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Diet and exercise in the management of obstructive sleep apnoea and cardiovascular disease risk.

Dobrosielski DA, Papandreou C, Patil SP, Salas-Salvadó J.

Eur Respir Rev. 2017 Jun 28;26(144). pii: 160110. doi: 10.1183/16000617.0110-2016. Print 2017 Jun 30. Review.

PMID: 28659501


Obstructive sleep apnoea (OSA) is associated with increased cardiovascular disease (CVD) morbidity and mortality. It is accepted that OSA and obesity commonly coexist. The American Academy of Sleep Medicine recommends dietary-induced weight loss and exercise as lifestyle treatment options for OSA. However, most clinical trials upon which this recommendation is based have focused on establishing the effectiveness of calorie-restricted, often low-fat diets for improving OSA severity, whereas less attention has been given to the means through which weight loss is achieved (e.g. altered dietary quality) or whether diet or exercise mediates the associations between reduced weight, improved OSA severity and the CVD substrate. The current evidence suggests that the benefits of a low-carbohydrate or Mediterranean diet in overweight and obese individuals go beyond the recognised benefits of weight reduction. In addition, exercise has an independent protective effect on vascular health, which may counter the increased oxidative stress, inflammation and sympathetic activation that occur in OSA patients. This review aims to expand our understanding of the effects of diet and exercise on OSA and associated CVD complications, and sets the stage for continued research designed to explore optimal lifestyle strategies for reducing the CVD burden in OSA patients.


Upregulation of circulating myomiR following short-term energy restriction is inversely associated with whole-body protein synthesis.

Margolis LM, Rivas DA, Pasiakos SM, McClung JP, Ceglia L, Fielding RA.

Am J Physiol Regul Integr Comp Physiol. 2017 Jun 28:ajpregu.00054.2017. doi: 10.1152/ajpregu.00054.2017. [Epub ahead of print]

PMID: 28659285


The objective of the present investigation was to determine whether energy restriction (ER) influences expression of skeletal muscle specific microRNA in circulation (c-myomiR), and if changes in c-myomiR are associated with rates of whole-body protein synthesis. Sixteen older (64 ± 2 yrs) overweight (28.5 ± 1.2 kg·m-2) males enrolled in this 35-day controlled feeding trial. A 7-day weight maintenance (WM) period was followed by 28 days of 30% ER. Whole-body protein turnover was determined from 15N-glycine enrichments in 24-hr urine collections, and c-myomiR (miR-1-3p, miR-133a-3p, miR-133b, and miR-206) expressions were assessed from serum samples using RT-qPCR at the conclusions of WM and ER. Participants lost 4.4 ± 0.3 kg body mass during ER (P < 0.05). Following 28 days of ER miR-133a and miR-133b expression was upregulated (P < 0.05) compared to WM. When all four c-myomiR were grouped as a c-myomiR Score (sum of the median fold change of all myomiR), overall expression of c-myomiR was higher (P < 0.05) at ER versus WM. Backward linear regression analysis of whole-body protein synthesis, breakdown, and carbohydrate, fat and protein oxidation determined protein synthesis to be the strongest predictor of c-myomiR Score. An inverse association (P < 0.05) was observed with ER c-myomiR Scores and whole-body protein synthesis (r = -0.729, r2 = -0.530). Findings from the present investigation provide evidence that upregulation in c-myomiR expression profiles in response to short-term ER are associated with lower rates of whole-body protein synthesis.


Energy deficit; microRNA; weight loss; whole-body protein turnover


Maintenance diets following rapid weight loss in obstructive sleep apnea: a pilot 1-year clinical trial.

Cayanan EA, Marshall NS, Hoyos CM, Phillips CL, Serinel Y, Wong KKH, Yee BJ, Grunstein RR.

J Sleep Res. 2017 Jun 30. doi: 10.1111/jsr.12572. [Epub ahead of print]

PMID: 28664540


Very low energy diets (VLED) appear to be the most efficacious dietary-based obesity reduction treatments in obstructive sleep apnea (OSA); however, effective weight loss maintenance strategies remain untested in this condition. Our study aimed to assess the feasibility, tolerability and efficacy of two common maintenance diets during a 10-month follow-up period after rapid weight loss using a 2-month VLED. In this two-arm, single-centre, open-label pilot trial, obese adult OSA patients received a 2-month VLED before being allocated to either the Australian Guide to Healthy Eating diet (AGHE) or a low glycaemic index high-protein diet (LGHP). Outcomes were measured at 0, 2 and 12 months. We recruited 44 patients [113.1 ± 19.5 kg, body mass index (BMI): 37.2 ± 5.6 kg m-2 , 49.3 ± 9.2 years, 12 females]. Twenty-four patients were on continuous positive airway pressure (CPAP) or mandibular advancement splint (MAS) therapy for OSA. Forty-two patients completed the VLED. The primary outcome of waist circumference was reduced by 10.6 cm at 2 months [95% confidence interval (CI): 9.2-12.1], and patients lost 12.9 kg in total weight (95% CI: 11.2-14.6). There were small but statistically significant regains in waist circumference between 2 and 12 months [AGHE = 3.5 cm (1.3-5.6) and LGHP = 2.8 cm (0.6-5.0]. Other outcomes followed a similar pattern of change. After weight loss with a 2-month VLED in obese patients with OSA, a structured weight loss maintenance programme incorporating commonly used diets was feasible, tolerable and efficacious for 10 months. This programme may be deployed easily within sleep clinics; however, future research should first test its translation within general clinical practice.


Very Low Calorie Diet; cardiovascular; metabolic syndrome quality of life; weight regain

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Life-extending dietary restriction and ovariectomy each increase leucine oxidation and alter leucine allocation in grasshoppers.

Hatle JD, Awan A, Nicholas J, Koch R, Vokrri JR, McCue MD, Williams CM, Davidowitz G, Hahn DA.

Exp Gerontol. 2017 Jun 28. pii: S0531-5565(17)30189-4. doi: 10.1016/j.exger.2017.06.019. [Epub ahead of print]

PMID: 28668481


Reduced reproduction and dietary restriction each extend lifespan in many animal models, but possible contributions of nutrient oxidation and allocation are largely unknown. Ovariectomy and eating 70% of ad libitum-feeding each extend lifespan in lubber grasshoppers. When feeding levels between the two groups are matched, ovariectomy increases fat and protein storage while dietary restriction reduces fat storage. Because of these disparities in nutrient investment, metabolism may differ between these two life-extending treatments. Therefore, we examined the allocation and organismal oxidation of one representative of each macronutrient class: leucine, oleic acid, and glucose. Ovariectomy and dietary restriction each increased oxidation of dietary leucine. Dietary leucine may play a special role in aging because amino acids stimulate cellular growth. Speeding oxidation of leucine may attenuate cellular growth. Allocation of leucine to muscle was the clearest difference between ovariectomy and dietary restriction in this study. Ovariectomy reduced allocation of leucine to femur muscle, whereas dietary restriction increased allocation of leucine to femur muscle. This allocation likely corresponds to muscle maintenance for locomotion, suggesting dietary restriction increases support for locomotion, perhaps to search for food. Last, ovariectomy decreased oxidation of dietary oleic acid and glucose, perhaps to save them for storage, but the site of storage is unclear. This study suggests that the oxidation of branched-chain amino acids may be an underappreciated mechanism underlying lifespan extension.


Branched-chain amino acids; Glucose; Oleic acid; Storage; Target of rapamycin

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Caloric restriction impacts plasma microRNAs in rhesus monkeys.

Schneider A, Dhahbi JM, Atamna H, Clark JP, Colman RJ, Anderson RM.

Aging Cell. 2017 Jul 5. doi: 10.1111/acel.12636. [Epub ahead of print]

PMID: 28677323



Caloric restriction (CR) is one of the most robust interventions shown to delay aging in diverse species, including rhesus monkeys (Macaca mulatta). Identification of factors involved in CR brings a promise of translatability to human health and aging. Here, we show that CR induced a profound change in abundance of circulating microRNAs (miRNAs) linked to growth and insulin signaling pathway, suggesting that miRNAs are involved in CR's mechanisms of action in primates. Deep sequencing of plasma RNA extracts enriched for short species revealed a total of 243 unique species of miRNAs including 47 novel species. Approximately 70% of the plasma miRNAs detected were conserved between rhesus monkeys and humans. CR induced or repressed 24 known and 10 novel miRNA species. Regression analysis revealed correlations between bodyweight, adiposity, and insulin sensitivity for 10 of the CR-regulated known miRNAs. Sequence alignment and target identification for these 10 miRNAs identify a role in signaling downstream of the insulin receptor. The highly abundant miR-125a-5p correlated positively with adiposity and negatively with insulin sensitivity and was negatively regulated by CR. Putative target pathways of CR-associated miRNAs were highly enriched for growth and insulin signaling that have previously been implicated in delayed aging. Clustering analysis further pointed to CR-induced miRNA regulation of ribosomal, mitochondrial, and spliceosomal pathways. These data are consistent with a model where CR recruits miRNA-based homeostatic mechanisms to coordinate a program of delayed aging.


aging; caloric restriction; miR-125a-5p; microRNA; rhesus monkeys


Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application.

Zhao P, Sui BD, Liu N, Lv YJ, Zheng CX, Lu YB, Huang WT, Zhou CH, Chen J, Pang DL, Fei DD, Xuan K, Hu CH, Jin Y.

Aging Cell. 2017 Jul 5. doi: 10.1111/acel.12635. [Epub ahead of print]

PMID: 28677234



Cutaneous wounds are among the most common soft tissue injuries and are particularly hard to heal in aging. Caloric restriction (CR) is well documented to extend longevity; pharmacologically, profound rejuvenative effects of CR mimetics have been uncovered, especially metformin (MET), resveratrol (RSV), and rapamycin (RAPA). However, locally applied impacts and functional differences of these agents on wound healing remain to be established. Here, we discovered that chronic topical administration of MET and RSV, but not RAPA, accelerated wound healing with improved epidermis, hair follicles, and collagen deposition in young rodents, and MET exerted more profound effects. Furthermore, locally applied MET and RSV improved vascularization of the wound beds, which were attributed to stimulation of adenosine monophosphate-activated protein kinase (AMPK) pathway, the key mediator of wound healing. Notably, in aged skin, AMPK pathway was inhibited, correlated with impaired vasculature and reduced healing ability. As therapeutic approaches, local treatments of MET and RSV prevented age-related AMPK suppression and angiogenic inhibition in wound beds. Moreover, in aged rats, rejuvenative effects of topically applied MET and RSV on cell viability of wound beds were confirmed, of which MET showed more prominent anti-aging effects. We further verified that only MET promoted wound healing and cutaneous integrity in aged skin. These findings clarified differential effects of CR-based anti-aging pharmacology in wound healing, identified critical angiogenic and rejuvenative mechanisms through AMPK pathway in both young and aged skin, and unraveled chronic local application of MET as the optimal and promising regenerative agent in treating cutaneous wound defects.


