

PMID: 28038468



Established animal models have accelerated our understanding of the mechanisms involved in lifespan determination. However, more experimental animals are required to clarify the complex mechanisms behind the phenomena of aging and lifespan. In this study, we reported the variation of lifespan in nine distinct silkworm strains. Lifespan correlated significantly with BmFoxO gene expression in the representative silkworm strains tested (Xiafang, Dazao-N, and N4). In general, the female silkworm was longer lived than the male of the same strain. Dietary restriction extended the silkworm lifespan compared with that of silkworms fed ad libitum. The expression of BmFoxO was significantly elevated in the dietary restriction group on day 3 of the 4th instar and day 3 of the 5th instar, suggesting that BmFoxO contributes to dietary restriction-mediated lifespan extension. The RNA interference and overexpression of the BmFoxO gene significantly shortened and extended the silkworm adulthood, respectively. In conclusion, our findings suggest that the silkworm might serve as a promising experimental animal to explore the complex biological mechanisms of lifespan determination.


BmFoxO; Gerotarget; dietary restriction; experimental animal; lifespan; silkworm


[The below paper is pdf-availed.]

Alterations to mitochondrial fatty-acid use in skeletal muscle after chronic exposure to hypoxia depend on metabolic phenotype.

Malgoyre A, Chabert C, Tonini J, Koulmann N, Bigard X, Sanchez H.

J Appl Physiol (1985). 2016 Dec 29:jap.00090.2016. doi: 10.1152/japplphysiol.00090.2016. [Epub ahead of print]

PMID: 28035013


We investigated the effects of chronic hypoxia on the maximal use of and sensitivity of mitochondrial to different substrates in rat slow-oxidative (soleus, SOL) and fast-glycolytic (extensor digitorum longus, EDL) muscles. We studied mitochondrial respiration in situ in permeabilized myofibers, using pyruvate, octanoate, palmitoyl-carnitine (PC) or palmitoyl-coenzyme A (PCoA). The hypophagia induced by hypoxia may also alter metabolism. We therefore used a group of pair-fed rats (reproducing the same caloric restriction as observed in hypoxic animals) in addition to the normoxic control fed ad libitum. The resting respiratory exchange ratio decreased after 21 days of exposure to hypobaric hypoxia (simulated elevation of 5,500 m). The respiration of pyruvate and octanoate were unaffected. By contrast, the maximal oxidative respiratory rate for PCoA, the transport of which depends on CPT-1, decreased in the rapid-glycolytic EDL and increased in the slow-oxidative SOL, although hypoxia improved affinity for this substrate in both muscle types. PC and PCoA were oxidized similarly in normoxic EDL, whereas chronic hypoxia limited transport at the CPT-1 step in this muscle. The effects of hypoxia were mediated by caloric restriction in the SOL, and by hypoxia itself in the EDL. We conclude that improvements in mitochondrial affinity for PCoA, a physiological long-chain fatty acid, would facilitate fatty-acid use at rest after chronic hypoxia independently of quantitative alterations of mitochondria. Conversely, decreasing the maximal oxidation of PCoA in fast-glycolytic muscles would limit fatty-acid use during exercise.


chronic hypoxia; fatty acid; mitochondrial affinity; oxidative capacities; rat skeletal muscle


Table 1. Anatomical data and biochemical plasma parameters.




Body weight (BW) (g) 388 ± 8 328 ± 9 *** 337 ± 8 ***

Delta body weight (g) 83 ± 9 24 ± 6 *** 14 ± 9 ***

Food intake1 (g) 10.1 ± 0.2 6.6 ± 0.3 *** 6.9 ± 0.2 ***

Retroperitoneal fat mass (g) 8.8 ± 0.6 5.9 ± 0.7 * 7.0 ± 0.7

Retroperitoneal fat mass2 (g) 2.2 ± 0.2 1.6 ± 0.1 * 2.0 ± 0.2

Plasma free fatty acid (µmol/L) 74.4 ± 8.9 72.5 ± 7.1$ 156.7 ± 32.5**

Hematocrit (%) 44.8 ± 0.9 60.2 ± 0.9** $$ 46.3 ± 0.9


Data are expressed as mean ± SE.

1 expressed in grams per 100g body weight per day

2 expressed in grams per 100g body weight

Statistically different from N group, * P<0.05, ** P<0.01; *** P<0.001. Statistically

different from PF group, $ P<0.05, $$ P<0.01.


Table 2. Muscle maximal oxidative capacities expressed as the oxygen consumption of

skinned fibers in presence of saturated concentrations of glutamate and succinate (Vmax),

citrate synthase (CS) and 3-hydroxyl-acyl coenzyme A dehydrogenase (3-HAD) activities, in

soleus (SOL) and extensor digitorum longus (EDL) muscles.



Vmax CS 3-HAD Vmax CS 3-HAD Vmax CS 3-HAD


SOL 11.4± 0.6 34.6± 1.0 3.1± 0.2 10.3± 0.5 37.9± 3.1 3.0± 0.4 11.7± 0.7 31.4± 1.6 3.2± 0.3

EDL 9.2 ££± 0.4 28.0 £± 2.5 1.3 £££± 0.8 8.2 ££± 0.3 27.7 ££± 1.5 1.2 £££± 0.1 9.1 £££± 0.6 27.8 £± 0.5 1.3 £££± 0.1


Data are means ± SE. Vmax values are expressed as µmole O2.min-1.g-1 of dw, and enzymatic

activities as UI.g-1 of wt.

Statistically different from SOL data of the same group of animal, £ P <0.05, ££ P <0.01, £££

P <0.001.

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Clinical trial, recruiting:


Intermittent Calorie Restriction, Insulin Resistance, and Biomarkers of Brain Function

http://washingtondc.craigslist.org/mld/vol/5938486419.htmlposted: 2 days ago, Dec. 20/16


This study is currently recruiting participants. (see Contacts and Locations)

Verified November 2016 by National Institutes of Health Clinical Center (CC)


National Institute on Aging (NIA)

Information provided by (Responsible Party):

National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )

ClinicalTrials.gov Identifier: NCT02460783

First received: May 30, 2015

Last updated: November 18, 2016

Last verified: November 2016




- Insulin removes sugar from the blood to use for energy. Insulin resistance means that cells may not respond to insulin normally. It can lead to serious diseases. Researchers want to see how diet affects insulin resistance, weight, and brain chemicals related to Alzheimer s disease.




- To compare two forms of diet and their effects on insulin resistance and the brain.




- Women ages 55 70 with insulin resistance.




This study requires 6 clinic visits over 9 12 weeks. Participants must fast before visits.

Visit 1, screening:

Medical history, physical exam, and blood and urine tests.

Participants will get a wrist device to wear for 4 days.

Visit 2:

Weight and waist measurement.

Blood drawn.

Questionnaires and thinking tests.

Lumbar puncture. Skin will be numbed and a needle inserted between bones in the back will remove <TAB>fluid.

Participants will drink a nutrition shake. Blood will be taken 12 times over 4 <TAB>hours through a thin tube in <TAB>the arm.

Brain MRI. Participants will lie on a table that slides in and out of a cylinder in a strong magnetic field. <TAB>They will have a coil on their head and may do tasks.

Participants will get advice about healthy eating and be randomly put in one of 2 groups. One group will get <TAB>nutrition shakes to drink.

Visits 3 5:

Weight and waist measurements, vital signs, blood draw, and questionnaires.

Between visits, participants will get a call or email to check how they are doing.

Visit 6: Repeat of visit 1.

Participants will wear the wrist device for 4 more days, have a follow-up contact, then the study is finished.


Condition Intervention Phase

Alzheimer's Disease


Diabetes Mellitus

Dietary Supplement: Boost A

Behavioral: Healthy Living Diet

Phase 2


Study Type: Interventional

Study Design: Allocation: Randomized

Endpoint Classification: Safety/Efficacy Study

Intervention Model: Parallel Assignment

Masking: Open Label

Primary Purpose: Prevention

Official Title: Intermittent Calorie Restriction, Insulin Resistance, and Biomarkers of Brain Function


Resource links provided by NLM:


Genetics Home Reference related topics: Alzheimer disease

Genetic and Rare Diseases Information Center resources: Familial Alzheimer Disease

U.S. FDA Resources


Further study details as provided by National Institutes of Health Clinical Center (CC):


Primary Outcome Measures:

Exosomal p-S312-IRS-1/p-panY-IRS-1 ratio (index of brain insulin resistance) [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]


Secondary Outcome Measures:

Hormones (GLP-1, insulin) during a mixed [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

Anthropometric measures (weight, waist) [ Time Frame: 0, 2, 4, 6, 8 weeks ] [ Designated as safety issue: Yes ]

Measure: CSF, plasma BDNF [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

Cognitive performance (Examiner, Memory) [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

Mood, energy, concentration, etc. symptom [ Time Frame: 0, 2, 4, 6, 8 weeks ] [ Designated as safety issue: Yes ]

Si and HOMA-IR (indices of peripheral insulin resistance) [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

Lipid panel, uric acid [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

MRS metabolites [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

fMRI activation to food preference task [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

fMRI activation to Stroop [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

CSF, plasma AD biomarkers (A(SqrRoot) <=42,p181Tau) [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

Cytokines: IL-6, IL-8, IL-12, IL-23 [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

Physical activity (Accelerometry) [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

DNA methylation [ Time Frame: 0, 2, 4, 6, 8 weeks ] [ Designated as safety issue: No ]

Measure: Exosomal proteins and mRNA [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

ROS, AGES [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

Resting fMRI [ Time Frame: 0, 8 weeks ] [ Designated as safety issue: No ]

Gene expression [ Time Frame: 0, 2, 4, 6, 8 weeks ] [ Designated as safety issue: No ]


Estimated Enrollment: 100

Study Start Date: April 2015

Estimated Study Completion Date: July 2017

Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)

