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Effects of A One-week Fasting Therapy in Patients with Type-2 Diabetes Mellitus and Metabolic Syndrome - A Randomized Controlled Explorative Study.

Li C, Sadraie B, Steckhan N, Kessler C, Stange R, Jeitler M, Michalsen A.

Exp Clin Endocrinol Diabetes. 2017 Apr 13. doi: 10.1055/s-0043-101700. [Epub ahead of print]

PMID: 28407662


There is increasing experimental evidence for beneficial effects of calorie restriction and intermittent fasting in type 2 diabetes mellitus (T2DM). In humans, prolonged fasting is established as a health-promoting complementary treatment in Europe and claimed to improve metabolism by a complex hormetic response. We aimed to investigate effects of a one-week fasting period compared to usual care in T2DM by means of a pilot trial. Patients with manifest T2DM medically treated with oral hypoglycemic agents and/or insulin were randomly assigned to a 7-day fasting program followed by dietary advice or to usual care and dietary advice only. Fasting was performed according to the method of Buchinger with a nutritional energy intake of 300kcal/day by liquids only and stepwise re-introduction of solid food thereafter. Outcomes were assessed baseline and after 4 months. Of 46 enrolled participants, 32 (n=16 each group) completed the trial and were included for final analyses. Fasting was well accepted, there were no serious adverse events. After 4 months mean weight decreased by 3.5 kg and 2.0 kg in the fasting vs. control group (p=0.03) paralleled by greater reduction of abdominal circumference (p=0.001). Fasting led to a significant decrease of systolic/diastolic blood pressure (p=0.01; p=0.003) and increased quality-of-life (p=0.04), while for HbA1c, insulin and HOMA-index only non-significant improvements were observed. Results of this study suggest that prolonged fasting is feasible and might have beneficial clinical effects. The effectiveness of fasting should be proved in larger confirmatory trials that include intermittent fasting in follow-ups to enable more pronounced and long-term effects.

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Long-Term Calorie Restriction Enhances Cellular Quality-Control Processes in Human Skeletal Muscle.

Yang L, Licastro D, Cava E, Veronese N, Spelta F, Rizza W, Bertozzi B, Villareal DT, Hotamisligil GS, Holloszy JO, Fontana L.

Cell Rep. 2016 Jan 26;14(3):422-8. doi: 10.1016/j.celrep.2015.12.042. Epub 2016 Jan 7.

PMID: 26774472 Free Article




Calorie restriction (CR) retards aging, acts as a hormetic intervention, and increases serum corticosterone and HSP70 expression in rodents. However, less is known regarding the effects of CR on these factors in humans. Serum cortisol and molecular chaperones and autophagic proteins were measured in the skeletal muscle of subjects on CR diets for 3-15 years and in control volunteers. Serum cortisol was higher in the CR group than in age-matched sedentary and endurance athlete groups (15.6 ± 4.6 ng/dl versus 12.3 ± 3.9 ng/dl and 11.2 ± 2.7 ng/dl, respectively; p ≤ 0.001). HSP70, Grp78, beclin-1, and LC3 mRNA and/or protein levels were higher in the skeletal muscle of the CR group compared to controls. Our data indicate that CR in humans is associated with sustained rises in serum cortisol, reduced inflammation, and increases in key molecular chaperones and autophagic mediators involved in cellular protein quality control and removal of dysfunctional proteins and organelles.


HSP70; aldosterone; autophagy; calorie restriction; cortisol


Time-dependent association of glucocorticoids with adverse outcome in community-acquired pneumonia: a 6-year prospective cohort study.

Nickler M, Ottiger M, Steuer C, Kutz A, Christ-Crain M, Zimmerli W, Thomann R, Hoess C, Henzen C, Bernasconi L, Huber A, Mueller B, Schuetz P; ProHOSP Study Group..

Crit Care. 2017 Mar 24;21(1):72. doi: 10.1186/s13054-017-1656-7.

PMID: 28335807 Free PMC Article



The hypothalamic-pituitary-adrenal stress axis plays a crucial role in community-acquired pneumonia (CAP), with high cortisol being associated with disease severity and corticosteroid treatment resulting in earlier time to recovery. Our aim in the present study was to compare different glucocorticoid hormones, including cortisol, 11-deoxycortisol, cortisone, and corticosterone, regarding their association with short- and long-term adverse outcomes in a well-defined CAP cohort.


We prospectively followed 285 patients with CAP from a previous Swiss multicenter trial for a median of 6.1 years and measured different admission glucocorticoid serum levels by liquid chromatography coupled with tandem mass spectrometry. We used adjusted Cox regression models to investigate associations between admission hormone levels and all-cause mortality at different time points.


Mortality was 5.3% after 30 days and increased to 47.3% after 6 years. High admission cortisol was associated with adverse outcome after 30 days (adjusted OR 3.85, 95% CI 1.10-13.49, p = 0.035). In the long term (i.e.,), however, high admission cortisol was associated with better survival (adjusted HR after 3 years 0.53, 95% CI 0.32-0.89, p = 0.017; adjusted HR after 6 years 0.57, 95% CI 0.36-0.90, p = 0.015). Compared with 11-deoxycortisol, cortisone, and corticosterone, cortisol showed the highest association with mortality.


Among different glucocorticoid hormones, cortisol showed the highest association with mortality in CAP. Whereas a more pronounced glucocorticoid stress response on hospital admission was associated with higher short-term adverse outcome, long-term outcome was favorable in these patients. These data should support the correct interpretation of glucocorticoid blood data.


11-Deoxycortisol; Community-acquired pneumonia; Corticosterone; Cortisol; Cortisone; Disease severity; Glucocorticoid hormones; Mortality/outcome prediction; Pneumonia severity index

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Nutrition modulation of human aging: The calorie restriction paradigm.

Das SK, Balasubramanian P, Weerasekara YK.

Mol Cell Endocrinol. 2017 Apr 12. pii: S0303-7207(17)30224-1. doi: 10.1016/j.mce.2017.04.011. [Epub ahead of print]

PMID: 28412520



Globally, the aging population is growing rapidly, creating an urgent need to attenuate age-related health conditions, including metabolic disease and disability. A promising strategy for healthy aging based on consistently positive results from studies with a variety of species, including non-human primates (NHP), is calorie restriction (CR), or the restriction of energy intake while maintaining intake of essential nutrients. The burgeoning evidence for this approach in humans is reviewed and the major study to date to address this question, CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy), is described. CALERIE findings indicate the feasibility of CR in non-obese humans, confirm observations in NHP, and are consistent with improvements in disease risk reduction and potential anti-aging effects. Finally, the mechanisms of CR in humans are reviewed which sums up the fact that evolutionarily conserved mechanisms mediate the anti-aging effects of CR. Overall, the prospect for further research in both NHP and humans is highly encouraging.


Aging; CALERIE; Calorie restriction; Nutritional modulation


During yeast chronological aging resveratrol supplementation results in a short-lived phenotype Sir2-dependent.

Orlandi I, Stamerra G, Strippoli M, Vai M.

Redox Biol. 2017 Apr 9;12:745-754. doi: 10.1016/j.redox.2017.04.015. [Epub ahead of print]

PMID: 28412652


Resveratrol (RSV) is a naturally occurring polyphenolic compound endowed with interesting biological properties/functions amongst which are its activity as an antioxidant and as Sirtuin activating compound towards SIRT1 in mammals. Sirtuins comprise a family of NAD+-dependent protein deacetylases that are involved in many physiological and pathological processes including aging and age-related diseases. These enzymes are conserved across species and SIRT1 is the closest mammalian orthologue of Sir2 of Saccharomyces cerevisiae. In the field of aging researches, it is well known that Sir2 is a positive regulator of replicative lifespan and, in this context, the RSV effects have been already examined. Here, we analyzed RSV effects during chronological aging, in which Sir2 acts as a negative regulator of chronological lifespan (CLS). Chronological aging refers to quiescent cells in stationary phase; these cells display a survival-based metabolism characterized by an increase in oxidative stress. We found that RSV supplementation at the onset of chronological aging, namely at the diauxic shift, increases oxidative stress and significantly reduces CLS. CLS reduction is dependent on Sir2 presence both in expired medium and in extreme Calorie Restriction. In addition, all data point to an enhancement of Sir2 activity, in particular Sir2-mediated deacetylation of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (Pck1). This leads to a reduction in the amount of the acetylated active form of Pck1, whose enzymatic activity is essential for gluconeogenesis and CLS extension.


Chronological aging; Oxidative stress; Resveratrol; Saccharomyces cerevisiae; Sir2

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Effect of Whey Protein in Conjunction With a Caloric-Restricted Diet and Resistance Training.

Dudgeon WD, Kelley EP, Scheett TP.

J Strength Cond Res. 2017 May;31(5):1353-1361. doi: 10.1519/JSC.0000000000001196.

PMID: 28415067


Caloric-restricted weight loss, especially rapid weight loss, results from a decrease in both lean and fat mass (FM). The goal for many is to lose FM while retaining lean body mass (LBM) and muscular performance thus many turn to supplements. Sixteen resistance-trained men (24 ± 1.6 years of age) completed a 4 d·wk body building style split resistance training program for 8 weeks in conjunction with a pre-exercise, periexercise, and postexercise ingestion of whey protein (WHEY) nutritional supplement or carbohydrate (CON)-based nutritional supplement. There were no differences in body mass change between the WHEY and CON groups although both groups lost body mass (p ≤ 0.05); however, WHEY group maintained LBM whereas the CON group lost (p ≤ 0.05), and the WHEY group lost FM (p > 0.05) and the CON group did not, although the change in FM between groups was not different. Both the WHEY and CON (p ≤ 0.05) groups significantly increased lower-body strength. The WHEY group increased upper-body strength (p ≤ 0.05), whereas the CON did not change. Both groups (p ≤ 0.05) increased lower-body repetitions to fatigue with the increase greater in the CON group (p ≤ 0.05). The CON group also increased upper-body repetitions (p ≤ 0.05) whereas WHEY did not. WHEY group lost body mass, composed of FM, whereas CON also experienced a loss in body mass, but this loss was due to decrease in LBM. Neither group experienced a loss in muscle performance, with the WHEY group tending to show improvement in strength and CON group in endurance. These data indicate WHEY supplementation compared with carbohydrate supplementation, during a caloric-restricted "cut" diet can assist in maintaining LBM while allowing for the loss of FM.

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Caloric restriction delays early phases of carcinogenesis via effects on the tissue microenvironment.

Cadoni E, Marongiu F, Fanti M, Serra M, Laconi E.