AMPK pathway; aged skin; anti-aging pharmacology; metformin; vascularization; wound healing

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Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding.

Versteeg RI, Schrantee A, Adriaanse SM, Unmehopa UA, Booij J, Reneman L, Fliers E, la Fleur SE, Serlie MJ.

FASEB J. 2017 Jul 5. pii: fj.201601234R. doi: 10.1096/fj.201601234R. [Epub ahead of print]

PMID: 28679529



Recent studies have shown that meal timing throughout the day contributes to maintaining or regaining weight after hypocaloric diets. Although brain serotonin and dopamine are well known to be involved in regulating feeding, it is unknown whether meal timing during energy restriction affects these neurotransmitter systems. We studied the effect of a 4 wk hypocaloric diet with either 50% of daily calories consumed at breakfast (BF group) or at dinner (D group) on hypothalamic and thalamic serotonin transporter (SERT) binding and on striatal dopamine transporter (DAT) binding. The BF and D group lost a similar amount of weight. Striatal DAT and thalamic SERT binding increased in the BF group, while decreasing in the D group after the diet (ΔDAT 0.37 ± 0.63 vs. -0.53 ± 0.77, respectively; P = 0.005; ΔSERT 0.12 ± 0.25 vs. -0.13 ± 0.26 respectively, P = 0.032). Additional voxel-based analysis showed an increase in DAT binding in the ventral striatum in the BF group and a decrease in the dorsal striatum in the D group. During weight loss, striatal DAT and thalamic SERT binding increased weight independently when 50% of daily calories were consumed at breakfast, whereas it decreased when caloric intake was highest at dinner. These findings may contribute to the earlier reported favorable effect of meal timing on weight maintenance after hypocaloric diets.


brain; neuroimaging; obesity; striatum; thalamus


Mice under Caloric Restriction Self-Impose a Temporal Restriction of Food Intake as Revealed by an Automated Feeder System.

Acosta-Rodríguez VA, de Groot MHM, Rijo-Ferreira F, Green CB, Takahashi JS.

Cell Metab. 2017 Jul 5;26(1):267-277.e2. doi: 10.1016/j.cmet.2017.06.007.

PMID: 28683292



Caloric restriction (CR) extends lifespan in mammals, yet the mechanisms underlying its beneficial effects remain unknown. The manner in which CR has been implemented in longevity experiments is variable, with both timing and frequency of meals constrained by work schedules. It is commonplace to find that nocturnal rodents are fed during the daytime and meals are spaced out, introducing prolonged fasting intervals. Since implementation of feeding paradigms over the lifetime is logistically difficult, automation is critical, but existing systems are expensive and not amenable to scale. We have developed a system that controls duration, amount, and timing of food availability and records feeding and voluntary wheel-running activity in mice. Using this system, mice were exposed to temporal or caloric restriction protocols. Mice under CR self-imposed a temporal component by consolidating food intake and unexpectedly increasing wheel-running activity during the rest phase, revealing previously unrecognized relationships among feeding, metabolism, and behavior.


alternate day feeding; automated feeder system; body weight; caloric restriction; circadian rhythm; feeding pattern; intermittent fasting; mouse; temporal restriction; wheel-running activity

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Experimental models for aging and their potential for novel drug discovery.

Folch J, Busquets O, Sánchez-López ME, Pallàs M, Beas-Zarate C, Marin M, Casadesus G, Olloquequi J, Auladell C, Camins A.

Curr Neuropharmacol. 2017 Jul 7. doi: 10.2174/1570159X15666170707155345. [Epub ahead of print]

PMID: 28685671


The development of antiaging drugs is an interesting area of scientific research. In order to evaluate the beneficial effects of new potential drugs, it is necessary to gather the specific knowledge on the adequate preclinical models that are available. This review focuses on invertebrate and vertebrate preclinical models used to evaluate the efficacy of antiaging compounds, with the objective to extend lifespan and health span. Dietary restriction (DR), a common experimental process to extend lifespan in all organisms, is also discussed. Besides, classical antiaging drugs such as resveratrol, rapamycin and metformin, denominated DR mimetics, are reviewed. The main therapeutic targets of these drugs include sirtuins, IGF-1, and mTOR, all of them being modulated by DR. The National Institute on Aging (NIA) developed the Interventions Testing Program (ITP). At the preclinical level, the ITP uses genetically heterogeneous mice model (HET), which is probably the most suitable rodent model to study potential drugs preventing aging-related diseases. The accelerated-senescence mouse P8 is also an interesting rodent model for the research in the field of aging. Notwithstanding, non-human primates are still necessary prior to clinical trials, since they allow an easier extrapolation to humans due to their anatomical and physiological similarities. In this review, the different models and approaches for antiaging studies were evaluated.


Aging; IGF-1; Resveratrol; SAMP8.; heterogeneous mice model; mTOR; sirtuins


Resveratrol ameliorates diet-induced dysregulation of lipid metabolism in zebrafish (Danio rerio).

Ran G, Ying L, Li L, Yan Q, Yi W, Ying C, Wu H, Ye X.

PLoS One. 2017 Jul 7;12(7):e0180865. doi: 10.1371/journal.pone.0180865. eCollection 2017.

PMID: 28686680


Defective lipid metabolism is associated with increased risk of various chronic diseases, such as obesity, cardiovascular diseases, and diabetes. Resveratrol (RSV), a natural polyphenol, has been shown the potential of ameliorating disregulations of lipid metabolism. The objective of this study was to investigate the effects of feed intake and RSV on lipid metabolism in zebrafish (Danio rerio). The adult males were randomly allocated to 6 groups: control (Con, 8 mg cysts/fish/day), control with 20 μmol/L RSV (Con+RSV), calorie restriction (CR, 5 mg cysts/fish/day), calorie restriction with RSV (CR+RSV), overfeed (OF, 60 mg cysts/fish/day), and overfeed with RSV (OF+RSV) groups. The treatment period was 8 weeks. Results showed that CR reduced body length, body weight, and condition factor of zebrafish. CR reduced levels of plasma triglyceride (TG) and induced protein expression of phosphorylated AMP-activated protein kinase-α (pAMPKα), silent information regulator 2 homolog 1 (Sirt1), and peroxisome proliferator activated receptor gamma coactivator-1α (PGC1α). RSV attenuated CR-induced pAMPKα/AMPKαincreases. RSV increased levels of Sirt1 protein in the OF zebrafish, and decreased OF-induced increase in peroxisome proliferator-activated receptor-γ (PPARγ) protein level. Additionally, RSV down-regulated caveolin-1 and up-regulated microtubule-associated protein 1 light chain 3 -II (LC3-II) protein levels in OF zebrafish. In conclusion, these results suggest that 1) CR reduces plasma TG level through activation of the AMPKα-Sirt1- PGC1α pathway; 2) under different dietary stress conditions RSV might regulate AMPK phosphorylation bi-directionally; 3) RSV might regulate lipid metabolism through the AMPKα-Sirt1-PPARγ pathway in OF zebrafish.

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Intermittent Fasting Pretreatment Prevents Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion.

Hu Y, Yang Y, Zhang M, Deng M, Zhang JJ.

J Nutr. 2017 Jul;147(7):1437-1445. doi: 10.3945/jn.116.245613. Epub 2017 May 17.

PMID: 28515159



Background: Whether intermittent fasting (IF) pretreatment can prevent vascular cognitive dysfunction remains unknown to our knowledge.Objective: We investigated the effects and underlying mechanisms of IF pretreatment on cognitive dysfunction in a permanent 2-vessel occlusion (2VO) vascular dementia rat model.Methods: Male Wistar rats weighing 200 g were subjected to either IF or ad libitum feeding for 12 wk before 2VO surgery. Rats in the IF protocol underwent alternative-day feed deprivation (FD). Memory of the animals was assessed by using the Morris water maze (MWM) and the novel object recognition (NOR) test 6 wk after the surgery. After behavioral testing, malondialdehyde and glutathione concentrations, superoxide dismutase (SOD) activity, gene expression of antioxidative enzymes, inflammatory protein concentrations, and microglia density were determined in the hippocampus of rats.Results: 2-vessel occlusion operation ad libitum (2VO-AL) rats had significantly longer escape latencies on day 4 of the training phase and spent a lower percentage of time in the target quadrant (25% compared with 38% and 41%) in the MWM, and had lower discrimination ratios (47% compared with 65% and 67%) in the NOR test than 2-vessel operation and alternate-day feed deprivation (2VO-FD) and sham operation ad libitum (Sham-AL) rats, respectively (P < 0.05). This indicates that IF helps to prevent vascular cognitive deficits. 2VO-AL rats also had higher malondialdehyde (3.54 compared with 2.15 and 1.66 nmol/mg protein) and lower glutathione concentrations (53.25 compared with 66.41 and 91.71 nmol/mg protein), lower SOD activity (100.1 compared with 133.3 and 138.5 U/mg protein), lower gene expression of antioxidative enzymes, higher expression of inflammatory proteins, and higher microglia density in the hippocampus than 2VO-FD and Sham-AL rats, respectively (P < 0.05). This suggests that IF has antioxidative and anti-inflammatory effects.Conclusions: IF pretreatment provided sustained neuroprotection in a rat model of vascular dementia. These effects were associated with reduced oxidative stress and neuroinflammation.


NADPH oxidase 1; cognitive impairment; intermittent fasting; neuroinflammation; oxidative stress; toll-like receptor 4; vascular dementia


Malaria parasites able to sense their hosts calorie intake

July 5, 2017


"Parasitaemia (green and red areas) of P. berghei ANKA infection in BALB/c scid (severe combined immune deficiency) mice. The mouse on the left was fed ad libitum and the one on the right was under caloric restriction. Credit: Liliana Mancio-Silva, Maria Mota lab, iMM Lisboa"


Nutrient sensing modulates malaria parasite virulence.

Mancio-Silva L, Slavic K, Grilo Ruivo MT, Grosso AR, Modrzynska KK, Vera IM, Sales-Dias J, Gomes AR, MacPherson CR, Crozet P, Adamo M, Baena-Gonzalez E, Tewari R, Llinás M, Billker O, Mota MM.