Arms Assigned Interventions

Experimental: 5-2 CR

Healthy living diet for 5 days/week;

Dietary Supplement: Boost A

Supplement providing 530 Kcal/Bottle

Active Comparator: Healthy Living

Healthy living diet for 7 days/week

Behavioral: Healthy Living Diet

Counseling and educational material on diet portion, consistency


Detailed Description:

Being overweight or obese can cause insulin resistance (IR), which is defined as reduced responsiveness to insulin by the cells of various tissues or organs. IR at midlife increases the risk of developing Alzheimer s disease (AD). We recently discovered novel biomarkers of brain IR (altered Tyr and Ser phosphorylated forms of insulin receptor substrate 1; IRS-1) in plasma exosomes enriched for neuronal origin. Moreover, IR is associated with AD biomarkers including deficits in resting state brain activity and cognitive performance. Calorie restriction is defined as consuming fewer calories than what is considered normal without a lack of nutrients. A certain type of calorie restriction, in which one consumes 500-600 calories a day for two consecutive days, followed by non-restricted eating for 5 days (5-2 CR), has been shown to lower peripheral insulin resistance effectively. Effects of CR and lowering peripheral IR on brain IR and cognition are unknown. The goal of this exploratory pilot study is to provide proof-of-concept that 5-2 CR at midlife can reverse brain IR, lower peripheral IR, improve cognitive performance, and increase brain activation at rest and during tasks. Specifically, we will study the effects of 8 weeks of 5-2 CR versus a control dietary intervention on brain and peripheral IR, memory and executive function, resting state default mode network activity, brain metabolism, and AD biomarkers. Forty overweight to obese women and men (between 55 and 70 years of age) will be randomized 1:1 into 5-2 CR and control groups. In the 5-2 CR group, participants will be offered healthy living dietary counseling at baseline, which they will be instructed to implement for five days/week. For each of the other two consecutive days/week, they will consume two shakes (Boost , CWI Medical), providing a total of 480 Kcal/day. In the control group, participants will be offered healthy living dietary counseling at baseline, which they will be asked to implement for every day of the week. Participants will undergo screening including a history and physical examination, calculation of Body Mass Index (BMI, which must be greater than or equal to 27) and a blood draw for insulin and glucose to determine whether they have insulin resistance. If participants meet eligibility criteria, they will continue with a baseline visit involving anthropometric measures, questionnaires, tests of cognitive function, brain MRI, blood draws for plasma and peripheral blood mononuclear cells, and lumbar puncture for cerebrospinal fluid biomarkers of AD. After 8 weeks, we will collect the same measures. To assess and reinforce compliance with their respective diet, participants will come into the clinic every 2 weeks to discuss compliance, measure their body weight and perform blood draws for measurement of ketones to objectively confirm energy restriction for the 5-2 CR group. We will also contact participants every week to further ensure compliance. To assess the effects of the diets on physical activity, participants will be asked to wear an accelerometer for 96 hours before and after they are on the diet.



Ages Eligible for Study: 55 Years to 70 Years (Adult, Senior)

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No



BMI greater than or equal to 27; in addition, weight less than or equal to 350 lbs (weight limit for MRI scanner);

Age of 55-70 years;

HOMA-IR greater than or equal to 1.8;

MMSE greater than or equal to 26



History of cardiovascular disease;

History of clinically significant stroke or other neurological disease of the central nervous system;

History of substance abuse in the past 6 months or positive urine drug screen;

History of clinically significant endocrine disorders (common mild endocrine disorders, such as untreated subclinical hypothyroidism with TSH < 10 mU/l or successfully treated hypothyroidism may be allowed);

History of eating disorders, significant GI disorders or malabsorption disorders;

History of type 2 diabetes; and/or use of anti-diabetes medications or insulin; and/or type 2 diabetes diagnosed during the screening visit based on fasting glucose > 125 mg/dL;

History of hypoglycemia; and/or a fasting glucose < 70 mg/dL during the screening visit.

Current use of systemic corticosteroids;

Positive screening tests for HIV, HCV or HBV;

Hematocrit less than 35% or hemoglobin less than 11 mg/dL;

ALT or AST > 1.5 times the upper normal limit;

Contraindications for MRI (pacemakers, ferrous metal implants or shrapnel in or around the head, etc.).

Contraindications to LP, such as Coumadin, coagulopathy (international normalized ratio, or INR > 1.5; prothrombin time (PT), partial prothrombin time (PTT) > 1.5 x upper normal limit). Aspirin 81 mg qd is allowed. Aspirin up to 325 mg qd is allowed, if withheld for 7 days prior to the LP.

Pregnancy or nursing.

Refusal to consent to genetic testing for APOE.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.


Please refer to this study by its ClinicalTrials.gov identifier: NCT02460783



Contact: Onyinye U Erondu, R.N. (410) 350-7319 onyinye.erondu@nih.gov

Contact: Dimitrios I Kapogiannis, M.D. (410) 350-3953 kapogiannisd@mail.nih.gov



United States, Maryland

National Institute of Aging, Clinical Research Unit Recruiting

Baltimore, Maryland, United States, 21224

Sponsors and Collaborators

National Institute on Aging (NIA)


Principal Investigator: Dimitrios I Kapogiannis, M.D. National Institute on Aging (NIA)

More Information


Additional Information:

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site


Responsible Party: National Institute on Aging (NIA)

ClinicalTrials.gov Identifier: NCT02460783 History of Changes

Other Study ID Numbers: 150123 15-AG-0123

Study First Received: May 30, 2015

Last Updated: November 18, 2016

Health Authority: United States: Federal Government


Keywords provided by National Institutes of Health Clinical Center (CC):




Dementia of the Alzheimer Type

Functional Magnetic Resonance Imaging (fMRI)


Additional relevant MeSH terms:

Diabetes Mellitus

Alzheimer Disease

Insulin Resistance

Glucose Metabolism Disorders

Metabolic Diseases

Endocrine System Diseases


Brain Diseases

Central Nervous System Diseases

Nervous System Diseases


Neurodegenerative Diseases

Neurocognitive Disorders

Mental Disorders



ClinicalTrials.gov processed this record on December 30, 2016

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Effects of age and caloric restriction in the vascular response of renal arteries to endothelin-1 in rats.

Amor S, García-Villalón AL, Rubio C, Carrascosa JM, Monge L, Fernández N, Martín-Carro B, Granado M.

Exp Gerontol. 2016 Dec 27. pii: S0531-5565(16)30624-6. doi: 10.1016/j.exger.2016.12.020. [Epub ahead of print]

PMID: 28039024



Cardiovascular alterations are the most prevalent cause of impaired physiological function in aged individuals with kidney being one the most affected organs. Aging-induced alterations in renal circulation are associated with a decrease in endothelium-derived relaxing factors such as nitric oxide (NO) and with an increase in contracting factors such as endothelin-1(ET-1). As caloric restriction (CR) exerts beneficial effects preventing some of the aging-induced alterations in cardiovascular system, the aim of this study was to analyze the effects of age and caloric restriction in the vascular response of renal arteries to ET-1 in aged rats. Vascular function was studied in renal arteries from 3-month-old Wistar rats fed ad libitum (3m) and in renal arteries from 8-and 24-month-old Wistar rats fed ad libitum (8m and 24m), or subjected to 20% caloric restriction during their three last months of life (8m-CR and 24m-CR). The contractile response to ET-1 was increased in renal arteries from 8m and 24m compared to 3m rats. ET-1-induced contraction was mediated by ET-A receptors in all experimental groups and also by ET-B receptors in 24m rats. Caloric restriction attenuated the increased contraction to ET-1 in renal arteries from 8m but not from 24m rats possibly through NO release proceeding from ET-B endothelial receptors. In 24m rats, CR did not attenuate the aging-increased response of renal arteries to ET-1, but it prevented the aging-induced increase in iNOS mRNA levels and the aging-induced decrease in eNOS mRNA levels in arterial tissue. In conclusion, aging is associated with an increased response to ET-1 in renal arteries that is prevented by CR in 8m but not in 24m rats.


The impact of exercise intensity on whole body and adipose tissue metabolism during energy restriction in sedentary overweight men and postmenopausal women.

Walhin JP, Dixon NC, Betts JA, Thompson D.

Physiol Rep. 2016 Dec;4(24). pii: e13026. doi: 10.14814/phy2.13026.

PMID: 28039399




This study aimed to establish whether vigorous-intensity exercise offers additional adipose-related health benefits and metabolic improvements compared to energy-matched moderate-intensity exercise. Thirty-eight sedentary overweight men (n = 24) and postmenopausal women (n = 14) aged 52 ± 5 years (mean ± standard deviations [sD]) were prescribed a 3-week energy deficit (29302 kJ∙week-1) achieved by increased isocaloric moderate or vigorous-intensity exercise (+8372 kJ∙week-1) and simultaneous restricted energy intake (-20930 kJ∙week-1). Participants were randomly assigned to either an energy-matched vigorous (VIG; n = 18) or moderate (MOD; n = 20) intensity exercise group (five times per week at 70% or 50% maximal oxygen uptake, respectively). At baseline and follow-up, fasted blood samples and abdominal subcutaneous adipose tissue biopsies were obtained and oral glucose tolerance tests conducted. Body mass was reduced similarly in both groups (∆ 2.4 ± 1.1 kg and ∆ 2.4 ± 1.4 kg, respectively, P < 0.05). Insulinemic responses to a standard glucose load decreased similarly at follow-up relative to baseline in VIG (∆ 8.6 ± 15.4 nmol.120 min.l-1) and MOD (∆ 5.4 ± 8.5 nmol.120 min.l-1; P < 0.05). Expression of SREBP-1c and FAS in adipose tissue was significantly down-regulated, whereas expression of PDK4 and hormone-sensitive lipase (HSL) was significantly up-regulated in both groups (P < 0.05). Thus, when energy expenditure and energy deficit are matched, vigorous or moderate-intensity exercise combined with energy restriction provide broadly similar (positive) changes in metabolic control and adipose tissue gene expression.


