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Moderate calorie restriction attenuates age‑associated alterations and improves cardiac function by increasing SIRT1 and SIRT3 expression.
Yu W, Qin J, Chen C, Fu Y, Wang W.
Mol Med Rep. 2018 Aug 16. doi: 10.3892/mmr.2018.9390. [Epub ahead of print]
PMID: 30132522
Abstract
Calorie restriction (CR) extends the lifespan of mammals and improves cardiac function by attenuation of age‑associated alterations. Sirtuins (SIRT) are involved in these mechanisms, however, the extent to which CR affects cardiac function and sirtuin expression remains unknown. Therefore, the present study aimed to determine to what extent CR affects cardiac function and sirtuin expression. A total of 60 female Sprague‑Dawley rats were randomly divided into four groups, including normal control (NC), 25% calorie restriction (25% CR), 45% calorie restriction (45% CR) and high‑fat diet (HF). The groups were maintained on these specific regimens for 2 months. CR rats were observed to have significantly lower body weight, heart weight, and left ventricle mass index compared with NC and HF rats. Visceral fat, triglyceride, and low density lipoprotein levels were significantly decreased in CR rats. Compared with the 25% CR group, the 45% CR group heart function decreased. The heart rate, left ventricular systolic pressure, +dp/dt and ‑dp/dt of the 45% CR rats decreased, whereas the left ventricular end‑diastolic pressure increased. To explore the molecular mechanism of CR on cardiac function, immunoblotting was used to detect the protein expression of SIRT1 and SIRT3. The 25% CR diet increased the expression of SIRT1 and SIRT3 in myocardium, whereas the 45% CR and HF diets resulted in a decrease in SIRT1 and SIRT3 expression. Moderate calorie restriction (25% CR) improves cardiac function by attenuation of age‑associated alterations in rats. SIRT1 and SIRT3 are associated with these effects.

Resistance training and caloric restriction prevent systolic blood pressure rise by improving the nitric oxide effect on smooth muscle and morphological changes in the aorta of ovariectomized rats.
Lino ADS, Vianna D, Oishi JC, Souza MVC, Ruffoni LD, Marin CT, de Avó LRDS, Perez SEA, Rodrigues GJ, Tirapegui J, Shiguemoto GE.
PLoS One. 2018 Aug 22;13(8):e0201843. doi: 10.1371/journal.pone.0201843. eCollection 2018.
PMID: 30133537 Free Article
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201843
http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0201843&type=printable
Abstract
In this study, we investigated the effects of resistance training (RT), caloric restriction (CR), and the association of both interventions in aortic vascular reactivity and morphological alterations, matrix metalloproteinase-2 (MMP-2) activity, insulin resistance and systolic blood pressure (SBP) in ovariectomized rats. Fifty female Holtzman rats were subjected to ovariectomy and Sham surgery and distributed into the following groups: Sham-sedentary, ovariectomized-sedentary, ovariectomized-resistance training, ovariectomized-caloric restriction, and ovariectomized-resistance training and caloric restriction groups. RT and 30% CR protocols were performed for 13 weeks. Analyses were conducted to evaluate the following: acetylcholine and sodium nitroprusside-induced relaxation of aortic rings, MMP-2 activity, insulin tolerance test, highlighting of the aorta wall cross-sectional area by hematoxylin-eosin stain, aorta vessel remodeling and SBP. We observed that ovariectomy decreased the potency of dependent and independent endothelium relaxation and MMP-2 activity, prevented insulin resistance, promoted aorta vessel remodeling in the cross-sectional area, and promoted the media-to-lumen ratio, the collagen content, and the alteration of the structure and elastic fibers of the vessel. The effects of the ovariectomy could contribute to SBP increases. However, the association of exercise and diet improved the relaxation potency in dependent and independent endothelium relaxation, elevated MMP-2 activity, ameliorate insulin sensitivity, increased the aorta cross-sectional area and media-to-lumen ratio, decreased collagen content and promoted histological parameters of the aorta vessel wall, preventing the increase of SBP.
CONCLUSION:
Our study revealed that the RT and CR separately, and even associatively, improved vascular function, activated MMP-2, and produced a beneficial hypertrophic remodeling, preventing the elevation of SBP in ovariectomized rats.

Fasting/Refeeding Cycles Prevent Myocardial Dysfunction and Morphology Damage in the Spontaneously Hypertensive Rats.
Pinotti MF, Matias AM, Sugizaki MM, Nascimento AFD, Pai MD, Leopoldo APL, Cicogna AC, Leopoldo AS.
Arq Bras Cardiol. 2018 Aug 20. pii: S0066-782X2018005011103. doi: 10.5935/abc.20180152. [Epub ahead of print] English, Portuguese.
PMID: 30133552
http://publicacoes.cardiol.br/portal/abc/ingles/aop/2018/AOP_9689_i.pdf
Abstract
BACKGROUND:
Caloric restriction is known to impair the cardiac function and morphology in hypertrophied hearts of spontaneously hypertensive rats (SHR); however, the influence of fasting/refeeding (RF) is unknown.
OBJECTIVE:
To investigate the fasting/refeeding approach on myocardial remodeling and function. In addition, the current study was designed to bring information regarding the mechanisms underlying the participation of Ca2+ handling and b-adrenergic system.
METHODS:
Sixty-day-old male SHR rats were submitted to food ad libitum (C), 50% food restriction (R50) or RF cycles for 90 days. Cardiac remodeling was assessed by ultrastructure analysis and isolated papillary muscle function. The level of significance considered was 5% (a = 0.05).
RESULTS:
The RF rats presented lower cardiac atrophy than R50 in relation to C rats. The C rats increased weight gain, R50 maintained their initial body weight and RF rats increased and decreased weight during RF. The RF did not cause functional impairment because the isotonic and isometric parameters showed similar behavior to those of C. The isotonic and isometric cardiac parameters were significantly elevated in RF rats compared to R50 rats. In addition, the R50 rats had cardiac damage in relation to C for isotonic and isometric variables. While the R50 rats showed focal changes in many muscle fibers, the RF rats displayed mild alterations, such as loss or disorganization of myofibrils.
CONCLUSION:
Fasting/refeeding promotes cardiac beneficial effects and attenuates myocardial injury caused by caloric restriction in SHR rats, contributing to reduce the cardiovascular risk profile and morphological injuries. Furthermore, RF promotes mild improvement in Ca2+ handling and b-adrenergic system.

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Randomized Trial of a High Protein, Partial Meal Replacement Program with or without Alternate Day Fasting: Similar Effects on Weight Loss, Retention Status, Nutritional, Metabolic, and Behavioral Outcomes.
Bowen J, Brindal E, James-Martin G, Noakes M.
Nutrients. 2018 Aug 23;10(9). pii: E1145. doi: 10.3390/nu10091145.
PMID: 30142886
http://www.mdpi.com/2072-6643/10/9/1145/htm
Abstract
Higher-protein diets, meal replacements, and greater early weight loss have separately been associated with greater weight loss. We compared a high-protein, meal replacement program with daily energy restriction (DER) to one which provided greater energy restriction adding alternate day fasting (ADF + DER; alternating days of modified-fasting and DER plus 1 ad libitum day/week) on retention, weight loss, physiological, nutritional, and behavioral markers. Participants were randomized to ADF + DER or DER for 16 weeks (n = 162, age 40 ± 8 years BMI 36 ± 6 kg/m² (Mean ± SD)) plus 8 weeks weight maintenance. At week 16 weight change was -10.7 ± 0.5 kg and -11.2 ± 0.6 kg in ADF + DER and DER groups (treatment NS). Fat mass, visceral adipose tissue, and lean mass (p < 0.05) were similarly reduced between treatments. Weight loss was sustained to 24 weeks (treatment NS). Fasting LDL-cholesterol, triglycerides, insulin, hsCRP, glucose, and blood pressure all improved (p < 0.05; treatment NS). Transferrin saturation, ferritin, serum zinc, folate, and B12 improved (p < 0.05; treatment NS). Plasma thiamine and vitamin D levels decreased, reflecting lower carbohydrate intakes and seasonal changes, respectively. Food cravings, quality of life, and mood improved (treatment NS). Energy, fatigue, and pain improved slightly more in DER (p < 0.05). This study supports the use of higher protein, meal replacement programs with or without ADF in weight management.
KEYWORDS:
fasting; meal replacement; weight loss

