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Polymorphism rs16147 of the Neuropeptide Y Gene Modifies the Response of Cardiovascular Risk Biomarkers and Adipokines to Two Hypocaloric Diets.

de Luis DA, Izaola O, Primo D, Aller R.

J Nutrigenet Nutrigenomics. 2017 Aug 5;10(1-2):63-72. doi: 10.1159/000478528. [Epub ahead of print]

PMID: 28787737

Abstract

AIMS:

Our aim was to evaluate the relationship of weight loss and changes in adipokine levels after two hypocaloric diets in obese subjects with polymorphism rs16147 of the neuropeptide Y gene.

SUBJECTS AND METHODS:

A population of 283 obese patients was analyzed. At the basal visit, patients were randomly allocated to one of two diets for a period of 3 months (diet I, low in carbohydrates; diet II, low in fat).

RESULTS:

With diet I and in both genotype groups (major versus minor allele), body mass index (BMI), weight, fat mass, waist circumference, and leptin decreased. With diet II and in all genotypes, BMI, weight, fat mass, waist circumference, and leptin decreased. With both diets and in subjects with the minor allele, insulin levels (diet I: major allele -1.7 ± 7.8 IU/L versus minor allele -4.2 ± 6.1 IU/L, p = 0.01; diet II: major allele -2.3 ± 6.1 IU/L versus minor allele -4.0 ± 5.2 IU/L, p = 0.02) and insulin resistance (diet I: major allele -0.2 ± 3.1 units versus minor allele -1.7 ± 3.0 units, p = 0.03; diet II: major allele -0.9 ± 2.0 units versus minor allele -1.7 ± 1.3 units, p = 0.01) decreased.

CONCLUSION:

The rs16147 genotype affected the reduction in insulin resistance and insulin levels in response to two different hypocaloric diets in obese subjects, with a lack of response in subjects with the major allele.

KEYWORDS:

<italic>Neuropeptide Y</italic> gene; <italic>rs16147</italic>; Adipokines; Hypocaloric diets; Single nucleotide polymorphisms

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[Mice were prevented from becoming obese by food restriction (given 70-90% of ad libitum consumption amount).}

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Voluntary running exercise protects against sepsis-induced early inflammatory and pro-coagulant responses in aged mice.

Tyml K, Swarbreck S, Pape C, Secor D, Koropatnick J, Feng Q, Veldhuizen RAW, Gill SE.

Crit Care. 2017 Aug 8;21(1):210. doi: 10.1186/s13054-017-1783-1.

PMID: 28789683

https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1783-1

https://ccforum.biomedcentral.com/track/pdf/10.1186/s13054-017-1783-1?site=ccforum.biomedcentral.com

Abstract

BACKGROUND:

Despite many animal studies and clinical trials, mortality in sepsis remains high. This may be due to the fact that most experimental studies of sepsis employ young animals, whereas the majority of septic patients are elderly (60 - 70 years). The objective of the present study was to examine the sepsis-induced inflammatory and pro-coagulant responses in aged mice. Since running exercise protects against a variety of diseases, we also examined the effect of voluntary running on septic responses in aged mice.

METHODS:

Male C57BL/6 mice were housed in our institute from 2-3 to 22 months (an age mimicking that of the elderly). Mice were prevented from becoming obese by food restriction (given 70-90% of ad libitum consumption amount). Between 20 and 22 months, a subgroup of mice ran voluntarily on wheels, alternating 1-3 days of running with 1-2 days of rest. At 22 months, mice were intraperitoneally injected with sterile saline (control) or 3.75 g/kg fecal slurry (septic). At 7 h post injection, we examined (1) neutrophil influx in the lung and liver by measuring myeloperoxidase and/or neutrophil elastase in the tissue homogenates by spectrophotometry, (2) interleukin 6 (IL6) and KC in the lung lavage by ELISA, (3) pulmonary surfactant function by measuring percentage of large aggregates, (4) capillary plugging (pro-coagulant response) in skeletal muscle by intravital microscopy, (5) endothelial nitric oxide synthase (eNOS) protein in skeletal muscle (eNOS-derived NO is putative inhibitor of capillary plugging) by immunoblotting, and (6) systemic blood platelet counts by hemocytometry.

RESULTS:

Sepsis caused high levels of pulmonary myeloperoxidase, elastase, IL6, KC, liver myeloperoxidase, and capillary plugging. Sepsis also caused low levels of surfactant function and platelet counts. Running exercise increased eNOS protein and attenuated the septic responses.

CONCLUSIONS:

Voluntary running protects against exacerbated sepsis-induced inflammatory and pro-coagulant responses in aged mice. Protection against pro-coagulant responses may involve eNOS upregulation. The present discovery in aged mice calls for clinical investigation into potential beneficial effects of exercise on septic outcomes in the elderly.

KEYWORDS:

Aging; Capillary plugging; Pulmonary inflammation; Voluntary running; sepsis

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Opposing effects on cardiac function by calorie restriction in different-aged mice.

Sheng Y, Lv S, Huang M, Lv Y, Yu J, Liu J, Tang T, Qi H, Di W, Ding G.

Aging Cell. 2017 Aug 11. doi: 10.1111/acel.12652. [Epub ahead of print]

PMID: 28799249

http://onlinelibrary.wiley.com.sci-hub.cc/doi/10.1111/acel.12652/abstract;jsessionid=BCABAF7FB8E2FD29596E3F42F73B7A44.f03t02

Abstract

Calorie restriction (CR) increases average and maximum lifespan and exhibits an apparent beneficial impact on age-related diseases. Several studies have shown that CR initiated either in middle or old age could improve ischemic tolerance and rejuvenate the aging heart; however, the data are not uniform when initiated in young. The accurate time to initiate CR providing maximum benefits for cardiac remodeling and function during aging remains unclear. Thus, whether a similar degree of CR initiated in mice of different ages could exert a similar effect on myocardial protection was investigated in this study. C57BL/6 mice were subjected to a calorically restricted diet (40% less than the ad libitum diet) for 3 months initiated in 3, 12, and 19 months. It was found that CR significantly reversed the aging phenotypes of middle-aged and old mice including cardiac remodeling (cardiomyocyte hypertrophy and cardiac fibrosis), inflammation, mitochondrial damage, telomere shortening, as well as senescence-associated markers but accelerated in young mice. Furthermore, whole-genome microarray demonstrated that the AMP-activated protein kinase (AMPK)-Forkhead box subgroup 'O' (FOXO) pathway might be a major contributor to contrasting regulation by CR initiated in different ages; thus, increased autophagy was seen in middle-aged and old mice but decreased in young mice. Together, the findings demonstrated promising myocardial protection by 40% CR should be initiated in middle or old age that may have vital implications for the practical nutritional regimen.

KEYWORDS:

AMPK; FOXO; autophagy; calorie restriction; cardiac aging

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Molecular signatures of longevity: insights from cross-species comparative studies.

Ma S, Gladyshev VN.

Semin Cell Dev Biol. 2017 Aug 8. pii: S1084-9521(16)30338-X. doi: 10.1016/j.semcdb.2017.08.007. [Epub ahead of print] Review.

PMID: 28800931

http://linkinghub.elsevier.com.sci-hub.cc/retrieve/pii/S108495211630338X

Abstract

Much of the current research on longevity focuses on the aging process within a single species. Several molecular players (e.g. IGF1 and MTOR), pharmacological compounds (e.g. rapamycin and metformin), and dietary approaches (e.g. calorie restriction and methionine restriction) have been shown to be important in regulating and modestly extending lifespan in model organisms. On the other hand, natural lifespan varies much more significantly across species. Within mammals alone, maximum lifespan differs more than 100 fold, but the underlying regulatory mechanisms remain poorly understood. Recent comparative studies are beginning to shed light on the molecular signatures associated with exceptional longevity. These include genome sequencing of microbats, naked mole rat, blind mole rat, bowhead whale and African turquoise killifish, and comparative analyses of gene expression, metabolites, lipids and ions across multiple mammalian species. Together, they point towards several putative strategies for lifespan regulation and cancer resistance, as well as the pathways and metabolites associated with longevity variation. In particular, longevity may be achieved by both lineage-specific adaptations and common mechanisms that apply across the species. Comparing the resulting cross-species molecular signatures with the within-species lifespan extension strategies will improve our understanding of mechanisms of longevity control and provide a starting point for novel and effective interventions.

 

Keeping the Rhythm while Changing the Lyrics: Circadian Biology in Aging.

Hatanaka F, Ocampo A, Izpisua Belmonte JC.

Cell. 2017 Aug 10;170(4):599-600. doi: 10.1016/j.cell.2017.07.039.

PMID: 28802034

http://sci-hub.cc/10.1016/j.cell.2017.07.039

Abstract

Aging and circadian rhythms have been linked for decades, but their molecular interplay has remained obscure. Sato et al. and Solanas et al. now reveal that, while core clock components remain nearly unaltered, aging is associated with tissue-specific rewiring, which can be prevented by calorie restriction.

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Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Stress.

Solanas G, Peixoto FO, Perdiguero E, Jardí M, Ruiz-Bonilla V, Datta D, Symeonidi A, Castellanos A, Welz PS, Caballero JM, Sassone-Corsi P, Muñoz-Cánoves P, Benitah SA.

Cell. 2017 Aug 10;170(4):678-692.e20. doi: 10.1016/j.cell.2017.07.035.

PMID: 28802040

http://sci-hub.cc/10.1016/j.cell.2017.07.035

Abstract

Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during aging. Unexpectedly, we find that aged mice remain behaviorally circadian and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging. While age-associated rewiring of the oscillatory diurnal transcriptome is not recapitulated by a high-fat diet in young adult mice, it is significantly prevented by long-term caloric restriction in aged mice. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age-related traits.

KEYWORDS:

Circadian rhythms; aging; caloric restriction; circadian reprogramming; diet; epidermal stem cells; hallmarks of aging; high fat diet; muscle stem cells (satellite cells); stem cells

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Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging.

Sato S, Solanas G, Peixoto FO, Bee L, Symeonidi A, Schmidt MS, Brenner C, Masri S, Benitah SA, Sassone-Corsi P.

Cell. 2017 Aug 10;170(4):664-677.e11. doi: 10.1016/j.cell.2017.07.042.

PMID: 28802039

http://sci-hub.cc/10.1016/j.cell.2017.07.042

Abstract

The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD+-related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging.

KEYWORDS:

Acetylation; Aging; Circadian Clock; Liver Metabolism; NAD; Reprogramming; SIRT1

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Caloric-restriction induced alterations in CG and non-CG methylation attenuate age-associated changes in the old brain.