Adipose tissue; energy restriction; exercise intensity; gene expression; metabolism

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Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes: A Mini-Review.

Longchamp A, Harputlugil E, Corpataux JM, Ozaki CK, Mitchell JR.

Gerontology. 2017 Jan 5. doi: 10.1159/000453109. [Epub ahead of print]

PMID: 28052287




Dietary restriction (DR) is best known for extending lifespan in experimental model organisms, but also increases resistance to a variety of clinically relevant stressors, including those associated with surgery. Extended periods of DR, lasting months to years, are required for optimal longevity benefits in rodents, but short-term dietary preconditioning (less than 1 week) remarkably protects from acute injury. Here, we discuss recent advances in our understanding of the mechanistic basis of short-term DR and fasting in the context of surgical stress resistance, including upstream amino acid sensing by the GCN2 and mTORC1 pathways, and downstream effector mechanisms including increased insulin-dependent prosurvival signaling and elevated endogenous hydrogen sulfide production. We also review the current trend in preoperative nutrition away from preoperative fasting and towards carbohydrate loading. Finally, we discuss the rationale for the nonmutually exclusive use of brief DR or pharmacological DR mimetics to precondition against the stress and potential complications of surgery.


[The below paper is now in Medline.]

Prior Dietary Practices and Connections to a Human Gut Microbial Metacommunity Alter Responses to Diet Interventions.

Griffin NW, Ahern PP, Cheng J, Heath AC, Ilkayeva O, Newgard CB, Fontana L, Gordon JI.

Cell Host Microbe. 2016 Dec 22. pii: S1931-3128(16)30517-0. doi: 10.1016/j.chom.2016.12.006. [Epub ahead of print]

PMID: 28041931


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Global Metabolic Profiling of Plasma Shows that Three-Year Mild-Caloric Restriction Lessens an Age-Related Increase in Sphingomyelin and Reduces L-leucine and L-phenylalanine in Overweight and Obese Subjects.

Kim M, Lee SH, Lee JH.

Aging Dis. 2016 Dec 1;7(6):721-733. doi: 10.14336/AD.2016.0330.

PMID: 28053823




The effect of weight loss from long-term, mild-calorie diets (MCD) on plasma metabolites is unknown. This study was to examine whether MCD-induced weight reduction caused changes in the extended plasma metabolites. Overweight and obese subjects aged 40-59 years consumed a MCD (approximately 100 kcal/day deficit, n=47) or a weight-maintenance diet (control, n=47) in a randomized, controlled design with a three-year clinical intervention period and plasma samples were analyzed by using UPLC-LTQ-Orbitrap mass spectrometry. The three-year MCD intervention resulted in weight loss (-8.87%) and significant decreases in HOMA-IR and TG. The three-year follow-up of the MCD group showed reductions in the following 13 metabolites: L-leucine; L-phenylalanine; 9 lysoPCs; PC (18:0/20:4); and SM (d18:0/16:1). The three-year MCD group follow-up identified increases in palmitic amide, oleamide, and PC (18:2/18:2). Considering the age-related alterations in the identified metabolites, the MCD group showed a greater decrease in L-leucine, L-phenylalanine, and SM (d18:0/16:1) compared with those of the control group. Overall, the change (Δ) in BMI positively correlated with the ΔTG, ΔHOMA-IR, ΔL-leucine, and ΔSM (d18:0/16:1). The ΔHOMA-IR positively correlated with ΔTG, ΔL-leucine, ΔL-phenylalanine, and ΔSM (d18:0/16:1). The weight loss resulting from three-year mild-caloric restriction lessens the age-related increase in SM and reduces L-leucine and L-phenylalanine in overweight and obese subjects. These changes were coupled with improved insulin resistance.


BMI; L-leucine; L-phenylalanine; mild-calorie diet; sphingomyelin

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Metabolic effects of fasting on human and mouse blood in vivo.

Pietrocola F, Demont Y, Castoldi F, Enot D, Durand S, Semeraro M, Baracco EE, Pol J, Bravo-San Pedro JM, Bordenave C, Levesque S, Humeau J, Chery A, Métivier D, Madeo F, Maiuri MC, Kroemer G.

Autophagy. 2017 Jan 6:0. doi: 10.1080/15548627.2016.1271513. [Epub ahead of print]

PMID: 28059587



Starvation is a strong physiological stimulus of macroautophagy/autophagy. In this study, we addressed the question as to whether it would be possible to measure autophagy in blood cells after nutrient deprivation. Fasting of mice for 48 h (which causes ∼20% weight loss) or starvation of human volunteers for up to 4 days (which causes <2% weight loss) provokes major changes in the plasma metabolome, yet induces only relatively minor alterations in the intracellular metabolome of circulating leukocytes. White blood cells from mice and human volunteers responded to fasting with a marked reduction in protein lysine acetylation, affecting both nuclear and cytoplasmic compartments. In circulating leukocytes from mice that underwent 48-h fasting, an increase in LC3B lipidation (as assessed by immunoblotting and immunofluorescence) only became detectable if the protease inhibitor leupeptin was injected 2 h before drawing blood. Consistently, measurement of an enhanced autophagic flux was only possible if white blood cells from starved human volunteers were cultured in the presence or absence of leupeptin. Whereas all murine leukocyte subpopulations significantly increased the number of LC3B+ puncta per cell in response to nutrient deprivation, only neutrophils from starved volunteers showed signs of activated autophagy (as determined by a combination of multi-color immunofluorescence, cytofluorometry and image analysis). Altogether, these results suggest that white blood cells are suitable for monitoring autophagic flux. In addition, we propose that the evaluation of protein acetylation in circulating leukocytes can be adopted as a biochemical marker of organismal energetic status.


Autophagy; IGF1; caloric restriction; leukocytes; longevity; metabolome; p62; protein acetylation


[The below paper is not pdf-availed.]

Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease.

Tönnies E, Trushina E.

J Alzheimers Dis. 2017 Dec 3. doi: 10.3233/JAD-161088. [Epub ahead of print]

PMID: 28059794


Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.


Alzheimer’s disease; amyloid-β; antioxidants; caloric restriction; exercise; mitochondria; mitohormesis; neurotransmission; oxidative stress; synaptic function; tau protein


Targeting retinal ganglion cell recovery.

Crowston JG, Fahy ET, Fry L, Trounce IA, van Wijngaarden P, Petrou S, Chrysostomou V.

Eye (Lond). 2017 Jan 6. doi: 10.1038/eye.2016.281. [Epub ahead of print]

PMID: 28060359



Accumulating evidence from experimental and clinical studies suggest that retinal ganglion cells at least in the earlier stages of glaucoma have the capacity to recover function following periods of functional loss. The capacity for recovery may be negatively impacted by advancing age but can be boosted by interventions such as diet restriction and exercise.

14. Impact of aging and diet restriction on retinal function during and after acute intraocular pressure injury.

Kong YX, van Bergen N, Bui BV, Chrysostomou V, Vingrys AJ, Trounce IA, Crowston JG.

Neurobiol Aging. 2012 Jun;33(6):1126.e15-25. doi: 10.1016/j.neurobiolaging.2011.11.026.

PMID: 22217415


Advancing age is a major risk factor for many neurodegenerative diseases but the underlying pathophysiology is not clear. We hypothesize that aging impairs the ability of neurons in the central nervous system to recover functionally after injury. To test this in retinal ganglion cells in vivo, we developed an optic nerve "stress test" which monitors the functional capacity of the optic nerve and retina, during and after a subischemic injury induced by intraocular pressure elevation. We report that older (18-month) C57BL/6J mice suffered greater loss of inner retinal function compared with younger adult mice following intraocular pressure (IOP) challenge. To investigate whether age-related vulnerability to IOP challenge can be modified, we subjected 12-month-old mice to dietary restriction (DR) (alternate-day fasting) for 6 months. Compared with age-matched ad libitum fed controls, DR mice showed greater recovery in inner retinal function following IOP challenge. DR was associated with reduced oxidative stress level following injury and improved mitochondrial oxidative phosphorylation enzyme activity compared with ad libitum controls. Taken together, this study provides in vivo evidence that DR improves functional recovery of the retina following injury and points to the potential benefits of therapies that target mitochondria for the protection of the aging retina and optic nerve against injury.


Influence of Energy Balance and Glycemic Index on Metabolic Endotoxemia in Healthy Men.

Breusing N, Lagerpusch M, Engstler AJ, Bergheim I, Mueller MJ, Bosy-Westphal A.

J Am Coll Nutr. 2017 Jan 6:1-8. doi: 10.1080/07315724.2016.1156036. [Epub ahead of print]

PMID: 28060600




Overfeeding with a high-fat and/or high-carbohydrate (CHO) diet is known to increase plasma concentrations of endotoxin (lipopolysaccharide [LPS]) that may lead to metabolic disturbances like insulin resistance. The impact of CHO quality (i.e., the glycemic index [GI]) independent of fat intake on metabolic endotoxemia remains unclear. In the present study, the effects of changes in energy balance and GI on plasma endotoxin were studied.


Fifteen healthy young men overconsumed diets containing 65% CHO and 20% fat for 1 week (OF; +50% of energy requirement) followed by 3 weeks of caloric restriction (CR; -50% of energy requirement) and were then randomized to 2 weeks hypercaloric refeeding (RF, +50% of energy requirement) with either a low- or high-GI (40 vs 74) diet.