Oncotarget. 2017 Mar 21. doi: 10.18632/oncotarget.16421. [Epub ahead of print]

PMID: 28415598


Caloric restriction (CR) is an effective and consistent means to delay aging and the incidence of chronic diseases related to old age, including cancer. However, the precise mechanisms responsible for the beneficial effect of CR on carcinogenic process are yet to be identified.In the present studies the hypothesis was tested that the CR might delay carcinogenesis via modulatory effects exerted on the age-associated, neoplastic-prone tissue microenvironment. Using a well characterized, orthotopic cell transplantation (Tx) system in the rat, preneoplastic hepatocytes isolated from liver nodules were injected into either old syngeneic rats fed ad libitum (AL) or animals of the same age given a CR diet (70% of AL feeding). Analysis of donor-derived cell clusters performed at 10 weeks post-Tx revealed a significant shift towards smaller class sizes in the group receiving CR diet. Clusters comprising more than 50 cells, including large hepatic nodules, were thrice more frequent in AL vs. CR animals. Incidence of spontaneous endogenous nodules was also decreased by CR. Markers of cell senescence were equally expressed in the liver of AL and CR groups. However, higher levels of SIRT1 and FOXO1 proteins were detected in CR-exposed livers, while expression of HDAC1 and C/EBPβ were decreased. These results are interpreted to indicate that CR delays the emergence of age-associated neoplastic disease through effects exerted, at least in part, on the tissue microenvironment. Nutrient-sensing pathways might mediate such modulatory effect.


aging; caloric restriction; carcinogenesis; microenvironment; pre-neoplastic hepatocytes


Association of Diet With Skin Histological Features in UV-B-Exposed Mice.

Bhattacharyya TK, Hsia Y, Weeks DM, Dixon TK, Lepe J, Thomas JR.

JAMA Facial Plast Surg. 2017 Apr 13. doi: 10.1001/jamafacial.2017.0060. [Epub ahead of print]

PMID: 28418519



Long-term exposure to solar radiation produces deleterious photoaging of the skin. It is not known if diet can influence skin photoaging.


To study the influence of a calorie-restricted diet and an obesity diet in mice exposed to long-term UV-B irradiation to assess if there is an association between diet and histopathological response to UV-B irradiation.


In this animal model study in an academic setting, the dorsal skin of SKH1 hairless mice receiving normal, calorie-restricted, and obesity diets was exposed to UV-B irradiation 3 times a week for 10 weeks and were compared with corresponding controls. The mice were placed in the following groups, with 8 animals in each group: (1) intact control © with regular diet and no UV-B exposure, (2) intact control with UV-B exposure (CR), (3) calorie-restricted diet (CrC), (4) calorie-restricted diet with UV-B exposure (CrR), (5) obesity diet (OC), and (6) obesity diet with UV-B exposure (OR). The experiment was conducted during October through December 2013. Tissue processing and histological analysis were completed in 2016.


Histomorphometric analysis was performed on paraffin-embedded skin sections stained by histological and immunohistochemical methods for estimation of epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, mast cells, dermal cellularity, and adipose layer ratio. Changes in wrinkles were noted.


Hairless female mice (age range, 6-8 weeks) were obtained. With a normal diet, changes from UV-B irradiation occurred in epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, and mast cells, which were modestly influenced by an obesity diet. Calorie restriction influenced the skin in nonirradiated control animals, with higher values for most variables. After UV-B exposure in animals with calorie restriction, epidermal thickness was increased, but other variables were unaffected. Animals receiving the calorie-restricted diet lost weight when exposed to long-term UV-B irradiation. Wrinkles were reduced in the calorie-restricted control group and in UV-B-exposed animals who received the obesity diet.


Dietary alterations seem to modify histopathological responses to UV-B exposure in the skin of hairless mice.



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Chocolate Consumption and Risk of Heart Failure: A Meta-Analysis of Prospective Studies.

Gong F, Yao S, Wan J, Gan X.

Nutrients. 2017 Apr 20;9(4). pii: E402. doi: 10.3390/nu9040402.

PMID: 28425931


Epidemiological studies have shown inconsistent findings on the association between chocolate consumption and risk of heart failure (HF). We, therefore, performed a meta-analysis of prospective studies to determine the role of chocolate intake in the prevention of HF. We searched databases of PubMed, Web of Science, and Scopus through December 2016 and scrutinized the reference lists of relevant literatures to identify eligible studies. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were aggregated using random effect models. The dose-response relationship between chocolate consumption and incident HF was also assessed. This meta-analysis is registered with PROSPERO, number CRD42017054230. Five prospective studies with 106,109 participants were finally included. Compared to no consumption of chocolate, the pooled HRs (95% CIs) of HF were 0.86 (0.82-0.91) for low-to-moderate consumption (<7 servings/week) and 0.94 (0.80-1.09) for high consumption (≥7 servings/week). In dose-response meta-analysis, we detected a curve linear relationship between chocolate consumption and risk of HF (p for nonlinearity = 0.005). Compared with non-consumption, the HRs (95% CIs) of HF across chocolate consumption levels were 0.92 (0.88-0.97), 0.86 (0.78-0.94), 0.93 (0.85-1.03), and 1.07 (0.92-1.23) for 1, 3, 7, and 10 servings/week, respectively. In conclusion, chocolate consumption in moderation may be associated with a decreased risk of HF.


chocolate consumption; heart failure; meta-analysis; prevention


Sirtuin 3 Deregulation Promotes Pulmonary Fibrosis.

Sosulski ML, Gongora R, Feghali-Bostwick C, Lasky JA, Sanchez CG.

J Gerontol A Biol Sci Med Sci. 2017 May 1;72(5):595-602. doi: 10.1093/gerona/glw151.

PMID: 27522058



Oxidative stress leads to alveolar epithelial cell injury and fibroblast-myofibroblast differentiation (FMD), key events in the pathobiology of pulmonary fibrosis (PF). Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase regulator of antioxidant response and mitochondrial homeostasis. Here, we demonstrate reduced SIRT3 expression in the lungs of old mice compared to young mice, as well as in two murine models of PF. The analysis of the pattern of SIRT3 expression in the lungs of patients with PF revealed low SIRT3 staining within the fibrotic regions. We also demonstrated, using murine models of PF and human lung fibroblasts, that reduced SIRT3 expression in response to transforming growth factor beta 1 (TGFβ1) promotes acetylation (inactivation) of major oxidative stress response regulators, such as SOD2 and isocitrate dehydrogenase 2. Reduction of SIRT3 in human lung fibroblasts promoted FMD. By contrast, overexpression of SIRT3 attenuated TGFβ1-mediated FMD and significantly reduced the levels of SMAD family member 3 (SMAD3). Resveratrol induced SIRT3 expression and ameliorated acetylation changes induced by TGFβ1. We demonstrated that SIRT3-deficient mice are more susceptible to PF compared to control mice, and concomitantly exhibit enhanced SMAD3 expression. Collectively, these data define a SIRT3/TGFβ1 interaction during aging that may play a significant role in the pathobiology of PF.


Age-related pathology; Lungs/pulmonary; Mitochondria; Reactive oxygen species; SIRT3


SIRT6 Overexpression Improves Various Aspects of Mouse Healthspan.

Roichman A, Kanfi Y, Glazz R, Naiman S, Amit U, Landa N, Tinman S, Stein I, Pikarsky E, Leor J, Cohen HY.

J Gerontol A Biol Sci Med Sci. 2017 May 1;72(5):603-615. doi: 10.1093/gerona/glw152.

PMID: 27519885


The extension in human lifespan in the last century results in a significant increase in incidence of age related diseases. It is therefore crucial to identify key factors that control elderly healthspan. Similar to dietary restriction, mice overexpressing the NAD+ dependent protein deacylase SIRT6 (MOSES) live longer and have reduced IGF-1 levels. However, it is as yet unknown whether SIRT6 also affects various healthspan parameters. Here, a range of age related phenotypes was evaluated in MOSES mice. In comparison to their wild-type (WT) littermates, old MOSES mice showed amelioration of a variety of age-related disorders, including: improved glucose tolerance, younger hormonal profile, reduced age-related adipose inflammation and increased physical activity. The increased activity was accompanied with increased muscle AMP-activated protein kinase (AMPK) activity. Altogether, these results indicate that overexpression of SIRT6 in mice retards important aspects of the aging process and suggest SIRT6 to be a potential therapeutic target for the treatment of a set of age-related disorders.


AMPK; Adipose inflammation; Sirtuins; Voluntary activity


Life-extending Dietary Restriction Reduces Oxidative Damage of Proteins in Grasshoppers but Does Not Alter Allocation of Ingested Nitrogen to Somatic Tissues.

Heck MJ, Pehlivanovic M, Purcell JU, Hahn DA, Hatle JD.

J Gerontol A Biol Sci Med Sci. 2017 May 1;72(5):616-623. doi: 10.1093/gerona/glw094.

PMID: 27307298


Dietary restriction (DR) extends life span and reduces reproduction in most animals. The disposable soma hypothesis suggests that this longevity is the result of reduced investment in reproduction and increased nutrient allocation to the soma, permitting an increase in cellular maintenance. To investigate the role of nutrient allocation upon life-extending DR, tissue-specific nitrogen allocation was tracked in grasshoppers (Romalea microptera) upon a full or restricted (60% of full) diet. In addition, carbonyl (oxidized protein) assays addressed tissue maintenance. To develop a labeled diet on which grasshoppers could thrive, hydroponically grown Romaine lettuce was enriched with 15N. This allowed quantification of nitrogen allocation upon a normal or restricted diet. There was a 50% decrease in reproductive investment upon DR. At the same time, relative allocation of 15N to the ovary did not change. Most important, relative allocation was similar between restricted and full diet grasshoppers for somatic tissues (ie, mandibular and femur muscle, dried hemolymph, gut, and fat body). Carbonyl assays of muscles, hemolymph, and gut revealed an overall reduction in protein oxidation upon DR. These data suggest that DR does not alter nutrient allocation but does reduce protein oxidation, an observation that is inconsistent with the basic predictions of the disposable soma hypothesis.


Invertebrate; Longevity; Nutrition; Reactive oxygen species

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Caloric Restriction-Induced Extension of Chronological Lifespan Requires Intact Respiration in Budding Yeast.

Kwon YY, Lee SK, Lee CK.

Mol Cells. 2017 Apr 20. doi: 10.14348/molcells.2017.2279. [Epub ahead of print]

PMID: 28427248


Caloric restriction (CR) has been shown to extend lifespan and prevent cellular senescence in various species ranging from yeast to humans. Many effects of CR may contribute to extend lifespan. Specifically, CR prevents oxidative damage from reactive oxygen species (ROS) by enhancing mitochondrial function. In this study, we characterized 33 single electron transport chain (ETC) gene-deletion strains to identify CR-induced chronological lifespan (CLS) extension mechanisms. Interestingly, defects in 17 of these 33 ETC genedeleted strains showed loss of both respiratory function and CR-induced CLS extension. On the contrary, the other 16 respiration-capable mutants showed increased CLS upon CR along with increased mitochondrial membrane potential (MMP) and intracellular adenosine triphosphate (ATP) levels, with decreased mitochondrial superoxide generation. We measured the same parameters in the 17 non-respiratory mutants upon CR. CR simultaneously increased MMP and mitochondrial superoxide generation without altering intracellular ATP levels. In conclusion, respiration is essential for CLS extension by CR and is important for balancing MMP, ROS, and ATP levels.


Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat.

Park TJ, Reznick J, Peterson BL, Blass G, Omerbašić D, Bennett NC, Kuich PHJL, Zasada C, Browe BM, Hamann W, Applegate DT, Radke MH, Kosten T, Lutermann H, Gavaghan V, Eigenbrod O, Bégay V, Amoroso VG, Govind V, Minshall RD, Smith ESJ, Larson J, Gotthardt M, Kempa S, Lewin GR.