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Gut microbiota mediates the anti-obesity effect of calorie restriction in mice.
Wang S, Huang M, You X, Zhao J, Chen L, Wang L, Luo Y, Chen Y.
Sci Rep. 2018 Aug 29;8(1):13037. doi: 10.1038/s41598-018-31353-1.
PMID: 30158649
https://www.nature.com/articles/s41598-018-31353-1
Abstract
Calorie restriction (CR) extends lifespan and elicits numerous effects beneficial to health and metabolism in various model organisms, but the underlying mechanisms are not completely understood. Gut microbiota has been reported to be associated with the beneficial effects of CR; however, it is unknown whether these effects of CR are causally mediated by gut microbiota. In this study, we employed an antibiotic-induced microbiota-depleted mouse model to investigate the functional role of gut microbiota in CR. Depletion of gut microbiota rendered mice resistant to CR-induced loss of body weight, accompanied by the increase in fat mass, the reduction in lean mass and the decline in metabolic rate. Depletion of gut microbiota led to increases in fasting blood glucose and cholesterol levels independent of CR. A few metabolism-modulating hormones including leptin and insulin were altered by CR and/or gut microbiota depletion. In addition, CR altered the composition of gut microbiota with significant increases in major probiotic genera such as Lactobacillus and Bifidobacterium, together with the decrease of Helicobacter. In addition, we performed fecal microbiota transplantation in mice fed with high-fat diet. Mice with transferred microbiota from calorie-restricted mice resisted high fat diet-induced obesity and exhibited metabolic improvement such as alleviated hepatic lipid accumulation. Collectively, these data indicate that CR-induced metabolic improvement especially in body weight reduction is mediated by intestinal microbiota to a certain extent.

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Gut bacteria helps develop more beige fat with restricted calorie intake
Reviewed by James Ives, 
Aug 31 2018
https://www.news-medical.net/news/20180831/Gut-bacteria-helps-develop-more-beige-fat-with-restricted-calorie-intake.aspx
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Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements
Salvatore Fabbiano, Nicolas Suárez-Zamorano, Claire Chevalier, Vladimir Lazarević, Silas Kieser, Dorothée Rigo, Stefano Leo, Christelle Veyrat-Durebex, Nadia Gaïa, Marcello Maresca, Doron Merkler, Mercedes Gomez de Agüero, Andrew Macpherson, Jacques Schrenzel, Mirko Trajkovski
Published online: August 30, 2018
Open Access
https://www.cell.com/cell-metabolism/pdfExtended/S1550-4131(16)30374-6
Highlights
CR-microbiota transplantation improves glycemic control and insulin sensitivity
CR microbiota promotes beige fat development and reduces weight gain
CR suppresses key microbial genes for LPS biosynthesis and dictates the immune tone
LPS-TLR4 inhibition in bone marrow-derived cells improves metabolism and browning
Summary
Caloric restriction (CR) stimulates development of functional beige fat and extends healthy lifespan. Here we show that compositional and functional changes in the gut microbiota contribute to a number of CR-induced metabolic improvements and promote fat browning. Mechanistically, these effects are linked to a lower expression of the key bacterial enzymes necessary for the lipid A biosynthesis, a critical lipopolysaccharide (LPS) building component. The decreased LPS dictates the tone of the innate immune response during CR, leading to increased eosinophil infiltration and anti-inflammatory macrophage polarization in fat of the CR animals. Genetic and pharmacological suppression of the LPS-TLR4 pathway or transplantation with Tlr4−/− bone-marrow-derived hematopoietic cells increases beige fat development and ameliorates diet-induced fatty liver, while Tlr4−/− or microbiota-depleted mice are resistant to further CR-stimulated metabolic alterations. These data reveal signals critical for our understanding of the microbiota-fat signaling axis during CR and provide potential new anti-obesity therapeutics.

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The effect of fasting or calorie restriction on autophagy induction: a review of the literature.
Bagherniya M, Butler AE, Barreto GE, Sahebkar A.
Ageing Res Rev. 2018 Aug 30. pii: S1568-1637(18)30147-8. doi: 10.1016/j.arr.2018.08.004. [Epub ahead of print] Review.
PMID: 30172870
Abstract
Autophagy is a lysosomal degradation process and protective housekeeping mechanism to eliminate damaged organelles, long-lived misfolded proteins and invading pathogens. Autophagy functions to recycle building blocks and energy for cellular renovation and homeostasis, allowing cells to adapt to stress. Modulation of autophagy is a potential therapeutic target for a diverse range of diseases, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. Traditionally, food deprivation and calorie restriction (CR) have been considered to slow aging and increase longevity. Since autophagy inhibition attenuates the anti-aging effects of CR, it has been proposed that autophagy plays a substantive role in CR-mediated longevity. Among several stress stimuli inducers of autophagy, fasting and CR are the most potent non-genetic autophagy stimulators, and lack the undesirable side effects associated with alternative interventions. Despite the importance of autophagy, the evidence connecting fasting or CR with autophagy promotion has not previously been reviewed. Therefore, our objective was to weigh the evidence relating the effect of CR or fasting on autophagy promotion. We conclude that both fasting and CR have a role in the upregulation of autophagy, the evidence overwhelmingly suggesting that autophagy is induced in a wide variety of tissues and organs in response to food deprivation.
KEYWORDS:
Autophagy; Calorie restriction; Fasting

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Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories
Sarah J. Mitchell, Michel Bernier, Julie A. Mattison, Miguel A. Aon, Tamzin A. Kaiser, R. Michael Anson, Yuji Ikeno, Rozalyn M. Anderson, Donald K. Ingram, Rafael de Cabo
Cell Metab Published:September 06, 2018DOI:https://doi.org/10.1016/j.cmet.2018.08.011
https://sci-hub.tw/10.1016/j.cmet.2018.08.011
Highlights
The duration of eating/fasting varies based on diet type and feeding protocol
Meal feeding and CR, unlike AL, show high metabolic flexibility in male mice
Eating patterns rather than diet composition influence longevity regulation
A prolonged daily fasting is associated with delayed onset of liver pathologies
Summary
The importance of dietary composition and feeding patterns in aging remains largely unexplored, but was implicated recently in two prominent nonhuman primate studies. Here, we directly compare in mice the two diets used in the primate studies focusing on three paradigms: ad libitum (AL), 30% calorie restriction (CR), and single-meal feeding (MF), which accounts for differences in energy density and caloric intake consumed by the AL mice. MF and CR regimes enhanced longevity regardless of diet composition, which alone had no significant impact within feeding regimens. Like CR animals, MF mice ate quickly, imposing periods of extended daily fasting on themselves that produced significant improvements in morbidity and mortality compared with AL. These health and survival benefits conferred by periods of extended daily fasting, independent of dietary composition, have major implications for human health and clinical applicability.
Keywords
caloric restrictionfastingaginglongevitydiet compositiontime-restricted feedingdietary restrictionlifespan extension

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Researchers identify molecule with anti-aging effects on vascular system, study finds
September 10, 2018 
by Latina Emerson
https://medicalxpress.com/news/2018-09-molecule-anti-aging-effects-vascular.html
β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4.
Han YM, Bedarida T, Ding Y, Somba BK, Lu Q, Wang Q, Song P, Zou MH.
Mol Cell. 2018 Aug 28. pii: S1097-2765(18)30605-1. doi: 10.1016/j.molcel.2018.07.036. [Epub ahead of print]
PMID: 30197300
https://sci-hub.tw/10.1016/j.molcel.2018.07.036
Abstract
β-hydroxybutyrate (β-HB) elevation during fasting or caloric restriction is believed to induce anti-aging effects and alleviate aging-related neurodegeneration. However, whether β-HB alters the senescence pathway in vascular cells remains unknown. Here we report that β-HB promotes vascular cell quiescence, which significantly inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms. Further, we identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of β-HB. β-HB binding to hnRNP A1 markedly enhances hnRNP A1 binding with Octamer-binding transcriptional factor (Oct) 4 mRNA, which stabilizes Oct4 mRNA and Oct4 expression. Oct4 increases Lamin B1, a key factor against DNA damage-induced senescence. Finally, fasting and intraperitoneal injection of β-HB upregulate Oct4 and Lamin B1 in both vascular smooth muscle and endothelial cells in mice in vivo. We conclude that β-HB exerts anti-aging effects in vascular cells by upregulating an hnRNP A1-induced Oct4-mediated Lamin B1 pathway.

Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories.
Mitchell SJ, Bernier M, Mattison JA, Aon MA, Kaiser TA, Anson RM, Ikeno Y, Anderson RM, Ingram DK, de Cabo R.
Cell Metab. 2018 Aug 24. pii: S1550-4131(18)30512-6. doi: 10.1016/j.cmet.2018.08.011. [Epub ahead of print]
PMID: 30197301
https://www.crsociety.org/topic/11800-als-cr-updates/?page=16&tab=comments#comment-29793

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Effects of intermittent versus continuous dieting on weight and body composition in obese and overweight people: a systematic review and meta-analysis of randomized controlled trials.
Roman YM, Dominguez MC, Easow TM, Pasupuleti V, White CM, Hernandez AV.
Int J Obes (Lond). 2018 Sep 11. doi: 10.1038/s41366-018-0204-0. [Epub ahead of print]
PMID: 30206335
Abstract
BACKGROUND:
Intermittent dieting may be an alternative to continuous dieting for weight reduction.
OBJECTIVE:
To evaluate the effect of intermittent dieting versus continuous dieting on weight and body composition in overweight or obese adults.
DESIGN:
A systematic review and meta-analysis of randomized controlled trials (RCTs). Five databases were searched until February 2018 for RCTs comparing intermittent versus continuous dieting. Intermittent dieting consisted of two types: regular intermittent was caloric restriction interspersed with days of weight maintenance or ad libitum eating; intensified intermittent was caloric restriction interspersed with days of even lower caloric restriction. Continuous was continual caloric restriction. Primary outcomes were weight, body fat, lean mass, waist circumference, hip circumference, and energy expenditure. Data were pooled by the inverse variance method using random-effects models and expressed as mean differences (MD) and their 95% confidence intervals (CI).
RESULTS:
Nine trials met the inclusion criteria (n = 782), six comparing regular intermittent vs continuous (n = 553), and three comparing intensified intermittent vs continuous (n = 229). Populations were heterogeneous: obese only in five studies, and overweight or obese (mixed) in four studies. Lean mass was significantly lower in regular intermittent vs continuous (MD -0.86 kg; 95% CI -1.62 to -0.10; p = 0.03). No differences were found for the remaining outcomes for both comparisons (regular intermittent or intensified intermittent vs continuous). There was low heterogeneity of effects across trials. Subgroup effects by time to follow-up, gender, per-protocol versus intention-to-treat, enforced exercise, and diabetes were similar to main analyses.
CONCLUSIONS:
This systematic review in obese and overweight individuals showed that regular intermittent dieting decreased lean mass compared to continuous dieting. There were no differences in effects for either intermittent vs continuous interventions across all other outcomes. In contrast to previous systematic reviews, this study suggested that lean mass is better preserved in continuous dieting compared to regular intermittent dieting.

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Mechanisms of the anti-aging and prolongevity effects of caloric restriction: evidence from studies of genetically modified animals.
Hoshino S, Kobayashi M, Higami Y.
Aging (Albany NY). 2018 Sep 16. doi: 10.18632/aging.101557. [Epub ahead of print]
PMID: 30222593
http://www.aging-us.com/article/101557/text
Abstract
It is widely accepted that caloric restriction (CR) extends lifespan and suppresses various pathophysiological changes. CR suppresses growth hormone/insulin-like growth factor signaling and mechanistic target of rapamycin complex 1 activity, activates sirtuin and enhances mitochondrial redox regulation, but the exact mechanisms are still under debate. In this review, we discuss the mechanisms of CR using evidence from studies of animals that were genetically modified according to recent advances in molecular and genetic technologies, from the viewpoint of the adaptive response hypothesis proposed by Holliday (1989). We then explain the beneficial actions of CR, classified according to whether they operate under feeding or fasting conditions.
KEYWORDS:
aging; caloric restriction; growth hormone/insulin-like growth factor 1; mitochondria/redox regulation; remodeling of white adipose tissue

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Which is the Most Reasonable Anti-aging Strategy: Meta-analysis.
Liang Y, Wang Z.
Adv Exp Med Biol. 2018;1086:267-282. doi: 10.1007/978-981-13-1117-8_17.
PMID: 30232765
https://sci-hub.tw/10.1007/978-981-13-1117-8_17
Abstract
An organism's lifespan is inevitably accompanied by the aging process, which involves functional decline, a steady increase of a plethora of chronic diseases, and ultimately death. Thus, it has been an ongoing dream of mankind to improve health span and extend the lifespan. In the last century, there is a great increase in the search for eternal youth and an insatiable appetite for methods which could turn back the clock. Survival curves are key components of lifespan experiments. Many interventions have been reported to extend the lifespan, including the administration of pharmaceuticals, calorie restriction, and genetic alteration. However, few studies have attempted to provide a comprehensive analysis of the mechanism by which these various methods function to extend lifespan. We recently collected survival curves from published papers and recovered data by fitting models. The analysis results highlight the overall advantage of calorie restriction and its mimetics in aging and demonstrate that hypoglycemic agents and antioxidants have a superior effect on lifespan extension via a pattern of global integrity compared to other medications. This review provides a scientific foundation for the discovery of effective anti-aging agents and the formulation of scientific anti-aging strategies.
KEYWORDS:
Aging and anti-aging; Calorie restriction; Meta-analysis; Survival curve

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Caffeine Modulates Food Intake Depending on the Context That Gives Access to Food: Comparison With Dopamine Depletion.
Correa M, SanMiguel N, López-Cruz L, Carratalá-Ros C, Olivares-García R, Salamone JD.
Front Psychiatry. 2018 Sep 6;9:411. doi: 10.3389/fpsyt.2018.00411. eCollection 2018.
PMID: 30237771
https://www.frontiersin.org/articles/10.3389/fpsyt.2018.00411/full
Abstract
Caffeine is a methylxanthine consumed in different contexts to potentiate alertness and reduce fatigue. However, caffeine can induce anxiety at high doses. Caffeine is also a minor psychostimulant that seems to act as an appetite suppressant, but there are also reports indicating that it could stimulate appetite. Dopamine also is involved in food motivation and in behavioral activation. In the present series of experiments, we evaluated the effects of acute administration of caffeine on food consumption under different access conditions. CD1 male adult mice had access to highly palatable food (50% sucrose) in a restricted but habitual context, under continuous or intermittent access as well as under anxiogenic, or effortful conditions. Caffeine (2.5-20.0 mg/kg) increased intake at the highest dose under familiar continuous and intermittent access. However, this high dose reduced food intake in the dark-light paradigm. In contrast, a dopamine-depleting agent, tetrabenazine (TBZ; 1.0-8.0 mg/kg) did not affect food intake in any of those experimental conditions. In the T-maze-barrier task that evaluates seeking and taking of food under effortful conditions, caffeine (10.0 mg/kg) decreased latency to reach the food, but did not affect selection of the high-food density arm that required more effort, or the total amount of food consumed. In contrast, TBZ (4.0 mg/kg) reduced selection of the high food density arm with the barrier, thus affecting amount of food consumed. Interestingly, a small dose of caffeine (5.0 mg/kg) was able to reverse the anergia-inducing effects produced by TBZ in the T-maze. These results suggest that caffeine can potentiate or suppress food consumption depending on the context. Moreover, caffeine did not change appetite, and did not impair orientation toward food under effortful conditions, but it rather helped to achieve the goal by improving speed and by reversing performance to normal levels when fatigue was induced by dopamine depletion.
KEYWORDS:
anxiety; appetite; decision-making; methylxanthine; sucrose; tetrabenazine

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Calorie Restriction off the Menu for the Time Being?….
Moore A.
Bioessays. 2018 Oct;40(10):e1800170. doi: 10.1002/bies.201800170. No abstract available.
PMID: 30246504
https://onlinelibrary.wiley.com/doi/10.1002/bies.201800170
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Do-It-Yourself Calorie Restriction: The Risks of Simplistically Translating Findings in Animal Models to Humans.
Le Bourg E, Redman LM.
Bioessays. 2018 Sep;40(9):e1800087. doi: 10.1002/bies.201800087. Epub 2018 Jun 13. No abstract available.
PMID: 29897135
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Does Calorie Restriction in Primates Increase Lifespan? Revisiting Studies on Macaques (Macaca mulatta) and Mouse Lemurs (Microcebus murinus).
Le Bourg E.
Bioessays. 2018 Aug 1:e1800111. doi: 10.1002/bies.201800111. [Epub ahead of print] Review.
PMID: 30067295
Abstract
The effects of calorie restriction have now been studied in two non-human primates, the macaque Macaca mulatta and the mouse lemur Microcebus murinus. The study on lemurs and one of the two studies on macaques have reported a lifespan increase. In this review, I argue that these results are better explained by a lifespan decrease in the control group because of a bad diet and/or overfeeding, rather than by a real lifespan increase in calorie-restricted animals. If these results can be readily translated to humans, it would mean that no beneficial effect of calorie restriction on lifespan can be expected in normal-weight or lean people, but that overweight and/or obese people could benefit to some extent from a decrease in excessive food intake.
KEYWORDS:
calorie restriction; human beings; non-human primates

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However, the details aren't in this summary -- so it's unclear whether Moore's evaluation of the ineffectiveness of lemur and macaque CR might have some value -- or else be the result of "sour grapes" -- a "healthy eating" ad libber "proving" that his diet is the best.