During OF, subjects gained 1.9 ± 0.7 kg body weight (+0.6 ± 0.8% fat mass) followed by a weight loss of 6.1 ± 0.8 kg (-2.0 ± 0.6% fat mass) and weight regain of 4.0 ± 0.6 kg (0.9 ± 0.8% fat mass). Fasting insulin and homeostasis model assessment-insulin resistance (HOMAIR) increased with OF and RF and decreased with CR, MatsudaISI decreased by 37% after RF (all p < 0.05). Endotoxin significantly increased by 30.8% with OF and by 24.7% with RF (both p < 0.05), whereas CR normalized endotoxin levels. No difference in endotoxin levels was observed between refeeding a hypercaloric high- or low-GI diet. Changes in endotoxin levels with RF were not related to changes in insulin sensitivity.


A hypercaloric diet (OF and RF) increased plasma endotoxin irrespective of GI, whereas a negative energy balance did not reduce endotoxemia. Impaired insulin sensitivity with hypercaloric refeeding on a high-GI diet was not explained by metabolic endotoxemia.


endotoxin; energy balance; glycemic index; insulin sensitivity; weight cycle


Glucagon-Like Peptide-1 and its Analogues Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight.

Anderberg RH, Richard JE, Eerola K, Ferreras LL, Nordbeck EB, Hansson C, Nissbrandt H, Berqquist F, Gribble FM, Reimann F, Wernstedt-Asterholm I, Lamy C, Skibicka KP.

Diabetes. 2017 Jan 5. pii: db160755. doi: 10.2337/db16-0755. [Epub ahead of print]

PMID: 28057699



Glucagon-like peptide-1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as anti-obesity strategies. Surprisingly whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the CNS. Serotonin depletion impaired the ability of exendin-4, a clinically utilized GLP-1 analogue, to reduce body weight in rats, suggesting serotonin is a critical mediator of the energy balance impact of GLP-1R activation. Serotonin turnover and expression of 5HT2A and 5HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that 5HT2A, but surprisingly not 5HT2C, receptor is critical for weight-loss, anorexia and fat mass reduction induced by central GLP-1R activation. Importantly, central 5HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase electrical activity of the DR serotonin neurons. Finally our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as new critical neural substrate for GLP-1 impact on energy homeostasis, and expands the current map of brain areas impacted by GLP-1R activation.


Starving leukemia to induce differentiation

volume 23 | number 1 | january 2017 nature medicine pp14 - 15

Chia-Wei Cheng and Omer H Yilmaz



A new study shows that fasting induces the differentiation and elimination of some types of leukemia in mice, which implicates fasting or its mimetics as a novel strategy for the treatment of this disease.


Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation.

Lu Z, Xie J, Wu G, Shen J, Collins R, Chen W, Kang X, Luo M, Zou Y, Huang LJ, Amatruda JF, Slone T, Winick N, Scherer PE, Zhang CC.

Nat Med. 2016 Dec 12. doi: 10.1038/nm.4252. [Epub ahead of print]

PMID: 27941793



New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.

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Nutritional Control of Chronological Aging and Heterochromatin in Saccharomyces cerevisiae.

McCleary DF, Rine J.

Genetics. 2017 Jan 6. pii: genetics.116.196485. doi: 10.1534/genetics.116.196485. [Epub ahead of print]

PMID: 28064165



Calorie restriction extends lifespan in organisms as diverse as yeast and mammals through incompletely understood mechanism(s). The role of NAD+-dependent deacetylases, known as Sirtuins, in this process, particularly in the yeast S. cerevisiae is controversial. We measured chronological lifespan of wild-type and sir2Δ strains over a higher glucose range than typically used for studying yeast calorie restriction. sir2Δ extended lifespan in high-glucose complete minimal medium, and had little effect in low glucose medium, revealing a partial role for Sir2 in the calorie restriction response under these conditions. Experiments performed on cells grown in rich medium with a newly-developed genetic strategy revealed that sir2Δ shortened lifespan in low glucose while having little effect in high glucose, again revealing a partial role for Sir2. In complete minimal media, Sir2 shortened lifespan as glucose levels increased, whereas in rich media, Sir2 extended lifespan as glucose levels decreased. Using a genetic strategy to measure the strength of gene silencing at HML, we determined increasing glucose stabilized Sir2-based silencing during growth on complete minimal media. Conversely, increasing glucose destabilized Sir-based silencing during growth on rich media, specifically during late cell divisions. In rich medium, silencing was far less stable in high glucose than in low glucose during stationary phase. Therefore, Sir2 was involved in a response to nutrient cues including glucose that regulates chronological aging, possibly through Sir2-dependent modification of chromatin or deacetylation of a non-histone protein.


Sir2; aging; gene silencing; heterochromatin; nutrition


[The below paper is not pdf-availed.]


The rs1862513 Variant in Resistin Gene-Modified Insulin Resistance and Insulin Levels after Weight Loss Secondary to Hypocaloric Diet.

de Luis DA, Izaola O, Primo D, de la Fuente B, Mulero I, Aller R.

Ann Nutr Metab. 2017 Jan 7;69(3-4):256-262. doi: 10.1159/000453676. [Epub ahead of print]

PMID: 28064279



Polymorphisms of a single nucleotide in RETN have been associated with indexes of insulin resistance. Our aim was to analyze the effects of the rs1862513 RETN gene polymorphism on insulin resistance, insulin levels, and resistin levels changes after 3 months of a low-fat hypocaloric diet.


A Caucasian population of 133 obese patients was analyzed before and after 3 months on a low-fat hypocaloric diet.


Fifty-six patients (42.1%) had the genotype GG (wild group) and 77 (57.9%) patients had the other genotypes; GC (59 patients, 44.4%) or CC (18 patients, 13.5%; mutant group). In wild and mutant genotype groups, weight, body mass index, fat mass, waist circumference, and systolic blood pressure decreased. In the wild genotype group, the decrease in total cholesterol was -13.1 ± 25.3 mg/dL (vs. -4.4 ± 13.7 mg/dL in mutant group: p = 0.004 for group deltas), low density lipoprotein (LDL)-cholesterol was -13.0 ± 21.5 mg/dL (-4.3 ± 10.5 mg/dL: p = 0.007), glucose -7.2 ± 3.5 mg/dL (-0.8 ± 0.2 mg/dL: p = 0.01), insulin -5.6 ± 2.5 mUI/L (-2.9 ± 1.2 mUI/L: p = 0.03) and homeostasis model assessment-insulin resistance (HOMA-IR) -2.5 ± 1.1 (-0.6 ± 1.4: p = 0.02). Leptin levels decreased in both genotypes (-10.1 ± 9.5 ng/dL in wild type group vs. -13.1 ± 0.2 ng/dL in mutant type group: p > 0.05).


The present study suggests that the G/G genotype of RETN rs1862513 could be a predictor of the reduction of HOMA-IR, insulin, fasting glucose and LDL cholesterol secondary to a hypocaloric diet in obese subjects.

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Study Links Some Positive Effects to Calorie Restriction in Nonobese Adults



A 25 percent calorie restriction over two years by adults who were not obese was linked to better health-related quality of life, according to the results of a randomized clinical trial published online by JAMA Internal Medicine.

Calorie restriction can increase longevity in many species but concerns remain about potential negative effects of calorie restriction in humans.

Corby K. Martin, Ph.D., of the Pennington Biomedical Research Center, Baton Rouge, La., and coauthors tested the effects of calorie restriction on aspects of quality of life that have been speculated to be negatively affected by calorie restriction, including decreased libido, lower stamina, depressed mood and irritability. Their work extends the literature with a study group of nonobese individuals because beneficial effects of calorie restriction on health span (length of time free of disease) increase the possibility that more people will practice calorie restriction.

In this clinical trial conducted at three academic research institutions, 220 men and women with body mass index of 22 to 28 were enrolled and divided almost 2 to 1 into two groups: the larger group was assigned to two years of 25 percent calorie restriction and the other was an ad libitum (their own preference) control group for comparison. The analysis included 218 participants and self-report questionnaires were used to measure mood, quality of life, sleep and sexual function.

Data were collected at baseline, a year and two years. Of the 218 participants, the average age was nearly 38 and 70 percent were women. The calorie restriction group lost an average of 16.7 pounds compared with less than a pound in the control group at year two.

According to the authors, the calorie restriction group, compared with the control group, had improved mood, reduced tension and improved general health and sexual drive and relationship at year two, as well as improved sleep at year one. The bigger weight loss by the calorie restriction participants was associated with increased vigor, less mood disturbance, improved general health and better quality of sleep.

A limitation of the study is its selection of a sample of healthy individuals.

“Calorie restriction among primarily overweight and obese persons has been found to improve QOL [quality of life], sleep and sexual function, and the results of the present study indicate that two years of CR [calorie restriction] is unlikely to negatively affect these factors in healthy adults; rather, CR is likely to provide some improvement,” the authors conclude.


Obesity Management and Prevention: More Questions Than Answers.

Moin T.

JAMA Intern Med. 2016 Jun 1;176(6):753-4. doi: 10.1001/jamainternmed.2016.1211. No abstract available.

PMID: 27135966



Innovative Self-Regulation Strategies to Reduce Weight Gain in Young Adults: The Study of Novel Approaches to Weight Gain Prevention (SNAP) Randomized Clinical Trial.

Wing RR, Tate DF, Espeland MA, Lewis CE, LaRose JG, Gorin AA, Bahnson J, Perdue LH, Hatley KE, Ferguson E, Garcia KR, Lang W; Study of Novel Approaches to Weight Gain Prevention (SNAP) Research Group..

JAMA Intern Med. 2016 Jun 1;176(6):755-62. doi: 10.1001/jamainternmed.2016.1236.

PMID: 27136493



Weight gain occurs commonly in young adults and has adverse effects on health.


To compare 2 self-regulation interventions vs control in reducing weight gain in young adults over a mean follow-up of 3 years.


Randomized clinical trial in 2 academic settings of 599 participants aged 18 to 35 years with body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 21.0 to 30.0, recruited via mailings and emails from August 2010 to February 2012. Data were analyzed from January 2015 to January 2016.