Science. 2017 Apr 21;356(6335):307-311. doi: 10.1126/science.aab3896.

PMID: 28428423


The African naked mole-rat's (Heterocephalus glaber) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.

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Intermittent food restriction initiated late in life prolongs lifespan and retards the onset of age-related markers in the annual fish Nothobranchius guentheri.

Wang X, Du X, Zhou Y, Wang S, Su F, Zhang S.

Biogerontology. 2017 Apr 21. doi: 10.1007/s10522-017-9699-3. [Epub ahead of print]

PMID: 28432521


Two of the most studied and widely accepted conjectures on possible aging mechanisms are the oxidative stress hypothesis and the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway. Intermittent fasting (IF) is known to modulate aging and to prolong lifespan in a variety of organisms, but the mechanisms are still under debate. In this study, we first demonstrated that late-onset two consecutive days a week fasting, a form of IF, termed intermittent food restriction (IFR), exhibited a time-dependent effect, and long-term late-onset IFR extended the mean lifespan and maximum lifespan by approximately 3.5 and 3 weeks, respectively, in the annual fish Nothobranchius guentheri. We also showed that IFR reduced the accumulation of lipofuscin in the gills and the protein oxidation and lipid peroxidation levels in the muscles. Moreover, IFR was able to enhance the activities of antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase in the fish. Finally, IFR was also able to decelerate the decrease of SirT1 and Foxo3A, but accelerate the decrease of IGF-1. Collectively, our findings suggest that late-onset IFR can retard the onset of age-related markers, and prolong the lifespan of the aging fish, via a synergistic action of an anti-oxidant system and the IIS pathway. It also proposes that the combined assessment of anti-oxidant system and IIS pathway will contribute to providing a more comprehensive view of anti-aging process.


Aging; Annual fish; Intermittent fasting; Lifespan extension; Nothobranchius


Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue.

Boengler K, Kosiol M, Mayr M, Schulz R, Rohrbach S.

J Cachexia Sarcopenia Muscle. 2017 Apr 21. doi: 10.1002/jcsm.12178. [Epub ahead of print] Review.

PMID: 28432755


Age is the most important risk factor for most diseases. Mitochondria play a central role in bioenergetics and metabolism. In addition, several lines of evidence indicate the impact of mitochondria in lifespan determination and ageing. The best-known hypothesis to explain ageing is the free radical theory, which proposes that cells, organs, and organisms age because they accumulate reactive oxygen species (ROS) damage over time. Mitochondria play a central role as the principle source of intracellular ROS, which are mainly formed at the level of complex I and III of the respiratory chain. Dysfunctional mitochondria generating less ATP have been observed in various aged organs. Mitochondrial dysfunction comprises different features including reduced mitochondrial content, altered mitochondrial morphology, reduced activity of the complexes of the electron transport chain, opening of the mitochondrial permeability transition pore, and increased ROS formation. Furthermore, abnormalities in mitochondrial quality control or defects in mitochondrial dynamics have also been linked to senescence. Among the tissues affected by mitochondrial dysfunction are those with a high-energy demand and thus high mitochondrial content. Therefore, the present review focuses on the impact of mitochondria in the ageing process of heart and skeletal muscle. In this article, we review different aspects of mitochondrial dysfunction and discuss potential therapeutic strategies to improve mitochondrial function. Finally, novel aspects of adipose tissue biology and their involvement in the ageing process are discussed.


Ageing; Caloric restriction; Heart; Mitochondria; Reactive oxygen species; Skeletal muscle

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Caloric restriction prevents the progression of murine AApoAII amyloidosis.

Sawashita J, Li L, Liu Y, Ding X, Yang M, Xu Z, Higuchi K.

Amyloid. 2017 Mar;24(sup1):171-172. doi: 10.1080/13506129.2017.1295948. No abstract available.

PMID: 28434314



Microbial flora, probiotics, Bacillus subtilis and the search for a long and healthy human longevity.

Ayala FR, Bauman C, Cogliati S, Leñini C, Bartolini M, Grau R.

Microb Cell. 2017 Mar 16;4(4):133-136. doi: 10.15698/mic2017.04.569.

PMID: 28435840


Probiotics are live microorganisms that have beneficial effects on host health, including extended lifespan, when they are administered or present in adequate quantities. However, the mechanisms by which probiotics stimulate host longevity remain unclear and very poorly understood. In a recent study (Nat. Commun. 8, 14332 (2017) doi: 10.1038/ncomms14332), we used the spore-forming probiotic bacterium Bacillus subtilis and the model organism Caenorhabditis elegans to study the mechanism by which a probiotic bacterium affects host longevity. We found that biofilm-proficient B. subtilis colonized the C. elegans gut and extended the worm lifespan significantly longer than did biofilm-deficient isogenic strains. In addition to biofilm proficiency, the quorum-sensing pentapeptide CSF and nitric oxide (NO) represent the entire B. subtilis repertoire responsible for the extended longevity of C. elegans. B. subtilis grown under biofilm-supporting conditions synthesized higher levels of NO and CSF than under planktonic growth conditions, emphasizing the key role of the biofilm in slowing host aging. Significantly, the prolongevity effect of B. subtilis was primarily due to a downregulation of the insulin-like signaling system that precisely is a key partaker in the healthy longevity of human centenarians. These findings open the possibility to test if the regular consumption of B. subtilis incorporated in foods and beverages could significantly extend human life expectancy and contribute to stop the development of age-related diseases.


Bacillus subtilis; biofilms; dietary restriction; healthy longevity; insulin signaling; lifespan; probiotics

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Bacillus subtilis biofilm extends Caenorhabditis elegans longevity through downregulation of the insulin-like signalling pathway.

Donato V, Ayala FR, Cogliati S, Bauman C, Costa JG, Leñini C, Grau R.

Nat Commun. 2017 Jan 30;8:14332. doi: 10.1038/ncomms14332.

PMID: 28134244 Free PMC Article



Beneficial bacteria have been shown to affect host longevity, but the molecular mechanisms mediating such effects remain largely unclear. Here we show that formation of Bacillus subtilis biofilms increases Caenorhabditis elegans lifespan. Biofilm-proficient B. subtilis colonizes the C. elegans gut and extends worm lifespan more than biofilm-deficient isogenic strains. Two molecules produced by B. subtilis — the quorum-sensing pentapeptide CSF and nitric oxide (NO) — are sufficient to extend C. elegans longevity. When B. subtilis is cultured under biofilm-supporting conditions, the synthesis of NO and CSF is increased in comparison with their production under planktonic growth conditions. We further show that the prolongevity effect of B. subtilis biofilms depends on the DAF-2/DAF-16/HSF-1 signalling axis and the downregulation of the insulin-like signalling (ILS) pathway.

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Timeline of changes in appetite during weight loss with a ketogenic diet.

Nymo S, Coutinho SR, Jørgensen J, Rehfeld JF, Truby H, Kulseng B, Martins C.

Int J Obes (Lond). 2017 Apr 25. doi: 10.1038/ijo.2017.96. [Epub ahead of print]

PMID: 28439092



Diet-induced weight loss (WL) leads to increased hunger and reduced fullness feelings, increased ghrelin and reduced satiety peptides concentration (glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide YY (PYY)). Ketogenic diets seem to minimise or supress some of these responses. The aim of this study was to determine the timeline over which changes in appetite occur during progressive WL with a ketogenic very-low energy diet (VLED).


Thirty-one sedentary adults (18 men), with obesity (BMI: 37±4.5 kg/m2) underwent 8 weeks (wks) of a VLED followed by 4 wks of weight maintenance. Body weight and composition, subjective feelings of appetite and appetite related hormones (insulin, active ghrelin (AG), active GLP-1, total PYY and CCK) were measured in fasting and postprandially, at baseline, on day 3 of the diet, 5 and 10% WL, and at wks 9 and 13.Data shown as mean±s.d.


A significant increase in fasting hunger was observed by day 3 (2±1% WL), (P<0.01), 5% WL (12±8 days) (P<0.05) and wk 13 (17±2% WL) (P<0.05). Increased desire to eat was observed by day 3 (P<0.01) and 5% WL (P<0.05). Postprandial prospective food consumption was significantly reduced at wk 9 (16±2% WL) (P<0.01). Basal total PYY was significantly reduced at 10% WL (32±8 days) (P<0.05). Postprandial active GLP-1 was increased at 5% WL (P<0.01) and CCK reduced at 5 and 10% WL (P<0.01, for both) and wk 9 (P<0.001). Basal and postprandial AG were significantly increased at wk 13 (P<0.001, both).


WL with a ketogenic VLED transiently increases the drive to eat up to 3 weeks (5% WL). After that, and while participants are ketotic, a 10-17% WL is not associated with increased appetite. However, hunger feelings and AG concentrations increase significantly from baseline, once refeeding occurs.

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

Ghachem, Ahmed MSc; Prudhomme, Denis MD, MSc; Rabasa-Lhoret, Rémi MD, PhD; Brochu, Martin PhD

Menopause: Post Author Corrections: April 10, 2017

doi: 10.1097/GME.0000000000000862


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

Methods: Secondary analyses were performed on 73 inactive obese postmenopausal women (age 57.7 +/- 4.8 years; body mass index 32.4 +/- 4.6 kg/m2) who participated in the 6-month CR arm of a study of the Montreal-Ottawa New Emerging Team. The harmonized MetS definition was used to categorize participants with MetS (n = 20, 27.39%) and without MetS (n = 53, 72.61%). Variables of interest were: body composition (dual-energy X-ray absorptiometry), body fat distribution (computed tomography scan), glucose homeostasis at fasting state and during a euglycemic/hyperinsulinemic clamp, fasting lipids, and resting blood pressure.

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

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


NutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to Promote Healthy Aging.

Micó V, Berninches L, Tapia J, Daimiel L.

Int J Mol Sci. 2017 Apr 26;18(5). pii: E915. doi: 10.3390/ijms18050915. Review.

PMID: 28445443


Current sociodemographic predictions point to a demographic shift in developed and developing countries that will result in an unprecedented increase of the elderly population. This will be accompanied by an increase in age-related conditions that will strongly impair human health and quality of life. For this reason, aging is a major concern worldwide. Healthy aging depends on a combination of individual genetic factors and external environmental factors. Diet has been proved to be a powerful tool to modulate aging and caloric restriction has emerged as a valuable intervention in this regard. However, many questions about how a controlled caloric restriction intervention affects aging-related processes are still unanswered. Nutrient sensing pathways become deregulated with age and lose effectiveness with age. These pathways are a link between diet and aging. Thus, fully understanding this link is a mandatory step before bringing caloric restriction into practice. MicroRNAs have emerged as important regulators of cellular functions and can be modified by diet. Some microRNAs target genes encoding proteins and enzymes belonging to the nutrient sensing pathways and, therefore, may play key roles in the modulation of the aging process. In this review, we aimed to show the relationship between diet, nutrient sensing pathways and microRNAs in the context of aging.


Mediterranean diet; caloric restriction; cardiovascular disease; circulating microRNAs; dietary restriction; healthy aging; intermittent fasting; lifespan; microRNAs; type 2 diabetes


Repeated lifestyle interventions lead to progressive weight loss: A retrospective review chart study.