Niran Hadad, Archana Unnikrishnan, Jordan A. Jackson, Dustin R. Masser, Laura Otalora, David R. Stanford, Arlan Richardson, Willard Freeman

bioRxiv doi: https://doi.org/10.1101/175810

This article is a preprint and has not been peer-reviewed.

http://www.biorxiv.org/content/biorxiv/early/2017/08/13/175810.full.pdf

Abstract

Brain aging is marked by cognitive decline and increased susceptibility to neurodegeneration. Epigenetic mechanisms, including DNA methylation, are vital to CNS cellular function and memory formation, and are dysregulated with aging and age-related neurodegenerative disease. Caloric-restriction (CR), an established pro-longevity intervention, increases neurogenesis, improves memory function, and protects from age-associated pathologies. However, the molecular mechanisms promoting the neuroprotective effect of CR remain largely unknown. We tested the role of DNA methylation as a mechanism for CR-induced neuroprotection in the old hippocampus. Hippocampal DNA from young (3M) and old (24M) male mice fed ad libitum and 24M old mice fed 40% calorie-restricted diet from 3M of age were examined by genome-wide bisulfite sequencing to measure methylation levels at base-specific resolution. Over 22 million CG and CH (non-CG) sites were examined. Of the ~40,000 differentially methylated CGs (dmCGs) and ~80,000 CHs (dmCHs) observed with aging, 35% and 38%, respectively, were prevented by CR. Unique to dmCHs, CR preferentially prevented age-related hypermethylation. A diet-specific methylation response was observed in both CG and CH contexts. Diet-induced dmCHs were enriched in unexpected genomic locations including promoters and CG islands including hypermethylation of DNMT1 and Tet3 promoters corresponding to reduced gene expression. These findings demonstrate for the first time that caloric-restriction prevents age-induced cytosine methylation changes in the old brain in combination with diet-specific methylation changes that may function to maintain epigenetic homeostasis through epigenetic auto-regulation. The prevention of age-dmCGs/CHs by CR emphasizes the prominent role of DNA methylation as a driver of the aging process.

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Lipid droplets and lipotoxicity during autophagy.

Nguyen TB, Olzmann JA.

Autophagy. 2017 Aug 14:0. doi: 10.1080/15548627.2017.1359451. [Epub ahead of print]

PMID: 28806138

Abstract

Lipid droplets (LDs) are neutral lipid storage organelles that provide a rapidly accessible source of fatty acids (FAs) for energy during periods of nutrient deprivation. Surprisingly, lipids released by the macroautophagic/autophagic breakdown of membranous organelles are packaged and stored in new LDs during periods of prolonged starvation. Why cells would store FAs during an energy crisis was unknown. In our recent study, we demonstrated that FAs released during MTORC1-regulated autophagy are selectively channeled by DGAT1 (diacylglycerol O-acyltransferase 1) into triacylglycerol (TAG)-rich LDs. These DGAT1-dependent LDs sequester FAs and prevent the accumulation of acylcarnitines, which otherwise directly disrupt mitochondrial integrity. Our findings establish LD biogenesis as a general cellular response to periods of high autophagic flux that provide a lipid buffering system to mitigate lipotoxic cellular damage.

KEYWORDS:

DGAT1; MTORC1; acylcarnitine; autophagy; lipid droplets; lipotoxicity; mitochondria

 

The companion dog as a unique translation model for aging.

Mazzatenta A, Giulio CD, Robbe D, Carluccio A, Cellerino A.

Semin Cell Dev Biol. 2017 Aug 10. pii: S1084-9521(16)30443-8. doi: 10.1016/j.semcdb.2017.08.024. [Epub ahead of print] Review.

PMID: 28803893

http://sci-hub.cc/10.1016/j.semcdb.2017.08.024

Abstract

The dog is a unique species due to its wide variation among breeds in size, morphology, behavior and lifespan coupled with a genetic structure that facilitates the dissection of the genetic architecture controlling those traits. Dogs and humans coevolved and share recent evolutionary selection processes like, for example, adaptations to digest starch-rich diets. Many diseases of the dog have a human counterpart, notably Alzheimer's that is otherwise difficult to model in other organisms. Unlike laboratory animals, companion dogs share the human environment and lifestyle, are exposed to the same pollutants and are faced with pathogens and infections. Dogs represented very useful models to understand the relationship between size, IGF I genetic variation and lifespan and were used to test effects of dietary restriction and immunotherapy for Alzheimer's disease. Very recently, rapamycin was tested in companion dogs outside the laboratory and this approach where citizens are in involved in research aimed at the benefit of dog welfare may become a game changer in geroscience.

KEYWORDS:

Alzheimer’s; IGF I; aging dog; calorie restriction; dog breeding; dog genetics; dog interventions; dog pathology; evolutionary theory of aging; rapamycin

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Diet restriction and ageing in the dog: major observations over two decades.

Lawler DF, Larson BT, Ballam JM, Smith GK, Biery DN, Evans RH, Greeley EH, Segre M, Stowe HD, Kealy RD.

Br J Nutr. 2008 Apr;99(4):793-805. Epub 2007 Dec 6. Erratum in: Br J Nutr. 2009 Apr;101(7):1112.

PMID: 18062831

Abstract

This report reviews decade two of the lifetime diet restriction study of the dog. Labrador retrievers (n 48) were paired at age 6 weeks by sex and weight within each of seven litters, and assigned randomly within the pair to control-feeding (CF) or 25 % diet restriction (DR). Feeding began at age 8 weeks. The same diet was fed to all dogs; only the quantity differed. Major lifetime observations included 1.8 years longer median lifespan among diet-restricted dogs, with delayed onset of late life diseases, especially osteoarthritis. Long-term DR did not negatively affect skeletal maturation, structure or metabolism. Among all dogs, high static fat mass and declining lean body mass predicted death, most strongly at 1 year prior. Fat mass above 25 % was associated with increasing insulin resistance, which independently predicted lifespan and chronic diseases. Metabolizable energy requirement/lean body mass most accurately explained energy metabolism due to diet restriction; diet-restricted dogs required 17 % less energy to maintain each lean kilogram. Metabonomics-based urine metabolite trajectories reflected DR-related differences, suggesting that signals from gut microbiota may be involved in the DR longevity and health responses. Independent of feeding group, increased hazard of earlier death was associated with lower lymphoproliferative responses to phytohaemagglutinin, concanavalin A, and pokeweed mitogen; lower total lymphocytes, T-cells, CD4 and CD8 cells; lower CD8 percentages and higher B-cell percentages. When diet group was taken into account, PWM responses and cell counts and percentages remained predictive of earlier death.

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Knock-out of a mitochondrial sirtuin protects neurons from degeneration in Caenorhabditis elegans.

Sangaletti R, D'Amico M, Grant J, Della-Morte D, Bianchi L.

PLoS Genet. 2017 Aug 18;13(8):e1006965. doi: 10.1371/journal.pgen.1006965. [Epub ahead of print]

PMID: 28820880

Abstract

Sirtuins are NAD⁺-dependent deacetylases, lipoamidases, and ADP-ribosyltransferases that link cellular metabolism to multiple intracellular pathways that influence processes as diverse as cell survival, longevity, and cancer growth. Sirtuins influence the extent of neuronal death in stroke. However, different sirtuins appear to have opposite roles in neuronal protection. In Caenorhabditis elegans, we found that knock-out of mitochondrial sirtuin sir-2.3, homologous to mammalian SIRT4, is protective in both chemical ischemia and hyperactive channel induced necrosis. Furthermore, the protective effect of sir-2.3 knock-out is enhanced by block of glycolysis and eliminated by a null mutation in daf-16/FOXO transcription factor, supporting the involvement of the insulin/IGF pathway. However, data in Caenorhabditis elegans cell culture suggest that the effects of sir-2.3 knock-out act downstream of the DAF-2/IGF-1 receptor. Analysis of ROS in sir-2.3 knock-out reveals that ROS become elevated in this mutant under ischemic conditions in dietary deprivation (DD), but to a lesser extent than in wild type, suggesting more robust activation of a ROS scavenging system in this mutant in the absence of food. This work suggests a deleterious role of SIRT4 during ischemic processes in mammals that must be further investigated and reveals a novel pathway that can be targeted for the design of therapies aimed at protecting neurons from death in ischemic conditions.

 

Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats.

Ding S, Jiang J, Zhang G, Bu Y, Zhang G, Zhao X.

PLoS One. 2017 Aug 17;12(8):e0183541. doi: 10.1371/journal.pone.0183541. eCollection 2017.

PMID: 28817690

Abstract

BACKGROUND:

Studies have demonstrated that resveratrol (a natural polyphenol) and caloric restriction activate Sirtuin-1 (SIRT1) and induce autophagy. Furthermore, autophagy is induced by the SIRT1-FoxO signaling pathway and was recently shown to be a critical protective mechanism against non-alcoholic fatty liver disease (NAFLD) development. We aimed to compare the effects of resveratrol and caloric restriction on hepatic lipid metabolism and elucidate the mechanism by which resveratrol supplementation and caloric restriction alleviate hepatosteatosis by examining the molecular interplay between SIRT1 and autophagy.

METHODS AND RESULTS:

Eight-week-old male Wistar rats (40) were divided into four groups: the STD group, which was fed a standard chow diet; the HFD group, which was fed a high-fat diet; HFD-RES group, which was fed a high-fat diet plus resveratrol (200 mg/kg.bw); and the HFD-CR group, which was fed a high-fat diet in portions containing 70% of the mean intake of the HFD group rats. The groups were maintained for 18 weeks. Metabolic parameters, Oil Red O and hematoxylin-eosin staining of the liver, and the mRNA and protein expression of SIRT1, autophagy markers and endoplasmic reticulum(ER) stress-associated genes in the liver were assessed after the 18-week treatment. We found that resveratrol (200 mg/kg bw) and caloric restriction (30%) partially prevented hepatic steatosis and hepatocyte ballooning, increased the expression of SIRT1 and autophagy markers while decreasing ER stress markers in the liver and alleviated lipid metabolism disorder. Moreover, caloric restriction provided superior protection against HFD-induced hepatic fatty accumulation compared with resveratrol and the effects were associated with decreased total energy intake and body weight.

CONCLUSION:

We conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30%) and resveratrol (a pharmacological SIRT1 activator) supplementation against HFD-induced hepatic steatosis.

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Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction

Rigo Cintron-Colon, Manuel Sanchez-Alavez, William Nguyen, Simone Mori, Ruben Gonzalez-Rivera, Tiffany Lien, Tamas Bartfai, Saba Aïd, Jean-Christophe François, Martin Holzenberger, and Bruno Conti

PNAS 2017 ; published ahead of print August 21, 2017, doi:10.1073/pnas.1617876114

http://www.pnas.org/content/early/2017/08/17/1617876114.full

Significance

Energy homeostasis is fundamental for the survival of living organisms and contributes to their health, longevity, and aging. When food resources are scarce, and during experimental calorie restriction, endothermic animals can lower their core body temperature. Here, we found that this response is regulated by the insulin-like growth factor 1 receptor. This demonstrates that the three main factors affecting aging and longevity (calorie restriction, reduction of the insulin-like growth factor 1 signaling, and lowered temperature) are components of the same pathway that modulates energy homeostasis. The finding also identifies body temperature reduction as a common determinant of the effects of both calorie restriction and reduced insulin-like growth factor 1 receptor signaling.