Participants were randomized to control, self-regulation plus small changes, or self-regulation plus large changes. Both interventions focused on frequent self-weighing to cue behavior changes. "Small changes" taught participants to reduce intake and increase activity, both by approximately 100 calories per day. "Large changes" focused on losing 2.3 to 4.5 kg initially to buffer against expected weight gain.


Changes in weight from baseline over mean follow-up of 3 years. Secondary outcomes included proportion gaining at least 0.45 kg from baseline, proportion developing obesity (BMI, ≥30.0), and weight change baseline to 2 years.


Among the 599 participants (22% men; 27% minority; mean [sD] age, 27.7 [4.4] years; mean [sD] BMI, 25.4 [2.6]), mean (SE) weight changes over a mean follow-up of 3 years were 0.26 (0.22), -0.56 (0.22), and -2.37 (0.22) kg in the control, small-changes, and large-changes groups, respectively (P < .001). Differences among all 3 groups were significant (large changes vs control, P < .001; small changes vs control, P = .02; large changes vs small changes, P < .001). On secondary outcomes, both interventions significantly reduced incidence of obesity relative to control (mean [sE], 8.6% [2.0%], 7.9% [2.0%], and 16.9% [2.7%] in the large-changes, small-changes, and control groups, respectively; P = .02 for large changes vs control and P = .002 for small changes vs control); a smaller percentage of participants in the large-changes group gained 0.45 kg or more (mean [sE], 23.6% [2.8%], 32.5% [3.8%], and 40.8% [4.4%], respectively; P < .001 vs control and P = .02 vs small changes) and weight change from baseline to 2 years was greater in control than in small or large changes (mean [sE], 0.54 [0.33], -0.77 [0.33], and -1.50 [0.34] kg, respectively; P = .02 vs small changes and P < .001 vs large changes).


Self-regulation with large or small changes both reduced weight gain in young adults over 3 years relative to control, but the large-changes intervention was more effective.


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

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

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

PMID: 27136347




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


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


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


Two years of 25% CR or AL.


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


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


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


Healthy Behaviors Potentially Due to Calorie Restriction.

Tufan F, Soyluk O, Karan MA.

JAMA Intern Med. 2016 Nov 1;176(11):1724. doi: 10.1001/jamainternmed.2016.6190. No abstract available.

PMID: 27820642



Healthy Behaviors Potentially Due to Calorie Restriction-Reply.

Martin CK, Bhapkar M, Roberts SB; CALERIE Study Group..

JAMA Intern Med. 2016 Nov 1;176(11):1724. doi: 10.1001/jamainternmed.2016.6201. No abstract available.

PMID: 27820645


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Efficacy of nutritional recommendations given by registered dietitians compared to other healthcare providers in reducing arterial blood pressure: Systematic review and meta-analysis.

Riegel GR, Ribeiro PA, Rodrigues MP, Zuchinali P, Moreira LB.

Clin Nutr. 2016 Dec 28. pii: S0261-5614(16)31360-7. doi: 10.1016/j.clnu.2016.12.019. [Epub ahead of print]

PMID: 28065482




The multidisciplinary health practitioners can facilitate adherence to treatment of hypertension. Nutritional recommendations delivered by an expert in nutrition might increase the blood pressure control through a better comprehension about how nutrition plays a role on hypertension.


To evaluate the effect of nutritional intervention performed by a multidisciplinary team with and without registered dietitians compared to usual care in blood pressure control of hypertensive patients.


Systematic review including randomized clinical trials that assessed participants >18 years, both sexes, with blood pressure ≥140/90 mmHg or use of antihypertensive, ≥8 weeks duration and at least one nutritional planned intervention versus usual care. The search was conducted in July 2015 in MEDLINE, EMBASE, BIREME, Web of Science and LILACS without limitation to language. Outcome was defined as deltas of systolic (SBP) and diastolic blood pressure (DBP). Sub-group analysis was conducted according to the presence or not of the registered dietitians in the staff. The analyses were performed in RevMan 5.3 software, using random effects model with heterogeneity assessed by statistical I2.


From 7280 identified titles, 62 studies were selected for data extraction, and 13 were included in the meta-analysis, with a total of 2050 participants. There was a greater reduction in ΔSBP -2.82 mmHg (95% CI: 4.03 to -1.62) and ΔDBP -1.37 mmHg (95% CI: -2.11 to -0.62) when diet recommendations have been delivered by multi-professional team versus usual care. In stratified analyses only the subgroup of studies with registered dietitians showed statistical significant reduction in blood pressure ΔSBP -3.21 mmHg (95% CI: -4.14 to -2.27); ΔDBP -1.46 mmHg (95% CI: -2.06 to -0.86). There were significant differences between the deltas of blood pressure according to sodium restriction (ΔSBP -3.5 mmHg (95% CI: -4.52 to -2.48), ΔDBP -1.69 mmHg (95% CI: -2.36 to -1, 02)) and caloric restriction (ΔSBP -2.83 mmHg (95% CI: -5.11 to -0.54); ΔDBP -0.92 mmHg (95% CI: -2.21 to 0.37)) only when there was a registered dietitians in the multidisciplinary team.


Nutritional recommendation made by multidisciplinary team has a statistical significant effect on blood pressure control in hypertensive patients, mainly when a registered dietitian is present in the team.


blood pressure; dietitian; efficacy; hypertension; metanalysis; multi-disciplinary team


Two Days of Calorie Deprivation Induced by Underfeeding and Aerobic Exercise Degrades Mood and Lowers Interstitial Glucose but Does Not Impair Cognitive Function in Young Adults.

Lieberman HR, Bukhari AS, Caldwell JA, Wilson MA, Mahoney CR, Pasiakos SM, McClung JP, Smith TJ.

J Nutr. 2017 Jan;147(1):110-116. doi: 10.3945/jn.116.238246.

PMID: 27807037 Free Article





In studies assessing the effects of acute undernutrition on cognitive function, volunteers are sedentary and findings are equivocal, even though glucose concentrations fall substantially. However, military personnel and endurance athletes often are underfed when physical demands, and consequently energy expenditure, are substantial.


The objective of this study was to determine whether 2 d of near-total calorie deprivation combined with aerobic exercise degraded cognitive performance and mood.


A double-blind, placebo-controlled, crossover design was used. Twenty-three volunteers [17 men (mean ± SD age: 20.5 ± 0.7 y) and 6 women (mean ± SD age: 23.3 ± 1.4 y); mean ± SD body mass index (in kg/m2): 25 ± 3] participated for 68 h, including a 51-h inpatient phase in a calorie-deprived or fully fed state during which behavioral testing was conducted and interstitial glucose was monitored continuously. Mood and cognitive performance, including psychomotor and visual vigilance, visual match-to-sample, repeated acquisition (motor learning), N-back (working memory), and grammatical reasoning, were repeatedly assessed. During each condition, individual daily energy intake and expenditure were controlled. During calorie deprivation, volunteers consumed 266 ± 61 kcal/d; during full feeding, they consumed 3935 ± 769 kcal/d. Participants engaged in identical exercise sessions for 4 h/d at 40-65% of peak volume of oxygen uptake attained.


Calorie deprivation did not affect any aspect of cognitive performance, but produced robust effects on mood measured by the Profile of Mood States, including increased tension (P < 0.001), fatigue (P < 0.001), and total mood disturbance (from -0.80 ± 5.1 to 20.1 ± 6.1; P < 0.001), and decreased vigor (P = 0.002), as indicated by treatment × trial (time) effects on ANOVA. Interstitial glucose concentrations were lower during calorie deprivation than in the fully fed condition (P = 0.002, treatment × trial interaction) and declined to 61 mg/dL by the end of the treatment condition.


In healthy young men and women, 2 d of severe calorie deprivation in combination with substantial aerobic exercise adversely affects multiple aspects of mood, but not cognition, in spite of substantial reductions in interstitial glucose concentrations. This trial was registered at clinicaltrials.gov as NCT01603550.


POMS; depression; fatigue; reasoning; vigilance; working memory

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Plasticity of adipose tissue in response to fasting and refeeding in male mice.

Tang HN, Tang CY, Man XF, Tan SW, Guo Y, Tang J, Zhou CL, Zhou HD.

Nutr Metab (Lond). 2017 Jan 5;14:3. doi: 10.1186/s12986-016-0159-x.

PMID: 28070205




Fasting is the most widely prescribed and self-imposed strategy for treating excessive weight gain and obesity, and has been shown to exert a number of beneficial effects. The aim of the present study was to determine the exact role of fasting and subsequent refeeding on fat distribution in mice.


C57/BL6 mice fasted for 24 to 72 h and were then subjected to refeeding for 72 h. At 24, 48 and 72 h of fasting, and 12, 24, 48 and 72 h of refeeding, the mice were sacrificed, and serum and various adipose tissues were collected. Serum biochemical parameters, adipose tissue masses and histomorphological analysis of different depots were detected. MRNA was isolated from various adipose tissues, and the expressions of thermogenesis, visceral signature and lipid metabolism-related genes were examined. The phenotypes of adipose tissues between juvenile and adult mice subjected to fasting and refeeding were also compared.


Fasting preferentially consumed mesenteric fat mass and decreased the cell size of mesenteric depots; however, refeeding recovered the mass and morphology of inguinal adipose tissues preferentially compared with visceral depots. Thermogenesis-related gene expression in the inguinal WAT and interscapular BAT were suppressed. Mitochondrial biogenesis was affected by fasting in a depot-specific manner. Furthermore, a short period of fasting led to an increase in visceral signature genes (Wt1, Tcf21) in subcutaneous adipose tissue, while the expression of these genes decreased sharply as the fasting time increased. Additionally, lipogenesis-related markers were enhanced to a greater extent greater in subcutaneous depots compared with those in visceral adipose tissues by refeeding. Although similar phenotypic changes in adipose tissue were observed between juvenile mice and adult mice subjected to fasting and refeeding, the alterations appeared earlier and more sensitively in juvenile mice.