Nature. 2017 Jul 5. doi: 10.1038/nature23009. [Epub ahead of print]

PMID: 28678779


The lifestyle of intracellular pathogens, such as malaria parasites, is intimately connected to that of their host, primarily for nutrient supply. Nutrients act not only as primary sources of energy but also as regulators of gene expression, metabolism and growth, through various signalling networks that enable cells to sense and adapt to varying environmental conditions. Canonical nutrient-sensing pathways are presumed to be absent from the causative agent of malaria, Plasmodium, thus raising the question of whether these parasites can sense and cope with fluctuations in host nutrient levels. Here we show that Plasmodium blood-stage parasites actively respond to host dietary calorie alterations through rearrangement of their transcriptome accompanied by substantial adjustment of their multiplication rate. A kinome analysis combined with chemical and genetic approaches identified KIN as a critical regulator that mediates sensing of nutrients and controls a transcriptional response to the host nutritional status. KIN shares homology with SNF1/AMPKα, and yeast complementation studies suggest that it is part of a functionally conserved cellular energy-sensing pathway. Overall, these findings reveal a key parasite nutrient-sensing mechanism that is critical for modulating parasite replication and virulence.

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Sean Giorgianni

3 days ago

Jumping off a 1 foot wall 1000 times is far different than jumping off a 1000-foot wall once.



Dr. Jason Fung

Jun 21

The difference between fasting and caloric restriction



The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women.

Harvie MN, Pegington M, Mattson MP, Frystyk J, Dillon B, Evans G, Cuzick J, Jebb SA, Martin B, Cutler RG, Son TG, Maudsley S, Carlson OD, Egan JM, Flyvbjerg A, Howell A.

Int J Obes (Lond). 2011 May;35(5):714-27. doi: 10.1038/ijo.2010.171. Epub 2010 Oct 5.

PMID: 20921964 Free PMC Article




The problems of adherence to energy restriction in humans are well known.


To compare the feasibility and effectiveness of intermittent continuous energy (IER) with continuous energy restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers.


Randomized comparison of a 25% energy restriction as IER (∼ 2710 kJ/day for 2 days/week) or CER (∼ 6276 kJ/day for 7 days/week) in 107 overweight or obese (mean (± s.d.) body mass index 30.6 (± 5.1) kg m(-2)) premenopausal women observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months.


Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95% confidence interval ) weight change for IER was -6.4 (-7.9 to -4.8) kg vs -5.6 (-6.9 to -4.4) kg for CER (P-value for difference between groups = 0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than with CER; difference between groups for fasting insulin was -1.2 (-1.4 to -1.0) μU ml(-1) and for insulin resistance was -1.2 (-1.5 to -1.0) μU mmol(-1) l(-1) (both P = 0.04).


IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.

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Differentiating constitutional thinness from anorexia nervosa in DSM 5 era.

Estour B, Marouani N, Sigaud T, Lang F, Fakra E, Ling Y, Diamondé A, Minnion JS, Galusca B, Germain N.

Psychoneuroendocrinology. 2017 Jun 23;84:94-100. doi: 10.1016/j.psyneuen.2017.06.015. [Epub ahead of print]

PMID: 28692876



Constitutional thinness (CT) is an underweight state characterized by normal menstruations and no change in feeding behaviour. Thinness is the only resemblance between Anorexia Nervosa (AN) and CT. Removal of amenorrhea from the new DSM 5 definition of AN might result in misdiagnosis between these two populations. The objective of this study was to compare CT, AN and Control subjects in terms of biological, anthropometric, and psychological markers in order to better distinguish AN from CT subjects.


Body composition, nutritional markers, pituitary hormones, bone markers and psychological scores were evaluated in three groups of young women: fifty-six CT, forty restrictive-type AN and fifty-four Control subjects. For every marker, a receiver Operator Characteristics (ROC) curve was calculated to evaluate the accuracy of differentiation between AN and CT groups.


For most studied parameters, CT subjects were similar to Controls but dramatically different from AN subjects. DEBQ Restrained Eating subscale score was identified by ROC data analysis as the only psychological parameter tested to successfully differentiate AN from CT. Free-T3 and Leptin were shown to be powerful markers to differentiate AN and CT populations as they were highly specific and sensitive ones.


The exclusive use of psychological testing criteria is not always sufficient to differentiate AN and CT patients. Minimally, additional testing of Free T3 levels, which is cheap and widely accessible for general practitioners, should be completed to avoid misdiagnosis which could result in the implementation of ineffective treatment plans and social stigmatization for CT women.


Anorexia nervosa; Biological differentiation markers; Constitutional thinness; DSM 5; Psychological questionnaires; ROC curves

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Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice.

Fang Y, McFadden S, Darcy J, Hill CM, Huber JA, Verhulst S, Kopchick JJ, Miller RA, Sun LY, Bartke A.

Geroscience. 2017 May 18. doi: 10.1007/s11357-017-9978-6. [Epub ahead of print]

PMID: 28523599



There is increasing evidence that growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling (collectively referred to as somatotropic signaling) during development has a profound influence on aging and longevity. Moreover, the absence of GH action was shown to modify responses of adult mice to calorie restriction (CR) and other antiaging interventions. It was therefore of interest to determine whether GH resistance in GH receptor knockout (GHR-KO) mice would modify the effects of mild pre-weaning CR imposed by increasing the number of pups in a litter (the so-called litter crowding). In addition to the expected impact on body weight, litter crowding affected glucose homeostasis, hepatic expression of IGF-1 and genes related to lipid metabolism, and expression of inflammatory markers in white adipose tissue, with some of these effects persisting until the age of 2 years. Litter crowding failed to further extend the remarkable longevity of GHR-KO mice and, instead, reduced late life survival of GHR-KO females, an effect opposite to the changes detected in normal animals. We conclude that the absence of GH actions alters the responses to pre-weaning CR and prevents this intervention from extending longevity.


Aging; GHR-KO; Growth hormone; Litter crowding


Lack of Additive Effects of Resveratrol and Energy Restriction in the Treatment of Hepatic Steatosis in Rats.

Milton-Laskibar I, Aguirre L, Fernández-Quintela A, Rolo AP, Soeiro Teodoro J, Palmeira CM, Portillo MP.

Nutrients. 2017 Jul 11;9(7). pii: E737. doi: 10.3390/nu9070737.

PMID: 28696376



The aims of the present study were to analyze the effect of resveratrol on liver steatosis in obese rats, to compare the effects induced by resveratrol and energy restriction and to research potential additive effects. Rats were initially fed a high-fat high-sucrose diet for six weeks and then allocated in four experimental groups fed a standard diet: a control group, a resveratrol-treated group, an energy restricted group and a group submitted to energy restriction and treated with resveratrol. We measured liver triacylglycerols, transaminases, FAS, MTP, CPT1a, CS, COX, SDH and ATP synthase activities, FATP2/FATP5, DGAT2, PPARα, SIRT1, UCP2 protein expressions, ACC and AMPK phosphorylation and PGC1α deacetylation. Resveratrol reduced triacylglycerols compared with the controls, although this reduction was lower than that induced by energy restriction. The mechanisms of action were different. Both decreased protein expression of fatty acid transporters, thus suggesting reduced fatty acid uptake from blood stream and liver triacylglycerol delivery, but only energy restriction reduced the assembly. These results show that resveratrol is useful for liver steatosis treatment within a balanced diet, although its effectiveness is lower than that of energy restriction. However, resveratrol is unable to increase the reduction in triacylglycerol content induced by energy restriction.


energy restriction; liver steatosis; rat; resveratrol


DGAT1-Dependent Lipid Droplet Biogenesis Protects Mitochondrial Function during Starvation-Induced Autophagy.

Nguyen TB, Louie SM, Daniele JR, Tran Q, Dillin A, Zoncu R, Nomura DK, Olzmann JA.

Dev Cell. 2017 Jul 10;42(1):9-21.e5. doi: 10.1016/j.devcel.2017.06.003.

PMID: 28697336


Lipid droplets (LDs) provide an "on-demand" source of fatty acids (FAs) that can be mobilized in response to fluctuations in nutrient abundance. Surprisingly, the amount of LDs increases during prolonged periods of nutrient deprivation. Why cells store FAs in LDs during an energy crisis is unknown. Our data demonstrate that mTORC1-regulated autophagy is necessary and sufficient for starvation-induced LD biogenesis. The ER-resident diacylglycerol acyltransferase 1 (DGAT1) selectively channels autophagy-liberated FAs into new, clustered LDs that are in close proximity to mitochondria and are lipolytically degraded. However, LDs are not required for FA delivery to mitochondria but instead function to prevent acylcarnitine accumulation and lipotoxic dysregulation of mitochondria. Our data support a model in which LDs provide a lipid buffering system that sequesters FAs released during the autophagic degradation of membranous organelles, reducing lipotoxicity. These findings reveal an unrecognized aspect of the cellular adaptive response to starvation, mediated by LDs.


ATGL; DGAT1; DGAT2; autophagy; lipid droplet; lipotoxicity; mTORC1; mitochondria; starvation; triacylglycerol


Role of DNA methylation in the dietary restriction mediated cellular memory.

Unnikrishnan A, Jackson J, Matyi SA, Hadad N, Wronowski B, Georgescu C, Garrett KP, Wren JD, Freeman WM, Richardson A.

Geroscience. 2017 May 5. doi: 10.1007/s11357-017-9976-8. [Epub ahead of print]

PMID: 28477138


An important facet of dietary restriction (DR) that has been largely overlooked is that DR can have early effects that create a cellular memory, which persists even when DR is discontinued. The goal of this study was to determine if DNA methylation played a role in the cellular memory of DR by examining the effect of short-term DR on gene expression and DNA methylation and determining if the changes in expression and DNA methylation persist when DR is discontinued and mice returned to ad libitum (AL) feeding. We show that DR can induce substantial changes in gene expression within 1 month of its implementation in various tissues, and more interestingly, ~19-50% of these changes in gene expression persist across the tissues even when DR is discontinued. We then determined whether DR induced changes in DNA methylation in the promoter of three candidate genes identified from our gene expression analysis (Pomc, Hsph1, and Nts1) that correlated with the changes in the expression of these genes. Decreased methylation at three specific CG sites in the promoter of the Nts1 gene encompassing the distal consensus AP-1 site was correlated with increased Nts1 expression. Both the promoter hypomethylation and increased Nts1 expression persisted even after DR was discontinued and mice fed AL, supporting our hypothesis that DNA methylation could play a role in the memory effect of DR. The changes in DNA methylation in the Nts1 gene are likely to occur in intestinal stem cells and could play a role in preserving the intestinal stem cell pool in DR mice.