Abstract

When food resources are scarce, endothermic animals can lower core body temperature (Tb). This phenomenon is believed to be part of an adaptive mechanism that may have evolved to conserve energy until more food becomes available. Here, we found in the mouse that the insulin-like growth factor 1 receptor (IGF-1R) controls this response in the central nervous system. Pharmacological or genetic inhibition of IGF-1R enhanced the reduction of temperature and of energy expenditure during calorie restriction. Full blockade of IGF-1R affected female and male mice similarly. In contrast, genetic IGF-1R dosage was effective only in females, where it also induced transient and estrus-specific hypothermia in animals fed ad libitum. These effects were regulated in the brain, as only central, not peripheral, pharmacological activation of IGF-1R prevented hypothermia during calorie restriction. Targeted IGF-1R knockout selectively in forebrain neurons revealed that IGF signaling also modulates calorie restriction-dependent Tb regulation in regions rostral of the canonical hypothalamic nuclei involved in controlling body temperature. In aggregate, these data identify central IGF-1R as a mediator of the integration of nutrient and temperature homeostasis. They also show that calorie restriction, IGF-1R signaling, and body temperature, three of the main regulators of metabolism, aging, and longevity, are components of the same pathway.

Keywords:

IGF-1R temperature calorie restriction energy homeostasis aging

 

β-Hydroxybutyrate: A Signaling Metabolite

Annual Review of Nutrition

Vol. 37:51-76 (Volume publication date August 2017)

https://doi.org/10.1146/annurev-nutr-071816-064916

John C. Newman and Eric Verdin

http://www.annualreviews.org.sci-hub.cc/doi/10.1146/annurev-nutr-071816-064916

Abstract

Various mechanisms in the mammalian body provide resilience against food deprivation and dietary stress. The ketone body β-hydroxybutyrate (BHB) is synthesized in the liver from fatty acids and represents an essential carrier of energy from the liver to peripheral tissues when the supply of glucose is too low for the body's energetic needs, such as during periods of prolonged exercise, starvation, or absence of dietary carbohydrates. In addition to its activity as an energetic metabolite, BHB is increasingly understood to have cellular signaling functions. These signaling functions of BHB broadly link the outside environment to epigenetic gene regulation and cellular function, and their actions may be relevant to a variety of human diseases as well as human aging.

Keywords

metabolism, epigenetics, ketone bodies, fasting, aging

Edited by AlPater

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HEALTHLINE NEWS

Do Low Calorie Diets Help You Live Longer?

Written by Shawn Radcliffe on August 23, 2017

Cutting calories from the diets of many animals dramatically increases their life span, leading some people to try to extend their own lives in the same way.

http://www.healthline.com/health-news/do-low-calorie-diets-help-you-live-longer#1

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Association of the rs10830963 polymorphism in melatonin receptor type 1B (MTNR1B) with metabolic response after weight loss secondary to a hypocaloric diet based in Mediterranean style.

de Luis DA, Izaola O, Primo D, Aller R.

Clin Nutr. 2017 Aug 23. pii: S0261-5614(17)30298-4. doi: 10.1016/j.clnu.2017.08.015. [Epub ahead of print]

PMID: 28869073

Abstract

BACKGROUND & AIMS:

Some genetic variants within MTNR1B were related with fasting glucose levels or the increased prevalence of diabetes mellitus and obesity. The aims of the present investigation were to determine the influence of rs10830963 MTNR1B variant in relation to body weight loss, insulin resistance and adipokine levels in response to a hypocaloric diet with Mediterranean pattern.

METHODS:

A Caucasian population of 80 obese patients was studied before and after 12 weeks on a hypocaloric diet. Body weight, fat mass, waist circumference, blood pressure, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipoprotein levels and adipocytokines levels (leptin, adiponectin and resistin) were measured. Genotype of MTNR1B gene single nucleotide polymorphism (rs10830963) was evaluated.

RESULTS:

In total, 44 patients (55%) had the genotype CC, 27 patients CG (33.8%) and 9 patients GG (11.2%). With the dietary intervention body mass index, weight, fat mass, systolic blood pressure, leptin levels and waist circumference decreased in both groups. There were no significant differences between gender groups on the reported effects in each genotype group. However, the improvement of anthropometric parameters was higher in subjects with CC genotype than (GC + GG) genotype. After dietary intervention and in males with CC genotype, insulin levels (-5.3 ± 4.8 UI/L vs 1.2 ± 4.1 UI/L; p < 0.05) and HOMA-IR (-1.4 ± 2.1 units vs 0.4 ± 2.0 units; p < 0.05) decreased. In the group of females with CC genotype, insulin levels (-3.5 ± 2.1 UI/L vs. -1.4 ± 2.2 UI/L: p < 0.05) and HOMA-IR (-1.4 ± 1.2 units vs. -0.1 ± 1.3 units: p < 0.05) decreased, too. However, these parameters remained unchanged in (GC + GG) group. Fasting glucose levels were higher in patients in (GC + GG).

CONCLUSIONS:

This study showed the association of rs10830963 MTNR1B single nucleotide polymorphism with body weight loss and changes in fasting insulin levels and HOMA-IR in obese subjects.

KEYWORDS:

Adipokines; Hypocaloric diet; MTNR1B; rs10830963

 

The Scientist » The Nutshell

Studies: Ketogenic Mice Live Longer, Healthier Lives

High-fat, low-carbohydrate diets are shown to increase lifespan and preserve memory in two independent mouse experiments.

By Bob Grant | September 5, 2017

http://www.the-scientist.com/?articles.view/articleNo/50252/title/Studies--Ketogenic-Mice-Live-Longer--Healthier-Lives/&utm_campaign=NEWSLETTER_TS_The-Scientist-Daily_2016&utm_source=hs_email&utm_medium=email&utm_content=56019487&_hsenc=p2ANqtz-9QM-MmtW9ko8IWXLMpPU7Tnw_M3YOydII5E0rSHYp29VNzDisCyvWQbBRZWP8dlJk57hfGKHcmEn1VNZRQIvKnvN0V3g&_hsmi=56019487

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Eat Fat, Live Longer?

Mouse Study Shows a Ketogenic Diet Increases Longevity, Strength

By Trina Wood on September 5, 2017 in Human & Animal Health

https://www.ucdavis.edu/news/eat-fat-live-longer/

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A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice.

Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, Perez G, Gutierrez-Casado E, Koike S, Knotts TA, Imai DM, Griffey SM, Kim K, Hagopian K, Haj FG, Baar K, Cortopassi GA, Ramsey JJ, Lopez-Dominguez JA.

Cell Metab. 2017 Sep 5;26(3):539-546.e5. doi: 10.1016/j.cmet.2017.08.005.

PMID: 28877457

http://sci-hub.cc/10.1016/j.cmet.2017.08.005

Highlights

A low-carbohydrate, ketogenic diet extends longevity in adult male mice

Motor function, memory, and muscle mass are preserved in aged ketogenic mice

Protein acetylation is increased in the liver and skeletal muscle of ketogenic mice

Abstract

Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD extends longevity and healthspan in mice.

KEYWORDS:

aging; beta-hydroxybutyrate; healthspan; ketogenic diet; ketone bodies; ketones; lifespan; longevity; low-carbohydrate diet; memory

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Refers To

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice.

Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng CP, Huang Y, Haldar S, Verdin E.

Cell Metab. 2017 Sep 5;26(3):547-557.e8. doi: 10.1016/j.cmet.2017.08.004.

PMID: 28877458

http://sci-hub.cc/10.1016/j.cmet.2017.08.004

Highlights

Feeding isoprotein ketogenic diet to mice every other week (Cyclic KD) avoids obesity

Cyclic KD reduces midlife mortality with no change in maximum lifespan

Cyclic KD prevents memory decline with modest other healthspan effects

Gene expression of KD is similar to high-fat diet, except for activation of PPARα targets

Abstract

Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies downregulation of insulin, protein synthesis, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, upregulation of PPARα target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice.

Keywords: ketogenic diet; beta-hydroxybutyrate; longevity; healthspan

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Referred to by

Disentangling High Fat, Low Carb, and Healthy Aging.

Brown-Borg HM.

Cell Metab. 2017 Sep 5;26(3):458-459. doi: 10.1016/j.cmet.2017.08.020.

PMID: 28877453

Abstract

Dietary interventions are simple, non-invasive tools that can be utilized to improve health and lifespan. In this issue, Roberts et al. (2017) and Newman et al. (2017) reveal the physiological benefits of feeding mice ketogenic diets and suggest different underlying mechanisms that may promote healthy aging.

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12-SEP-2017

In mice, calorie restriction reduces fat but increases fur

https://www.eurekalert.org/pub_releases/2017-09/cp-imc090617.php

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Caloric Restriction Promotes Structural and Metabolic Changes in the Skin.

Forni MF, Peloggia J, Braga TT, Chinchilla JEO, Shinohara J, Navas CA, Camara NOS, Kowaltowski AJ.

Cell Rep. 2017 Sep 12;20(11):2678-2692. doi: 10.1016/j.celrep.2017.08.052.

PMID: 28903047

Open Access

DOI: http://dx.doi.org/10.1016/j.celrep.2017.08.052

http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31177-4

http://www.cell.com/cell-reports/pdf/S2211-1247(17)31177-4.pdf

Highlights

•Caloric restriction (CR) remodels the skin and fur and expands the local stem cell pool

•CR promotes metabolic reprogramming in both the dermis and epidermis

•CR imposes a thermoregulatory challenge in the absence of fur

•Changes in CR fur are necessary for thermal homeostasis and metabolic fitness

Summary

Caloric restriction (CR) is the most effective intervention known to enhance lifespan, but its effect on the skin is poorly understood. Here, we show that CR mice display fur coat remodeling associated with an expansion of the hair follicle stem cell (HFSC) pool. We also find that the dermal adipocyte depot (dWAT) is underdeveloped in CR animals. The dermal/vennule annulus vasculature is enlarged, and a vascular endothelial growth factor (VEGF) switch and metabolic reprogramming in both the dermis and the epidermis are observed. When the fur coat is removed, CR mice display increased energy expenditure associated with lean weight loss and locomotion impairment. Our findings indicate that CR promotes extensive skin and fur remodeling. These changes are necessary for thermal homeostasis and metabolic fitness under conditions of limited energy intake, suggesting a potential adaptive mechanism.

 

The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan.

Mittal N, Guimaraes JC, Gross T, Schmidt A, Vina-Vilaseca A, Nedialkova DD, Aeschimann F, Leidel SA, Spang A, Zavolan M.

Nat Commun. 2017 Sep 6;8(1):457. doi: 10.1038/s41467-017-00539-y.