Dandanell S, Ritz C, Verdich E, Dela F, Helge JW.

Scand J Public Health. 2017 May;45(3):305-313. doi: 10.1177/1403494817693709. Epub 2017 Mar 8.

PMID: 28443486



This study aimed to investigate whether repeated lifestyle interventions lead to progressive weight loss or to weight cycling.


A retrospective review chart study with follow-up on 2120 participants (mean±SD age 36±15 years; body weight 116±28 kg; fat 43±6%). All had participated in one to four 11-12 week lifestyle interventions (residential weight loss programme, mixed activities). Weight loss was promoted through a hypocaloric diet (-500 to -700 kcal/day) and daily physical activity (1-3 hours/day). Primary outcomes were weight loss and change in body composition (bioimpedance measurements) after the intervention periods and at follow-up.


A total of 2120, 526, 139 and 47 people participated in one to four interventions with mean±SEM times from start to follow-up of 1.3±0.1, 2.9±0.2, 4.2±0.3 and 5.2±0.4 years respectively. Overall 50, 41, 18 and 11% of the participants were lost to follow-up after one to four interventions, respectively. The cumulated weight loss at follow-up increased with the number of interventions from one to four: 12.2±0.1, 15.9±0.7, 16.1±1.2 and 18.5±2.0 kg ( p<0.001). The ratios between cumulated loss of fat and fat free mass after one to four interventions decreased with the number of interventions (2.4, 2.2, 2.1 and 1.4). Rates of weight loss during the interventions ranged from 0.70±0.06 to 1.06±0.01 kg/week and the maximum weight regain during the follow-up periods was 0.039±0.007 kg/week.


Repeated relatively short lifestyle interventions in a selected and motivated group can be an efficient method for weight loss maintenance with only limited body weight cycling in the interim periods. However, the relationship between loss of fat and fat free mass might change in an unfavourable direction.


Weight cycling; body composition; fat free mass; fat mass; weight loss camp; weight regain

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Compensatory mechanisms activated with intermittent energy restriction: A randomized control trial.

Coutinho SR, Halset EH, Gåsbakk S, Rehfeld JF, Kulseng B, Truby H, Martins C.

Clin Nutr. 2017 Apr 7. pii: S0261-5614(17)30125-5. doi: 10.1016/j.clnu.2017.04.002. [Epub ahead of print]

PMID: 28446382



Strong compensatory responses, with reduced resting metabolic rate (RMR), increased exercise efficiency (ExEff) and appetite, are activated when weight loss (WL) is achieved with continuous energy restriction (CER), which try to restore energy balance. Intermittent energy restriction (IER), where short spells of energy restriction are interspaced by periods of habitual energy intake, may offer some protection in minimizing those responses. We aimed to compare the effect of IER versus CER on body composition and the compensatory responses induced by WL.


35 adults (age: 39 ± 9 y) with obesity (BMI: 36 ± 4 kg/m2) were randomized to lose a similar weight with an IER (N = 18) or a CER (N = 17) diet over a 12 week period. Macronutrient composition and overall energy restriction (33% reduction) were similar between groups. Body weight/composition, RMR, fasting respiratory quotient (RQ), ExEff (10, 25, and 50 W), subjective appetite ratings (hunger, fullness, desire to eat, and prospective food consumption (PFC)), and appetite-regulating hormones (active ghrelin (AG), cholecystokinin (CCK), total peptide YY (PYY), active glucagon-like peptide-1 (GLP-1), and insulin) were measured before and after WL.


Changes in body weight (≈12.5% WL) and composition were similar in both groups. Fasting RQ and ExEff at 10 W increased in both groups. Losing weight, either by IER or CER dieting, did not induce significant changes in subjective appetite ratings. RMR decreased and ExEff at 25 and 50 W increased (P < 0.001 for all) in IER group only. Basal and postprandial AG increased (P < 0.05) in IER group, whereas basal active GLP-1 decreased (P = 0.033) in CER group only. Postprandial CCK decreased in both groups (P = 0.0012 and P = 0.009 for IER and CER groups, respectively). No between group differences were apparent for any of the outcomes.


The technique used to achieve energy restriction, whether it is continuous or intermittent, does not appear to modulate the compensatory mechanisms activated by weight loss.


Appetite; Body composition; Continuous energy restriction; Energy expenditure; Intermittent energy restriction; Weight loss


Circadian clocks, diets and aging.

Chaudhari A, Gupta R, Makwana K, Kondratov R.

Nutr Healthy Aging. 2017 Mar 31;4(2):101-112. doi: 10.3233/NHA-160006. Review.

PMID: 28447065


Diets and feeding regimens affect many physiological systems in the organism and may contribute to the development or prevention of various pathologies including cardiovascular diseases or metabolic syndromes. Some of the dietary paradigms, such as calorie restriction, have many well-documented positive metabolic effects as well as the potential to extend longevity in different organisms. Recently, the circadian clocks were put forward as integral components of the calorie restriction mechanisms. The circadian clocks generate the circadian rhythms in behavior, physiology, and metabolism; circadian disruption is associated with reduced fitness and decreased longevity. Here we focus on recent advances in the interplay between the circadian clocks and dietary paradigms. We discuss how the regulation of the circadian clocks by feeding/nutrients and regulation of nutrient signaling pathways by the clocks may contribute to the beneficial effects of calorie restriction on metabolism and longevity, and whether the circadian system can be engaged for future medical applications.


Biological rhythms and clocks; cell signaling; food anticipation; transcription




Long-term calorie restriction in humans is not associated with indices of delayed immunologic aging: A descriptive study.

Tomiyama AJ, Milush JM, Lin J, Flynn JM, Kapahi P, Verdin E, Sinclair E, Melov S, Epel ES.

Nutr Healthy Aging. 2017 Mar 31;4(2):147-156. doi: 10.3233/NHA-160017.

PMID: 28447069



BACKGROUND: Delayed immunologic aging is purported to be a major mechanism through which calorie restriction (CR) exerts its anti-aging effects in non-human species. However, in non-obese humans, the effect of CR on the immune system has been understudied relative to its effects on the cardiometabolic system. OBJECTIVE: To examine whether CR is associated with delayed immunologic aging in non-obese humans. METHODS: We tested whether long-term CR practitioners (average 10.03 years of CR) evidenced decreased expression of T cell immunosenescence markers and longer immune cell telomeres compared to gender-, race/ethnicity-, age-, and education-matched "healthy" Body Mass Index (BMI) and "overweight"/"obese" BMI groups. RESULTS: Long-term human CR practitioners had lower BMI (p <  0.001) and fasting glucose (p <  0.001), as expected. They showed similar frequencies of pre-senescent cells (CD8+CD28- T cells and CD57 and PD-1 expressing T cells) to the comparison groups. Even after adjusting for covariates, including cytomegalovirus status, we observed shorter peripheral blood mononuclear cell telomeres in the CR group (p = 0.012) and no difference in granulocyte telomeres between groups (p = 0.42). CONCLUSIONS: We observed no clear evidence that CR as it is currently practiced in humans delays immune aging related to telomere length or T cell immunosenescent markers.


Caloric restriction; T-cells; cellular aging; eating behavior; immunosenescence; telomeres

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Dietary Restriction of Serine and Glycine May Have Antitumor Effects.

[No authors listed]

Cancer Discov. 2017 Apr 28. doi: 10.1158/2159-8290.CD-RW2017-082. [Epub ahead of print]

PMID: 28455396


Serine/glycine restriction extends survival in mouse models of lymphoma and intestinal cancer.


Modulating the therapeutic response of tumours to dietary serine and glycine starvation.

Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, Mackay GM, Labuschagne CF, Gay D, Kruiswijk F, Blagih J, Vincent DF, Campbell KJ, Ceteci F, Sansom OJ, Blyth K, Vousden KH.

Nature. 2017 Apr 19;544(7650):372-376. doi: 10.1038/nature22056.

PMID: 28425994



The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

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Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial.

Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, Gabel K, Freels S, Rigdon J, Rood J, Ravussin E, Varady KA.

JAMA Intern Med. 2017 May 1. doi: 10.1001/jamainternmed.2017.0936. [Epub ahead of print]

PMID: 28459931



Alternate-day fasting has become increasingly popular, yet, to date, no long-term randomized clinical trials have evaluated its efficacy.


To compare the effects of alternate-day fasting vs daily calorie restriction on weight loss, weight maintenance, and risk indicators for cardiovascular disease.


A single-center randomized clinical trial of obese adults (18 to 64 years of age; mean body mass index, 34) was conducted between October 1, 2011, and January 15, 2015, at an academic institution in Chicago, Illinois.


Participants were randomized to 1 of 3 groups for 1 year: alternate-day fasting (25% of energy needs on fast days; 125% of energy needs on alternating "feast days"), calorie restriction (75% of energy needs every day), or a no-intervention control. The trial involved a 6-month weight-loss phase followed by a 6-month weight-maintenance phase.


The primary outcome was change in body weight. Secondary outcomes were adherence to the dietary intervention and risk indicators for cardiovascular disease.


Among the 100 participants (86 women and 14 men; mean [sD] age, 44 [11] years), the dropout rate was highest in the alternate-day fasting group (13 of 34 [38%]), vs the daily calorie restriction group (10 of 35 [29%]) and control group (8 of 31 [26%]). Mean weight loss was similar for participants in the alternate-day fasting group and those in the daily calorie restriction group at month 6 (-6.8% [95% CI, -9.1% to -4.5%] vs -6.8% [95% CI, -9.1% to -4.6%]) and month 12 (-6.0% [95% CI, -8.5% to -3.6%] vs -5.3% [95% CI, -7.6% to -3.0%]) relative to those in the control group. Participants in the alternate-day fasting group ate more than prescribed on fast days, and less than prescribed on feast days, while those in the daily calorie restriction group generally met their prescribed energy goals. There were no significant differences between the intervention groups in blood pressure, heart rate, triglycerides, fasting glucose, fasting insulin, insulin resistance, C-reactive protein, or homocysteine concentrations at month 6 or 12. Mean high-density lipoprotein cholesterol levels at month 6 significantly increased among the participants in the alternate-day fasting group (6.2 mg/dL [95% CI, 0.1-12.4 mg/dL]), but not at month 12 (1.0 mg/dL [95% CI, -5.9 to 7.8 mg/dL]), relative to those in the daily calorie restriction group. Mean low-density lipoprotein cholesterol levels were significantly elevated by month 12 among the participants in the alternate-day fasting group (11.5 mg/dL [95% CI, 1.9-21.1 mg/dL]) compared with those in the daily calorie restriction group.


Alternate-day fasting did not produce superior adherence, weight loss, weight maintenance, or cardioprotection vs daily calorie restriction.


Exercise improves femoral whole-bone and tissue-level biomechanical properties in hyperphagic OLETF rats.

Ortinau LC, Linden MA, Rector RS, Hinton PS.