DNA methylation; Dietary restriction; Epigenetics; Gene expression; Stem cells; Transcriptome

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Differential control of ageing and lifespan by isoforms and splice variants across the mTOR network.

Razquin Navas P, Thedieck K.

Essays Biochem. 2017 Jul 11;61(3):349-368. doi: 10.1042/EBC20160086. Print 2017 Jul 15. Review.

PMID: 28698309


Ageing can be defined as the gradual deterioration of physiological functions, increasing the incidence of age-related disorders and the probability of death. Therefore, the term ageing not only reflects the lifespan of an organism but also refers to progressive functional impairment and disease. The nutrient-sensing kinase mTOR (mammalian target of rapamycin) is a major determinant of ageing. mTOR promotes cell growth and controls central metabolic pathways including protein biosynthesis, autophagy and glucose and lipid homoeostasis. The concept that mTOR has a crucial role in ageing is supported by numerous reports on the lifespan-prolonging effects of the mTOR inhibitor rapamycin in invertebrate and vertebrate model organisms. Dietary restriction increases lifespan and delays ageing phenotypes as well and mTOR has been assigned a major role in this process. This may suggest a causal relationship between the lifespan of an organism and its metabolic phenotype. More than 25 years after mTOR's discovery, a wealth of metabolic and ageing-related effects have been reported. In this review, we cover the current view on the contribution of the different elements of the mTOR signalling network to lifespan and age-related metabolic impairment. We specifically focus on distinct roles of isoforms and splice variants across the mTOR network. The comprehensive analysis of mouse knockout studies targeting these variants does not support a tight correlation between lifespan prolongation and improved metabolic phenotypes and questions the strict causal relationship between them.


ageing; isoforms; mTOR; metabolism; splice variants


The effect of calorie restriction on mouse skeletal muscle is sex, strain and time-dependent.

Boldrin L, Ross JA, Whitmore C, Doreste B, Beaver C, Eddaoudi A, Pearce DJ, Morgan JE.

Sci Rep. 2017 Jul 11;7(1):5160. doi: 10.1038/s41598-017-04896-y.

PMID: 28698572


Loss of skeletal muscle mass and function occurs with increasing age. Calorie restriction (CR) increases the lifespan of C57Bl/6 mice, but not in the shorter-lived DBA/2 strain. There is some evidence that calorie restriction reduces or delays many of the age-related defects that occur in rodent skeletal muscle. We therefore investigated the effect of short (2.5 month) and longer term (8.5 and 18.5 months) CR on skeletal muscle in male and female C57Bl/6 and DBA/2 mice. We found that short-term CR increased the satellite cell number and collagen VI content of muscle, but resulted in a delayed regenerative response to injury.Consistent with this, the in vitro proliferation of satellite cells derived from these muscles was reduced by CR. The percentage of stromal cells, macrophages, hematopoietic stem cells and fibroadipogenic cells in the mononucleated cell population derived from skeletal muscle was reduced by CR at various stages. But overall, these changes are neither consistent over time, nor between strain and sex. The fact that changes induced by CR do not persist with time and the dissimilarities between the two mouse strains, combined with sex differences, urge caution in applying CR to improve skeletal muscle function across the lifespan in humans.


Acute Dietary Restriction Acts via TOR, PP2A, and Myc Signaling to Boost Innate Immunity in Drosophila.

Lee JE, Rayyan M, Liao A, Edery I, Pletcher SD.

Cell Rep. 2017 Jul 11;20(2):479-490. doi: 10.1016/j.celrep.2017.06.052.

PMID: 28700947


Dietary restriction promotes health and longevity across taxa through mechanisms that are largely unknown. Here, we show that acute yeast restriction significantly improves the ability of adult female Drosophila melanogaster to resist pathogenic bacterial infections through an immune pathway involving downregulation of target of rapamycin (TOR) signaling, which stabilizes the transcription factor Myc by increasing the steady-state level of its phosphorylated forms through decreased activity of protein phosphatase 2A. Upregulation of Myc through genetic and pharmacological means mimicked the effects of yeast restriction in fully fed flies, identifying Myc as a pro-immune molecule. Short-term dietary or pharmacological interventions that modulate TOR-PP2A-Myc signaling may provide an effective method to enhance immunity in vulnerable human populations.


Myc; dietary restriction; innate immunity; melanization; pathogenic bacterial infection; phenoloxidase; protein phosphatase 2A; target of rapamycin; tolerance; yeast restriction

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Low carbohydrate diet induces metabolic depression: a possible mechanism to conserve glycogen.

Winwood-Smith HS, Franklin CE, White CR.

Am J Physiol Regul Integr Comp Physiol. 2017 Jul 12:ajpregu.00067.2017. doi: 10.1152/ajpregu.00067.2017. [Epub ahead of print]

PMID: 28701319


Long-term studies have found low carbohydrate diets are more effective for weight loss than calorie restricted diets in the short-term, but equally or only marginally more effective in the long-term. Low carbohydrate diets have been linked to reduced glycogen stores and increased feelings of fatigue. We propose that reduced physical activity in response to lowered glycogen explains the diminishing weight loss advantage of low carbohydrate compared to low calorie diets over longer time scales. We explored this possibility by feeding adult Drosophila melanogaster either a standard or low carbohydrate diet for nine days and measured changes in metabolic rate, glycogen stores, activity, and body mass. We hypothesized that a low carbohydrate diet would cause a reduction in glycogen stores that recovers over time, reduced physical activity, and an increase in resting metabolic rate. The low carbohydrate diet was found to reduce glycogen stores, which recovered over time. Activity was unaffected by diet but the low carbohydrate group experienced a reduction in metabolic rate. We conclude that metabolic depression could explain the decreased effectiveness of low carbohydrate diets over time and recommend further investigation of long-term metabolic effects of dietary interventions and a greater focus on physiological plasticity within the study of human nutrition.


drosophila; nutrition; obesity; plasticity; protein

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Interindividual Variability in Biomarkers of Cardiometabolic Health after Consumption of Major Plant-Food Bioactive Compounds and the Determinants Involved

Dragan Milenkovic, Christine Morand, Aedin Cassidy, Aleksandra Konic-Ristic, Francisco Tomás-Barberán, José M Ordovas, Paul Kroon, Raffaele De Caterina, and Ana Rodriguez-Mateos

Adv Nutr 2017; 8:558-570 doi:10.3945/an.116.013623 OPEN ACCESS ARTICLE




Cardiometabolic disease, comprising cardiovascular diseases, type 2 diabetes, and their associated risk factors including metabolic syndrome and obesity, is the leading cause of death worldwide. Plant foods are rich sources of different groups of bioactive compounds, which might not be essential throughout life but promote health and well-being by reducing the risk of age-related chronic diseases. However, heterogeneity in the responsiveness to bioactive compounds can obscure associations between their intakes and health outcomes, resulting in the hiding of health benefits for specific population groups and thereby limiting our knowledge of the exact role of the different bioactive compounds for health. The heterogeneity in response suggests that some individuals may benefit more than others from the health effects of these bioactive compounds. However, to date, this interindividual variation after habitual intake of plant bioactive compounds has been little explored. The aim of this review is to provide an overview of the existing research that has revealed interindividual variability in the responsiveness to plant-food bioactive compound consumption regarding cardiometabolic outcomes, focusing on polyphenols, caffeine and plant sterols, and the identified potential determinants involved.


plant-food bioactives interindividual variability cardiometabolic health determinants of interindividual variability biological responsiveness


The Role of Ghrelin and Ghrelin Signaling in Aging.

Amitani M, Amitani H, Cheng KC, Kairupan TS, Sameshima N, Shimoshikiryo I, Mizuma K, Rokot NT, Nerome Y, Owaki T, Asakawa A, Inui A.

Int J Mol Sci. 2017 Jul 12;18(7). pii: E1511. doi: 10.3390/ijms18071511. Review.

PMID: 28704966


With our aging society, more people hope for a long and healthy life. In recent years, researchers have focused on healthy longevity factors. In particular, calorie restriction delays aging, reduces mortality, and extends life. Ghrelin, which is secreted during fasting, is well known as an orexigenic peptide. Because ghrelin is increased by caloric restriction, ghrelin may play an important role in the mechanism of longevity mediated by calorie restriction. In this review, we will discuss the role of orexigenic peptides with a particular focus on ghrelin. We conclude that the ghrelin-growth hormone secretagogue-R signaling pathway may play an important role in the anti-aging mechanism.


calorie restriction; ghrelin; ghrelin agonist; ghrelin resistance; longevity

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The Effects of Fasting During Ramadan on the Concentration of Serotonin, Dopamine, Brain-Derived Neurotrophic Factor and Nerve Growth Factor.

Bastani A, Rajabi S, Kianimarkani F.

Neurol Int. 2017 Jun 23;9(2):7043. doi: 10.4081/ni.2017.7043. eCollection 2017 Jun 23.

PMID: 28713531


Neurotransmitters and neurotrophic factors are signaling molecules that play a crucial role in cell proliferation, differentiation, survival and functions of neurons. It is believed that caloric restriction could help the health of the nervous system by affecting the synthesis of neurotrophins and neurotransmitter and oxygen radical metabolism. The objective was to investigate the plasma levels of serotonin, dopamine, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in 29 healthy fasted subjects (22 women and 7 men) during the month of fasting in Ramadan. The levels of these factors were measured (using ELISA method) three times, 2 days before the fasting month as a control, on the 14th and 29th day of Ramadan as test groups. In addition, these factors were investigated in the group of women only. According to our investigation, the plasma levels of serotonin, BDNF and NGF were significantly increased during fasting month of Ramadan. In detail, the levels of these factors were increased in 14th and 29th day test groups compared to controls (P<0.05). Moreover, these levels were significantly increased on the 29th day compared to the 14th day test groups, but there were no differences between dopamine levels in all groups. Furthermore, the results obtained in women's groups were the same as those obtained in previous groups. Our findings suggest that plasma levels of serotonin, BDNF and NGF were significantly increased during fasting month of Ramadan.


BDNF; Caloric restriction; Dopamine; NGF; Serotonin

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It takes two to tango: NAD<sup>+</sup> and sirtuins in aging/longevity control.

Imai SI, Guarente L.

NPJ Aging Mech Dis. 2016 Aug 18;2:16017. doi: 10.1038/npjamd.2016.17. eCollection 2016. Review.