PMID: 28878244 Free PMC Article

Abstract

In Saccharomyces cerevisiae, deletion of large ribosomal subunit protein-encoding genes increases the replicative lifespan in a Gcn4-dependent manner. However, how Gcn4, a key transcriptional activator of amino acid biosynthesis genes, increases lifespan, is unknown. Here we show that Gcn4 acts as a repressor of protein synthesis. By analyzing the messenger RNA and protein abundance, ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that Gcn4 is sufficient to reduce protein synthesis and increase yeast lifespan. Chromatin immunoprecipitation reveals Gcn4 binding not only at genes that are activated, but also at genes, some encoding ribosomal proteins, that are repressed upon Gcn4 overexpression. The promoters of repressed genes contain Rap1 binding motifs. Our data suggest that Gcn4 is a central regulator of protein synthesis under multiple perturbations, including ribosomal protein gene deletions, calorie restriction, and rapamycin treatment, and provide an explanation for its role in longevity and stress response.The transcription factor Gcn4 is known to regulate yeast amino acid synthesis. Here, the authors show that Gcn4 also acts as a repressor of protein biosynthesis in a range of conditions that enhance yeast lifespan, such as ribosomal protein knockout, calorie restriction or mTOR inhibition.

 

Circadian and economic factors affect food acquisition in rats restricted to discrete feeding opportunities.

Minaya DM, Robertson KL, Rowland NE.

Physiol Behav. 2017 Sep 5;181:10-15. doi: 10.1016/j.physbeh.2017.09.003. [Epub ahead of print]

PMID: 28886965

http://sci-hub.cc/10.1016/j.physbeh.2017.09.003

Abstract

The purpose of this study is to examine aspects of operant behavior-modeled economic choice for food in rats in closed economy protocols in which food is available for only a few discrete times per daily 23-h session, designed to emulate clustering of human food intake into meals. In the first experiment, rats performed lever press responses for food pellets in an ascending series of ratios or fixed unit prices (FUP) when food was available for four 40-min food opportunities (FO) per day. Daily intake at low FUP was comparable to ad libitum intakes. Intake declined as FUP increased and was not distributed equally among the four FOs. In particular, the last FO of a session (occurring at about lights on in a 12:12cycle) was the smallest, even when total intake was low due to the response requirement at high FUP. Within FOs, satiation was evident at low FUPs by a decrease in rate of intake across a 40min FO; at high FUPs responding was evenly distributed. In the second experiment, rats had a choice of responding on two levers for either intermittent inexpensive (II; low FUP according to a four FO schedule) or costly continuous (CC; 20-fold higher FUP but available throughout 23-h sessions) food. Most (73%) of the rats consistently chose almost all of their food from the II source. Further, as the timing of the four II FOs were changed relative to the light: dark Zeitgeber, the time of the smallest meal changed such that the smallest meal (s) were during the light period regardless of ordinal position within a session. These data are discussed in terms of economic and Zeitgeber effects on consumption when food is available intermittently, and are contrasted with results from comparable protocols in mice.

KEYWORDS:

Closed economy; Operant behavior; Satiation; Unit price; Zeitgeber

 

Caloric restriction promotes rapid expansion and long-lasting increase of Lactobacillus in the rat fecal microbiota.

Fraumene C, Manghina V, Cadoni E, Marongiu F, Abbondio M, Serra M, Palomba A, Tanca A, Laconi E, Uzzau S.

Gut Microbes. 2017 Sep 11:0. doi: 10.1080/19490976.2017.1371894. [Epub ahead of print]

PMID: 28891744

http://sci-hub.cc/10.1080/19490976.2017.1371894

Abstract

Previous studies indicated that caloric restricted diet enables to lower significantly the risk of cardiovascular and metabolic diseases. In experimental animal models, life-long lasting caloric restriction (CR) was demonstrated to induce changes of the intestinal microbiota composition, regardless of fat content and/or exercise. To explore the potential impact of short and long-term CR treatment on the gut microbiota, we conducted an analysis of fecal microbiota composition in young and adult Fisher 344 rats treated with a low fat feed under ad libitum (AL) or CR conditions (70%). We report here significant changes of the rat fecal microbiota that arise rapidly in young growing animals after short-term administration of a CR diet. In particular, Lactobacillus increased significantly after 8 weeks of CR treatment and its relative abundance was significantly higher in CR vs AL fed animals after 36 weeks of dietary intervention. Taken together, our data suggest that Lactobacillus intestinal colonization is hampered in AL fed young rats compared to CR fed ones, while health-promoting CR diet intervention enables the expansion of this genus rapidly and persistently up to adulthood.

 

Pronounced energy restriction with elevated protein intake results in no change in proteolysis and reductions in skeletal muscle protein synthesis that are mitigated by resistance exercise.

Hector AJ, McGlory C, Damas F, Mazara N, Baker SK, Phillips SM.

FASEB J. 2017 Sep 12. pii: fj.201700158RR. doi: 10.1096/fj.201700158RR. [Epub ahead of print]

PMID: 28899879

Abstract

Preservation of lean body mass (LBM) may be important during dietary energy restriction (ER) and requires equal rates of muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Currently, the relative contribution of MPS and MPB to the loss of LBM during ER in humans is unknown. We aimed to determine the impact of dietary protein intake and resistance exercise on MPS and MPB during a controlled short-term energy deficit. Adult men (body mass index, 28.6 ± 0.6 kg/m2; age 22 ± 1 yr) underwent 10 d of 40%-reduced energy intake while performing unilateral resistance exercise and consuming lower protein (1.2 g/kg/d, n = 12) or higher protein (2.4 g/kg per d, n = 12). Pre- and postintervention testing included dual-energy X-ray absorptiometry, primed constant infusion of ring-[13C6]phenylalanine, and 15[N]phenylalanine to measure acute postabsorptive MPS and MPB; D2O to measure integrated MPS; and gene and protein expression. There was a decrease in acute MPS after ER (higher protein, 0.059 ± 0.006 to 0.051 ± 0.009%/h; lower protein, 0.061 ± 0.005-0.045 ± 0.006%/h; P < 0.05) that was attenuated with resistance exercise (higher protein, 0.067 ± 0.01%/h; lower protein, 0.061 ± 0.006%/h), and integrated MPS followed a similar pattern. There was no change in MPB (energy balance, 0.080 ± 0.01%/hr; ER rested legs, 0.078 ± 0.008%/hr; ER exercised legs, 0.079 ± 0.006%/hr). We conclude that a reduction in MPS is the main mechanism that underpins LBM loss early in ER in adult men.

KEYWORDS:

dietary protein; muscle protein turnover; weight loss

 

Changes in expression of neuropeptides and their receptors in the hypothalamus and gastrointestinal tract of calorie restricted hens.

Simon Á, Oláh J, Komlósi I, Jávor A, Németh J, Szilvássy Z, Reglődi D, Tamás A, Czeglédi L.

Acta Biol Hung. 2017 Sep;68(3):237-247. doi: 10.1556/018.68.2017.3.1.

PMID: 28901800

Abstract

The list of orexigenic and anorexigenic peptides, those are known to alter feed intake, is continuously growing. However, most of them are studied in mammalian species. We aimed to investigate plasma level and mRNA expression of the pituitary adenylate cyclase-activating polypeptide (PACAP), gene expression of its receptor (PAC1), furthermore the gene expression of galanin (GAL), neuromedin U (NMU), and its two receptors (NMUR1 and NMUR2) in the hypothalamus, proventriculus, and jejunum of hens exposed to 40% calorie restriction. Feed restriction resulted in a 88% increase in mRNA and a 27% increase in peptide level of PACAP in proventriculus measured with qPCR and RIA, respectively. Increases were found in the gene expression of PAC1 (49%) and NMUR1 (63%) in the hypothalamus. Higher expressions of peptide encoding genes (76% for PACAP, 41% for NMU, 301% for NMUR1 and 308% for GAL, P < 0.05) were recorded in the jejunum of hens exposed to restricted nutrition. The results indicate that PACAP level responds to calorie restriction in the proventriculus and jejunum, but not in the hypothalamus and plasma.

KEYWORDS:

Calorie restriction; GAL; NMU; PAC1; PACAP

 

Effect of food deprivation on the hypothalamic gene expression of the secretogranin II-derived peptide EM66 in rat.

Trebak F, Dubuc I, Picot M, Alaoui A, Leprince J, Prévost G, Anouar Y, Magoul R, Chartrel N.

Neuroreport. 2017 Sep 11. doi: 10.1097/WNR.0000000000000889. [Epub ahead of print]

PMID: 28902709

Abstract

EM66 is a peptide derived from the chromogranin, secretogranin II (SG-II). Recent findings in mice indicate that EM66 is a novel anorexigenic neuropeptide that regulates hypothalamic feeding behavior, at least in part, by activating the POMC neurons of the arcuate nucleus. The present study aimed to investigate the mechanism of action of EM66 in the control of feeding behavior and, more specifically, its potential interactions with the NPY and POMC systems in rat. We analyzed by Q-PCR the gene expression of the EM66 precursor, SG-II, in hypothalamic extracts following 2, 3, or 4 days of food deprivation and compared it with the expression levels of the two major neuropeptidergic systems, that is, POMC and NPY, modulating feeding behavior. Our results show that fasting for 2 and 3 days has no effect on SG-II mRNA levels. However, 4 days of food deprivation induced a significant alteration in the expression levels of the three genes studied, with a significant increase in SG-II and NPY mRNAs, and conversely, a significant decrease in POMC mRNA. These data indicate that the EM66 gene expression is modulated by a negative energy status and suggest interactions between EM66 and NPY to regulate food intake through the POMC system.

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The influence of ketogenic therapy on the 5 R's of radiobiology.

Klement RJ.

Int J Radiat Biol. 2017 Sep 14:1-36. doi: 10.1080/09553002.2017.1380330. [Epub ahead of print]

PMID: 28905672

http://sci-hub.cc/10.1080/09553002.2017.1380330

Abstract

PURPOSE:

Radiotherapy (RT) is a mainstay in the treatment of solid tumors and works by inducing free radical stress in tumor cells, leading to loss of reproductive integrity. The optimal treatment strategy has to consider damage to both tumor and normal cells and is determined by five factors known as the 5 R's of radiobiology: Reoxygenation, DNA Repair, Radiosensitivity, Redistribution in the cell cycle and Repopulation. The aim of this review is (i) to present evidence that these 5 R's are strongly influenced by cellular and whole body metabolism that in turn can be modified through ketogenic therapy in form of ketogenic diets and short term fasting, and (ii) to stimulate new research into this field including some research questions deserving further study.

CONCLUSIONS:

Preclinical and some preliminary clinical data support the hypothesis that ketogenic therapy could be utilized as a complementary treatment in order to improve the outcome after RT, both in terms of higher tumor control as well as lower normal tissue complication probability. The first effect relates to the metabolic shift from glycolysis towards mitochondrial metabolism which selectively increases ROS production and impairs ATP production in tumor cells. The second effect is based on the differential stress resistance phenomenon which is achieved when glucose and growth factors are reduced and ketone bodies are elevated, reprogramming normal but not tumor cells from proliferation towards maintenance and stress resistance. Underlying both effects are metabolic differences between normal and tumor cells that ketogenic therapy seeks to exploit. Specifically the recently discovered role of the ketone body β-hydroxybutyrate as an endogenous class I histone deacetylase inhibitor suggests a dual role as a radioprotector of normal cells and a radiosensitzer of tumor cells that opens up exciting possibilities to employ ketogenic therapy as a cost-effective adjunct to radiotherapy against cancer.