  ?

     --  saul 

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Exercise training and/or diet on reduction of intra-abdominal adipose tissue and risk factors for cardiovascular disease.
Borges JH, Carter SJ, Bryan DR, Hunter GR.
Eur J Clin Nutr. 2018 Sep 24. doi: 10.1038/s41430-018-0318-4. [Epub ahead of print]
PMID: 30250134
Abstract
BACKGROUND/OBJECTIVES:
To test the effects of weight loss with and without exercise training (aerobic or resistance) on intra-abdominal adipose tissue (IAAT) and risk factors for cardiovascular disease (CVD). Additionally, CVD risk factors was evaluated before and after weight loss using previously established IAAT cut-points.
SUBJECTS/METHODS:
One hundred twenty-two overweight premenopausal women were randomly assigned to one of three groups: (1) diet only (Diet); (2) diet and aerobic training (Diet + AT); or (3) diet and resistance training (Diet + RT); until a BMI of < 25 kg/m2 was reached. Computerized tomography was used to measure IAAT and blood lipids were measured by assay. Evaluations were made before and after weight loss.
RESULTS:
Though no group-by-time effects were found after weight loss, we observed significant time effects for: IAAT (-38.0%, P < 0.001), total cholesterol (TC) (-2.2%, P = 0.008), low-density lipoprotein cholesterol (LDL-C) (-4.8%, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (+20.2%, P < 0.001), triglycerides (-18.7%, P < 0.001), TC/HDL-C (-16.3%, P < 0.001), and LDL-C/HDL-C (-18.0%, P < 0.001). Following weight loss, 40.2% of all participants reduced IAAT to < 40 cm2 (IAAT associated with low CVD risk). Furthermore, only 2.5% of participants had an IAAT > 110 cm2 (IAAT associated with high CVD risk) after weight loss. We also observed that decreases of IAAT were associated with decreased CVD risk factors after weight loss independent of race, changes in %fat mass and changes in maximal oxygen uptake.
CONCLUSIONS:
Caloric restriction leading to significant weight loss with or without exercise training appears to be equally effective for reducing IAAT and CVD risk factors.

Calorie restriction for human aging: is there a potential benefit for cancer?
Gilmore A, Redman L.
Mol Cell Oncol. 2018 Aug 17;5(4):e1481811. doi: 10.1080/23723556.2018.1481811. eCollection 2018.
PMID: 30250926
https://sci-hub.tw/10.1080/23723556.2018.1481811
Abstract
Caloric restriction in non-obese humans improves metabolic efficiency and reduces oxidative damage markers which may decrease cancer incidence and progression.
KEYWORDS:
Aging; Biology of malignant cells; Caloric restriction; Metabolism; Obesity; Oxidative stress; Tumor metabolism

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Exploring the effect of diet composition in calorie restriction interventions.
Morris A.
Nat Rev Endocrinol. 2018 Sep 26. doi: 10.1038/s41574-018-0103-4. [Epub ahead of print] No abstract available.
PMID: 30258090
https://sci-hub.tw/10.1038/s41574-018-0103-4
>>>>>>>>>>>>>>>>>
Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories.
Mitchell SJ, Bernier M, Mattison JA, Aon MA, Kaiser TA, Anson RM, Ikeno Y, Anderson RM, Ingram DK, de Cabo R.
Cell Metab. 2018 Aug 24. pii: S1550-4131(18)30512-6. doi: 10.1016/j.cmet.2018.08.011. [Epub ahead of print]
PMID: 30197301
https://www.crsociety.org/topic/11800-als-cr-updates/?page=16&tab=comments#comment-29811
https://sci-hub.tw/10.1016/j.cmet.2018.08.011

Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis.
Poekes L, Gillard J, Farrell GC, Horsmans Y, Leclercq IA.
Lab Invest. 2018 Sep 26. doi: 10.1038/s41374-018-0120-x. [Epub ahead of print]
PMID: 30258096
https://sci-hub.tw/10.1038/s41374-018-0120-x
Abstract
Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with β3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, β3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a β3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, β3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.

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90th Anniversary Commentary: Caloric Restriction Effects on Aging.
Couteur DGL, Simpson SJ.
J Nutr. 2018 Oct 1;148(10):1656-1659. doi: 10.1093/jn/nxy146. No abstract available.
PMID: 30281103
https://sci-hub.tw/10.1093/jn/nxy146

Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates.
Pifferi F, Terrien J, Marchal J, Dal-Pan A, Djelti F, Hardy I, Chahory S, Cordonnier N, Desquilbet L, Hurion M, Zahariev A, Chery I, Zizzari P, Perret M, Epelbaum J, Blanc S, Picq JL, Dhenain M, Aujard F.
Commun Biol. 2018 Apr 5;1:30. doi: 10.1038/s42003-018-0024-8. eCollection 2018.
PMID: 30271916
https://www.nature.com/articles/s42003-018-0024-8.pdf
Abstract
The health benefits of chronic caloric restriction resulting in lifespan extension are well established in many short-lived species, but the effects in humans and other primates remain controversial. Here we report the most advanced survival data and the associated follow-up to our knowledge of age-related alterations in a cohort of grey mouse lemurs (Microcebus murinus, lemurid primate) exposed to a chronic moderate (30%) caloric restriction. Compared to control animals, caloric restriction extended lifespan by 50% (from 6.4 to 9.6 years, median survival), reduced aging-associated diseases and preserved loss of brain white matter in several brain regions. However, caloric restriction accelerated loss of grey matter throughout much of the cerebrum. Cognitive and behavioural performances were, however, not modulated by caloric restriction. Thus chronic moderate caloric restriction can extend lifespan and enhance health of a primate, but it affects brain grey matter integrity without affecting cognitive performances.

Effects of Acute Exercise Combined with Calorie Restriction Initiated Late-in-Life on Insulin Signaling, Lipids and Glucose Uptake in Skeletal Muscle from Old Rats.
Oki K, Arias EB, Kanzaki M, Cartee GD.
J Gerontol A Biol Sci Med Sci. 2018 Oct 1. doi: 10.1093/gerona/gly222. [Epub ahead of print]
PMID: 30272137
https://sci-hub.tw/10.1093/gerona/gly222
Abstract
We evaluated effects of calorie restriction (CR: consuming 60-65% of ad libitum [AL] intake) initiated late-in-life with or without acute exercise on insulin-stimulated glucose uptake (ISGU) of skeletal muscle by studying 4 groups of 26-month-old rats: sedentary-AL, sedentary-CR (8-week duration), 3-hours post-exercise (3hPEX)-AL and 3hPEX-CR. ISGU was determined in isolated epitrochlearis muscles incubated ±insulin. Muscles were assessed for signaling proteins (immunoblotting) and lipids (mass spectrometry). ISGU from sedentary-CR and 3hPEX-AL exceeded sedentary-AL; 3hPEX-CR exceeded all other groups. Akt (Ser473, Thr308) and Akt substrate of 160 kDa (AS160; Ser588, Thr642, Ser704) phosphorylation levels tracked with ISGU. Among the 477 lipids detected, 114 were altered by CR (including reductions in 15 of 25 acylcarnitines), and 27 were altered by exercise (including reductions in 18 of 22 lysophosphatidylcholines) with only 6 lipids overlapping between CR and exercise. ISGU significantly correlated with 23 lipids, including: acylcarnitine 20:1 (r=0.683), lysophosphatidylethanolamine19:0 (r=-0.662), acylcarnitine 24:0 (r=0.611), and plasmenyl-phosphatidylethanolamine 37:5 (r=-0.603). Muscle levels of ceramides (a lipid class previously linked to insulin resistance) were not altered by CR and/or exercise nor significantly correlated with ISGU, implicating other mechanisms (which potentially involve other lipids identified in this study) for greater ISGU and Akt and AS160 phosphorylation with these interventions.