PMID: 28721271




The coupling of nicotinamide adenine dinucleotide (NAD+) breakdown and protein deacylation is a unique feature of the family of proteins called 'sirtuins.' This intimate connection between NAD+ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator. The tight connection between NAD+ and sirtuins is regulated at several different levels, adding further complexity to their coordination in metabolic and aging/longevity control. Interestingly, it has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level. These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and the pathogenesis of diseases of aging. To mitigate these age-associated problems, supplementation of key NAD+ intermediates is currently drawing significant attention. In this review article, we will summarize these important aspects of the intimate connection between NAD+ and sirtuins in aging/longevity control.


Metabolic Effects of Intermittent Fasting.

Patterson RE, Sears DD.

Annu Rev Nutr. 2017 Jul 17. doi: 10.1146/annurev-nutr-071816-064634. [Epub ahead of print]

PMID: 28715993


The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved health outcomes. A MEDLINE search was performed using PubMed and the terms "intermittent fasting," "fasting," "time-restricted feeding," and "food timing." Modified fasting regimens appear to promote weight loss and may improve metabolic health. Several lines of evidence also support the hypothesis that eating patterns that reduce or eliminate nighttime eating and prolong nightly fasting intervals may result in sustained improvements in human health. Intermittent fasting regimens are hypothesized to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and © modifiable lifestyle behaviors, such as sleep. If proven to be efficacious, these eating regimens offer promising nonpharmacological approaches to improving health at the population level, with multiple public health benefits.


Gene expression signatures of human cell and tissue longevity.

Seim I, Ma S, Gladyshev VN.

NPJ Aging Mech Dis. 2016 Jul 7;2:16014. doi: 10.1038/npjamd.2016.14. eCollection 2016.

PMID: 28721269


Different cell types within the body exhibit substantial variation in the average time they live, ranging from days to the lifetime of the organism. The underlying mechanisms governing the diverse lifespan of different cell types are not well understood. To examine gene expression strategies that support the lifespan of different cell types within the human body, we obtained publicly available RNA-seq data sets and interrogated transcriptomes of 21 somatic cell types and tissues with reported cellular turnover, a bona fide estimate of lifespan, ranging from 2 days (monocytes) to a lifetime (neurons). Exceptionally long-lived neurons presented a gene expression profile of reduced protein metabolism, consistent with neuronal survival and similar to expression patterns induced by longevity interventions such as dietary restriction. Across different cell lineages, we identified a gene expression signature of human cell and tissue turnover. In particular, turnover showed a negative correlation with the energetically costly cell cycle and factors supporting genome stability, concomitant risk factors for aging-associated pathologies. In addition, the expression of p53 was negatively correlated with cellular turnover, suggesting that low p53 activity supports the longevity of post-mitotic cells with inherently low risk of developing cancer. Our results demonstrate the utility of comparative approaches in unveiling gene expression differences among cell lineages with diverse cell turnover within the same organism, providing insights into mechanisms that could regulate cell longevity.

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Effects of rapid or slow body weight reduction on intramuscular protein degradation pathways during equivalent weight loss on rats.

Nonaka Y, Urashima S, Inai M, Nishimura S, Higashida K, Terada S.

Physiol Res. 2017 Jul 18. [Epub ahead of print]

PMID: 28730836


The purpose of this study was to compare the effects of short-term fasting-induced rapid weight loss with those of slower but equivalent body weight loss induced by daily calorie restriction on muscle protein degradation pathways and muscle protein content. Male Fischer rats were subjected to either 30 % calorie restriction for 2 weeks to slowly decrease body weight (Slow) or 3-day fasting to rapidly decrease body weight by a comparable level of that of the Slow group (Rapid). The final body weights were about 15 % lower in both the Slow and Rapid groups than in the Con group (p<0.001). The total protein content and wet weight of fast-twitch plantaris muscle, but not slow-twitch soleus muscle, were significantly lower in the Rapid group compared with the control rats fed ad libitum. Substantial increases in the expression ratio of autophagosomal membrane proteins (LC3-II/-I ratio) and polyubiquitinated protein concentration, used as biomarkers of autophagy-lysosome and ubiquitin-proteasome activities, respectively, were observed in the plantaris muscle of the Rapid group. Moreover, the LC3-II/-I ratio and polyubiquitinated protein concentration were negatively correlated with the total protein content and wet weight of plantaris muscle. These results suggest that short-term fasting-induced rapid body weight loss activates autophagy-lysosome and ubiquitin-proteasome systems more strongly than calorie restriction-induced slower weight reduction, resulting in muscular atrophy in fast-twitch muscle.


Interaction of direct and social genetic effects with feeding regime in growing rabbits.

Piles M, David I, Ramon J, Canario L, Rafel O, Pascual M, Ragab M, Sánchez JP.

Genet Sel Evol. 2017 Jul 20;49(1):58. doi: 10.1186/s12711-017-0333-2.

PMID: 28728597



Most rabbit production farms apply feed restriction at fattening because of its protective effect against digestive diseases that affect growing rabbits. However, it leads to competitive behaviour between cage mates, which is not observed when animals are fed ad libitum. Our aim was to estimate the contribution of direct (dd) and social (ss) genetic effects (also known as indirect genetic effects) to total heritable variance of average daily gain (ADGADG) in rabbits on different feeding regimens (FR), and the magnitude of the interaction between genotype and FR (G × FR).


A total of 6264 contemporary kits were housed in cages of eight individuals and raised on full (FF) or restricted (RR) feeding to 75% of the ad libitum intake. A Bayesian analysis of weekly records of ADGADG (from 32 to 60 days of age) in rabbits on FF and RR was performed with a two-trait model including dd and ss.


The ratio between total heritable variance and phenotypic variance (T2T2) was low (<0.10) and did not differ significantly between FR. However, the ratio between h2h2 (i.e. variance of dd relative to phenotypic variance) and T2T2 was ~0.52 and 0.86 for animals on RR and FF, respectively, thus ss contributed more to the heritable variance of animals on RR than on FF. Feeding regimen also affected the sign and magnitude of the correlation between dd and ss, i.e. −0.5 and ~0 for animals on RR and FF, respectively. The posterior mean (posterior sd) of the correlation between estimated total breeding values (ETBV) of animals on RR and FF was 0.26 (0.20), indicating very strong G × FR interactions. The correlations between dd and ss in rabbits on FF and RR ranged from −0.47 (dd on FF and ss on RR) to 0.64.


Our results suggest that selection of rabbits for ADGADG under FF may completely fail to improve ADGADG in rabbits on RR. Social genetic effects contribute substantially to ETBV of rabbits on RR but not on FF. Selection for ADGADG should be performed under production conditions regarding the FR, by accounting for ss if the amount of food is limited.


Severe energy deficit up-regulates leptin receptors, leptin signaling and PTP1B in human skeletal muscle.

Perez-Suarez I, Ponce-Gonzalez JG, de La Calle-Herrero J, Losa-Reyna J, Martin-Rincon M, Morales-Alamo D, Santana A, Holmberg HC, Calbet JAL.

J Appl Physiol (1985). 2017 Jul 20:jap.00454.2017. doi: 10.1152/japplphysiol.00454.2017. [Epub ahead of print]

PMID: 28729389



In obesity, leptin receptors (OBR) and leptin signaling in skeletal muscle are down-regulated. To determine whether OBR and leptin signaling are up-regulated with a severe energy deficit fifteen overweight men were assessed before (PRE), after 4 days of caloric restriction (3.2 Kcal/kg BW/day) in combination with prolonged exercise (CRE) (8h walking + 45min single-arm cranking/day) to induce an energy deficit of ~5500 Kcal/d, and following 3 days of control diet (isoenergetic) and reduced exercise (CD). During CRE, the diet consisted solely of whey protein (n=8) or sucrose (n=7) (0.8 g/kg BW/day). Muscle biopsies were obtained from the exercised and the non-exercised deltoid muscles, and from the vastus lateralis. From PRE to CRE, serum glucose, insulin, and leptin were reduced. OBR expression was augmented in all examined muscles associated to increased maximal fat oxidation. Compared to PRE, after CD phospho-Tyr1141OBR, phospho-Tyr985OBR, JAK2, and phospho-Tyr1007/1008JAK2 protein expression were increased in all muscles, while STAT3 and phospho-Tyr705STAT3 were increased only in the arms. The expression of PTP1B in skeletal muscle was increased by 18 and 45%, after CRE and CD, respectively (P<0.05). SOCS3 tended to increase in the legs and decrease in the arm muscles (ANOVA interaction P<0.05). Myosin heavy chain I isoform was associated with OBR protein expression (r=-0.75), phospho-Tyr985OBR (r=0.88) and phospho-Tyr705STAT3 /STAT3 (r=0.74). In summary, despite increased PTP1B expression, skeletal muscle OBRs and signaling are up-regulated by a severe energy deficit with greater response in the arm than in the legs likely due to SOCS3 up-regulation in the leg muscles.


Leptin; PTP1B; STAT3; energy balance; ultra-endurance


A time-efficient reduction of fat mass in 4 days with exercise and caloric restriction.

Calbet JA, Ponce-González JG, Pérez-Suárez I, de la Calle Herrero J, Holmberg HC.

Scand J Med Sci Sports. 2015 Apr;25(2):223-33. doi: 10.1111/sms.12194. Epub 2014 Mar 6.

PMID: 24602091



To determine whether a fast reduction in fat mass can be achieved in 4 days by combining caloric restriction (CR: 3.2 kcal/kg body weight per day) with exercise (8-h walking + 45-min arm cranking per day) to induce an energy deficit of ∼5000 kcal/day, 15 overweight men underwent five experimental phases: pretest, exercise + CR for 4 days (WCR), control diet + reduced exercise for 3 days (DIET), and follow-up 4 weeks (POST1) and 1 year later (POST2). During WCR, the diet consisted solely of whey protein (n = 8) or sucrose (n = 7) (0.8 g/kg body weight per day). After WCR, DIET, POST1, and POST2, fat mass was reduced by a mean of 2.1, 2.8, 3.8, and 1.9 kg (P < 0.05), with two thirds of this loss from the trunk; and lean mass by 2.8, 1.0, 0.5, and 0.4 kg, respectively. After WCR, serum glucose, insulin, homeostatic model assessment, total and low-density lipoprotein cholesterol and triglycerides were reduced, and free fatty acid and cortisol increased. Serum leptin was reduced by 64%, 50%, and 33% following WCR, DIET, and POST1, respectively (P < 0.05). The effects were similar in both groups. In conclusion, a clinically relevant reduction in fat mass can be achieved in overweight men in just 4 days by combining prolonged exercise with CR.