Appl Physiol Nutr Metab. 2017 May 1. doi: 10.1139/apnm-2017-0077. [Epub ahead of print]

PMID: 28460190


An often-overlooked comorbidity of type 2 diabetes (T2D) is increased fracture risk. Since traditional T2D therapies focus solely on glucose homeostasis, there is an increased need for effective treatment strategies that improve both metabolic and bone health. The current study evaluated if previously reported protective effects of exercise (EX) on cortical bone geometry and biomechanical properties are due to the prevention of obesity compared to obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats or the unique skeletal effects of exercise. Four-week old, male OLETF rats were randomly assigned to one of three groups, each fed a standard rodent chow diet until 40 weeks of age: ad libitum fed sedentary (O-SED), ad libitum fed EX (O-EX), or a control group body-weight matched to the O-EX group by caloric restriction (O-CR). Ad libitum fed sedentary Long-Evans Tokushima Otsuka (L-SED) were used as a lean control. EX or CR prevented the excess body mass accumulation and elevated HbA1c observed in O-SED. Total body BMD was greater in O-EX than O-CR, but similar to L-SED and O-SED. O-EX and O-CR had lower osteocalcin and TRAP5b than O-SED and L-SED. EX or CR prevented the ~3-fold increase in CTx in O-SED vs L-SED. EX increased femoral cortical mass accumulation and expansion at the mid-diaphysis compared to O-CR. EX or CR significantly increased tissue-level stiffness and strength compared to O-SED and L-SED, but O-EX had greater whole-bone stiffness than all other groups. In summary, EX has distinct advantages over CR for improving bone biomechanical properties in hyperphagic OLETF rats.

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Macronutrients and the FTO gene expression in hypothalamus; a systematic review of experimental studies.

Doaei S, Kalantari N, Mohammadi NK, Tabesh GA, Gholamalizadeh M.

Indian Heart J. 2017 Mar - Apr;69(2):277-281. doi: 10.1016/j.ihj.2017.01.014. Epub 2017 Jan 24. Review.

PMID: 28460778


The various studies have examined the relationship between FTO gene expression and macronutrients levels. In order to obtain better viewpoint from this interactions, all of existing studies were reviewed systematically. All published papers have been obtained and reviewed using standard and sensitive keywords from databases such as CINAHL, Embase, PubMed, PsycInfo, and the Cochrane, from 1990 to 2016. The results indicated that all of 6 studies that met the inclusion criteria (from a total of 428 published article) found FTO gene expression changes at short-term follow-ups. Four of six studies found an increased FTO gene expression after calorie restriction, while two of them indicated decreased FTO gene expression. The effect of protein, carbohydrate and fat were separately assessed and suggested by all of six studies. In Conclusion, The level of FTO gene expression in hypothalamus is related to macronutrients levels. Future research should evaluate the long-term impact of dietary interventions.


FTO; Gene expression; Macronutrients; Obesity


Effect of caloric restriction on plasma melatonin levels in aged rhesus macaques.

Aghazadeh-Sanai N, Downs JL, Mattison JA, Ingram DK, Kohama SG, Urbanski HF.

Neurobiol Aging. 2017 Apr 8. pii: S0197-4580(17)30115-X. doi: 10.1016/j.neurobiolaging.2017.03.032. [Epub ahead of print]

PMID: 28461102



In this study, we examined the 24-hour plasma melatonin patterns of young adult (∼11 years of age) and old (∼24 years of age) rhesus macaques, and determined how they would be influenced by 30% caloric restriction (CR). Well-defined 24-hour plasma melatonin rhythms were observed in all the males but only the old animals showed significant attenuation of night-time melatonin levels. Moreover, 4.5 years of CR failed to prevent the age-associated decline in plasma melatonin levels in the old males and caused a significant decrease in the young adult males. Similar plasma melatonin rhythms were also observed in all the females but no age-related decline was detected, and 2 years of CR had no obvious effect on plasma melatonin levels. If anything, there was a trend for the CR to decrease melatonin levels in the young adult females. Taken together, the results fail to show any clear benefit of CR on plasma melatonin levels in old rhesus macaques and may even be detrimental to plasma melatonin levels in young adults.


Aging; Caloric restriction; Circadian; Endocrine rhythms; Melatonin; Primate


Stimulatory Effect of Food Restriction on the Steroidogenesis of Aldosterone in Ovariectomized Rats.

Kau MM, Yu CH, Tsai SC, Wang JR, Wang PS.

Chin J Physiol. 2017 Apr 30;60(2):97-105. doi: 10.4077/CJP.2017.BAF500.

PMID: 28466626


Food or calorie restriction (FR or CR) induces several physiological changes including weight loss, metabolic adaptations, mineral and hormonal changes. However, the effects of FR on aldosterone steroidogenesis in zona glomerulosa (ZG) cells have not been elucidated. Therefore, the present study was designed to investigate the effects of FR on aldosterone secretion and the involved mechanisms in ovariectomized (Ovx) rats. Ovx rats were divided into ad libitum fed (control) and FR groups. The FR rats exhibited decreased body weight, water intake, urine flow, sodium excretion and increased plasma aldosterone in comparison with control rats. FR elevated the basal and angiotensin II-stimulated aldosterone secretion from ZG cells. The conversions of 25-hydroxy-cholesterol to pregnenolone or corticosterone to aldosterone in ZG cells of FR group were greater than that in control group. FR group had a higher protein expression of steroidogenic acute regulatory (StAR) protein in ZG cells. However, there was no different protein expression of cytochrome P450 sidechain cleavage enzyme (P450scc) in ZG cells between control and FR groups. In summary, the increased activities of P450scc and aldosterone synthase as well as the protein expression of StAR protein in ZG cells are involved in the effects of FR on aldosterone steroidogenesis in Ovx rats. We also suggest that the increase of aldosterone might be associated with anti-diuresis and antinatriuresis in FR group. These results are helpful for understanding the role of aldosterone in physiological adaptation and renal sodium conservation during FR.


aldosterone; food restriction; P450scc; StAR protein; zona glomerulosa cells

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Telomerase and mTOR in the brain: the mitochondria connection.

Miwa S, Saretzki G.

Neural Regen Res. 2017 Mar;12(3):358-361. doi: 10.4103/1673-5374.202922. Review.

PMID: 28469639


Telomerase is an enzyme that maintains telomeres in dividing cells using a template on its inherent RNA component. Additionally, the protein part TERT (Telomerase Reverse Transcriptase) has various non-canonical functions. For example, it can localize to mitochondria under increased stress and protect cells in vitro from oxidative stress, DNA damage and apoptosis. Recently it has been demonstrated that TERT protein persists in adult neurons in the brain and data emerge suggesting that it might have a protective function in these post-mitotic cells as well. We have recently published that TERT protein accumulated in mitochondria from brain tissue of mice that have undergone short-term dietary restriction (DR) and rapamycin treatment. This localization correlated to lower levels of oxidative stress in these brain mitochondria. Since rapamycin treatment decreases mTOR signaling which is also thought to play an important role for the beneficial effects of DR, we conclude that the mTOR pathway might be involved in the TERT localization and its effects in brain mitochondria in vivo. These data are in line with previous findings from our group about increased mitochondrial localization of TERT in Alzheimer's disease (AD) brains and a protective function of TERT protein in neurons in vitro against pathological tau.


ROS; brain; dietary restriction; mTOR; mitochondria; neuron; rapamycin; telomerase

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Weight loss achieved using an energy restriction diet with normal or higher dietary protein decreased the number of CD14<sup>++</sup>CD16<sup>+</sup> proinflammatory monocytes and plasma lipids and lipoproteins in middle-aged, overweight, and obese adults.

Kim JE, Lin G, Zhou J, Mund JA, Case J, Campbell WW.

Nutr Res. 2017 Apr;40:75-84. doi: 10.1016/j.nutres.2017.02.007. Epub 2017 Mar 14.

PMID: 28473063


Monocytes are involved in immune responses, and specific monocyte subpopulations (MS) that express intermediate to high levels of CD16 are associated with obesity and cardiovascular events. Consuming high protein (HP) when dieting improves body composition and cardiometabolic health outcomes, but whether HP affects MS during weight loss remains unknown. We assessed the effect of HP on energy restriction (ER)-induced changes in MS in overweight and obese adults. The relations between MS and plasma lipids and lipoproteins were also examined. We hypothesized that, independent of protein intake, ER-induced weight loss would decrease the numbers of MS and that MS and plasma lipids and lipoproteins would be related. Thirty-two adults (age 52 ± 1 years, body mass index 31.3 ± 0.5 kg/m2, means ± S.E.) consumed either a normal protein (n=18) or HP (n=14) (0.8 vs 1.5 g•kg-1•d-1 protein) ER diet (750-kcal/d [3138-kJ/d] deficit) for 16 weeks. The HP diet included 0.7 g•kg-1•d-1 of milk protein isolate. Fasting plasma lipids, lipoproteins, and the numbers of MS were analyzed. Over time, independent of protein intake, CD14++CD16+ cell number decreased, whereas CD14dimCD16++, CD14+CD16+, and CD14+CD16- cell numbers remained unchanged. CD14dimCD16++ cell number was negatively associated with total cholesterol (TC) and triglyceride, while CD14++CD16+ cell number was positively associated with TC, low-density lipoprotein cholesterol (LDL), TC to high-density lipoprotein cholesterol (HDL) ratio, and LDL to HDL ratio. Weight loss achieved while consuming an ER diet with either normal or high protein may improve immunity by partially decreasing proinflammatory monocytes. Associations between MS and plasma lipids and lipoproteins are confirmed in overweight and obese adults.


Dietary protein; Energy restriction; Lipid-lipoprotein; Monocyte subpopulations; Randomized controlled trial

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Intermittent fasting combined with supplementation with Ayurvedic herbs reduces anxiety in middle aged female rats by anti-inflammatory pathways.

Singh H, Kaur T, Manchanda S, Kaur G.

Biogerontology. 2017 May 6. doi: 10.1007/s10522-017-9706-8. [Epub ahead of print]

PMID: 28478492


Intermittent fasting-dietary restriction (IF-DR) is an increasingly popular intervention to promote healthy aging and delay age associated decline in brain functions. Also, the use of herbal interventions is gaining attention due to their non-pharmacological approach to treat several abnormalities and promote general health with least side effects. The present study was aimed to investigate the synergistic effects of IF-DR regimen with herbal supplementation on anxiety-like behavior and neuroinflammation in middle aged female rats. We used dried leaf powder of Withania somnifera and dried stem powder of Tinospora cordifolia for our study. The rats were divided into three groups: (1) Control group fed ad libitum (AL); (2) rats deprived of food for full day and fed ad libitum on every alternate day (IF-DR); and (3) IF-DR and herbal extract (DRH) group in which rats were fed ad libitum with herbal extract supplemented diet, every alternate day. Post regimen, the rats were tested for anxiety-like behavior and further used for study of key inflammatory molecules (NFκB, Iba1, TNFα, IL-1β, IL-6) and glial marker (GFAP) in hippocampus and piriform cortex regions of brain. The study was further extended to explore the effect of DRH regimen on stress response protein (HSP70) and calcium dependent regulators of synaptic plasticity (CaMKIIα, Calcineurin). Our data demonstrated that DRH regimen reduced anxiety-like behavior in middle age female rats and associated neuroinflammation by ameliorating key inflammatory cytokines and modulated stress response. The present data may provide scientific validation for anxiolytic and anti-inflammatory potential of herbal intervention combined with short term IF-DR regimen.