Peripheral interleukin-6 levels and working memory in non-obese adults: A post-hoc analysis from the CALERIE study.
Trevizol AP, Brietzke E, Grigolon RB, Subramaniapillai M, McIntyre RS, Mansur RB.
Nutrition. 2018 Jul 12;58:18-22. doi: 10.1016/j.nut.2018.06.010. [Epub ahead of print]
PMID: 30273821
https://sci-hub.tw/10.1016/j.nut.2018.06.010
Abstract
OBJECTIVES:
This analysis aimed to investigate the association among interleukin 6 (IL-6) levels, caloric intake, and working memory and to explore the potential mediators of these associations using the public dataset from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) clinical trial.
METHODS:
The CALERIE study was designed to evaluate the effects of 2 y of prolonged caloric restriction in humans. Individuals were randomized to caloric restriction (CR; n = 145) or an ad libitum diet (AL; n = 75) for 2 y. The outcome measures used herein were spatial working memory tests (i.e., total number of errors and strategy). Generalized estimating equations were used to assess the effects of treatment, time, and potential moderators (e.g., sleep and physical activities).
RESULTS:
At baseline, there was an effect of hours of sleep, alcohol intake, and physical activities (i.e., mean total metabolic equivalent of task hours per day [MET-hours/day]) on IL-6 levels. The association between IL-6 and energy intake was moderated by MET-hours/day. The longitudinal analysis indicated that there was an effect of time, but not of treatment, on IL-6 levels, with decreasing values in both the CR and AL groups. Changes in IL-6 levels were associated with changes in working memory performance, but there were no between-group (i.e., CR vs. AL) differences.
CONCLUSIONS:
We observed an association between changes in IL-6 levels and improvement in spatial working memory tests. IL-6 was associated with higher caloric consumption, poorer sleep quality, and lower levels of physical activity.
KEYWORDS:
CALERIE; Caloric restriction; Exercise; IL-6; Inflammation; Obesity

Calorie restriction prevents diet-induced insulin resistance independently of PGC-1-driven mitochondrial biogenesis in white adipose tissue.
Pardo R, Vilà M, Cervela L, de Marco M, Gama-Pérez P, González-Franquesa A, Statuto L, Vilallonga R, Simó R, Garcia-Roves PM, Villena JA.
FASEB J. 2018 Oct 2:fj201800310R. doi: 10.1096/fj.201800310R. [Epub ahead of print]
PMID: 30277821
https://sci-hub.tw/10.1096/fj.201800310R
Abstract
Calorie restriction (CR) exerts remarkable, beneficial effects on glucose homeostasis by mechanisms that are not fully understood. Given the relevance of white adipose tissue (WAT) in glucose homeostasis, we aimed at identifying the main cellular processes regulated in WAT in response to CR in a pathologic context of obesity. For this, a gene-expression profiling study was first conducted in mice fed ad libitum or subjected to 40% CR. We found that the gene network related to mitochondria was the most highly upregulated in WAT by CR. To study the role that increased mitochondrial biogenesis plays on glucose homeostasis following CR, we generated a mouse model devoid of the coactivators peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1)α and PGC-1β specifically in adipocytes. Our results show that mice lacking PGC-1s in adipocytes are unable to increase mitochondrial biogenesis in WAT upon CR. Despite a blunted induction of mitochondrial biogenesis in response to calorie deprivation, mice lacking adipose PGC-1s still respond to CR by improving their glucose homeostasis. Our study demonstrates that PGC-1 coactivators are major regulators of CR-induced mitochondrial biogenesis in WAT and that increased mitochondrial biogenesis and oxidative function in adipose tissue are not required for the improvement of glucose homeostasis mediated by CR.-Pardo, R., Vilà, M., Cervela, L., de Marco, M., Gama-Pérez, P., González-Franquesa, A., Statuto, L., Vilallonga, R., Simó, R., Garcia-Roves, P. M., Villena, J. A. Calorie restriction prevents diet-induced insulin resistance independently of PGC-1-driven mitochondrial biogenesis in white adipose tissue.
KEYWORDS:
adipocytes; glucose homeostasis; mitochondria; oxidative metabolism

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Caloric restriction promotes functional changes involving short-chain fatty acid biosynthesis in the rat gut microbiota.
Tanca A, Abbondio M, Palomba A, Fraumene C, Marongiu F, Serra M, Pagnozzi D, Laconi E, Uzzau S.
Sci Rep. 2018 Oct 3;8(1):14778. doi: 10.1038/s41598-018-33100-y.
PMID: 30283130
https://www.nature.com/articles/s41598-018-33100-y.pdf
Abstract
Caloric restriction (CR) is known to promote health and longevity, likely via modification of the gut microbiota (GM). However, functional and metabolic changes induced in the GM during CR are still unidentified. Here, we investigated the short- and long-term effects of CR on the rat GM using a metaproteogenomic approach. We show that a switch from ad libitum (AL) low fat diet to CR in young rats is able to induce rapid and deep changes in their GM metaproteomic profile, related to a reduction of the Firmicutes/Bacteroidetes ratio and an expansion of lactobacilli. Specifically, we observed a significant change in the expression of the microbial enzymes responsible for short-chain fatty acid biosynthesis, with CR boosting propionogenesis and limiting butyrogenesis and acetogenesis. Furthermore, these CR-induced effects were maintained up to adulthood and started to be reversed after a short-term diet change. We also found that CR alters the abundance of an array of host proteins released in stool, mainly related to epithelial barrier integrity and inflammation. Hence, our results provide thorough information about CR-induced modifications to GM and host functional activity, and might constitute the basis for novel GM-based approaches aimed at monitoring the effectiveness of dietary interventions.

Calorie restriction attenuates hypertrophy-induced redox imbalance and mitochondrial ATP-sensitive K+ channel repression.
David CEB, Lucas AMB, Araújo MTS, Coelho BN, Neto JBS, Portela BRC, Varela ALN, Kowaltowski AJ, Facundo HT.
J Nutr Biochem. 2018 Sep 5;62:87-94. doi: 10.1016/j.jnutbio.2018.08.008. [Epub ahead of print]
PMID: 30286377
Abstract
Oxidative stress has been implicated in the pathogenesis of cardiac hypertrophy and associated heart failure. Cardiac tissue grows in response to pressure or volume overload, leading to wall thickening or chamber enlargement. If sustained, this condition will lead to a dysfunctional cardiac tissue and oxidative stress. Calorie restriction (CR) is a powerful intervention to improve health and delay aging. Here, we investigated whether calorie restriction in mice prevented isoproterenol-induced cardiac hypertrophy in vivo by avoiding reactive oxygen species (ROS) production and maintaining antioxidant enzymatic activity. Additionally, we investigated the involvement of mitochondrial ATP-sensitive K+ channels (mitoKATP) in cardiac hypertrophy. CR was induced by 40% reduction in daily calorie ingestion. After 3 weeks on CR or ad libitum (Control) feeding, Swiss mice were treated intraperitoneally with isoproterenol (30 mg/kg per day) for 8 days to induce hypertrophy. Isoproterenol-treated mice had elevated heart weight/tibia length ratios and cardiac protein levels. These gross hypertrophic markers were significantly reduced in CR mice. Cardiac tissue from isoproterenol-treated CR mice also produced less H2O2 and had lower protein sulfydryl oxidation. Additionally, calorie restriction blocked hypertrophic-induced antioxidant enzyme (catalase, superoxide dismutase and glutathione peroxidase) activity repression during cardiac hypertrophy. MitoKATP opening was repressed in isolated mitochondria from hypertrophic hearts, in a manner sensitive to calorie restriction. Finally, mitoKATP inhibition significantly blocked the protective effects of calorie restriction. Altogether, our results suggest that CR improves intracellular redox balance during cardiac hypertrophy and prevents this process in a mechanism involving mitoKATP activation.
KEYWORDS:
Antioxidants; Calorie restriction; Hypertrophy; Mitochondria; Oxidative stress

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Insulin, carbohydrate restriction, metabolic syndrome and cancer.
Fine EJ, Feinman RD.
Expert Rev Endocrinol Metab. 2015 Jan;10(1):15-24. doi: 10.1586/17446651.2014.960392. Epub 2014 Sep 22.
PMID: 30289045
https://sci-hub.tw/10.1586/17446651.2014.960392
Abstract
We propose that dietary carbohydrate restriction, particularly ketogenic diets, may provide benefit as a therapeutic or preventive strategy in cancer, alone or as an adjunct to pharmacology. The argument derives from several points of evidence: There is a close association between cancer and both diabetes and obesity. Extensive evidence shows that low carbohydrate diets are the most effective dietary treatment of Type 2 diabetes and dietary adjunct in Type 1. Such diets also target all the markers of metabolic syndrome. Finally, de facto reduction in carbohydrate likely contributes to total dietary restriction, which is effective in the prevention and treatment of cancer. The idea is consistent with recent interest in treating cancer with drugs that target diabetes. To move forward, we must understand obesity and diabetes as response to a hyperglycemic state rather than simply a cause of downstream effects.
KEYWORDS:
IGF; caloric restriction; cancer; insulin; ketogenic diet; low carbohydrate diet; metabolic syndrome