Obesity; hypocaloric diet; sucrose; walking; whey protein

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Calorie restriction reverses age-related alteration of cavernous neurovascular structure in the rat.

Limanjaya A, Song KM, Choi MJ, Ghatak K, Minh NN, Kang DH, Ock J, Yin GN, Chung HY, Ryu JK, Suh JK.

Andrology. 2017 Jul 25. doi: 10.1111/andr.12401. [Epub ahead of print]

PMID: 28743168




Calorie restriction (CR) refers to a reduction of calorie intake without compromising essential nutrients to avoid malnutrition. CR has been established as a non-genetic method of altering longevity and attenuating biological changes associated with aging. Aging is also an important risk factor for erectile dysfunction. The aim of this study was to examine whether CR diet can reverse the age-related alterations of erectile tissue in the aged rat. Four groups of rats were used: young rats (7 months) + ad libitum, aged rats (22 months) + ad libitum, young rats + CR diet, and aged rats + CR diet. The ad libitum group had free access to both food and water, and CR groups were fed 60% of the food intake of their ad libitum littermates, starting from 6 weeks before sacrifice. The penis was harvested and stained with antibodies to von Willebrand factor, smooth muscle α-actin, platelet-derived growth factor receptor-β, phospho-eNOS, nNOS, and neurofilament. We also performed Masson trichrome staining and TUNEL assay. The blood samples were collected for the measurement of serum total testosterone level. The contents of endothelial cells, smooth muscle cells, pericytes, and neuronal cells as well as serum testosterone levels were significantly lower in the penis of aged rats than in their young littermates. CR significantly restored cavernous endothelial cells, smooth muscle cells, pericytes, and neuronal cell contents and decreased cavernous endothelial cell apoptosis and fibrosis in both young and aged rats. CR also increased serum testosterone level in aged rats, but not in young rats. CR successfully improved age-related derangements in penile neurovascular structures and hormonal disturbance. Along with a variety of lifestyle modifications, our study gave us a scientific rationale for CR as a non-pharmaceutical strategy to reprogram damaged erectile tissue toward neurovascular repair in aged men.


ageing/aging; angiopathy; calorie restriction; erectile dysfunction; peripheral neuropathy


Controversies Surrounding Critical Care Nutrition: An Appraisal of Permissive Underfeeding, Protein, and Outcomes.

Patel JJ, Martindale RG, McClave SA.

JPEN J Parenter Enteral Nutr. 2017 Jul 1:148607117721908. doi: 10.1177/0148607117721908. [Epub ahead of print]

PMID: 28742432


Over the past few years, numerous studies have called into question the optimal dose, timing, composition, and advancement rate of nutrition during the early acute phase of critical illness. These studies suggest permissive underfeeding with slow advancement may be more beneficial than aggressive full feeding. These counterintuitive results were possibly explained by enhanced autophagy, less hyperglycemia, or prevention of refeeding syndrome. This review underscores the controversies surrounding permissive underfeeding, aims to answer whether permissive underfeeding is appropriate for all critically ill patients, describes the impact of optimal protein delivery on critical care outcomes, discusses nutrition risk, and cogitates on the impact of nutrition on critical care outcomes.


hypocaloric feeding; nutrition risk; permissive underfeeding; trophic feeding

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Increased Sensitivity of Thyroid Hormone-mediated Signaling Despite Prolonged Fasting.

Martinez B, Scheibner M, Soñanez-Organis JG, Jaques JT, Crocker DE, Ortiz RM.

Gen Comp Endocrinol. 2017 Jul 22. pii: S0016-6480(17)30086-2. doi: 10.1016/j.ygcen.2017.07.023. [Epub ahead of print]

PMID: 28743556


Thyroid hormones (TH) can increase cellular metabolism. Food deprivation in mammals is typically associated with reduced thyroid gland responsiveness, in an effort to suppress cellular metabolism and abate starvation. However, in prolonged-fasted, elephant seal pups, cellular TH-mediated proteins are up-regulated and TH levels are maintained with fasting duration. The function and contribution of the thyroid gland to this apparent paradox is unknown and physiologically perplexing. Here we show that the thyroid gland remains responsive during prolonged food deprivation, and that its function and production of TH increase with fasting duration in elephant seals. We discovered that our modeled plasma TH data in response to exogenous thyroid stimulating hormone predicted cellular signaling, which was corroborated independently by the enzyme expression data. The data suggest that the regulation and function of the thyroid gland in the northern elephant seal is atypical for a fasted animal, and can be better described as, "adaptive fasting". Furthermore, the modeling data help substantiate the in vivo responses measured, providing unique insight on hormone clearance, production rates, and thyroid gland responsiveness. Because these unique endocrine responses occur simultaneously with a nearly strict reliance on the oxidation of lipid, these findings provide an intriguing model to better understand the TH-mediated reliance on lipid metabolism that is not otherwise present in morbidly obese humans. When coupled with cellular, tissue-specific responses, these data provide a more integrated assessment of thyroidal status that can be extrapolated for many fasting/food deprived mammals.


Deiodinase; Fasting; Mathematical modeling; Obesity; Thyroid hormone receptor; Thyroid hormones; Thyroid stimulating hormone; Thyroxine


Can a Diet That Mimics Fasting Turn Back the Clock?

Abbasi J.

JAMA. 2017 Jul 18;318(3):227-229. doi: 10.1001/jama.2017.6648. No abstract available.

PMID: 28658487



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

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

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

PMID: 28235195


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Bayesian association scan reveals loci associated with human lifespan and linked biomarkers.

McDaid AF, Joshi PK, Porcu E, Komljenovic A, Li H, Sorrentino V, Litovchenko M, Bevers RPJ, Rüeger S, Reymond A, Bochud M, Deplancke B, Williams RW, Robinson-Rechavi M, Paccaud F, Rousson V, Auwerx J, Wilson JF, Kutalik Z.

Nat Commun. 2017 Jul 27;8:15842. doi: 10.1038/ncomms15842.

PMID: 28748955


The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR). Eleven of them replicate (5% FDR) in five independent longevity studies combined; all but three are depleted of the life-shortening alleles in older Biobank participants. Further analysis revealed that brain expression levels of nearby genes (RBM6, SULT1A1 and CHRNA5) might be causally implicated in longevity. Gene expression and caloric restriction experiments in model organisms confirm the conserved role for RBM6 and SULT1A1 in modulating lifespan.

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Angiopoietin-like 4 directs uptake of dietary fat away from adipose during fasting.

Cushing EM, Chi X, Sylvers KL, Shetty SK, Potthoff MJ, Davies BSJ.

Mol Metab. 2017 Jun 19;6(8):809-818. doi: 10.1016/j.molmet.2017.06.007. eCollection 2017 Aug.

PMID: 28752045



Angiopoietin-like 4 (ANGPTL4) is a fasting-induced inhibitor of lipoprotein lipase (LPL) and a regulator of plasma triglyceride metabolism. Here, we examined the kinetics of Angptl4 induction and tested the hypothesis that ANGPTL4 functions physiologically to reduce triglyceride delivery to adipose tissue during nutrient deprivation.


Gene expression, LPL activity, and triglyceride uptake were examined in fasted and fed wild-type and Angptl4-/- mice.


Angptl4 was strongly induced early in fasting, and this induction was suppressed in mice with access to food during the light cycle. Fasted Angptl4-/- mice manifested increased LPL activity and triglyceride uptake in adipose tissue compared to wild-type mice.


Angptl4 is induced early in fasting to divert uptake of fatty acids and triglycerides away from adipose tissues.


ANGPTL4, angiopoietin-like 4; BAT, brown adipose tissue; GPIHBP1, glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1; LPL, lipoprotein lipase; Lipase inhibition; Lipolysis; Lipoprotein metabolism; Plasma triglycerides; gWAT, gonadal white adipose tissue; mWAT, mesenchymal white adipose tissue; sWAT, subcutaneous white adipose tissue

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The beneficial effects of dietary restriction on learning are distinct from its effects on longevity and mediated by depletion of a neuroinhibitory metabolite.

Vohra M, Lemieux GA, Lin L, Ashrafi K.

PLoS Biol. 2017 Aug 1;15(8):e2002032. doi: 10.1371/journal.pbio.2002032. eCollection 2017 Aug.

PMID: 28763436




In species ranging from humans to Caenorhabditis elegans, dietary restriction (DR) grants numerous benefits, including enhanced learning. The precise mechanisms by which DR engenders benefits on processes related to learning remain poorly understood. As a result, it is unclear whether the learning benefits of DR are due to myriad improvements in mechanisms that collectively confer improved cellular health and extension of organismal lifespan or due to specific neural mechanisms. Using an associative learning paradigm in C. elegans, we investigated the effects of DR as well as manipulations of insulin, mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and autophagy pathways-processes implicated in longevity-on learning. Despite their effects on a vast number of molecular effectors, we found that the beneficial effects on learning elicited by each of these manipulations are fully dependent on depletion of kynurenic acid (KYNA), a neuroinhibitory metabolite. KYNA depletion then leads, in an N-methyl D-aspartate receptor (NMDAR)-dependent manner, to activation of a specific pair of interneurons with a critical role in learning. Thus, fluctuations in KYNA levels emerge as a previously unidentified molecular mechanism linking longevity and metabolic pathways to neural mechanisms of learning. Importantly, KYNA levels did not alter lifespan in any of the conditions tested. As such, the beneficial effects of DR on learning can be attributed to changes in a nutritionally sensitive metabolite with neuromodulatory activity rather than indirect or secondary consequences of improved health and extended longevity.


Balanced Caloric Restriction Minimizes Changes Caused by Aging on the Colonic Myenteric Plexus.

Mari RB, Stabille SR, de Faria HG, Pereira JNB, Guimarães JP, Marinsek GP, de Souza RR.