KEYWORDS:

Calorie restriction; Chemotherapy; Fasting; Ketogenic diet; Radiotherapy

 

Researchers uncover mechanism behind calorie restriction and lengthened lifespan

September 14, 2017

https://medicalxpress.com/news/2017-09-uncover-mechanism-calorie-restriction-lengthened.html

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OPEN

Caloric restriction delays age-related methylation drift

Shinji Maegawa, Yue Lu, Tomomitsu Tahara, Justin T. Lee, Jozef Madzo, Shoudan Liang, Jaroslav Jelinek, Ricki J. Colman & Jean-Pierre J. Issa

Nature Communications 8, Article number: 539 (2017)

doi:10.1038/s41467-017-00607-3

AgeingBiomarkersDNA methylation

Received:

14 September 2016

Accepted:

11 July 2017

Published online:

14 September 2017

https://www.nature.com/articles/s41467-017-00607-3

Abstract

In mammals, caloric restriction consistently results in extended lifespan. Epigenetic information encoded by DNA methylation is tightly regulated, but shows a striking drift associated with age that includes both gains and losses of DNA methylation at various sites. Here, we report that epigenetic drift is conserved across species and the rate of drift correlates with lifespan when comparing mice, rhesus monkeys, and humans. Twenty-two to 30-year-old rhesus monkeys exposed to 30% caloric restriction since 7–14 years of age showed attenuation of age-related methylation drift compared to ad libitum-fed controls such that their blood methylation age appeared 7 years younger than their chronologic age. Even more pronounced effects were seen in 2.7–3.2-year-old mice exposed to 40% caloric restriction starting at 0.3 years of age. The effects of caloric restriction on DNA methylation were detectable across different tissues and correlated with gene expression. We propose that epigenetic drift is a determinant of lifespan in mammals.

 

GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin.

Aoyama K, Bhadhprasit W, Watabe M, Wang F, Matsumura N, Nakaki T.

FASEB J. 2017 Sep 13. pii: fj.201700421R. doi: 10.1096/fj.201700421R. [Epub ahead of print]

PMID: 28904020

Abstract

Pro-opiomelanocortin (POMC)-expressing neurons provide α-melanocyte-stimulating hormone (α-MSH), which stimulates melanocortin 4 receptor to induce hypophagia by AMPK inhibition in the hypothalamus. α-MSH is produced by POMC cleavage in secretory granules and released. However, it is not known yet whether any posttranscriptional regulatory mechanism of POMC signaling exists upstream of the secretory granules in neurons. Here we show that glutamate transporter-associated protein 3-18 (GTRAP3-18), an anchor protein that retains interacting proteins in the endoplasmic reticulum, is a critical regulator of food intake and body weight by interacting with POMC. GTRAP3-18-deficient mice showed hypophagia, lean bodies, and lower blood glucose, insulin, and leptin levels with increased serum and brain α-MSH levels, leading to AMPK inhibition. Intraperitoneal glucose tolerance tests revealed significantly decreased blood glucose levels and areas under the curve in GTRAP3-18-deficient mice compared to wild-type mice. An intracerebroventricular infusion of a selective melanocortin 4 receptor antagonist to GTRAP3-18-deficient mice significantly increased their food intake and body weight. A fluorescence resonance energy transfer study showed an interaction between GTRAP3-18 and POMC in vitro These findings suggest that activation of the melanocortin pathway by modulating GTRAP3-18/POMC interaction could be an alternative strategy for obesity and/or type 2 diabetes.

KEYWORDS:

appetite; diabetes; hypothalamus; neuron; obesity

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Acid-base safety during the course of a very low-calorie-ketogenic diet.

Gomez-Arbelaez D, Crujeiras AB, Castro AI, Goday A, Mas-Lorenzo A, Bellon A, Tejera C, Bellido D, Galban C, Sajoux I, Lopez-Jaramillo P, Casanueva FF.

Endocrine. 2017 Sep 15. doi: 10.1007/s12020-017-1405-3. [Epub ahead of print]

PMID: 28914421

http://sci-hub.cc/10.1007/s12020-017-1405-3

Abstract

BACKGROUND AND AIMS:

Very low-calorie ketogenic (VLCK) diets have been consistently shown to be an effective obesity treatment, but the current evidence for its acid-base safety is limited. The aim of the current work was to evaluate the acid-base status of obese patients during the course of a VLCK diet.

METHOD:

Twenty obese participants undertook a VLCK diet for 4 months. Anthropometric and biochemical parameters, and venous blood gases were obtained on four subsequent visits: visit C-1 (baseline); visit C-2, (1-2 months); maximum ketosis; visit C-3 (2-3 months), ketosis declining; and visit C-4 at 4 months, no ketosis. Results were compared with 51 patients that had an episode of diabetic ketoacidosis as well as with a group that underwent a similar VLCK diet in real life conditions of treatment.

RESULTS:

Visit C1 blood pH (7.37 ± 0.03); plasma bicarbonate (24.7 ± 2.5 mmol/l); plasma glucose (96.0 ± 11.7 mg/l) as well as anion gap or osmolarity were not statistically modified at four months after a total weight reduction of 20.7 kg in average and were within the normal range throughout the study. Even at the point of maximum ketosis all variables measured were always far from the cut-off points established to diabetic ketoacidosis.

CONCLUSION:

During the course of a VLCK diet there were no clinically or statistically significant changes in glucose, blood pH, anion gap and plasma bicarbonate. Hence the VLCK diet can be considered as a safe nutritional intervention for the treatment of obesity in terms of acid-base equilibrium.

KEYWORDS:

Acidosis; Acid–base safety; Ketogenic diet; Ketosis; Obesity; Very low-energy diet

... Conflit of interest D.B., A.B.C. and F.F.C. received advisory board

fees and or research grants from Pronokal Protein Supplies Spain. IS is

Medical Director of Pronokal Spain SL.

 

Caloric restriction delays age-related methylation drift.

Maegawa S, Lu Y, Tahara T, Lee JT, Madzo J, Liang S, Jelinek J, Colman RJ, Issa JJ.

Nat Commun. 2017 Sep 14;8(1):539. doi: 10.1038/s41467-017-00607-3.

PMID: 28912502

http://sci-hub.cc/10.1038/s41467-017-00607-3

Abstract

In mammals, caloric restriction consistently results in extended lifespan. Epigenetic information encoded by DNA methylation is tightly regulated, but shows a striking drift associated with age that includes both gains and losses of DNA methylation at various sites. Here, we report that epigenetic drift is conserved across species and the rate of drift correlates with lifespan when comparing mice, rhesus monkeys, and humans. Twenty-two to 30-year-old rhesus monkeys exposed to 30% caloric restriction since 7-14 years of age showed attenuation of age-related methylation drift compared to ad libitum-fed controls such that their blood methylation age appeared 7 years younger than their chronologic age. Even more pronounced effects were seen in 2.7-3.2-year-old mice exposed to 40% caloric restriction starting at 0.3 years of age. The effects of caloric restriction on DNA methylation were detectable across different tissues and correlated with gene expression. We propose that epigenetic drift is a determinant of lifespan in mammals.Caloric restriction has been shown to increase lifespan in mammals. Here, the authors provide evidence that age-related methylation drift correlates with lifespan and that caloric restriction in mice and rhesus monkeys results in attenuation of age-related methylation drift.

 

[The below paper is not pdf-availed.]

Diet has independent effects on the pace and shape of aging in Drosophila melanogaster.

Ruth Archer C, Basellini U, Hunt J, Simpson SJ, Lee KP, Baudisch A.

Biogerontology. 2017 Sep 15. doi: 10.1007/s10522-017-9729-1. [Epub ahead of print]

PMID: 28914388

Abstract

Studies examining how diet affects mortality risk over age typically characterise mortality using parameters such as aging rates, which condense how much and how quickly the risk of dying changes over time into a single measure. Demographers have suggested that decoupling the tempo and the magnitude of changing mortality risk may facilitate comparative analyses of mortality trajectories, but it is unclear what biologically meaningful information this approach offers. Here, we determine how the amount and ratio of protein and carbohydrate ingested by female Drosophila melanogaster affects how much mortality risk increases over a time-standardised life-course (the shape of aging) and the tempo at which animals live and die (the pace of aging). We find that pace values increased as flies consumed more carbohydrate but declined with increasing protein consumption. Shape values were independent of protein intake but were lowest in flies consuming ~90 μg of carbohydrate daily. As protein intake only affected the pace of aging, varying protein intake rescaled mortality trajectories (i.e. stretched or compressed survival curves), while varying carbohydrate consumption caused deviation from temporal rescaling (i.e. changed the topography of time-standardised survival curves), by affecting pace and shape. Clearly, the pace and shape of aging may vary independently in response to dietary manipulation. This suggests that there is the potential for pace and shape to evolve independently of one another and respond to different physiological processes. Understanding the mechanisms responsible for independent variation in pace and shape, may offer insight into the factors underlying diverse mortality trajectories.

KEYWORDS:

Dietary restriction; Fruit flies; Geometric framework of nutrition; Gompertz; Pace; Shape

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[The below paper is pdf-availed.]

Dietary restriction delays the secretion of senescence associated secretory phenotype by reducing DNA damage response in the process of renal aging.

Wang W, Cai G, Chen X.

Exp Gerontol. 2017 Sep 12. pii: S0531-5565(17)30380-7. doi: 10.1016/j.exger.2017.09.005. [Epub ahead of print]

PMID: 28916310

Abstract

Dietary restriction (DR) has multiple and essential effects in protecting against DNA damage in model organisms. Persistent DNA damage plays a central role in the process of aging. Senescence-associated secretory phenotype (SASP), as a product of cellular aging, can accelerate the process of cellular senescence as a feedback. In this study, we directly observed whether a DR of 30% for 6months in aged rats could retard SASP by delaying the progression of DNA damage and also found the specific mechanism. The results revealed that a 30% DR could significantly improve renal pathology and some metabolic characteristics. The biomarkers and products of DNA damage were decreased in the process of renal aging on a 30% DR. A series of SASP, notably cytokine, chemokine, and growth factor, were obviously reduced by DR during renal aging. The phosphorylation levels of NF-κB and IκBα in aged kidneys of DR group were markedly reduced. These findings suggest that a 30% DR for 6months can delay renal aging and reduce the accumulation of SASP by retarding the progression of DNA damage and decreasing the transcription activity of NF-κB, thus providing a target to delay renal aging.

KEYWORDS:

DNA damage response; Dietary restriction; NF-κB; Renal aging; Senescence-associated secretory phenotypes

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Glucagon-like peptide-1 receptor signaling in the lateral dorsal tegmental nucleus regulates energy balance.