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Do the Effects of Resveratrol on Thermogenic and Oxidative Capacities in IBAT and Skeletal Muscle Depend on Feeding Conditions?
Milton-Laskibar I, Aguirre L, Etxeberria U, Milagro FI, Martínez JA, Portillo MP.
Nutrients. 2018 Oct 6;10(10). pii: E1446. doi: 10.3390/nu10101446.
PMID: 30301195
https://www.mdpi.com/2072-6643/10/10/1446/htm
Abstract
The aim of this study was to compare the effects of mild energy restriction and resveratrol on thermogenic and oxidative capacity in interscapular brown adipose tissue (IBAT) and in skeletal muscle. Rats were fed a high-fat high-sucrose diet for six weeks, and divided into four experimental groups fed a standard diet: a control group, a resveratrol-treated group, an energy-restricted group and an energy-restricted group treated with resveratrol. Weights of IBAT, gastrocnemius muscle and fat depots were measured. Activities of carnitine palmitoyltransferase (CPT) and citrate synthase (CS), protein levels of sirtuin (SIRT1 and 3), uncoupling proteins (UCP1 and 3), glucose transporter (GLUT4), mitochondrial transcription factor (TFAM), nuclear respiratory factor (NRF1), peroxisome proliferator-activated receptor (PPARα) and AMP activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator (PGC1α) activation were measured. No changes in IBAT and gastrocnemius weights were found. Energy-restriction, but not resveratrol, decreased the weights of adipose depots. In IBAT, resveratrol enhanced thermogenesis activating the SIRT1/PGC1α/PPARα axis. Resveratrol also induced fatty acid oxidation and glucose uptake. These effects were similar when resveratrol was combined with energy restriction. In the case of gastrocnemius muscle, the effects were not as clear as in the case of IBAT. In this tissue, resveratrol increased oxidative capacity. The combination of resveratrol and energy restriction seemingly did not improve the effects induced by the polyphenol alone.
KEYWORDS:
energy restriction; high-fat high-sucrose diet; rat; resveratrol; thermogenesis

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Metabolic memory of dietary restriction ameliorates DNA damage and adipocyte size in mouse visceral adipose tissue.
Ishaq A, Dufour D, Cameron K, von Zglinicki T, Saretzki G.
Exp Gerontol. 2018 Oct 9. pii: S0531-5565(18)30390-5. doi: 10.1016/j.exger.2018.10.008. [Epub ahead of print]
PMID: 30312736
Abstract
Dietary restriction (DR) is thought to exert its beneficial effects on healthspan at least partially by a senolytic and senostatic action, i.e. by reducing frequencies of cells with markers of DNA damage and senescence in multiple tissues. Due to its importance in metabolic and inflammation regulation, fat is a prime tissue for health span determination as well as a prime target for DR. We aimed to determine here whether the beneficial effects of DR would be retained over a subsequent period of ad libitum (AL) feeding. Male mice were kept under either 40% DR or AL feeding regimes from 3 to 12 months of age and then either switched back to the opposite feeding regimen or kept in the same state for another 3 months. Visceral adipose tissue from 4 to 5 mice per group for all conditions was analysed for markers of senescence (adipocyte size, γH2A.X, p16, p21) and inflammation (e.g. IL-6, TNFα, IL-1β) using immuno-staining or qPCR. Macrophages were detected by immunohistochemistry. We found that both 9 and 12 months DR (long term) as well as 3 month (short term, mid-life onset) DR reduced the number of cells harbouring DNA damage and adipocyte size (area and perimeter) in visceral adipocytes with similar efficiency. Importantly, beneficial health markers induced by DR such as small adipocyte size and low DNA damage were maintained for at least 3 month after termination of DR, demonstrating that the previously identified 'metabolic memory' of the DR state in male mice extends to senescence markers in visceral fat.
KEYWORDS:
Adipose tissue; Ageing; DNA damage; Dietary restriction; Metabolic; Mice; Senescence

New Study Shows that Whey Protein is the Best Way for Older Adults to Rebuild Muscle
PR Newswire (press release)
https://www.prnewswire.com/news-releases/new-study-shows-that-whey-protein-is-the-best-way-for-older-adults-to-rebuild-muscle-300727150.html
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A randomized controlled trial of the impact of protein supplementation on leg lean mass and integrated muscle protein synthesis during inactivity and energy restriction in older persons
Sara Y Oikawa  Chris McGlory  Lisa K D'Souza  Adrienne K Morgan  Nelson I Saddler Steven K Baker  Gianni Parise  Stuart M Phillips
The American Journal of Clinical Nutrition, nqy193, https://doi.org/10.1093/ajcn/nqy193
Published: 04 October 2018
https://sci-hub.tw/10.1093/ajcn/nqy193
ABSTRACT
Background
In older persons, muscle loss is accelerated during physical inactivity and hypoenergetic states, both of which are features of hospitalization. Protein supplementation may represent a strategy to offset the loss of muscle during inactivity, and enhance recovery on resumption of activity.
Objective
We aimed to determine if protein supplementation, with proteins of substantially different quality, would alleviate the loss of lean mass by augmenting muscle protein synthesis (MPS) while inactive during a hypoenergetic state.
Design
Participants (16 men, mean ± SD age: 69 ± 3 y; 15 women, mean ± SD age: 68 ± 4 y) consumed a diet containing 1.6 g protein · kg–1 · d–1, with 55% ± 9% of protein from foods and 45% ± 9% from supplements, namely, whey protein (WP) or collagen peptides (CP): 30 g each, consumed 2 times/d. Participants were in energy balance (EB) for 1 wk, then began a period of energy restriction (ER; –500 kcal/d) for 1 wk, followed by ER with step reduction (ER + SR; <750 steps/d) for 2 wk, before a return to habitual activity in recovery (RC) for 1 wk.
Results
There were significant reductions in leg lean mass (LLM) from EB to ER, and from ER to ER + SR in both groups (P < 0.001) with no differences between WP and CP or when comparing the change from phase to phase. During RC, LLM increased from ER + SR, but in the WP group only. Rates of integrated muscle protein synthesis decreased during ER and ER + SR in both groups (P < 0.01), but increased during RC only in the WP group (P = 0.05).
Conclusions
Protein supplementation did not confer a benefit in protecting LLM, but only supplemental WP augmented LLM and muscle protein synthesis during recovery from inactivity and a hypoenergetic state. This trial was registered at http://www.clinicaltrials.gov as NCT03285737.
Keyword:
muscle protein synthesis, older adults, whey protein, collagen peptides, step reduction

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Hypocaloric Diet Prevents the Decrease in FGF21 Elicited by High Phosphorus Intake.
Pineda C, Rios R, Raya AI, Rodriguez M, Aguilera-Tejero E, Lopez I.
Nutrients. 2018 Oct 13;10(10). pii: E1496. doi: 10.3390/nu10101496.
PMID: 30322116
https://www.mdpi.com/2072-6643/10/10/1496/htm
Abstract
The effect of dietary phosphorus (P) on fibroblast growth factor 21 (FGF21)/β-klotho axis was investigated in rats that were fed diets with: Normal (NP) or high P (HP) and either normal (NC), high (HC) or low calories (LC). Sampling was performed at 1, 4 and 7 months. Plasma FGF21 concentrations were higher (p < 0.05) in NC and HC than in LC groups. Increasing P intake had differing effects on plasma FGF21 in rats fed NC and HC vs. rats fed LC at the three sampling times. When compared with the NP groups, FGF21 concentrations decreased at the three sampling points in rats fed NC-HP (80 vs. 194, 185 vs. 382, 145 vs. 403 pg/mL) and HC-HP (90 vs. 190, 173 vs. 353, 94 vs. 434 pg/mL). However, FGF21 did not decrease in rats fed LC-HP (34 vs. 20, 332 vs. 164 and 155 vs. 81 pg/mL). In addition, LC groups had a much lower liver FGF21 messenger ribonucleic acid/glyceraldehyde 3-phosphate dehydrogenase (mRNA/GAPDH) ratio (0.51 ± 0.08 and 0.56 ± 0.07) than the NC-NP (0.97 ± 0.14) and HC-NP (0.97 ± 0.22) groups. Increasing P intake reduced liver FGF21 mRNA/GAPDH in rats fed NC and HC to 0.42 ± 0.05 and 0.37 ± 0.04. Liver β-klotho mRNA/GAPDH ratio was lower (p < 0.05) in LC groups (0.66 ± 0.06 and 0.59 ± 0.10) than in NC (1.09 ± 0.17 and 1.03 ± 0.14) and HC (1.19 ± 0.12 and 1.34 ± 0.19) groups. A reduction (p < 0.05) in β-klotho protein/α-tubulin ratio was also observed in LC groups (0.65 ± 0.05 and 0.49 ± 0.08) when compared with NC (1.12 ± 0.11 and 0.91 ± 0.11) and HC (0.93 ± 0.17 and 0.87 ± 0.09) groups. In conclusion β-klotho is potently regulated by caloric restriction but not by increasing P intake while FGF21 is regulated by both caloric restriction and increased P intake. Moreover, increased P intake has a differential effect on FGF21 in calorie repleted and calorie depleted rats.
KEYWORDS:
calories; fibroblast growth factor 21; phosphorus; rat