J Diet Suppl. 2017 Jul 31:1-15. doi: 10.1080/19390211.2017.1341446. [Epub ahead of print]

PMID: 28759281


Aging can promote significant morphofunctional changes in the gastrointestinal tract (GIT). Regulation of GIT motility is mainly controlled by the myenteric neurons of the enteric nervous system. Actions that aim at decreasing the aging effects in the GIT include those related to diet, with caloric restriction (CR). The CR is achieved by controlling the amount of food or by manipulating the components of the diet. Therefore, the objective of this study was to evaluate different levels of CR on the plasticity of nicotinamide adenine dinucleotide phosphate- (NADPH-) reactive myenteric neurons in the colon of Wistar rats during the aging process using ultrastructural (transmission electron microscopy) and morphoquantitative analysis. Wistar male rats (Rattus norvegicus) were distributed into 4 groups (n = 10/group): C, 6-month-old animals; SR, 18-month-old animals fed a normal diet; CRI, 18-month-old animals fed a 12% CR diet; CRII, 18-month-old animals fed a 31% CR diet. At 6 months of age, animals were transferred to the laboratory animal facility, where they remained until 18 months of age. Animals of the CRI and CRII groups were submitted to CR for 6 months. In the ultrastructural analysis, a disorganization of the periganglionar matrix with the aging was observed, and this characteristic was not observed in the animals that received hypocaloric diet. It was observed that the restriction of 12.5% and 31% of calories in the diet minimized the increase in density and cell profile of the reactive NADPH neurons, increased with age. This type of diet may be adapted against gastrointestinal disturbances that commonly affect aging individuals.


aging; enteric nervous system; food restriction; nitric oxide

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[References 12 and 14 are given in the first below paper.]

"Calories in, calories out" and macronutrient intake: The Hope, Hype, and Science of Calories.

Howell S, Kones R.

Am J Physiol Endocrinol Metab. 2017 Aug 1:ajpendo.00156.2017. doi: 10.1152/ajpendo.00156.2017. [Epub ahead of print]

PMID: 28765272



One of the central tenets in obesity prevention and management is caloric restriction. This perspective presents salient features of how calories and energy balance matter, also called the "calories in, calories out paradigm." Determinants of energy balance and relationships to dietary macronutrient content are reviewed. The rationale and features of the carbohydrate-insulin hypothesis postulate that carbohydrate restriction confers a metabolic advantage. According to this model, a large amount of fat intake is enabled without weight gain. Evidence concerning this possibility is detailed. The relationship and application of the laws of thermodynamics are then clarified with current primary research. Strong data indicate that energy balance is not materially changed during isocaloric substitution of dietary fats for carbohydrates. Results from a number of sources refute both the theory and effectiveness of the carbohydrate-insulin hypothesis. Instead, risk for obesity is primarily determined by total calorie intake.


calories in calories out; carbohydrate-insulin hypothesis; low carb; metabolic advantage; obesity


12. Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity.

Hall KD, Bemis T, Brychta R, Chen KY, Courville A, Crayner EJ, Goodwin S, Guo J, Howard L, Knuth ND, Miller BV 3rd, Prado CM, Siervo M, Skarulis MC, Walter M, Walter PJ, Yannai L.

Cell Metab. 2015 Sep 1;22(3):427-36. doi: 10.1016/j.cmet.2015.07.021. Epub 2015 Aug 13.

PMID: 26278052 Free PMC Article




Dietary carbohydrate restriction has been purported to cause endocrine adaptations that promote body fat loss more than dietary fat restriction. We selectively restricted dietary carbohydrate versus fat for 6 days following a 5-day baseline diet in 19 adults with obesity confined to a metabolic ward where they exercised daily. Subjects received both isocaloric diets in random order during each of two inpatient stays. Body fat loss was calculated as the difference between daily fat intake and net fat oxidation measured while residing in a metabolic chamber. Whereas carbohydrate restriction led to sustained increases in fat oxidation and loss of 53 ± 6 g/day of body fat, fat oxidation was unchanged by fat restriction, leading to 89 ± 6 g/day of fat loss, and was significantly greater than carbohydrate restriction (p = 0.002). Mathematical model simulations agreed with these data, but predicted that the body acts to minimize body fat differences with prolonged isocaloric diets varying in carbohydrate and fat.


14. Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men.

Hall KD, Chen KY, Guo J, Lam YY, Leibel RL, Mayer LE, Reitman ML, Rosenbaum M, Smith SR, Walsh BT, Ravussin E.

Am J Clin Nutr. 2016 Aug;104(2):324-33. doi: 10.3945/ajcn.116.133561. Epub 2016 Jul 6.

PMID: 27385608 Free PMC Article





The carbohydrate-insulin model of obesity posits that habitual consumption of a high-carbohydrate diet sequesters fat within adipose tissue because of hyperinsulinemia and results in adaptive suppression of energy expenditure (EE). Therefore, isocaloric exchange of dietary carbohydrate for fat is predicted to result in increased EE, increased fat oxidation, and loss of body fat. In contrast, a more conventional view that "a calorie is a calorie" predicts that isocaloric variations in dietary carbohydrate and fat will have no physiologically important effects on EE or body fat.


We investigated whether an isocaloric low-carbohydrate ketogenic diet (KD) is associated with changes in EE, respiratory quotient (RQ), and body composition.


Seventeen overweight or obese men were admitted to metabolic wards, where they consumed a high-carbohydrate baseline diet (BD) for 4 wk followed by 4 wk of an isocaloric KD with clamped protein. Subjects spent 2 consecutive days each week residing in metabolic chambers to measure changes in EE (EEchamber), sleeping EE (SEE), and RQ. Body composition changes were measured by dual-energy X-ray absorptiometry. Average EE during the final 2 wk of the BD and KD periods was measured by doubly labeled water (EEDLW).


Subjects lost weight and body fat throughout the study corresponding to an overall negative energy balance of ∼300 kcal/d. Compared with BD, the KD coincided with increased EEchamber (57 ± 13 kcal/d, P = 0.0004) and SEE (89 ± 14 kcal/d, P < 0.0001) and decreased RQ (-0.111 ± 0.003, P < 0.0001). EEDLW increased by 151 ± 63 kcal/d (P = 0.03). Body fat loss slowed during the KD and coincided with increased protein utilization and loss of fat-free mass.


The isocaloric KD was not accompanied by increased body fat loss but was associated with relatively small increases in EE that were near the limits of detection with the use of state-of-the-art technology.


body composition; carbohydrate; energy expenditure; fat; insulin; ketogenic diet; macronutrients

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The effects of graded levels of calorie restriction: XI. Evaluation of the main hypotheses underpinning the life extension effects of CR using the hepatic transcriptome.

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

Aging (Albany NY). 2017 Jul 31;9(7):1770-1824. doi: 10.18632/aging.101269.

PMID: 28768896




Calorie restriction (CR) may extend longevity by modulating the mechanisms involved in aging. Different hypotheses have been proposed for its main mode of action. We quantified hepatic transcripts of male C57BL/6 mice exposed to graded levels of CR (0% to 40% CR) for three months, and evaluated the responses relative to these various hypotheses. Of the four main signaling pathways implied to be linked to the impact of CR on lifespan (insulin/insulin like growth factor 1 (IGF-1), nuclear factor-kappa beta (NF-ĸB), mechanistic target of rapamycin (mTOR) and sirtuins (SIRTs)), all the pathways except SIRT were altered in a manner consistent with increased lifespan. However, the expression levels of SIRT4 and SIRT7 were decreased with increasing levels of CR. Changes consistent with altered fuel utilization under CR may reduce reactive oxygen species production, which was paralleled by reduced protection. Downregulated major urinary protein (MUP) transcription suggested reduced reproductive investment. Graded CR had a positive effect on autophagy and xenobiotic metabolism, and was protective with respect to cancer signaling. CR had no significant effect on fibroblast growth factor-21 (FGF21) transcription but affected transcription in the hydrogen sulfide production pathway. Responses to CR were consistent with several different hypotheses, and the benefits of CR on lifespan likely reflect the combined impact on multiple aging related processes.


aging; calorie restriction; gene expression; liver; transcriptomics


Comparing the Effects of Melatonin with Caloric Restriction in the Hippocampus of Aging Mice: Involvement of Sirtuin1 and the FOXOs Pathway.

Jenwitheesuk A, Park S, Wongchitrat P, Tocharus J, Mukda S, Shimokawa I, Govitrapong P.

Neurochem Res. 2017 Aug 2. doi: 10.1007/s11064-017-2369-7. [Epub ahead of print]

PMID: 28770437


It has been suggested that age-related neurodegeneration might be associated with neuropeptide Y (NPY); sirtuin1 (SIRT1) and forkhead box transcription factors O subfamily (FOXOs) pathways. Melatonin, a hormone mainly secreted by the pineal gland, is another anti-aging agent associated with the SIRT1-FOXOs pathway. This study aimed to compare the effects of melatonin (Mel) and caloric restriction (CR) on the expression of Sirt1, FoxO1, FoxO3a and FOXOs target genes in the aging mouse hippocampus. Neuropeptide Y-knockout (NpyKO) and wild-type (WT) male mice aged 19 months were previously treated either with food ad libitum or CR for 16 months. WT old animals were divided into four groups: control, CR, Mel and CR+Mel treated groups. The Mel and CR+Mel were treated with melatonin 10 mg/kg, daily, subcutaneously for 7 consecutive days. Mel treatment upregulated the mRNA expression of Sirt1, FOXOs (FoxO1 and FoxO3a) target genes that regulated the cell cycle [e.g., cyclin-dependent kinase inhibitor 1B (p27)], Wingless and INT-1 (Wnt1) and inducible signaling pathway protein 1 (Wisp1) in the aged mouse hippocampus. CR treatment also showed the similar actions. However, the mRNA expression of Sirt1, FoxO1, FoxO3a, p27 or Wisp1 did not alter in the CR+Mel group when compared with CR or Mel group. Melatonin could not produce any additive effect on the CR treatment group, suggesting that both treatments mimicked the effect, possibly via the same pathway. NPY which mediates physiological adaptations to energy deficits is an essential link between CR and longevity in mice. In order to focus on the role of Npy in mediating the effects of melatonin, the gene expression between NpyKO and WT male mice were compared. Our data showed that, in the absence of Npy, melatonin could not mediate effects on those gene expressions, suggesting that Npy was required for melatonin to mediate the effect, possibly, on life extension.


Aging; Caloric restriction; FoxO1; Melatonin; Neuropeptide Y; Sirtuin1


Elucidating the role of leptin in systemic inflammation: a study targeting physiological leptin levels in rats and their macrophages.

Flatow EA, Komegae EN, Fonseca MT, Brito CF, Musteata FM, Antunes-Rodrigues J, Steiner AA.