Reiner DJ, Leon RM, McGrath LE, Koch-Laskowski K, Hahn JD, Kanoski SE, Mietlicki-Baase EG, Hayes MR.

Neuropsychopharmacology. 2017 Sep 18. doi: 10.1038/npp.2017.225. [Epub ahead of print]

PMID: 28920591

Abstract

The neurobiological substrates that mediate the anorectic effects of both endogenous glucagon-like peptide-1 (GLP-1) and exogenous GLP-1 receptor (GLP-1R) agonists are an active area of investigation. As the lateral dorsal tegmental nucleus (LDTg) expresses the GLP-1R and represents a potential neuroanatomical hub connecting the nucleus tractus soliartius (NTS), the major central source of GLP-1, with the other nuclei in the midbrain and forebrain, we tested the hypothesis that GLP-1R signaling in the LDTg controls food intake. Direct activation of LDTg GLP-1R suppresses food intake through a reduction in average meal size and independent of nausea/malaise. Immunohistochemical data show that GLP-1-producing neurons in the NTS project to the LDTg, providing anatomical evidence of endogenous central GLP-1 in the LDTg. Pharmacological blockade of LDTg GLP-1Rs with exendin-(9-39) dose-dependently increases food intake and attenuates the hypophagic effects of gastric distension. As GLP-1 mimetics are administered systemically in humans, we evaluated whether peripherally administered GLP-1R agonists access the LDTg to affect feeding. Immunohistochemical data show that a systemically-administered fluorescent GLP-1R agonist accesses the LDTg and is juxtaposed with neurons. Additionally, blockade of LDTg GLP-1Rs attenuates the hypophagic effects of a systemic GLP-1R agonist. Together, these data indicate that LDTg GLP-1R signaling controls energy balance and underscores the role of the LDTg in integrating energy balance-relevant signals to modulate feeding.

 

Effects of Chronic and Intermittent Calorie Restriction on Adropin Levels in Breast Cancer.

Tuna BG, Atalay PB, Altunbek M, Kalkan BM, Dogan S.

Nutr Cancer. 2017 Sep 18:1-8. doi: 10.1080/01635581.2017.1359314. [Epub ahead of print]

PMID: 28922017

http://sci-hub.cc/10.1080/01635581.2017.1359314

Abstract

Adropin is a peptide hormone that has been implicated in insulin resistance and as a potential regulator of growth. The aim of this study is to determine the effect of calorie restriction on circulating levels of adropin in the MMTV-TGFα breast cancer mouse model and investigate the effects of adropin peptide on the viability of MCF-7 and MDA-231 breast cancer cells in culture. Ten-week-old mice were assigned to either ad libitum-fed (AL), chronic calorie-restricted, or intermittent calorie-restricted groups. Concentrations of serum adropin were measured using an enzyme-linked immunosorbent assay. Results showed an inverse correlation between serum adropin levels and mouse age that was attenuated by calorie restriction. In the AL group the level of adropin was significantly lower at week 50 compared to levels at week 10. However, among the calorie-restricted groups, serum levels of adropin remained high at week 50. The cell-line-specific effects were observed after treatment of cancer cell lines with a series of adropin concentrations (5, 10, 25, 50 ng/mL). Flow cytometry analysis showed that MCF-7 cells entered the early phase of apoptosis after treatment with 50 ng/mL for 24 h. Adropin may be involved in the protective effects that calorie restriction has on breast cancer risk.

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Lifelong caloric restriction reprograms hepatic fat metabolism in mice.

Kuhla A, Hahn S, Butschkau A, Lange S, Wree A, Vollmar B.

J Gerontol A Biol Sci Med Sci. 2014 Aug;69(8):915-22. doi: 10.1093/gerona/glt160. Epub 2013 Oct 22.

PMID: 24149425

Abstract

Calorie lowering slows the aging process and extends life span in diverse species by so far unknown mechanisms. The inverse linear relationship between calorie intake and life span suggests that regulators of energy metabolism are of importance in aging. The present study shows that lifelong caloric restriction in mice induces a metabolic adaptation with reduced lipogenesis and enhanced lipolysis and ketogenesis. This process, that is, the reprogramming of hepatic fat metabolism, is associated with a marked rise of fibroblastic growth factor 21 as a putative starvation master regulator. Due to the life span-extending properties of fibroblastic growth factor 21, the rise in fibroblastic growth factor 21 might contribute to the markedly better health status found in mice upon lifelong caloric restriction feeding. In addition, adropin, known as a peptide that controls lipid homeostasis, is significantly upregulated, underlining the diminution of lipogenesis that was further substantiated by decreased expression of liver-X-receptor α and its target genes sterol regulatory element-binding protein-1c, fatty acid synthase, and member 1 of human transporter subfamily ABCA upon lifelong caloric restriction feeding.

KEYWORDS:

Adropin; FGF21; Ketogenesis.; Leptin; Lipolysis

 

The Effects of Ramadan Fasting on Body Composition, Blood Pressure, Glucose Metabolism, and Markers of Inflammation in NAFLD Patients: An Observational Trial.

Aliasghari F, Izadi A, Gargari BP, Ebrahimi S.

J Am Coll Nutr. 2017 Sep 18:1-6. doi: 10.1080/07315724.2017.1339644. [Epub ahead of print]

PMID: 28922096

https://sci-hub.cc/https://www.tandfonline.com/doi/full/10.1080/07315724.2017.1339644

Abstract

BACKGROUND AND AIM:

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and is a serious global health problem. Regarding the increasing prevalence of NAFLD, finding various strategies to prevent and manage the disease is of great importance. The aim of this study was to determine the effects of caloric restriction during Ramadan fasting on anthropometric indices, fasting glucose, plasma insulin, insulin resistance, and inflammatory cytokines (C-reactive protein and interleukin 6) in patients with NAFLD.

METHODS:

We conducted this study with 83 patients with NAFLD, 42 of whom decided to fast and 41 controls who decided not to fast for Ramadan, between June 18 and July 17, 2015. Anthropometric parameters were measured and a sample of venous blood was obtained for biochemical assays before and after Ramadan.

RESULTS:

There was a significant decrease in all anthropometric parameters as well as fasting glucose, plasma insulin, and insulin resistance. Relative to the nonfasting group, fasting significantly reduced circulating inflammatory, but changes in blood pressure after Ramadan were not significant.

CONCLUSIONS:

This study shows significant effects on parameters during Ramadan fasting such as anthropometric indices, fasting glucose, plasma insulin, and inflammatory cytokines in patients with NAFLD. The results of this study suggest that Ramadan fasting may be useful to improve NAFLD, so further studies are needed in this area.

KEYWORDS:

HOMA-IR; Nonalcoholic fatty liver disease; Ramadan fasting; blood pressure; blood sugar; body composition; caloric restriction; insulin

 

Steroid hormones could hold further clues about age-related bone loss

4 days agoby Jennifer Hilliard Scott

"To simulate the aging process, the mice were placed on a calorie-restricted diet, which also has been shown to result in lower bone density and increased marrow fat – just like what happens as we age. Extreme caloric restriction, such as with anorexia nervosa, can also lead to weak and brittle bones."

http://jagwire.augusta.edu/archives/47424

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SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis.

Zainabadi K, Liu CJ, Caldwell ALM, Guarente L.

PLoS One. 2017 Sep 22;12(9):e0185236. doi: 10.1371/journal.pone.0185236. eCollection 2017.

PMID: 28937996

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185236

Abstract

Overexpression or pharmacological activation of SIRT1 has been shown to extend the lifespan of mice and protect against aging-related diseases. Here we show that pharmacological activation of SIRT1 protects in two models of osteoporosis. Ovariectomized female mice and aged male mice, models for post-menopausal and aging-related osteoporosis, respectively, show significant improvements in bone mass upon treatment with SIRT1 agonist, SRT1720. Further, we find that calorie restriction (CR) results in a two-fold upregulation of sirt1 mRNA expression in bone tissue that is associated with increased bone mass in CR mice. Reciprocally, SIRT1 whole-body knockout (KO) mice, as well as osteoblast and osteoclast specific KOs, show a low bone mass phenotype; though double knockout mice (containing SIRT1 deleted in both osteoblasts and osteoclasts) do not show a more severe phenotype. Altogether, these findings provide strong evidence that SIRT1 is a positive regulator of bone mass and a promising target for the development of novel therapeutics for osteoporosis.

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Epigenetic drift is a determinant of mammalian lifespan.

Mendelsohn AR, Larrick J.

Rejuvenation Res. 2017 Sep 25. doi: 10.1089/rej.2017.2024. [Epub ahead of print]

PMID: 28942711

http://sci-hub.cc/http://online.liebertpub.com/doi/10.1089/rej.2017.2024

Abstract

The epigenome, which controls cell identity and function, is not maintained with 100 percent fidelity in somatic animal cells. Errors in the maintenance of the epigenome lead to epigenetic drift, an important hallmark of aging. Numerous studies have described DNA methylation clocks that correlate epigenetic drift with increasing age. The question of how significant a role epigenetic drift plays in creating the phenotypes associated with aging remains open. A recent study describes a new DNA methylation clock that can be slowed by caloric restriction (CR) in a way that correlates with the degree of lifespan and healthspan extension conferred by CR, suggesting that epigenetic drift itself is a determinant of mammalian lifespan. Genetic transplantation using genomic editing of DNA methylation homeostatic genes from long-lived to short-lived species is one way to potentially demonstrate a causative role for DNA methylation. Whether the DNA methylation clock be reset to youthful state, eliminating the effects of epigenetic drift without requiring a pluripotent cell intermediate is a critical question with profound implications for the development of aging therapeutics. Methods that transiently erase the DNA methylation patterns of somatic cells may be developed that reset this aging hallmark with potentially profound effects on lifespan, if DNA methylation-based epigenetic drift really plays a primary role in aging.

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Caloric restriction delays age-related methylation drift.

Maegawa S, Lu Y, Tahara T, Lee JT, Madzo J, Liang S, Jelinek J, Colman RJ, Issa JJ.

Nat Commun. 2017 Sep 14;8(1):539. doi: 10.1038/s41467-017-00607-3.

PMID: 28912502 Free PMC Article

https://www.crsociety.org/topic/11800-als-cr-updates/page-12?hl=tahara&do=findComment&comment=23719

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Caloric restriction stabilizes body weight and accelerates behavioral recovery in aged rats after focal ischemia.

Ciobanu O, Elena Sandu R, Tudor Balseanu A, Zavaleanu A, Gresita A, Petcu EB, Uzoni A, Popa-Wagner A.