Fasting preferentially consumes lipids in visceral adipose tissues, whereas refeeding recovers lipids predominantly in subcutaneous adipose tissues, which indicated the significance of plasticity of adipose organs for fat distribution when subject to food deprivation or refeeding.


Adipose tissue; Fasting and refeeding; Fat distribution; Obesity; Plasticity


Starved epithelial cells uptake extracellular matrix for survival.

Muranen T, Iwanicki MP, Curry NL, Hwang J, DuBois CD, Coloff JL, Hitchcock DS, Clish CB, Brugge JS, Kalaany NY.

Nat Commun. 2017 Jan 10;8:13989. doi: 10.1038/ncomms13989.

PMID: 28071763



Extracellular matrix adhesion is required for normal epithelial cell survival, nutrient uptake and metabolism. This requirement can be overcome by oncogene activation. Interestingly, inhibition of PI3K/mTOR leads to apoptosis of matrix-detached, but not matrix-attached cancer cells, suggesting that matrix-attached cells use alternate mechanisms to maintain nutrient supplies. Here we demonstrate that under conditions of dietary restriction or growth factor starvation, where PI3K/mTOR signalling is decreased, matrix-attached human mammary epithelial cells upregulate and internalize β4-integrin along with its matrix substrate, laminin. Endocytosed laminin localizes to lysosomes, results in increased intracellular levels of essential amino acids and enhanced mTORC1 signalling, preventing cell death. Moreover, we show that starved human fibroblasts secrete matrix proteins that maintain the growth of starved mammary epithelial cells contingent upon epithelial cell β4-integrin expression. Our study identifies a crosstalk between stromal fibroblasts and epithelial cells under starvation that could be exploited therapeutically to target tumours resistant to PI3K/mTOR inhibition.

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Serum Polychlorinated Biphenyls Increase and Oxidative Stress Decreases with a Protein-Pacing Caloric Restriction Diet in Obese Men and Women.

He F, Zuo L, Ward E, Arciero PJ.

Int J Environ Res Public Health. 2017 Jan 10;14(1). pii: E59. doi: 10.3390/ijerph14010059.

PMID: 28075418



The purposes were to compare the effects of a: (1) 12-week P-CR weight loss (WL) diet (Phase 1) between obese men and women and; (2) 52-week modified P-CR (mP-CR) vs. heart healthy (HH) weight maintenance (WM) diet (Phase 2) on serum PCBs and oxidative stress biomarkers (thiobarbituric acid reactive substances, TBARS; total antioxidant capacity, TAC) in 40 obese participants (men, n = 21; women, n = 19). Participants received dietary counseling and monitoring of compliance. PCBs, TBARS, and TAC were assessed at weeks -1 (CON), 12 (WL), and 64 (WM). Following WL (Week 12), concomitant with reductions in TBARS (0.24 ± 0.15 vs. 0.18 ± 0.11 µM; p < 0.01), PCB serum concentrations (86.7 ± 45.6 vs. 115.6 ± 65.9 ng/g lipid; p < 0.01) and TAC (18.9 ± 2.6 vs. 19.9 ± 2.3 nmol/mL; p < 0.02) were increased similarly in men and women. At the end of WM (Week 64), a significant effect of time × group interaction was observed for % change in PCB 170 and 187; whereby mP-CR values were higher compared to HH (PCB170: 19.31% ± 26.48% vs. -6.61% ± 28.88%, p = 0.02; PCB187: -3.04% ± 17.78% vs. -21.4% ± 27.31%, p = 0.04). PCB changes were positively correlated with TBARS levels (r > 0.42, p < 0.05) and negatively correlated with body weight, fat mass, and abdominal fat (r < -0.46, p < 0.02). Our results support mobilization of stored PCBs as well as enhanced redox status following a 12-week P-CR WL diet. Additionally, a 52-week mP-CR WM diet demonstrated an advantage in preventing weight gain relapse accompanied by an increase in circulating PCBs compared to a traditional HH diet.


caloric restriction; intermittent-fasting; oxidative stress; polychlorinated biphenyls (PCBs)

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Melatonin produces a rapid onset and prolonged efficacy in reducing depression-like behaviors in adult rats exposed to chronic unpredictable mild stress.

Sun X, Wang Y, Wang M, Lian B, Sun H, Wang G, Li Q, Sun L.

Neurosci Lett. 2017 Jan 9. pii: S0304-3940(17)30025-3. doi: 10.1016/j.neulet.2017.01.015. [Epub ahead of print]

PMID: 28082153



The present study was aimed at evaluating the rapidity and duration of melatonin as an antidepressant in a rat model of depression. The rats were subjected to a six-week period of unpredictable mild stress followed by melatonin treatment. Three groups of rats were included in this study: Controls (CON - no stress exposure), Chronic Unpredictable Mild Stress (CUS) and CUS followed by melatonin (MT). Stressors consisted of exposure to rotation on a shaker, placement in a chamber maintained at 4°C, lights off for 3h, lights on overnight, exposure to an aversive odor, 45° tilted cages, food and water deprivation and crowding and isolated housing. Subsequently, the saline vehicle (CUS) or melatonin was administered at a dose of 10mg/kg for 14days period. Body weight and behavioral tests were used to evaluate depression-like behavior and its recovery following melatonin treatment. While body weight increases were significantly lower in rats exposed to CUS versus CON, body weights of the MT group increased significantly following melatonin treatment as compared with the CUS group. With regard to results obtained with behavioral assays indicative of depression, rapid and long-term functional recoveries in depression were observed in the MT as compared to the CUS group. The results indicate that not only does melatonin induce an antidepressant-like action within this rat model of depression, but does so with a rapid onset and prolonged efficacy. As most current treatments for depression require an extended period of administration, our current results suggest that melatonin may prove to be a particularly effect agent to promote a rapid onset and prolonged behavioral benefits in the treatment of depression.


Behavior Test; Depression; Melatonin; Rats

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[[There are lots of potential conflicts of interests for the author.]

Salba-chia (Salvia hispanica L.) in the treatment of overweight and obese patients with type 2 diabetes: A double-blind randomized controlled trial.

Vuksan V, Jenkins AL, Brissette C, Choleva L, Jovanovski E, Gibbs AL, Bazinet RP, Au-Yeung F, Zurbau A, Ho HV, Duvnjak L, Sievenpiper JL, Josse RG, Hanna A.

Nutr Metab Cardiovasc Dis. 2016 Dec 9. pii: S0939-4753(16)30329-5. doi: 10.1016/j.numecd.2016.11.124. [Epub ahead of print]

PMID: 28089080




Preliminary findings indicate that consumption of Salba-chia (Salvia hispanica L.), an ancient seed, improves management of type 2 diabetes and suppresses appetite. The aim of this study was to assesse the effect of Salba-chia on body weight, visceral obesity and obesity-related risk factors in overweight and obese adults with type 2 diabetes.


A double-blind, randomized, controlled trial with two parallel groups involved 77 overweight or obese patients with type 2 diabetes (HbA1c: 6.5-8.0%; BMI: 25-40 kg/m2). Both groups followed a 6-month calorie-restricted diet; one group received 30 g/1000 kcal/day of Salba-chia, the other 36 g/1000 kcal/day of an oat bran-based control. Primary endpoint was change in body weight over 6-months. Secondary endpoints included changes in waist circumference, body composition, glycemic control, C-reactive protein, and obesity-related satiety hormones.


At 6-months, participants on Salba-chia had lost more weight than those on control (1.9 ± 0.5 kg and 0.3 ± 0.4 kg, respectively; P = 0.020), accompanied by a greater reduction in waist circumference (3.5 ± 0.7 cm and 1.1 ± 0.7 cm, respectively; P = 0.027). C-reactive protein was reduced by 1.1 ± 0.5 mg/L (39 ± 17%) on Salba-chia, compared to 0.2 ± 0.4 mg/L (7 ± 20%) on control (P = 0.045). Plasma adiponectin on the test intervention increased by 6.5 ± 0.7%, with no change observed on control (P = 0.022).


The results of this study, support the beneficial role of Salba-chia seeds in promoting weight loss and improvements of obesity related risk factors, while maintaining good glycemic control. Supplementation of Salba-chia may be a useful dietary addition to conventional therapy in the management of obesity in diabetes. REGISTRATION: clinicaltrials.gov identifier: NCT01403571.


Clinical trial; Diet; Dietary seeds; Lifestyle; Obesity; Overweight; Type 2 diabetes; Weight loss


Amylin/leptin synergy is absent in extreme obesity and not restored by calorie restriction-induced weight loss in rats.

Trevaskis JL, Wittmer C, Athanacio J, Griffin PS, Parkes DG, Roth JD.

Obes Sci Pract. 2016 Dec;2(4):385-391. doi: 10.1002/osp4.62.

PMID: 28090343





Co-administration of amylin and leptin induces synergistic and clinically meaningful (>10%) weight loss that is attenuated as the degree of obesity increases. We explored whether calorie restriction (CR) could restore amylin/leptin synergy in very obese rats.


Sprague Dawley rats on high-fat diet (696 ± 8 g, n = 72) were randomized to three cohorts (C1-C3). Rats in C1 were administered vehicle, rat amylin (50 µg kg-1 d-1), murine leptin (125 µg kg-1 d-1) or amylin and leptin for 28 days (n = 6 per group) via subcutaneous minipump. Simultaneously, C2 and C3 rats initiated CR. After moderate (12.4 ± 0.3%, 86.7 ± 2.8 g; C2) or severe (24.9 ± 0.3%, 172.7 ± 4.7 g; C3) weight loss, amylin and/or leptin was administered as described.