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Fasting and cancer: molecular mechanisms and clinical application.
Nencioni A, Caffa I, Cortellino S, Longo VD.
Nat Rev Cancer. 2018 Oct 16. doi: 10.1038/s41568-018-0061-0. [Epub ahead of print] Review.
PMID: 30327499
https://sci-hub.tw/10.1038/s41568-018-0061-0
Abstract
The vulnerability of cancer cells to nutrient deprivation and their dependency on specific metabolites are emerging hallmarks of cancer. Fasting or fasting-mimicking diets (FMDs) lead to wide alterations in growth factors and in metabolite levels, generating environments that can reduce the capability of cancer cells to adapt and survive and thus improving the effects of cancer therapies. In addition, fasting or FMDs increase resistance to chemotherapy in normal but not cancer cells and promote regeneration in normal tissues, which could help prevent detrimental and potentially life-threatening side effects of treatments. While fasting is hardly tolerated by patients, both animal and clinical studies show that cycles of low-calorie FMDs are feasible and overall safe. Several clinical trials evaluating the effect of fasting or FMDs on treatment-emergent adverse events and on efficacy outcomes are ongoing. We propose that the combination of FMDs with chemotherapy, immunotherapy or other treatments represents a potentially promising strategy to increase treatment efficacy, prevent resistance acquisition and reduce side effects.

Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans.
Walters RO, Arias E, Diaz A, Burgos ES, Guan F, Tiano S, Mao K, Green CL, Qiu Y, Shah H, Wang D, Hudgins AD, Tabrizian T, Tosti V, Shechter D, Fontana L, Kurland IJ, Barzilai N, Cuervo AM, Promislow DEL, Huffman DM.
Cell Rep. 2018 Oct 16;25(3):663-676.e6. doi: 10.1016/j.celrep.2018.09.065.
PMID: 30332646
https://www.cell.com/action/showPdf?pii=S2211-1247(18)31525-0
Abstract
A hallmark of aging is a decline in metabolic homeostasis, which is attenuated by dietary restriction (DR). However, the interaction of aging and DR with the metabolome is not well understood. We report that DR is a stronger modulator of the rat metabolome than age in plasma and tissues. A comparative metabolomic screen in rodents and humans identified circulating sarcosine as being similarly reduced with aging and increased by DR, while sarcosine is also elevated in long-lived Ames dwarf mice. Pathway analysis in aged sarcosine-replete rats identify this biogenic amine as an integral node in the metabolome network. Finally, we show that sarcosine can activate autophagy in cultured cells and enhances autophagic flux in vivo, suggesting a potential role in autophagy induction by DR. Thus, these data identify circulating sarcosine as a biomarker of aging and DR in mammalians and may contribute to age-related alterations in the metabolome and in proteostasis.
KEYWORDS:
GNMT; aging; amino acids; autophagy; dietary restriction; glycerophospholipids; glycine; metabolomics; methionine; sarcosine

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  • 2 weeks later...

Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype.
Wang M, Zhang L, Zhu W, Zhang J, Kim SH, Wang Y, Ni L, Telljohann R, Monticone RE, McGraw K, Liu L, de Cabo R, Lakatta EG.
J Am Heart Assoc. 2018 Sep 18;7(18):e009112. doi: 10.1161/JAHA.118.009112.
PMID: 30371211
https://www.ahajournals.org/doi/pdf/10.1161/JAHA.118.009112
Abstract
Background Aging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial wall. Calorie restriction ( CR ) in rats improves arterial function and extends both health span and life span. How CR affects the proinflammatory landscape of molecular, cellular, and tissue phenotypic shifts within the arterial wall in rats, however, remains to be elucidated. Methods and Results Aortae were harvested from young (6-month-old) and old (24-month-old) Fischer 344 rats, fed ad libitum and a second group maintained on a 40% CR beginning at 1 month of age. Histopathologic and morphometric analysis of the arterial wall demonstrated that CR markedly reduced age-associated intimal medial thickening, collagen deposition, and elastin fractionation/degradation within the arterial walls. Immunostaining/blotting showed that CR effectively prevented an age-associated increase in the density of platelet-derived growth factor, matrix metalloproteinase type II activity, and transforming growth factor beta 1 and its downstream signaling molecules, phospho-mothers against decapentaplegic homolog-2/3 (p- SMAD -2/3) in the arterial wall. In early passage cultured vascular smooth muscle cells isolated from AL and CR rat aortae, CR alleviated the age-associated vascular smooth muscle cell phenotypic shifts, profibrogenic signaling, and migration/proliferation in response to platelet-derived growth factor. Conclusions CR reduces matrix and cellular proinflammation associated with aging that occurs within the aortic wall and that are attributable to platelet-derived growth factor signaling. Thus, CR reduces the platelet-derived growth factor-associated signaling cascade, contributing to the postponement of biological aging and preservation of a more youthful aortic wall phenotype.
KEYWORDS:
aging; arterial remodeling; calorie restriction; proinflammation; rats; vascular smooth muscle cells

Mechanisms of Age-Dependent Loss of Dietary Restriction Protective Effects in Acute Kidney Injury.
Andrianova NV, Jankauskas SS, Zorova LD, Pevzner IB, Popkov VA, Silachev DN, Plotnikov EY, Zorov DB.
Cells. 2018 Oct 22;7(10). pii: E178. doi: 10.3390/cells7100178.
PMID: 30360430
https://www.mdpi.com/2073-4409/7/10/178/htm
Abstract
Dietary restriction (DR) is one of the most efficient approaches ameliorating the severity of different pathological conditions including aging. We investigated the protective potential of short-term DR in the model of acute kidney injury (AKI) in young and old rats. In kidney tissue, the levels of autophagy and mitophagy were examined, and proliferative properties of renal cells obtained from rats of different age were compared. DR afforded a significant nephroprotection to ischemic kidneys of young rats. However, in old rats, DR did not provide such beneficial effect. On the assessment of the autophagy marker, the LC3 II/LC3 I ratio, and after staining the tissue with LysoTracker Green, we concluded that in old rats activity of the autophagic-lysosomal system decreased. Mitophagy, as assessed by the levels of PINK-1, was also deteriorated in old animals. Renal cells from old rats showed impaired proliferative capacity, a worse rate of recovery after ischemic injury, increased levels of oxidative stress, accumulation of lipofuscin granules and lower mitochondria membrane potential. The results suggest that the loss of DR benefits in old animals could be due to deterioration in the autophagy/mitophagy flux.
KEYWORDS:
acute kidney injury; aging; autophagy; dietary restriction; ischemia; mitochondria; mitophagy; renal tubular cells

Programmed longevity, youthspan, and juventology.
D Longo V.
Aging Cell. 2018 Oct 17:e12843. doi: 10.1111/acel.12843. [Epub ahead of print]
PMID: 30334314
https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.12843
Abstract
The identification of conserved genes and pathways that regulate lifespan but also healthspan has resulted in an improved understanding of the link between nutrients, signal transduction proteins, and aging but has also provided evidence for the existence of multiple "longevity programs," which are selected based on the availability of nutrients. Periodic fasting and other dietary restrictions can promote entry into a long-lasting longevity program characterized by cellular protection and optimal function but can also activate regenerative processes that lead to rejuvenation, which are independent of the aging rate preceding the restricted period. Thus, a "juventology"-based strategy can complement the traditional gerontology approach by focusing not on aging but on the longevity program affecting the life history period in which mortality is very low and organisms remain youthful, healthy, and fully functional.
KEYWORDS:
Juventology; Longevity; aging; gerontology; healthspan; youthspan