Aging Cell. 2017 Sep 29. doi: 10.1111/acel.12678. [Epub ahead of print]

PMID: 28961383

http://onlinelibrary.wiley.com/doi/10.1111/acel.12678/full

Abstract

Obesity and hyperinsulinemia are risk factors for stroke. We tested the hypothesis that caloric restriction, which reduces the incidence of age-related obesity and metabolic syndrome, may represent an efficient and cost-effective strategy for preventing stroke and its devastating consequences. To this end, we placed aged, obese Sprague-Dawley aged rats on a calorie-restricted diet for 8 weeks prior to the experimental infarction. Stroke in this animal model caused a progressive decrease in weight that reached a minimum at day 6 for the young rats, and at day 10 for the aged, ad libitum-fed rats. However, in aged animals that were calorie-restricted prior to stroke, body weight did not decrease after stroke, but we noted accelerated body weight gain shortly thereafter starting at day 5 poststroke. Moreover, calorie-restricted aged animals showed improved behavioral recovery in tasks requiring complex sensorimotor skills, or in tasks requiring cutaneous sensitivity and sensorimotor integration or spatial memory. Likewise, calorie-restricted aged rats showed significant poststroke increases in serum glucose, insulin, and IGF1 levels, as well as CR-specific changes in the expression of gene transcripts involved in glycogen metabolism, IGF signaling, apoptosis, arteriogenesis, and hypoxia. In conclusion, our study shows that recovery from stroke is enhanced in aged rats by a dietary regimen that reduces body weight prior to infarct.

KEYWORDS:

aging; behavior; body weight; calorie restriction; neuroprotection; stroke; transcriptomics

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Drosophila as a model for ageing.

Piper MDW, Partridge L.

Biochim Biophys Acta. 2017 Sep 27. pii: S0925-4439(17)30331-9. doi: 10.1016/j.bbadis.2017.09.016. [Epub ahead of print] Review.

PMID: 28964875

http://sci-hub.cc/10.1016/j.bbadis.2017.09.016

Abstract

Drosophila melanogaster has been a key model in developing our current understanding of the molecular mechanisms of ageing. Of particular note is its role in establishing the evolutionary conservation of reduced insulin and IGF-1-like signaling in promoting healthy ageing. Capitalizing on its many advantages for experimentation, more recent work has revealed how precise nutritional and genetic interventions can improve fly lifespan without obvious detrimental side effects. We give a brief summary of these recent findings as well as examples of how they may modify ageing via actions in the gut and muscle. These discoveries highlight how expanding our understanding of metabolic and signaling interconnections will provide even greater insight into how these benefits may be harnessed for anti-ageing interventions.

KEYWORDS:

Ageing; Dietary restriction; Drosophila; Insulin signaling; Tissue control of ageing; Tor

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Neuroimaging Biomarkers of Caloric Restriction on Brain Metabolic and Vascular Functions.

Lin AL, Parikh I, Hoffman JD, Ma D.

Curr Nutr Rep. 2017 Mar;6(1):41-48. doi: 10.1007/s13668-017-0187-9.

PMID: 28966881

http://sci-hub.cc/10.1007/s40778-017-0072-x

Abstract

PURPOSE OF REVIEW:

Non-invasive neuroimaging methods have been developed as powerful tools for identifying in vivo brain functions for studies in humans and animals. Here we review the imaging biomarkers that are being used to determine the changes within brain metabolic and vascular functions induced by caloric restriction (CR), and their potential usefulness for future studies with dietary interventions in humans.

RECENT FINDINGS:

CR causes an early shift in brain metabolism of glucose to ketone bodies, and enhances ATP production, neuronal activity and cerebral blood flow (CBF). With age, CR preserves mitochondrial activity, neurotransmission, CBF, and spatial memory. CR also reduces anxiety in aging mice. Neuroimaging studies in humans show that CR restores abnormal brain activity in the amygdala of women with obesity and enhances brain connectivity in old adults.

SUMMARY:

Neuroimaging methods have excellent translational values and can be widely applied in future studies to identify dietary effects on brain functions in humans.

KEYWORDS:

Alzheimer’s disease; anxiety; brain aging; caloric restriction; cerebral blood flow; glucose metabolism; ketone bodies; magnetic resonance imaging (MRI); magnetic resonance spectroscopy (MRS); mammalian target of rapamcyin (mTOR); memory; positron emission tomography (PET); translational research

 

Ageing: Live longer with small nucleoli.

Zlotorynski E.

Nat Rev Mol Cell Biol. 2017 Sep 27. doi: 10.1038/nrm.2017.100. [Epub ahead of print] No abstract available.

PMID: 28951566

http://sci-hub.cc/10.1038/nrm.2017.100

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Small nucleoli are a cellular hallmark of longevity.

Tiku V, Jain C, Raz Y, Nakamura S, Heestand B, Liu W, Späth M, Suchiman HED, Müller RU, Slagboom PE, Partridge L, Antebi A.

Nat Commun. 2016 Aug 30;8:16083. doi: 10.1038/ncomms16083.

PMID: 28853436 Free PMC Article

Abstract

Animal lifespan is regulated by conserved metabolic signalling pathways and specific transcription factors, but whether these pathways affect common downstream mechanisms remains largely elusive. Here we show that NCL-1/TRIM2/Brat tumour suppressor extends lifespan and limits nucleolar size in the major C. elegans longevity pathways, as part of a convergent mechanism focused on the nucleolus. Long-lived animals representing distinct longevity pathways exhibit small nucleoli, and decreased expression of rRNA, ribosomal proteins, and the nucleolar protein fibrillarin, dependent on NCL-1. Knockdown of fibrillarin also reduces nucleolar size and extends lifespan. Among wildtype C. elegans, individual nucleolar size varies, but is highly predictive for longevity. Long-lived dietary restricted fruit flies and insulin-like-peptide mutants exhibit small nucleoli and fibrillarin expression, as do long-lived dietary restricted and IRS1 knockout mice. Furthermore, human muscle biopsies from individuals who underwent modest dietary restriction coupled with exercise also display small nucleoli. We suggest that small nucleoli are a cellular hallmark of longevity and metabolic health conserved across taxa.

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Nucleolar expansion and elevated protein translation in premature aging.

Buchwalter A, Hetzer MW.

Nat Commun. 2017 Aug 30;8(1):328. doi: 10.1038/s41467-017-00322-z.

PMID: 28855503 Free PMC Article

Abstract

Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.HGPS is a premature aging disease caused by mutations in the nuclear protein lamin A. Here, the authors show that cells from patients with HGPS have expanded nucleoli and increased protein synthesis, and report that nucleoli also expand as aging progresses in cells derived from healthy individuals.

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Dietary methionine restriction modulates renal response and attenuates kidney injury in mice.

Cooke D, Ouattara A, Ables GP.

FASEB J. 2017 Sep 28. pii: fj.201700419R. doi: 10.1096/fj.201700419R. [Epub ahead of print]

PMID: 28970255

https://sci-hub.cc/http://www.fasebj.org/lookup/doi/10.1096/fj.201700419R

Abstract

Methionine restriction (MR) extends the lifespan across several species, such as rodents, fruit flies, roundworms, and yeast. MR studies have been conducted on various rodent organs, such as liver, adipose tissue, heart, bones, and skeletal muscle, to elucidate its benefits to the healthspan; however, studies of the direct effect of MR on kidneys are lacking. To investigate the renal effects of MR, we used young and aged unilateral nephrectomized and 5/6 nephrectomized (5/6Nx) mice. Our studies indicated that MR mice experienced polydipsia and polyuria compared with control-fed counterparts. Urine albumin, creatinine, albumin-to-creatinine ratio, sulfur amino acids, and electrolytes were reduced in MR mice. Kidneys of MR mice up-regulated genes that are involved in ion transport, such as Aqp2, Scnn1a, and Slc6a19, which indicated a response to maintain osmotic balance. In addition, we identified renoprotective biomarkers that are affected by MR, such as clusterin and cystatin C. Of importance, MR attenuated kidney injury in 5/6Nx mice by down-regulating inflammation and fibrosis mechanisms. Thus, our studies in mice show the important role of kidneys during MR in maintaining osmotic homeostasis. Moreover, our studies also show that the MR diet delays the progression of kidney disease.

KEYWORDS:

5/6 nephrectomy; fibrosis; inflammation; ion transport; osmotic homeostasis

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Pleiotropic responses to methionine restriction.

Ables GP, Johnson JE.

Exp Gerontol. 2017 Aug;94:83-88. doi: 10.1016/j.exger.2017.01.012. Epub 2017 Jan 17. Review.

PMID: 28108330 Free Article

https://ac.els-cdn.com/S0531556517300451/1-s2.0-S0531556517300451-main.pdf?_tid=d1679d50-a91e-11e7-b032-00000aab0f6c&acdnat=1507133728_1d3f2d6e1748a391aed622eab2237bd2

Abstract

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

KEYWORDS:

Bone; Cancer; Cardiovascular; Invertebrates; Lifespan extension; Methionine restriction; Yeast

 

Positive effects of meal frequency and calorie restriction on antioxidant systems in rats.

Savas HB, Gultekin F, Ciris IM.

North Clin Istanb. 2017 Aug 26;4(2):109-116. doi: 10.14744/nci.2017.21548. eCollection 2017.

PMID: 28971167

https://www.journalagent.com/nci/pdfs/NCI_4_2_109_116.pdf

Abstract

OBJECTIVE:

In living organisms, there is a balance between the oxidant and antioxidant systems. Reactive products continuously formed by exogenous and endogenous sources are rendered harmless by the antioxidant system. Oxidative stress is an etiological factor in aging and the development of various diseases. In the present study, the aim was to investigate the effects of meal frequency and calorie restriction on oxidant-antioxidant systems in rat serum and tissue.

METHODS:

Nine adult male Wistar Albino rats were used for the pilot study, and another 24 adult male Wistar Albino rats, also weighing 200 to 250 g each, were included in the main study. The rats were divided into 3 groups based on nutrition: the ad libitum group (AL) (n=8), the 2-meal group (n=8), and the 2-meal with calorie restriction group (TM-CR) (n=8). Following the 4-week pilot study, nutrition regulation was performed in all groups for 20 weeks, 7 days a week, with 60 minutes allotted per meal. Serum and tissues of rats were isolated at the end of the experiment. Total antioxidant status (TAS) and total oxidant status (TOS) were determined using the Erel method. Oxidative stress index (OSI) was calculated using the formula OSI = TOS/TAS. Liver tissue was examined histopathologically. Statistical analyses were performed using the IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA) program.

RESULTS:

There were significant differences between the AL and TM, and the AL and TM-CR groups in adipose tissue TOS and OSI, and between the AL and TM groups in the liver TAS of the rats (p<0.05).

CONCLUSION:

Calorie restriction and sparse meal frequency can increase the activity of antioxidants and can reduce oxidative stress. Thus, many diseases caused by oxidative stress may be prevented with the correct regulation of feeding.

KEYWORDS:

Antioxidant status; caloric restriction; meal frequency; nutrition; oxidant status; rat

 

The risk of acute coronary syndrome in Ramadan.

Sriha Belguith A, Baccouche H, Grissa MH, Boubaker H, Bouida W, Beltaief K, Sekma A, Fredj N, Bzeouiche N, Zina Z, Boukef R, Soltani M, Nouira S.