Anxiolytic effect; Herbal intervention; Inflammation; Intermittent fasting-dietary restriction; Tinospora cordifolia; Withania somnifera



Bettio LEB, Rajendran L, Gil-Mohapel J.

Neurosci Biobehav Rev. 2017 May 2. pii: S0149-7634(16)30766-7. doi: 10.1016/j.neubiorev.2017.04.030. [Epub ahead of print] Review.

PMID: 28476525


Aging is a natural process that is associated with cognitive decline as well as functional and social impairments. One structure of particular interest when considering aging and cognitive decline is the hippocampus, a brain region known to play an important role in learning and memory consolidation as well as in affective behaviours and mood regulation, and where both functional and structural plasticity (e.g., neurogenesis) occur well into adulthood. Neurobiological alterations seen in the aging hippocampus including increased oxidative stress and neuroinflammation, altered intracellular signalling and gene expression, as well as reduced neurogenesis and synaptic plasticity, are thought to be associated with age-related cognitive decline. Non-invasive strategies such as caloric restriction, physical exercise, and environmental enrichment have been shown to counteract many of the age-induced alterations in hippocampal signalling, structure, and function. Thus, such approaches may have therapeutic value in counteracting the deleterious effects of aging and protecting the brain against age-associated neurodegenerative processes.


aging; cognitive decline; hippocampus; learning; memory; neurogenesis; synaptic plasticity


Effect of essential amino acids on enteroids: Methionine deprivation suppresses proliferation and affects differentiation in enteroid stem cells.

Saito Y, Iwatsuki K, Hanyu H, Maruyama N, Aihara E, Tadaishi M, Shimizu M, Kobayashi-Hattori K.

Biochem Biophys Res Commun. 2017 May 5. pii: S0006-291X(17)30879-3. doi: 10.1016/j.bbrc.2017.05.029. [Epub ahead of print]

PMID: 28483523


We investigated the effects of essential amino acids on intestinal stem cell proliferation and differentiation using murine small intestinal organoids (enteroids) from the jejunum. By selectively removing individual essential amino acids from culture medium, we found that 24 h of methionine (Met) deprivation markedly suppressed cell proliferation in enteroids. This effect was rescued when enteroids cultured in Met deprivation media for 12 h were transferred to complete medium, suggesting that Met plays an important role in enteroid cell proliferation. In addition, mRNA levels of the stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) decreased in enteroids grown in Met deprivation conditions. Consistent with this observation, Met deprivation also attenuated Lgr5-EGFP fluorescence intensity in enteroids. In contrast, Met deprivation enhanced mRNA levels of the enteroendocrine cell marker chromogranin A (ChgA) and markers of K cells, enterochromaffin cells, goblet cells, and Paneth cells. Immunofluorescence experiments demonstrated that Met deprivation led to an increase in the number of ChgA-positive cells. These results suggest that Met deprivation suppresses stem cell proliferation, thereby promoting differentiation. In conclusion, Met is an important nutrient in the maintenance of intestinal stem cells and Met deprivation potentially affects cell differentiation.


Chromogranin A; Differentiation; Enteroids; Lgr5; Methionine; Stem cells

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Environmental conditions can modulate the links among oxidative stress, age, and longevity.

Marasco V, Stier A, Boner W, Griffiths K, Heidinger B, Monaghan P.

Mech Ageing Dev. 2017 May 6. pii: S0047-6374(16)30131-2. doi: 10.1016/j.mad.2017.04.012. [Epub ahead of print]

PMID: 28487181


Understanding the links between environmental conditions and longevity remains a major focus in biological research. We examined within-individual changes between early- and mid-adulthood in the circulating levels of four oxidative stress markers linked to ageing, using zebra finches (Taeniopygia guttata): a DNA damage product (8-hydroxy-2'-deoxyguanosine; 8-OHdG), protein carbonyls (PC), non-enzymatic antioxidant capacity (OXY), and superoxide dismutase activity (SOD). We further examined whether such within-individual changes differed among birds living under control (ad lib food) or more challenging environmental conditions (unpredictable food availability), having previously found that the latter increased corticosterone levels when food was absent but improved survival over a three year period. Our key findings were: (i) 8-OHdG and PC increased with age in both environments, with a higher increase in 8-OHdG in the challenging environment; (ii) SOD increased with age in the controls but not in the challenged birds, while the opposite was true for OXY; (iii) control birds with high levels of 8-OHdG died at a younger age, but this was not the case in challenged birds. Our data clearly show that while exposure to the potentially damaging effects of oxidative stress increases with age, environmental conditions can modulate the pace of this age-related change.


age; antioxidant defences; corticosterone; environmental challenging conditions; glucocorticoids; longevity; oxidative damage; oxidative stress

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Short-term caloric restriction exerts neuroprotective effects following mild traumatic brain injury by promoting autophagy and inhibiting astrocyte activation.

Liu Y, Wang R, Zhao Z, Dong W, Zhang X, Chen X, Ma L.

Behav Brain Res. 2017 May 8. pii: S0166-4328(17)30217-6. doi: 10.1016/j.bbr.2017.04.024. [Epub ahead of print]

PMID: 28495608



Cognitive deficits may occur after mild traumatic brain injury (mTBI), but effective treatment modalities are presently unavailable. Caloric restriction (CR) has beneficial effects on neurodegenerative diseases and brain injury. However, the underlying mechanisms have not yet been clearly defined. Therefore, the aim of the present study was to investigate the short-term effects of CR treatment on cognitive function in mice after mTBI. Forty-five 12-week-old C57/BL6 mice were subjected to closed-head mTBI using a weight drop device. The mice were then randomly divided into three groups according to their diet for 30 days: the normal calorie group (mTBI+NC group, n=15), the caloric restriction group (mTBI+CR group, n=15), and the high energy group (mTBI+HE group, n=15). After 30 days, the Morris water maze test was performed to evaluate learning abilities. Nissl staining, immunohistochemistry, and western blotting were used to monitor pathological changes and changes in autophagy-associated proteins in the hippocampus. The average escape latency was significantly shorter in the mTBI+CR group than in the mTBI+NC and mTBI+HE groups, and the number of target platform crossings in the mTBI+CR group was significantly higher than in the other two groups. In the hippocampus, the expression of GFAP and mTOR was increased in the mTBI+HE group and decreased in the mTBI+CR group. Conversely, the expression of LC3B was decreased in the mTBI+HE group and increased in the mTBI+CR group. Our findings suggest that short-term CR after mTBI may ameliorate cognitive dysfunction induced by mTBI by increasing the level of autophagy and suppressing astrocyte activation.


Mild traumatic brain injury, Caloric restriction, Learning ability, Autophagy


Exacerbation of liver steatosis following exposure to famine and overnutrition.

Ning Z, Zhang K, Zhao L, Lu Y, Sun H, Chen C, Nie X, Lu M, Wang N, Lu Y.

Mol Nutr Food Res. 2017 May 12. doi: 10.1002/mnfr.201700097. [Epub ahead of print]

PMID: 28499082




People suffering from famine in early life and overnutrition in adulthood may have an increased risk for liver steatosis. We aimed to investigate the effects and mechanisms of early nutrition restriction and overnutrition on de novo lipogenesis in the liver.


Three-week-old male rats were food restricted for 4 weeks and refed a high-fat or normal-fat diet individually in metabolic cages for 9 weeks. Weight-matched groups were also set up. Fatty acid synthetase expression was measured to estimate de novo lipogenesis in the liver. Parameters of glucose and lipid metabolism were measured with isotope assays. All four groups had comparable body weights. However, the famine-high fat diet group had the highest degree of liver steatosis, the greatest body fat ratio, and insulin resistance. Lipid accumulation, fatty acid synthetase expression and gluconeogenesis in the liver were significantly higher in the famine and high-fat diet groups (P <0.05). Moreover, these groups also had markedly lower muscle glucose uptake.


Under famine and high-fat refeeding stress, rats were extremely susceptible to developing hepatic steatosis. This is presumably a consequence of upregulation of de novo lipogenesis and enhanced glucose flux from muscle to de novo lipogenesis in the liver.


Famine; Lipogenesis; Liver steatosis; Overnutrition


Antinociceptive effects of caloric restriction on post-incisional pain in nonobese rats.

Liu Y, Ni Y, Zhang W, Sun YE, Ma Z, Gu X.

Sci Rep. 2017 May 11;7(1):1805. doi: 10.1038/s41598-017-01909-8.

PMID: 28496116


Caloric restriction (CR) increases lifespan, retards physiological signs of aging, and delays a variety of diseases. Reduction of inflammatory response was proposed as one of the molecular mechanisms for how CR exerts beneficial effects. The present study investigated the effects of CR on postoperative pain in rats. Adult nonobese rats were divided into two dietary groups, an ad libitum fed group (AL) and a caloric restriction group (CR) that was provided with 60% of the food intake of AL rats. After 6 weeks, the effects of CR on pain behaviors and inflammation induced by plantar incision were examined. CR rats displayed significantly reduced nonevoked pain, mechanical allodynia and thermal hyperalgesia induced by incision, and showed decreased levels of pro-inflammatory cytokines in serum, peri-incisional skin tissue and ipsilateral spinal cord dorsal horn at 6 h and 24 h after incision. The analgesic efficiency of parecoxib and morphine, two agents widely used for the management of postoperative pain clinically, was reinforced by CR. Together, CR generates antinociceptive effects on postoperative incisional pain in rats, perhaps providing some improvement of QOL in patients with postoperative pain, and the beneficial effects may be attributable to the inhibition of excessive inflammation induced by surgical injury.

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Green Tea Polyphenols, Mimicking the Effects of Dietary Restriction, Ameliorate High-Fat Diet-Induced Kidney Injury via Regulating Autophagy Flux.

Xie X, Yi W, Zhang P, Wu N, Yan Q, Yang H, Tian C, Xiang S, Du M, Getachew Assefa E, Zuo X, Ying C.

Nutrients. 2017 May 14;9(5). pii: E497. doi: 10.3390/nu9050497.

PMID: 28505110


Epidemiological and experimental studies reveal that Western dietary patterns contribute to chronic kidney disease, whereas dietary restriction (DR) or dietary polyphenols such as green tea polyphenols (GTPs) can ameliorate the progression of kidney injury. This study aimed to investigate the renal protective effects of GTPs and explore the underlying mechanisms. Sixty Wistar rats were randomly divided into 6 groups: standard diet (STD), DR, high-fat diet (HFD), and three diets plus 200 mg/kg(bw)/day GTPs, respectively. After 18 weeks, HFD group exhibited renal injuries by increased serum cystatin C levels and urinary N-acetyl-β-d-glucosaminidase activity, which can be ameliorated by GTPs. Meanwhile, autophagy impairment as denoted by autophagy-lysosome related proteins, including LC3-II, Beclin-1, p62, cathepsin B, cathepsin D and LAMP-1, was observed in HFD group, whereas DR or GTPs promoted renal autophagy activities and GTPs ameliorated HFD-induced autophagy impairment. In vitro, autophagy flux suppression was detected in palmitic acid (PA)-treated human proximal tubular epithelial cells (HK-2), which was ameliorated by epigallocatechin-3-gallate (EGCG). Furthermore, GTPs (or EGCG) elevated phosphorylation of AMP-activated protein kinase in the kidneys of HFD-treated rats and in PA-treated HK-2 cells. These findings revealed that GTPs mimic the effects of DR to induce autophagy and exert a renal protective effect by alleviating HFD-induced autophagy suppression.


autophagy; dietary restriction; green tea polyphenols; high-fat diet; renal function


Early-onset obesity and food restriction alter hepatocyte metabolism in adult Wistar rats.