Fat and Lean Mass Predict Bone Mass During Energy Restriction in Sedentary and Exercising Rodents.
Metzger CE, Swift SN, Baek K, De Souza MJ, Bloomfield SA.
Front Physiol. 2018 Sep 25;9:1346. doi: 10.3389/fphys.2018.01346. eCollection 2018.
PMID: 30356821
https://www.frontiersin.org/articles/10.3389/fphys.2018.01346/full
http://www.readcube.com/articles/10.3389/fphys.2018.01346
Abstract
Energy restriction (ER) causes bone loss, but the impact of exercise during ER is less understood. In this study, we examined the impact of metabolic hormones and body composition on both total body bone mineral content (BMC) and local (proximal tibia) volumetric bone mineral density (vBMD) during short- (4 weeks) and long-term (12 weeks) ER with and without exercise in adult female rats. Our first goal was to balance energy between sedentary and exercising groups to determine the impact of exercise during ER. Second, we aimed to determine the strongest predictors of bone outcomes during ER with energy-matched exercising groups. Methods: Female Sprague-Dawley rats were divided into three sedentary groups (ad libitum, -20% ER, and -40% ER) and three exercising groups (ad libitum, -10% ER, and -30% ER). Approximately a 10% increase in energy expenditure was achieved via moderate treadmill running (∼60-100 min 4 days/week) in EX groups. n per group = 25-35. Data were analyzed as a 2 × 3 ANOVA with multiple linear regression to predict bone mass outcomes. Results: At 4 weeks, fat and lean mass and serum insulin-like growth factor-I (IGF-I) predicted total body BMC (R 2 = 0.538). Fat mass decreased with ER at all levels, while lean mass was not altered. Serum IGF-I declined in the most severe ER groups (-40 and -30%). At 12 weeks, only fat and lean mass predicted total body BMC (R 2 = 0.718). Fat mass declined with ER level regardless of exercise status and lean mass increased due to exercise (+5.6-6.7% vs. energy-matched sedentary groups). At the same time point, BMC declined with ER, but increased with exercise (+7.0-12.5% vs. energy-matched sedentary groups). None of our models predicted vBMD at the proximal tibia at either time point. Conclusion: Both fat and lean mass statistically predicted total body BMC during both short- and long-term ER. Fat and lean mass decreased with ER, while lean mass increased with EX at each energy level. Measures that predicted total body skeletal changes did not predict site-specific changes. These data highlight the importance of maintaining lean mass through exercise during periods of ER.
KEYWORDS:
bone mineral content; energy restriction; fat mass; lean mass; treadmill running

Weight Cycling Increases Longevity Compared with Sustained Obesity in Mice.
Smith DL Jr, Yang Y, Nagy TR, Patki A, Vasselli JR, Zhang Y, Dickinson SL, Allison DB.
Obesity (Silver Spring). 2018 Nov;26(11):1733-1739. doi: 10.1002/oby.22290.
PMID: 30358151
https://onlinelibrary.wiley.com/doi/full/10.1002/oby.22290
https://onlinelibrary.wiley.com/doi/epdf/10.1002/oby.22290
Abstract
OBJECTIVE:
Despite the known health benefits of weight loss among persons with obesity, observational studies have reported that cycles of weight loss and regain, or weight cycling, are associated with increased mortality. To study whether weight loss must be sustained to achieve health and longevity benefits, we performed a randomized controlled feeding study of weight cycling in mice.
METHODS:
In early adult life, obese mice were randomized to ad libitum feeding to sustain obesity, calorie restriction to achieve a "normal" or intermediate body weight, or weight cycling (repeated episodes of calorie restriction and ad libitum refeeding). Body weight, body composition, and food intake were followed longitudinally until death. A subsample of mice was collected from each group for determination of adipose cell size, serum analytes, and gene expression.
RESULTS:
Weight loss significantly reduced adipose mass and adipocyte size in both sexes, whereas weight cycling animals regained body fat and cell size during refeeding. Sustained weight loss resulted in a dose-dependent decrease in mortality compared with ad libitum feeding.
CONCLUSIONS:
Weight cycling significantly increased life-span relative to remaining with obesity and had a similar benefit to sustained modest weight loss.

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SREBP-1c-Dependent Metabolic Remodeling of White Adipose Tissue by Caloric Restriction.
Kobayashi M, Fujii N, Narita T, Higami Y.
Int J Mol Sci. 2018 Oct 26;19(11). pii: E3335. doi: 10.3390/ijms19113335. Review.
PMID: 30373107
https://www.mdpi.com/1422-0067/19/11/3335/htm
Abstract
Caloric restriction (CR) delays the onset of many age-related pathophysiological changes and extends lifespan. White adipose tissue (WAT) is not only a major tissue for energy storage, but also an endocrine tissue that secretes various adipokines. Recent reports have demonstrated that alterations in the characteristics of WAT can impact whole-body metabolism and lifespan. Hence, we hypothesized that functional alterations in WAT may play important roles in the beneficial effects of CR. Previously, using microarray analysis of WAT from CR rats, we found that CR enhances fatty acid (FA) biosynthesis, and identified sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of FA synthesis, as a mediator of CR. These findings were validated by showing that CR failed to upregulate factors involved in FA biosynthesis and to extend longevity in SREBP-1c knockout mice. Furthermore, we revealed that SREBP-1c is implicated in CR-associated mitochondrial activation through the upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Notably, these CR-associated phenotypes were observed only in WAT. We conclude that CR induces SREBP-1c-dependent metabolic remodeling, including the enhancement of FA biosynthesis and mitochondrial activation, via PGC-1α in WAT, resulting in beneficial effects.
KEYWORDS:
PGC-1α; SREBP-1c; caloric restriction; fatty acid synthesis; mitochondrion; white adipose tissue

Caloric restriction improves the redox homeostasis in the aging male rat heart even when started in middle-adulthood and when the body weight is stable.
Simsek B, Yanar K, Kansu AD, Belce A, Aydin S, Çakatay U.
Biogerontology. 2018 Oct 29. doi: 10.1007/s10522-018-9781-5. [Epub ahead of print]
PMID: 30374677
Abstract
Evidence indicates that maintenance of redox homeostasis is fundamental for cellular longevity. Caloric-restriction (CR) is said to decrease the formation of oxidatively modified cellular macromolecules and improve health. On the other hand, some studies indicate that many CR studies are flawed, because ad libitum fed rats are not well-controlled. Thus, it is claimed that purported beneficial effects of CR could be not due to real CR effect, but due to control animals going obese. Also, it remains to be elucidated whether effects of CR could be observed even when CR is started in mid-adulthood. Male Sprague-Dawley rats were grouped as: non-CR 6-month-old rats (n = 7), 24-month-old rats subjected to 40% CR for 6 months between 18th and 24th months (n = 8), and non-CR 24-month-old animals (n = 8). We investigated 16 previously validated biomarkers of macromolecular redox homeostasis, ranging from protein and lipid oxidation to glycation and antioxidative capacity. In the present study, the protein, lipid and antioxidant capacity redox homeostasis biomarkers overwhelmingly indicate that, CR, even though not started very early in adulthood, could still offer potential therapeutic effects and it could significantly improve various redox homeostasis biomarkers associated with disease reliably in the heart tissue of aging male Sprague-Dawley rats. Therefore, the effects of CR likely operate through similar mechanisms throughout adulthood and CR seems to have real ameliorative effects on organisms that are not due to confounding factors that come from ad libitum fed rats.
KEYWORDS:
Aging; Caloric restriction; Cardiovascular disease; Oxidative stress; Redox homeostasis

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Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster.
Akagi K, Wilson KA, Katewa SD, Ortega M, Simons J, Hilsabeck TA, Kapuria S, Sharma A, Jasper H, Kapahi P.
PLoS Genet. 2018 Nov 1;14(11):e1007777. doi: 10.1371/journal.pgen.1007777. [Epub ahead of print]
PMID: 30383748
https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1007777&type=printable
Abstract
Loss of gut integrity is linked to various human diseases including inflammatory bowel disease. However, the mechanisms that lead to loss of barrier function remain poorly understood. Using D. melanogaster, we demonstrate that dietary restriction (DR) slows the age-related decline in intestinal integrity by enhancing enterocyte cellular fitness through up-regulation of dMyc in the intestinal epithelium. Reduction of dMyc in enterocytes induced cell death, which leads to increased gut permeability and reduced lifespan upon DR. Genetic mosaic and epistasis analyses suggest that cell competition, whereby neighboring cells eliminate unfit cells by apoptosis, mediates cell death in enterocytes with reduced levels of dMyc. We observed that enterocyte apoptosis was necessary for the increased gut permeability and shortened lifespan upon loss of dMyc. Furthermore, moderate activation of dMyc in the post-mitotic enteroblasts and enterocytes was sufficient to extend health-span on rich nutrient diets. We propose that dMyc acts as a barometer of enterocyte cell fitness impacting intestinal barrier function in response to changes in diet and age.

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