Tunis Med. 2016 Oct;94(10):599-603.

PMID: 28972251

http://www.latunisiemedicale.com/article-medicale-tunisie_3119_en

Abstract

BACKGROUND:

Data on the effect of fasting on coronary disease are rare and controversial. The aim of our study was to investigate the influence of Ramadan on the prevalence of acute coronary syndrome among chest pain patients in the emergency department of Monastir.

METHODS:

It was a prospective study, performed in the emergency department of Fattouma Bourguiba University Hospital of Monastir, during the 3 months before, during and after Ramadan from 2012 to 2014. We included all patients with non-traumatic chest pain during the study period. Data were collected using a standardized form. The uniformity chi 2 test, ANOVA test, Kruskal-Wallis test were performed at the 5% level. Binary logistic regression model was used for multivariate analysis.

RESULTS:

The SCA prevalence was 17% a month before Ramadan, 22% during Ramadan and 28% one month after Ramadan (p = 0.007). According to the results of the multivariate analysis, the period of Ramadan is not associated with increase of risk of SCA whereas the risk doubles after Ramadan in all group (p = 0.001). In subgroups analysis, the period of R was associated with an amplification of risk in men aged more than 55 years and women older than 65 years (OR: 2.1; p = 0.020) and among subjects with hypertension (OR: 2.4, p = 0.007). Ramadan and Shawwal were not associated with an increase of risk among subjects without CVX risk factor.

CONCLUSION:

We have demonstrated that the risk of SCA has increased in Ramadan only among the elderly and patient with hypertension. The increased risk in Shawwal can be explained by the lifting of dietary restriction.

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Caloric Restriction Study Design Limitations in Rodent and Nonhuman Primate Studies.

Vaughan KL, Kaiser T, Peaden R, Anson RM, de Cabo R, Mattison JA.

J Gerontol A Biol Sci Med Sci. 2017 Jun 13. doi: 10.1093/gerona/glx088. [Epub ahead of print]

PMID: 28977341

http://sci-hub.cc/10.1093/gerona/glx088

Abstract

For a century, we have known that caloric restriction influences aging in many species. However, only recently it was firmly established that the effect is not entirely dependent on the calories provided. Instead, rodent and nonhuman primate models have shown that the rate of aging depends on other variables, including the macronutrient composition of the diet, the amount of time spent in the restricted state, age of onset, the gender and genetic background, and the particular feeding protocol for the control group. The field is further complicated when attempts are made to compare studies across different laboratories, which seemingly contradict each other. Here, we argue that some of the contradictory findings are most likely due to methodological differences. This review focuses on the four methodological differences identified in a recent comparative report from the National Institute on Aging and University of Wisconsin nonhuman primate studies, namely feeding regimen, diet composition, age of onset, and genetics. These factors, that may be influencing the effects of a calorie restriction intervention, are highlighted in the rodent model to draw parallels and elucidate findings reported in a higher species, nonhuman primates.

KEYWORDS:

Calorie restriction; Dietary restriction; Monkey; Rodent; Translational

Edited by AlPater

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Impact of Age, Caloric Restriction, and Influenza Infection on Mouse Gut Microbiome: An Exploratory Study of the Role of Age-Related Microbiome Changes on Influenza Responses.

Bartley JM, Zhou X, Kuchel GA, Weinstock GM, Haynes L.

Front Immunol. 2017 Sep 20;8:1164. doi: 10.3389/fimmu.2017.01164. eCollection 2017.

PMID: 28979265

Abstract

Immunosenescence refers to age-related declines in the capacity to respond to infections such as influenza (flu). Caloric restriction represents a known strategy to slow many aging processes, including those involving the immune system. More recently, some changes in the microbiome have been described with aging, while the gut microbiome appears to influence responses to flu vaccination and infection. With these considerations in mind, we used a well-established mouse model of flu infection to explore the impact of flu infection, aging, and caloric restriction on the gut microbiome. Young, middle-aged, and aged caloric restricted (CR) and ad lib fed (AL) mice were examined after a sublethal flu infection. All mice lost 10-20% body weight and, as expected for these early time points, losses were similar at different ages and between diet groups. Cytokine and chemokine levels were also similar with the notable exception of IL-1α, which rose more than fivefold in aged AL mouse serum, while it remained unchanged in aged CR serum. Fecal microbiome phyla abundance profiles were similar in young, middle-aged, and aged AL mice at baseline and at 4 days post flu infection, while increases in Proteobacteria were evident at 7 days post flu infection in all three age groups. CR mice, compared to AL mice in each age group, had increased abundance of Proteobacteria and Verrucomicrobia at all time points. Interestingly, principal coordinate analysis determined that diet exerts a greater effect on the microbiome than age or flu infection. Percentage body weight loss correlated with the relative abundance of Proteobacteria regardless of age, suggesting flu pathogenicity is related to Proteobacteria abundance. Further, several microbial Operational Taxonomic Units from the Bacteroidetes phyla correlated with serum chemokine/cytokines regardless of both diet and age suggesting an interplay between flu-induced systemic inflammation and gut microbiota. These exploratory studies highlight the impact of caloric restriction on fecal microbiome in both young and aged animals, as well as the many complex relationships between flu responses and gut microbiota. Thus, these preliminary studies provide the necessary groundwork to examine how gut microbiota alterations may be leveraged to influence declining immune responses with aging.

KEYWORDS:

aging; caloric restriction; cytokines; gut microbiome; influenza

 

Mitochondria: the hub of energy deprivation-induced autophagy.

Yi C, Tong JJ, Yu L.

Autophagy. 2017 Oct 5:0. doi: 10.1080/15548627.2017.1382785. [Epub ahead of print]

PMID: 28980858

Abstract

Macroautophagy/autophagy, a process that is highly conserved from yeast to mammals, delivers unwanted cellular contents to lysosomes or the vacuole for degradation. It has been reported that autophagy is crucial for maintaining glucose homeostasis. However, the mechanism by which energy deprivation induces autophagy is not well established. Recently, we found that Mec1/ATR, originally identified as a sensor of DNA damage, is essential for glucose starvation-induced autophagy. Mec1 is recruited to mitochondria where it is phosphorylated by activated Snf1 in response to glucose starvation. Phosphorylation of Mec1 leads to the assembly of a Snf1-Mec1-Atg1 module on mitochondria, which promotes the association of Atg1 with Atg13. Furthermore, we found that mitochondrial respiration is specifically required for glucose starvation-induced autophagy but not autophagy induced by canonical stimuli. The Snf1-Mec1-Atg1 module is essential for maintaining mitochondrial respiration and regulating glucose starvation-induced autophagy.

KEYWORDS:

Snf1-Mec1-Atg1; autophagy; energy deprivation; mitochondria; respiration

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RFamide-related Peptide-3 and the Trade-off between Reproductive and Ingestive Behavior.

Schneider JE, Benton NA, Russo KA, Klingerman CM, Williams WP 3rd, Simberlund J, Abdulhay A, Brozek JM, Kriegsfeld LJ.

Integr Comp Biol. 2017 Jul 27. doi: 10.1093/icb/icx097. [Epub ahead of print]

PMID: 28985338

Abstract

Ingestive and sex behaviors are important for individual survival and reproductive success, but when environmental energy availability is limited, individuals of many different species make a trade-off, forfeiting sex for ingestive behavior. For example, food-deprived female Syrian hamsters (Mesocricetus auratus) forego vaginal scent marking and lordosis (sex behaviors) in favor of foraging, hoarding, and eating food (ingestive behavior). Reproductive processes tend to be energetically costly, and individual survival requires homeostasis in metabolic energy. Thus, during energetic challenges, the chances of survival are enhanced by decreasing the energy expended on reproductive processes. The entire hypothalamic-pituitary-gonadal (HPG) system is inhibited by severe energetic challenges, but comparatively little is known about the effects of mild energetic challenges. We hypothesized that (1) a trade-off is made between sex and ingestive behavior even when the level of food restriction is insufficient to inhibit the HPG system; (2) mild energetic challenges force a trade-off between appetitive ingestive and sex behaviors, but not consummatory versions of the same behaviors; and (3) the trade-off is orchestrated by ovarian steroid modulation of RFamide-related peptide 3 (RFRP-3). In other species, RFRP-3, an ortholog of avian gonadotropin-inhibitory hormone, is implicated in control of behavior in response to energetic challenges and stressful stimuli. In support of our three hypotheses, there is a "dose-response" effect of food restriction and re-feeding on the activation of RFRP-3-immunoreactive cells in the dorsomedial hypothalamus and on appetitive behaviors (food hoarding and sexual motivation), but not on consummatory behaviors (food intake and lordosis), with no significant effect on circulating levels of estradiol or progesterone. The effect of food restriction on the activation of RFRP-3 cells is modulated at the time of estrus in gonadally-intact females and in ovariectomized females treated with progesterone alone or with estradiol plus progesterone. Intracerebral treatment with RFRP-3 results in significant decreases in sexual motivation and results in significant but small increases in food hoarding in hamsters fed ad libitum. These and other results are consistent with the idea that ovarian steroids and RFRP-3 are part of a system that orchestrates trade-offs in appetitive behaviors in environments where energy availability fluctuates.

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The longevity gene INDY (I'm Not Dead Yet) in metabolic control: Potential as pharmacological target.

Willmes DM, Kurzbach A, Henke C, Zahn G, Heifetz A, Jordan J, Helfand SL, Birkenfeld AL.

Pharmacol Ther. 2017 Oct 4. pii: S0163-7258(17)30240-1. doi: 10.1016/j.pharmthera.2017.10.003. [Epub ahead of print] Review.

PMID: 28987323

Abstract

The regulation of metabolic processes by the Indy (I'm Not Dead Yet) (SLC13A5/NaCT) gene was revealed through studies in Drosophila melanogaster and Caenorhabditis elegans. Reducing the expression of Indy in these species extended their life span by a mechanism resembling caloric restriction, without reducing food intake. In D. melanogaster, mutating the Indy gene reduced body fat content, insulin-like proteins and reactive oxygen species production. Subsequent studies indicated that Indy encodes a citrate transporter located on the cell plasma membrane. The transporter is highly expressed in the mammalian liver. We generated a mammalian knock out model deleting the mammalian homolog mIndy (SLC13A5). The knock out animals were protected from HFD induced obesity, fatty liver and insulin resistance. Moreover, we have shown that inducible and liver selective knock down of mIndy protects against the development of fatty liver and insulin resistance and that obese humans with type 2 diabetes and non-alcoholic fatty liver disease have increased levels of mIndy. Therefore, the transporter mINDY (NaCT) has been proposed to be an 'ideal target for the treatment of metabolic disease'. A small molecule inhibitor of the mINDY transporter has been generated, normalizing glucose levels and reducing fatty liver in a model of diet induced obese mice. Taken together, studies from lower organisms, mammals and humans suggest that mINDY (NaCT) is an attractive target for the treatment of metabolic disease.

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