In C1, leptin did not alter weight, and amylin induced 40.2 ± 6.1 g weight loss (-6.0 ± 0.9%), which was not enhanced by leptin (44.4 ± 4.9 g, -6.1 ± 0.8%). In C2, vehicle-treated (75.1 ± 7.8 g weight change from start of treatment, 1.1 ± 0.8% difference from start of pre-CR phase) and leptin-treated rats (68.6 ± 9.2 g, -1.3 ± 1.0%) rebounded to pre-restriction weight that was attenuated by amylin (29.2 ± 11.4 g, -6.2 ± 0.7%). Leptin did not enhance the effect of amylin (22.8 ± 11.7 g, -8.3 ± 1.5%). In C3, vehicle-treated and leptin-treated rats regained most of their weight (161.9 ± 11.8, -2.3 ± 0.8% and 144.6 ± 9.5 g, -2.3 ± 0.9%, respectively), which was attenuated by amylin (91.1 ± 16.8 g, -11.2 ± 0.7%), but not enhanced by leptin (83.0 ± 7.6 g, -10.7 ± 0.8%).


Extreme obesity associated with leptin resistance perturbs amylin/leptin weight loss synergy in rats, which cannot be restored by pre-treatment weight loss.


Diabetes; obesity; synergy


Effects of intermittent fasting on glucose and lipid metabolism.

Antoni R, Johnston KL, Collins AL, Robertson MD.

Proc Nutr Soc. 2017 Jan 16:1-8. doi: 10.1017/S0029665116002986. [Epub ahead of print]

PMID: 28091348



Two intermittent fasting variants, intermittent energy restriction (IER) and time-restricted feeding (TRF), have received considerable interest as strategies for weight-management and/or improving metabolic health. With these strategies, the pattern of energy restriction and/or timing of food intake are altered so that individuals undergo frequently repeated periods of fasting. This review provides a commentary on the rodent and human literature, specifically focusing on the effects of IER and TRF on glucose and lipid metabolism. For IER, there is a growing evidence demonstrating its benefits on glucose and lipid homeostasis in the short-to-medium term; however, more long-term safety studies are required. Whilst the metabolic benefits of TRF appear quite profound in rodents, findings from the few human studies have been mixed. There is some suggestion that the metabolic changes elicited by these approaches can occur in the absence of energy restriction, and in the context of IER, may be distinct from those observed following similar weight-loss achieved via modest continuous energy restriction. Mechanistically, the frequently repeated prolonged fasting intervals may favour preferential reduction of ectopic fat, beneficially modulate aspects of adipose tissue physiology/morphology, and may also impinge on circadian clock regulation. However, mechanistic evidence is largely limited to findings from rodent studies, thus necessitating focused human studies, which also incorporate more dynamic assessments of glucose and lipid metabolism. Ultimately, much remains to be learned about intermittent fasting (in its various forms); however, the findings to date serve to highlight promising avenues for future research.


CER continuous energy restriction; FAO fatty-acid oxidation; FFA free-fatty acid; HOMA-IR homeostasis model assessment of insulin resistance; IER intermittent energy restriction; T2DM type 2 dibetes mellitus; TRF time-restricted feeding; Glucose; Intermittent fasting; Lipids; Weight-loss


Executive functions predict weight loss in a medically supervised weight loss programme.

Galioto R, Bond D, Gunstad J, Pera V, Rathier L, Tremont G.

Obes Sci Pract. 2016 Dec;2(4):334-340. doi: 10.1002/osp4.70.

PMID: 28090338





Deficits in executive functions are related to poorer weight loss after bariatric surgery; however, less is known about the role that these deficits may play during participation in nonsurgical weight loss programmes. This study examined associations between objectively measured executive functions and weight loss during participation in a medically supervised weight loss programme.


Twenty-three adult patients (age 50.4 ± 15.1, BMI 44.2 ± 8.8, 68% female, 92% White) enrolled in a medically supervised weight loss programme, involving prescription of a very low calorie diet and strategies to change eating and activity behaviours, underwent comprehensive computerized testing of executive functions at baseline. Weight was obtained at baseline and 8 weeks. Demographic and clinical information were obtained through medical chart review.


Participants lost an average of 9.8 ± 3.4% of their initial body weight at 8 weeks. Fewer correct responses on a set-shifting task and faster reaction time on a response inhibition task were associated with lower weight loss percentage at 8 weeks after adjusting for age, education and depressive symptoms. There were no associations between performance on tests of working memory or planning and weight loss.


This study shows that worse performance on a set-shifting task (indicative of poorer cognitive flexibility) and faster reaction times on a response inhibition test (indicative of higher impulsivity) are associated with lower weight loss among participants in a medically supervised weight loss programme. Pre-treatment assessment of executive functions may be useful in identifying individuals who may be at risk for suboptimal treatment outcomes. Future research is needed to replicate these findings in larger samples and identify underlying mechanisms.


Behavioural weight loss; cognition; executive functions; neuropsychology

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DAILY NEWS 17 January 2017

Calorie restriction diet extends life of monkeys by years

Eat less, live more?

plainpicture/Lubitz + Dorner

By Clare Wilson

Put down the cake. Going on a permanent diet could make you live longer, if findings from monkeys hold true for people.

A long-running trial in macaques has found that calorie restriction makes them live about three years longer than normal, which would translate to about nine years in people.

Such a strict diet might not be for everyone, but understanding the mechanisms behind any benefits of calorie restriction may one day lead to anti-ageing medicines, says Julie Mattison at the National Institute on Aging (NIA) in Baltimore, Maryland. “The goal is to improve human health,” she says.

Many studies have shown that calorie restriction extends lifespan for lab organisms, from yeast through to worms, flies and mice. This has prompted a few thousand people to choose to restrict their calories to between 1500 to 1800 kcal a day (women and men are usually advised to consume 2000 and 2500 kcal, respectively). Their hope is it will give them longer and healthier lives, and there’s some evidence that such people have better blood cholesterol and glucose levels.

Age record breakers

But it’s unclear if the approach can really lengthen the lives of long-lived animals like us. Two trials of calorie restriction in macaques, which live around 26 years in captivity, have until now produced conflicting results.

The trials were set up in the late 1980s, and not all the monkeys have died yet. But an interim report from one group, based at the University of Wisconsin, previously found that the monkeys on a restricted diet were indeed living longer than the control group. However, the second study, run by the NIA, found there was no difference in the survival rates of their animals, which cast doubt on the entire premise.

Now the teams have compared their most recent results and their analysis backs the earlier trial that had positive findings. The NIA study, on the other hand, had several problems, including issues with the control group eating fewer calories than expected, and some of the animals beginning their restricted diet as juveniles – which reduces lifespan.

Even so, in the NIA trial, four of the monkeys that began the diet as adults lived to be over 40, breaking all known records for macaques – an observation which may cheer those who practise calorie restriction. However, picking out single results like this from a larger study isn’t good evidence, says Mattison.

Side effects

In the Wisconsin trial, animals did live significantly longer than controls – calorie-restricted males lived about two years longer, while calorie-restricted females lived about six years longer. There were also lower rates of heart disease and cancer in these monkeys. These are the major causes of death in people, lending support to the idea that the results apply to humans, says Luigi Fontana of the University of Brescia in Italy.

However, Brian Delaney, who is president of the Calorie Restriction Society, an organisation that supports the practice in people, says some who follow this diet are disappointed by the relatively modest benefits in monkeys compared with mice, which have lived up to 50 per cent longer than normal.

“Is it worth it?” asks Delaney. “My choice is to do it. But I’m so used to the diet that it really isn’t very difficult for me anymore.”

Delaney has been practising calorie restriction for 24 years. Until someone is used to it, the diet involves planning every meal with precision, and side effects can include feeling cold and reduced libido.



Calorie restriction lets monkeys live long and prosper

January 17, 2017

A 2009 image of rhesus monkeys in a landmark study of the benefits of caloric restriction. The then 27-year-old monkey on the left was given a diet with fewer calories while the then 29-year-old monkey on the right was allowed to eat as much as it liked. Both animals have since died of natural causes. A new study of the effects of a restricted diet reinforces the idea that reducing caloric intake has health benefits that can extend lifespan.

Credit: Jeff Miller/University of Wisconsin-Madison

Settling a persistent scientific controversy, a long-awaited report shows that restricting calories does indeed help rhesus monkeys live longer, healthier lives.

A remarkable collaboration between two competing research teams—one from the University of Wisconsin-Madison and one from the National Institute on Aging—is the first time the groups worked together to resolve one of the most controversial stories in aging research.

The findings by the collaboration—including Senior Scientist Ricki Colman of the Wisconsin National Primate Research Center and UW-Madison Associate Professor of Medicine Rozalyn Anderson; and NIA Staff Scientist and Nonhuman Primate Core Facility Head Julie Mattison and Senior Investigator and Chief of the Translational Gerontology Branch Rafael de Cabo—were published today (Jan. 17, 2017) in the journal Nature Communications.

In 2009, the UW-Madison study team reported significant benefits in survival and reductions in cancer, cardiovascular disease, and insulin resistance for monkeys that ate less than their peers. In 2012, however, the NIA study team reported no significant improvement in survival, but did find a trend toward improved health.

"These conflicting outcomes had cast a shadow of doubt on the translatability of the caloric-restriction paradigm as a means to understand aging and what creates age-related disease vulnerability," says Anderson, one of the report's corresponding authors. Working together, the competing laboratories analyzed data gathered over many years and including data from almost 200 monkeys from both studies. Now, scientists think they know why the studies showed different results.

First, the animals in the two studies had their diets restricted at different ages. Comparative analysis reveals that eating less is beneficial in adult and older primates but is not beneficial for younger animals. This is a major departure from prior studies in rodents, where starting at an earlier age is better in achieving the benefits of a low-calorie diet.