Branquinho NTD, Cruz GHP, Borrasca CL, Alves LPS, de Godoy Gomes CR, Ferreira de Godoi VA, Pedrosa MMD.

Arch Physiol Biochem. 2017 May 13:1-9. doi: 10.1080/13813455.2017.1326942. [Epub ahead of print]

PMID: 28502193



Caloric restriction (CR) is suggested for overweight control.


Systemic and liver glucose metabolism in the reduced-litter (RL) rat model under 30% CR was investigated.


Newborn litters were organised in control (G9); RL with free diet (G3L); and RL with CR (G3R). Assessments were made at the age of 90 d.


Higher liver glycogen content and changes in systemic glucose handling were found in the RL groups. Hepatocyte glucose metabolism was similar in groups G9 and G3L, but basal glucose production and glycogenolysis were higher, while gluconeogenesis and basal glycolysis were lower in the G3R. Urea production was lower in the RL groups.


The altered glucose handling of the RL adult rats was not reversed by moderate (30%) CR. Hepatocyte glucose and nitrogen metabolism were changed by both early overfeeding and current feeding conditions.


RL and CR alter systemic and liver glucose metabolism.


Caloric restriction; glucose; liver metabolism; obesity; reduced litter


Augmenting brain metabolism to increase macro- and chaperone-mediated autophagy for decreasing neuronal proteotoxicity and aging.

Loos B, Klionsky DJ, Wong E.

Prog Neurobiol. 2017 May 11. pii: S0301-0082(16)30146-0. doi: 10.1016/j.pneurobio.2017.05.001. [Epub ahead of print] Review.

PMID: 28502807


Accumulation of toxic protein aggregates in the nerve cells is a hallmark of neuronal diseases and brain aging. Mechanisms to enhance neuronal surveillance to improve neuronal proteostasis have a direct impact on promoting neuronal health and forestalling age-related decline in brain function. Autophagy is a lysosomal degradative pathway pivotal for neuronal protein quality control. Different types of autophagic mechanisms participate in protein handling in neurons. Macroautophagy targets misfolded and aggregated proteins in autophagic vesicles to the lysosomes for destruction, while chaperone-mediated autophagy (CMA) degrades specific soluble cytosolic proteins delivered to the lysosomes by chaperones. Dysfunctions in macroautophagy and CMA contribute to proteo- and neuro-toxicity associated with neurodegeneration and aging. Thus, augmenting or preserving both autophagic mechanisms pose significant benefits in delaying physiological and pathological neuronal demises. Recently, life-style interventions that modulate metabolite ketone bodies, energy intake by caloric restriction and energy expenditure by exercise have shown to enhance both autophagy and brain health. However, to what extent these interventions affect neuronal autophagy to promote brain fitness remains largely unclear. Here, we review the functional connections of how macroautophagy and CMA are affected by ketone bodies, caloric restriction and exercise in the context of neurodegeneration. A concomitant assessment of yeast Saccharomyces cerevisiae is performed to reveal the conserved nature of such autophagic responses to substrate perturbations. In doing so, we provide novel insights and integrated evidence for a potential adjuvant therapeutic strategy to intervene in the neuronal decline in neurodegenerative diseases by controlling both macroautophagy and CMA fluxes favorably.


Autophagic Flux; Caloric Restriction; Exercise; Ketone Bodies; Longevity; Neurodegeneration


A review of the biomedical innovations for healthy longevity.

Moskalev A, Anisimov V, Aliper A, Artemov A, Asadullah K, Belsky D, Baranova A, de Grey A, Dixit VD, Debonneuil E, Dobrovolskaya E, Fedichev P, Fedintsev A, Fraifeld V, Franceschi C, Freer R, Fülöp T, Feige J, Gems D, Gladyshev V, Gorbunova V, Irincheeva I, Jager S, Jazwinski SM, Kaeberlein M, Kennedy B, Khaltourina D, Kovalchuk I, Kovalchuk O, Kozin S, Kulminski A, Lashmanova E, Lezhnina K, Liu GH, Longo V, Mamoshina P, Maslov A, Pedro de Magalhaes J, Mitchell J, Mitnitski A, Nikolsky Y, Ozerov I, Pasyukova E, Peregudova D, Popov V, Proshkina E, Putin E, Rogaev E, Rogina B, Schastnaya J, Seluanov A, Shaposhnikov M, Simm A, Skulachev V, Skulachev M, Solovev I, Spindler S, Stefanova N, Suh Y, Swick A, Tower J, Gudkov AV, Vijg J, Voronkov A, West M, Wagner W, Yashin A, Zemskaya N, Zhumadilov Z, Zhavoronkov A.

Aging (Albany NY). 2017 Jan 29;9(1):7-25. doi: 10.18632/aging.101163. No abstract available.

PMID: 28132958 Free PMC Article



"Aubrey de Grey (SENS Research Foundation) spoke on “Longevity escape velocity: incorporating technological progress into extrapolation”. Predictions of future longevity have historically failed, by and large, to prove accurate. I will argue that this is because they are in one or another way based on pure extrapolation of past trends, a method that incorporates the implicit assumption that it does not matter *how* we contrived to achieve longevity improvements. I will explain how a careful examination of the medical and other advances that led to increased longevity could have resulted in much better predictions of their impact. I will then focus on the future, and especially on the initially counterintuitive but ultimately inescapable conclusion that regenerative medicine applied to the health problems of old age will at some point, probably within the next few decades, create a sharp discontinuity - which others have termed the “Methuselarity” - in the longevity of successive cohorts. This discontinuity will be so dramatic that period life expectancy will literally cease to be calculable, because mortality rates for all ages so far attained will become so low that survival probabilities will multiply to more than 50%."

"Blanka Rogina (University of Connecticut Health) “Indy reduction maintains fly health and homeostasis”. Indy (I'm not dead yet) encodes the fly homologue of a mammalian transporter of the Krebs cycle intermediates. Reduced Indy gene activity has beneficial effects on energy balance in mice, worms and flies, and worm and fly longevity. In flies, longevity extension is not associated with negative effects on fertility, mobility or metabolic rate. Others and we show that Indy reduction extends longevity by mechanism similar to calorie restriction (CR). Some of the hallmarks of these changes are altered intermediate nutrient metabolism, increased spontaneous physical activity and increased mitochondrial biogenesis. These changes have been found in fly heads, thoraces and the midguts. The observed changes in midgut energy metabolism, specifically decreased production of free radicals, results in preservation of intestinal stem cell (ISC) homeostasis and midgut integrity. Our studies show a direct link between changes in energy metabolism, caused by the Indy reduction and preservation of ISC homeostasis. The data suggest that Indy reduction preserves homeostasis in tissues that contribute to extended health and longevity."

"Irina Irincheeva (Nestlé Institute of Health Sciences) presented “Why don't we all lose weight equally on Caloric Restriction?” Proteomics explanation to weight loss variability on a low-calorie diet in overweight and obese subjects” Obesity is characterized by a state of metabolic inflexibility and chronic inflammation leading to the development of comorbidities like type 2 diabetes, dyslipidemia or certain cancers and generally to a decreased life expectancy in obese individuals. Low calorie diets (LCD) (<1000 kcal per day) have been shown to be very effective in improving many of the metabolic dysfunctions. However, the capacity to lose weight and the associated metabolic improvements show significant variability in humans, even under the same controlled dietary regimes. To understand the molecular basis for these differences we screened the plasma expressions of over twelve hundred proteins in 500 overweight and obese subjects to determine whether we could predict at baseline the weight loss outcome of 8 weeks LCD diet (800 kcal per day). As discovery data to construct a weight loss predictive model we used the Pan-European cohort DiOGenes (Diet, Obesity and Genes, Larsen et al., 2010). To select weight loss predictive proteins we deployed elastic net bootstrap estimation of high-dimensional regression (Chatterjee and Lahiri, 2011) adjusting for gender, age and BMI at baseline. We evaluated the accuracy of our predictive model on the data set of 500 independent subjects from Ottawa Hospital Weight Management Clinic using LCD for weight loss. The accuracy of the predictive model was significantly higher than random in the independent data set.

To identify functional relationships and biochemical pathways shared between the predictive proteins we performed network analyses. The results allow us to formulate a first hypothesis on biological processes leading to successful weight loss for overweight and obese subjects on a low-calorie diet."

"Joao Pedro de Magalhaes (University of Liverpool) presented on “Gene expression profiling for the discovery of biomarkers of ageing”. There is widespread interest in identifying biomarkers of ageing in order to accelerate basic and translational research. Our lab has employed various gene expression profiling approaches to identify molecular signatures that can be used as biomarkers as well provide functional insights on ageing and its manipulation. We performed a meta-analysis of ageing gene expression profiles using microarray datasets from multiple mammalian tissues, which revealed several conserved molecular signatures of ageing. We also applied our network and meta-analysis methods to dietary manipulations of ageing, in particular caloric restriction (CR), and identified candidate genes and processes strongly associated with CR in mammals. Moreover, we have been employing whole transcriptome profiling (RNA-seq) to study ageing and its manipulation by diet, which has significant advantages when compared to microarrays. Lastly, to catalogue and help understand ageing changes, we developed the Digital Ageing Atlas (http://ageing-map.org/), a one-stop collection of human age-related data covering different biological levels (molecular, cellular, physiological, psychological and pathological)."

"Eugenia Dobrovolskaya, Ilya Solovev with co-authors (Institute of Biology of Komi Science Center of Russian Academy of Sciences) presented “Effects of caloric restriction on lifespan of Drosophila melanogaster individuals with tissue-specific overexpression of circadian clock genes”. The aging process is associated with changes in the expression level of various genes. Genes forming a system of “biological clock” of the body are not an exception, it evidenced by the worsening with age in physiological rhythms and aperiodizm of sleep and wakefulness cycles in old individuals. The molecular clock found in each cell of the peripheral tissues of multicellular organisms. A main environmental factor connected to the rhythms of biological processes is light, with daily and annual variations in the light intensity are associated with such phenomena as sleep, physical activity, rest, growth, reproduction, sexual behavior, moult and migration. Most human genes of circadian rhythms are evolutionarily conserved and have orthologs in the fruit fly Drosophila melanogaster. It was found that adults of D. melanogaster show the decrease in gene expression of photosensitive protein Cryptochrome with age, while its overexpression in old flies slows down the rate of aging. On the other hand, fruit flies with mutations in the genes of circadian rhythms are characterized by a reduced life span. The purpose of this study was to investigate wheather caloric restriction affected the life span of Drosophila melanogaster with overexpressed circadian rhythms' genes (Period, Timeless, Clock, Cycle, Cryptochrome). We chose UAS / GAL4 system to ensure conditioned (mifepristone-inducible) gene overexpression in flies' muscules, fat body and gut. Drosophila lines were placed on standard media with different caloric values and life span had been being observed once a day. The results of this study demonstrate the relationship of circadian rhythms' gene regulation mechanisms and caloric restriction response pathways."