Am J Physiol Regul Integr Comp Physiol. 2017 Aug 2:ajpregu.00171.2017. doi: 10.1152/ajpregu.00171.2017. [Epub ahead of print]

PMID: 28768659



To elucidate the role of leptin in acute systemic inflammation, we investigated how its infusion at low, physiologically relevant doses affects the responses to bacterial lipopolysaccharide (LPS) in rats subjected to 24 h of food deprivation. Leptin was infused subcutaneously (0-20 μg/kg/h) or intracerebroventricularly (0-1 μg/kg/h). Using hypothermia and hypotension as biomarkers of systemic inflammation, we identified the phase extending from 90 to 240 min post-LPS as the most susceptible to modulation by leptin. In this phase, leptin suppressed the rise in plasma TNF-α, and accelerated the recoveries from hypothermia and hypotension. Suppression of TNF-α was not accompanied by changes in other cytokines or prostaglandins. Leptin suppressed TNF-α when infused peripherally, but not when infused into the brain. Importantly, the leptin dose that suppressed TNF-α corresponded to the lowest dose that limited food consumption; this dose elevated plasma leptin within the physiological range (to 5.9 ng/ml). We then conducted in-vitro experiments to investigate whether an action of leptin on macrophages could parallel our in-vivo observations. The results revealed that, when sensitized by food deprivation, LPS-stimulated peritoneal macrophages can be inhibited by leptin at concentrations that are lower than those reported to promote cytokine release. It is concluded that physiological levels of leptin do not exert a pro-inflammatory effect, but rather an anti-inflammatory effect involving selective suppression of TNF-α via an action outside the brain. The mechanism of this effect might involve a previously unrecognized, suppressive action of leptin on macrophage subpopulations sensitized by food deprivation, but future studies are warranted.


TNF; fever; hypotension; hypothermia; lipopolysaccharide


Pet Product News / News / Purina Focuses on Weight Loss with New Food

Purina Focuses on Weight Loss with New Food BY PET PRODUCT NEWS STAFF

Published: 2017.08.03 10:24 AM


In January 2018, Purina Pro Plan, a brand of St. Louis-based Nestlé Purina PetCare Co., will deliver a patented weight loss system that’s easy to use and gives pets advanced nutrition, according to company officials. The company previewed its Simply Fit line of products at SuperZoo in Las Vegas in July.

The Simply Fit system is designed for efficiency, not speed, and works by changing calorie intake, not portion size. Efficiency of weight loss is calculated as total calories consumed divided by the percent of weight loss during the feeding period. This approach to weight loss is based on intermittent calorie restriction (ICR). Patented by Purina, ICR varies calorie intake over time. The method uses two foods—one with a base calorie amount (Metabolic Maintenance) and one with 25 percent fewer calories (Fat Burn) per serving.

Fed on an alternating schedule, the two foods work together to promote continuously active metabolism, helping pets lose body fat, maintain lean muscle mass and reach an ideal body condition, officials said. It is specially formulated to help avoid dietary upset when switching food each week. The week-over-week feeding pattern is continued until the pet’s ideal body condition is reached, with the length of time varying depending upon the pet’s beginning body condition.

The formula features high-quality protein, including chicken as the No. 1 ingredient, high protein levels to help maintain lean muscle mass during weight loss, natural prebiotic fiber, which helps promote digestive health, and omega-6 fatty acids to support healthy skin and coat. It is also rich in antioxidants to help support a healthy immune system.


Less is more: caloric regulation of neurogenesis and adult brain function.

Morgan AH, Andrews ZB, Davies JS.

J Neuroendocrinol. 2017 Aug 3. doi: 10.1111/jne.12512. [Epub ahead of print] Review.

PMID: 28771924



Calorie intake is essential for regulating normal physiological processes and is fundamental to maintaining life. Indeed, both extremes of calorie intake result in increased morbidity and mortality. In this review, we discuss the effect of calorie intake on adult brain function, with emphasis on the beneficial effects of mild calorie restriction. Recent findings relating to the regenerative and protective effect of the gastrointestinal hormone, ghrelin, suggest that it may underlie the beneficial effects of calorie restriction. We discuss the putative cellular mechanisms underlying ghrelin-action and their possible role in supporting healthy brain ageing.


Calorie restriction; acyl-ghrelin; adult hippocampal neurogenesis; diet induced obesity

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Obesity and malnutrition similarly alters the renin-angiotensin system and inflammation in mice and human adipose.

Pinheiro TA, Barcala-Jorge AS, Andrade JMO, Pinheiro TA, Ferreira ECN, Crespo TS, Batista-Jorge GC, Vieira CA, Lelis DF, Paraíso AF, Pinheiro UB, Bertagnolli M, Albuquerque CJB, Guimarães ALS, de Paula AMB, Caldeira AP, Santos SHS.

J Nutr Biochem. 2017 Jun 24;48:74-82. doi: 10.1016/j.jnutbio.2017.06.008. [Epub ahead of print]

PMID: 28779634


The main goal of the present study was to evaluate the metabolic profile, inflammatory markers and the gene expression of the renin-angiotensin system (RAS) components in the visceral adipose tissue of eutrophic, obese and malnourished individuals and mice models of obesity and food restriction. Male Swiss mice were divided into eight groups and fed different levels of food restriction (20%, 40%, or 60%) using standard or high-fat diet. Metabolic profile and adipose tissues were assessed. The expression of AGT (Angiotensinogen), ACE (Angiotensin-converting enzyme), ACE2 (Angiotensin-converting enzyme 2), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the mice epididymal adipose tissue and the human visceral adipose tissue was assessed. The main findings showed reduced body weight, improved metabolism, decreased adipose tissues weight and reduced adipocyte area in mice submitted to food restriction. Diminished expression of IL-6, TNF-α, AGT, AT1 and ACE was detected in the 20% and 40% food restriction animal groups, although they were increased in the 60% malnourished group. Increased expression of IL-6, TNF-α, AGT and ACE in obese and malnourished individuals was observed. Adipocytes size was increased in obese individuals and reduced in malnutrition. In conclusion, we found that food restriction of 20% and 40% improved the metabolic profile, ameliorated the inflammatory status and down-regulated the RAS in mice. Severe 60% food restriction (malnutrition), however, stimulated a proinflammatory state and increased AGT and ACE expression in the adipose tissue of mice. A similar profile was observed in the adipose tissue of obese and malnourished humans, supporting the critical role of inflammation and RAS as mediators of metabolic disorders.


Food restriction; Inflammatory mediators; Malnutrition; Obesity; Renin–angiotensin system

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Differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in a mouse model of Alzheimer's disease-like tau pathology fed with Western diet.

Gratuze M, Julien J, Morin F, Marette A, Planel E.

Prog Neuropsychopharmacol Biol Psychiatry. 2017 Aug 2. pii: S0278-5846(17)30259-2. doi: 10.1016/j.pnpbp.2017.08.001. [Epub ahead of print]

PMID: 28779908




Tau is a microtubule-associated protein that becomes pathological when it undergoes hyperphosphorylation and aggregation as seen in Alzheimer's disease (AD). AD is mostly sporadic, with environmental, biological and/or genetic risks factors, interacting together to promote the disease. In the past decade, reports have suggested that obesity in midlife could be one of these risk factors. On the other hand, caloric restriction and physical exercise have been reported to reduce the incidence and outcome of obesity as well as AD.


We evaluated the impact of voluntary physical exercise and caloric restriction on tau pathology during 2months in hTau mice under high caloric diet in order to evaluate if these strategies could prevent AD-like pathology in obese conditions.


We found no effects of obesity induced by Western diet on both Tau phosphorylation and aggregation compared to controls. However, exercise reduced tau phosphorylation while caloric restriction exacerbated its aggregation in the brains of obese hTau mice. We then examined the mechanisms underlying changes in tau phosphorylation and aggregation by exploring major tau kinases and phosphatases and key proteins involved in autophagy. However, there were no significant effects of voluntary exercise and caloric restriction on these proteins in hTau mice that could explain our results.


In this study, we report differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in our obese mice, namely beneficial effect of exercise on tau phosphorylation and deleterious effect of caloric restriction on tau aggregation. Our results suggest that lifestyle strategies used to reduce metabolic disorders and AD must be selected and studied carefully to avoid exacerbation of pathologies.


Alzheimer's disease; Caloric restriction; Exercise; Obesity; Tau pathology; Tau phosphorylation; Tauopathies; Western diet


Sex-Specific Gene Expression and Life Span Regulation.

Tower J.

Trends Endocrinol Metab. 2017 Aug 2. pii: S1043-2760(17)30099-1. doi: 10.1016/j.tem.2017.07.002. [Epub ahead of print] Review.

PMID: 28780002



Aging-related diseases show a marked sex bias. For example, women live longer than men yet have more Alzheimer's disease and osteoporosis, whereas men have more cancer and Parkinson's disease. Understanding the role of sex will be important in designing interventions and in understanding basic aging mechanisms. Aging also shows sex differences in model organisms. Dietary restriction (DR), reduced insulin/IGF1-like signaling (IIS), and reduced TOR signaling each increase life span preferentially in females in both flies and mice. Maternal transmission of mitochondria to offspring may lead to greater control over mitochondrial functions in females, including greater life span and a larger response to diet. Consistent with this idea, males show greater loss of mitochondrial gene expression with age.


Strehler–Mildvan; X chromosome; aging; dosage compensation; mitochondria; sex

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Aging and calorie restriction regulate the expression of miR-125a-5p and its target genes Stat3, Casp2 and Stard13.

Makwana K, Patel SA, Velingkaar N, Ebron JS, Shukla GC, Kondratov RVKV.

Aging (Albany NY). 2017 Jul 31;9(7):1825-1843. doi: 10.18632/aging.101270.

PMID: 28783714



Calorie restriction (CR) is a dietary intervention known to delay aging. In order, to understand molecular mechanisms of CR, we analyzed the expression of 983 MicroRNAs (miRNAs) in the liver of female mice after 2 years of 30% CR using micro-array. 16 miRNAs demonstrated significant changes in their expression upon CR in comparison with age-matched control. mmu-miR-125a-5p (miR-125a-5p) was significantly upregulated upon CR, and in agreement with this, the expression of mRNAs for its three predicted target genes: Stat3, Casp2, and Stard13 was significantly downregulated in the liver of CR animals. The expression of precursor miRNA for miR-125a-5p was also upregulated upon CR, which suggests its regulation at the level of transcription. Upon aging miR-125a-5p expression was downregulated while the expression of its target genes was upregulated. Thus, CR prevented age-associated changes in the expression of miR-125a-5p and its targets. We propose that miR-125a-5p dependent downregulation of Stat3, Casp2, and Stard13 contributes to the calorie restriction-mediated delay of aging.


MicroRNA ; aging; calorie restriction; longevity; transcription

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