Second, in the old-onset group of monkeys at NIA, the control monkeys ate less than the Wisconsin control group. This lower food intake was associated with improved survival compared to the Wisconsin controls. The previously reported lack of difference in survival between control and restricted groups for older-onset monkeys within NIA emerges as beneficial differences when compared to the UW-Madison data. In this way, it seems that small differences in food intake in primates could meaningfully affect aging and health.

Third, diet composition was substantially different between studies. The NIA monkeys ate naturally sourced foods and the UW-Madison monkeys, part of the colony at the Wisconsin National Primate Research Center, ate processed food with higher sugar content. The UW-Madison control animals were fatter than the control monkeys at NIA, indicating that at nonrestricted levels of food intake, what is eaten can make a big difference for fat mass and body composition.

Finally, the team identified key sex differences in the relationship between diet, adiposity (fat), and insulin sensitivity, where females seem to be less vulnerable to adverse effects of adiposity than males. This new insight appears to be particularly important in primates and likely is translatable to humans.

The upshot of the report is that caloric restriction does indeed seem to be a means to affect aging. However, for primates, age, diet and sex must all be factored in to realize the full benefits of lower caloric intake.


Caloric restriction improves health and survival of rhesus monkeys

Julie A. Mattison, Ricki J. Colman, T. Mark Beasley, David B. Allison, Joseph W. Kemnitz, George S. Roth, Donald K. Ingram, Richard Weindruch, Rafael de Cabo & Rozalyn M. Anderson

Nature Communications 8, Article number: 14063 (2017)


Ageing, Medical research, Rhesus macaque


31 May 2016


24 November 2016

Published online:

17 January 2017



Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Here we present a direct comparison of longitudinal data from both studies including survival, bodyweight, food intake, fasting glucose levels and age-related morbidity. We describe differences in study design that could contribute to differences in outcomes, and we report species specificity in the impact of CR in terms of optimal onset and diet. Taken together these data confirm that health benefits of CR are conserved in monkeys and suggest that CR mechanisms are likely translatable to human health.

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[it just popped up in Medline.]

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



FGF21 Mediates the Thermogenic and Insulin-Sensitizing Effects of Dietary Methionine Restriction but not its Effects on Hepatic Lipid Metabolism.

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

Diabetes. 2017 Jan 17. pii: db161212. doi: 10.2337/db16-1212. [Epub ahead of print]

PMID: 28096260



Dietary methionine restriction (MR) produces a rapid and persistent remodeling of white adipose tissue (WAT), increase in energy expenditure (EE), and enhancement of insulin sensitivity. Recent work established that hepatic expression of FGF21 is robustly increased by MR. Based on the known physiological effects of FGF21, Fgf21-/- mice were used to test whether FGF21 is an essential mediator of the physiological effects of dietary MR. The MR-induced increase in energy intake and EE, and activation of thermogenesis in WAT and BAT were lost in Fgf21-/- mice. However, dietary MR produced a comparable reduction in body weight and adiposity in both genotypes because of a negative effect of MR on energy intake in Fgf21-/- mice. Despite the similar loss in weight, dietary MR produced a more significant increase in in vivo insulin sensitivity in WT than Fgf21-/- mice, particularly in heart and inguinal WAT. In contrast, the ability of MR to regulate lipogenic and integrated stress response genes in liver was not compromised in Fgf21-/- mice. Collectively, these findings illustrate that FGF21 is a critical mediator of the effects of dietary MR on EE, remodeling of WAT, and increased insulin sensitivity, but not its effects on hepatic gene expression.

Edited by AlPater
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β hydroxybutyrate levels in serum and cerebrospinal fluid under ketone body metabolism in rats.

Wang X, Liu Q, Zhou J, Wu X, Zhu Q.

Exp Anim. 2017 Jan 19. doi: 10.1538/expanim.16-0090. [Epub ahead of print]

PMID: 28100888



A high-fat, low-carbohydrate diet (KD) or calorie restriction in the form of every-other-day fasting (EODF) results in ketone body metabolism with an increasing β-hydroxybutyrate (βOHB) level. Previous studies have supported that a KD and EODF have a neuroprotective effect. However, the βOHB levels in the cerebrospinal fluid (CSF) resulting from a KD and EODF remain unknown. The aim of this study was to detect βOHB levels in rats fed a KD, EODF diet, and every-other-day ketogenic diet (EODKD) and to compare the serum βOHB level with the CSF βOHB level. Twenty-four male Sprague-Dawley rats were randomly divided into KD, EODF, EODKD, and standard diet (SD) groups. A customized food with a ratio of carbohydrates to fats of 1:4 was used in the KD and EODKD groups. The βOHB level was measured using ELISA kits in 200 µl serum and 100 µl CSF samples for each rat after feeding for 2 weeks. The KD, EODF, and EODKD resulted in a significant increase in βOHB levels in both the serum and CSF. The βOHB levels in the EODKD group were the highest. The CSF βOHB level was, on average, 69% of the serum βOHB level. There was a positive correlation between the overall βOHB levels in serum and that in cerebrospinal fluid. This study demonstrated that the KD, EODF, and EODKD resulted in ketone body metabolism, as the βOHB levels increased significantly compared with those resulting from the standard diet. Our results suggested that the serum βOHB level was an indicator of the CSF βOHB level, and that the EODKD was an effective diet to enhance ketogenic metabolism.


Neuropeptide Y resists excess loss of fat by lipolysis in calorie-restricted mice: a trait potential for the life-extending effect of calorie restriction.

Park S, Komatsu T, Kim SE, Tanaka K, Hayashi H, Mori R, Shimokawa I.

Aging Cell. 2017 Jan 19. doi: 10.1111/acel.12558. [Epub ahead of print]

PMID: 28101970




Neuropeptide Y (NPY) is an orexigenic peptide that plays an essential role in caloric restriction (CR)-mediated lifespan extension. However, the mechanisms underlying the NPY-mediated effects in CR are poorly defined. Here, we report that NPY deficiency in male mice during CR increases mortality in association with lipodystrophy. NPY-/- mice displayed a rapid decrease in body weight and fat mass, as well as increased lipolysis during CR. These alterations in fat regulation were inhibited by the lipolysis inhibitor, acipimox, a treatment associated with reduced mortality. The lipolytic/thermogenic signaling, β3-adrenergic receptor/hormone sensitive lipase, was markedly activated in white adipose tissue of NPY-/- mice compared with that of NPY+/+ mice, and thermogenesis was controlled by NPY under negative energy balance. These results demonstrate the critical role of NPY in the regulation of lipid metabolic homeostasis and survival via control of lipolysis and thermogenesis in a state of negative energy balance.


adipose tissue; aging; calorie restriction; lipolysis; neuropeptide Y


Effects of Diet Restriction and Diet Complexity on Life History Strategies in Side-Blotched Lizards (Uta stansburiana).

Skinner HM, Durso AM, Neuman-Lee LA, Durham SL, Mueller SD, French SS.

J Exp Zool A Ecol Genet Physiol. 2016 Nov;325(9):626-637. doi: 10.1002/jez.2056.

PMID: 28102007



Organisms must balance energy invested into self-maintenance, reproduction, and somatic growth over their lifetime. In this study, the effects of diet restriction and diet complexity on side-blotched lizards (Uta stansburiana) were analyzed. Thirty male lizards, housed in the laboratory, were fed either an ad libitum or a restricted diet for 18 days (phase 1). Individuals from both treatments were then assigned to a diet of the same quantity of food that was either simple (only crickets) or complex (crickets, cockroaches, waxworms, and mealworms) for 35 days (phase 2). We evaluated (1) how diet restriction affected life history strategies and (2) how diet complexity affected recovery from diet restriction as measured at the end of phase 2 by body mass, snout-vent length, calculated body condition score, wound healing, tail regrowth, bacterial killing ability, oxidative stress, and plasma testosterone and corticosterone concentrations. Lizards without diet restriction allocated more energy to self-maintenance (i.e., maintaining higher body condition scores, healing wounds more quickly) than lizards with diet restriction. Lizards with diet restriction had higher plasma testosterone concentrations and larger increases in snout-vent lengths than those fed ad libitum, which may reflect allocations toward reproduction and somatic growth. A complex diet resulted in better body condition and faster tail regrowth than a simple diet, suggesting that a complex diet enhanced recovery from diet restriction, although long-term life history choices remained unaltered. Finally, lizards on a complex diet consumed substantially less food while maintaining higher body condition, suggesting that key nutrients may be lacking from a simple diet.


A signature of renal stress resistance induced by short-term dietary restriction, fasting, and protein restriction.

Jongbloed F, Saat TC, Verweij M, Payan-Gomez C, Hoeijmakers JH, van den Engel S, van Oostrom CT, Ambagtsheer G, Imholz S, Pennings JL, van Steeg H, IJzermans JN, Dollé ME, de Bruin RW.

Sci Rep. 2017 Jan 19;7:40901. doi: 10.1038/srep40901.

PMID: 28102354



During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels. Male C57BL/6 mice were fed control food ad libitum, underwent two weeks of 30%DR, 3-day fasting, or received a protein-, carbohydrate- or fat-free diet for various periods of time. After completion of each diet, renal gene expression was investigated using microarrays. After induction of renal IRI by clamping the renal pedicles, animals were monitored seven days postoperatively for signs of IRI. In addition to 3-day fasting and two weeks 30%DR, three days of a protein-free diet protected against renal IRI as well, whereas the other diets did not. Gene expression patterns significantly overlapped between all diets except the fat-free diet. Detailed meta-analysis showed involvement of nuclear receptor signaling via transcription factors, including FOXO3, HNF4A and HMGA1. In conclusion, three days of a protein-free diet is sufficient to induce protection against renal IRI similar to 3-day fasting and two weeks of 30%DR. The elucidated network of common protective pathways and transcription factors further improves our mechanistic insight into the increased stress resistance induced by short-term DR.

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