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The MicroRNA Machinery Regulates Fasting-Induced Changes in Gene Expression and Longevity in Caenorhabditis elegans.

Kogure A, Uno M, Ikeda T, Nishida E.

J Biol Chem. 2017 May 15. pii: jbc.M116.765065. doi: 10.1074/jbc.M116.765065. [Epub ahead of print]

PMID: 28507100


Intermittent fasting (IF) is a dietary restriction regimen that extends the lifespans of Caenorhabditis elegans and mammals by inducing changes in gene expression. However, how IF induces these changes and promotes longevity remains unclear. One proposed mechanism involves gene regulation by microRNAs (miRNAs), small non-coding RNAs (approximately 22 nucleotides) that repress gene expression and whose expression can be altered by fasting. To test this proposition, we examined the role of the miRNA machinery in fasting-induced transcriptional changes and longevity in C. elegans We revealed that fasting up-regulated the expression of miRNA-induced silencing complex (miRISC) components, including Argonaute and GW182, and of the miRNA-processing enzyme DRSH-1 (the ortholog of the Drosophila Drosha enzyme). Our lifespan measurements demonstrated that IF-induced longevity was suppressed by knockout or knockdown of miRISC components and was completely inhibited by drsh-1 ablation. Remarkably, drsh-1 ablation inhibited the fasting-induced changes in the expression of the target genes of DAF-16, the insulin/IGF-1 signaling effector in C. elegans Fasting-induced transcriptome alterations were substantially and modestly suppressed in the drsh-1 null mutant and the null mutant of ain-1, a gene encoding GW182, respectively. Moreover, miRNA array analyses revealed that the expression levels of numerous miRNAs changed after 2 days of fasting. These results indicate that components of the miRNA machinery, especially the miRNA-processing enzyme DRSH-1, play an important role in mediating IF-induced longevity via the regulation of fasting-induced changes in gene expression.


Caenorhabditis elegans (C. elegans); aging; microRNA (miRNA); microRNA mechanism; post-transcriptional regulation


Aging and the Inevitable Limit to Human Life Span.

Vijg J, Le Bourg E.

Gerontology. 2017 May 17. doi: 10.1159/000477210. [Epub ahead of print]

PMID: 28511176


There is a long-lasting debate about a natural limit to human life span, and it has been argued that the maximum reported age at death, which has not increased for ca 25 years, fluctuates around 115 years, even if some persons live beyond this age. We argue that the close connection of species-specific longevity with life history strategies explains why human life span is limited and cannot reach the considerably longer life spans of several other species.


Centenarians; Dietary restriction; Life expectancy; Life-history strategy; Limits to life span; Maximum life span; Maximum reported age at death; Negligible senescence

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Phenotypic plasticity, trade-offs and gene expression changes accompanying dietary restriction and switches in Bactrocera dorsalis (Hendel) (Diptera: Tephritidae).

Chen EH, Hou QL, Wei DD, Jiang HB, Wang JJ.

Sci Rep. 2017 May 16;7(1):1988. doi: 10.1038/s41598-017-02106-3.

PMID: 28512316


In this study, we investigated the effects of dietary restriction (DR) and variable diets on phenotypes and gene expression in oriental fruit fly, Bactrocera dorsalis (Hendel), one of the most economically important pests in the family Tephritidae around the world. As expected, we found that DR altered the B. dorsalis phenotypes by significantly increasing stress resistance and lifespan, but reduced egg production when compared with the control diet. The results suggested a trade-off between reproduction versus somatic maintenance (stress resistance) and lifespan in B. dorsalis. Diet also had a significant effect on hatchability, and DR could increase the egg hatching success of B. dorsalis. Furthermore, DR up-regulated metabolic pathways involved in energy homeostasis and down-regulated pathways in egg production, which might mediate trade-offs between somatic maintenance and reproduction under DR regimes. The gene expression profiles in response to the acute dietary switches indicated that the digestive and metabolic pathways maybe involved in the adaptability of flies to variable dietary resources. In summary, the research facilitates a better understanding of the molecular mechanisms responsible for the B. dorsalis' phenotypic adjustments to the different qualities of the available diets.

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Food restriction research: Its significance for human aging.

Masoro EJ.

Am J Hum Biol. 1989;1(3):339-345. doi: 10.1002/ajhb.1310010314.

PMID: 28514098


The total lack of knowledge concerning the nature of the primary aging processes coupled to the lack of biomarkers of aging has made it difficult to devise fruitful approaches for the study of aging. Indeed, the only index of aging about which there is general agreement is the life span of the species (i.e., the maximum age attained by members of the species). Only one manipulation has been found which extends the life span of a mammalian species and that is food restriction in rodents. In addition to increasing life span, food restriction also retards almost all age-associated physiological changes and diseases processes. It is concluded that food restriction has these diverse actions because it retards the primary aging processes. Recent research has been focused on the mechanisms by which food restriction influences the primary aging processes because it is believed that such knowledge will provide insight on the basis nature of aging. Available evidence pints to the neural an endocrine system as couplers of food restriction to the aging processes. Of particular current interest are the effects of food restriction on protein turnover and free radical metabolism. The importance of food restriction to human aging relates to the information it is expected to yield on the nature of the primary aging processes in all mammalian species and the database it should provide for interventions of human aging.


An integrative analysis of tissue-specific transcriptomic and metabolomic responses to short-term dietary methionine restriction in mice.

Ghosh S, Forney LA, Wanders D, Stone KP, Gettys TW.

PLoS One. 2017 May 16;12(5):e0177513. doi: 10.1371/journal.pone.0177513. eCollection 2017.

PMID: 28520765


Dietary methionine restriction (MR) produces a coordinated series of transcriptional responses in peripheral tissues that limit fat accretion, remodel lipid metabolism in liver and adipose tissue, and improve overall insulin sensitivity. Hepatic sensing of reduced methionine leads to induction and release of fibroblast growth factor 21 (FGF21), which acts centrally to increase sympathetic tone and activate thermogenesis in adipose tissue. FGF21 also has direct effects in adipose to enhance glucose uptake and oxidation. However, an understanding of how the liver senses and translates reduced dietary methionine into these transcriptional programs remains elusive. A comprehensive systems biology approach integrating transcriptomic and metabolomic readouts in MR-treated mice confirmed that three interconnected mechanisms (fatty acid transport and oxidation, tricarboxylic acid cycle, and oxidative phosphorylation) were activated in MR-treated inguinal adipose tissue. In contrast, the effects of MR in liver involved up-regulation of anti-oxidant responses driven by the nuclear factor, erythroid 2 like 2 transcription factor, NFE2L2. Metabolomic analysis provided evidence for redox imbalance, stemming from large reductions in the master anti-oxidant molecule glutathione coupled with disproportionate increases in ophthalmate and its precursors, glutamate and 2-aminobutyrate. Thus, cysteine and its downstream product, glutathione, emerge as key early hepatic signaling molecules linking dietary MR to its metabolic phenotype.


Lifestyle recommendations for the prevention and management of metabolic syndrome: an international panel recommendation.

Pérez-Martínez P, Mikhailidis DP, Athyros VG, Bullo M, Couture P, Covas MI, de Koning L, Delgado-Lista J, Díaz-López A, Drevon CA, Estruch R, Esposito K, Fitó M, Garaulet M, Giugliano D, García-Ríos A, Katsiki N, Kolovou G, Lamarche B, Maiorino MI, Mena-Sánchez G, Muñoz-Garach A, Nikolic D, Ordovás JM, Pérez-Jiménez F, Rizzo M, Salas-Salvadó J, Schröder H, Tinahones FJ, de la Torre R, van Ommen B, Wopereis S, Ros E, López-Miranda J.

Nutr Rev. 2017 May 1;75(5):307-326. doi: 10.1093/nutrit/nux014.

PMID: 28521334


The importance of metabolic syndrome (MetS) lies in its associated risk of cardiovascular disease and type 2 diabetes, as well as other harmful conditions such as nonalcoholic fatty liver disease. In this report, the available scientific evidence on the associations between lifestyle changes and MetS and its components is reviewed to derive recommendations for MetS prevention and management. Weight loss through an energy-restricted diet together with increased energy expenditure through physical activity contribute to the prevention and treatment of MetS. A Mediterranean-type diet, with or without energy restriction, is an effective treatment component. This dietary pattern should be built upon an increased intake of unsaturated fat, primarily from olive oil, and emphasize the consumption of legumes, cereals (whole grains), fruits, vegetables, nuts, fish, and low-fat dairy products, as well as moderate consumption of alcohol. Other dietary patterns (Dietary Approaches to Stop Hypertension, new Nordic, and vegetarian diets) have also been proposed as alternatives for preventing MetS. Quitting smoking and reducing intake of sugar-sweetened beverages and meat and meat products are mandatory. Nevertheless, there are inconsistencies and gaps in the evidence, and additional research is needed to define the most appropriate therapies for MetS. In conclusion, a healthy lifestyle is critical to prevent or delay the onset of MetS in susceptible individuals and to prevent cardiovascular disease and type 2 diabetes in those with existing MetS. The recommendations provided in this article should help patients and clinicians understand and implement the most effective approaches for lifestyle change to prevent MetS and improve cardiometabolic health.


dietary pattern; lifestyle; metabolic syndrome; panel recommendation

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Effects of diets on adipose tissue.

Ezquerro S, Rodríguez A, Portincasa P, Frühbeck G.

Curr Med Chem. 2017 May 17. doi: 10.2174/0929867324666170518102340. [Epub ahead of print]

PMID: 28521681


Obesity is a major health problem that has become a global epidemic. Overweight and obesity are commonly associated with the development of several pathologies, such as insulin resistance, cardiovascular diseases, sleep apnea and several types of cancer, which can lead to further morbidity and mortality. An increased abdominal adiposity renders overweight and obese individuals more prone to metabolic and cardiovascular problems. In this sense, excess adiposity leads to several changes in the biology, morphology and function of the adipose tissue, such as adipocyte hypertrophy and hyperplasia, adipose tissue inflammation and fibrosis and an impaired secretion of adipokines, contributing to the onset of obesity-related co-morbidities. Given the medical, social and economic consequences of obesity, there is an urgent need to develop strategies to deal with this epidemic. The first approach for obesity management and prevention is the implementation of a diet combined with physical activity. Dietary changes should be individualised, tailored to food preferences and allow for flexible approaches to reducing calorie intake in order to increase the motivation and compliance of overweight and obese patients. The present review summarizes the compelling evidence showing body composition changes, impact on cardiometabolism and potential adverse effects of very-low calorie, low- and high-carbohydrate, high-protein or low-fat diets. The use of macronutrients during the preprandial and postprandial state has been also reviewed to better understand the metabolic changes induced by different dietary interventions.


Excess adiposity; high-protein diets; low- and high-carbohydrate diets; low-fat diets; very-low calorie diets

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