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Metabolic Alterations at the Crossroad of Aging and Oncogenesis.

Raffaghello L, Longo V.

Int Rev Cell Mol Biol. 2017;332:1-42. doi: 10.1016/bs.ircmb.2017.01.003. Epub 2017 Feb 28.

PMID: 28526131


Aging represents the major risk factor for cancer. Cancer and aging are characterized by a similar dysregulated metabolism consisting in upregulation of glycolysis and downmodulation of oxidative phosphorylation. In this respect, metabolic interventions can be viewed as promising strategies to promote longevity and to prevent or delay age-related disorders including cancer. In this review, we discuss the most promising metabolic approaches including chronic calorie restriction, periodic fasting/fasting-mimicking diets, and pharmacological interventions mimicking calorie restriction. Metabolic interventions can also be viewed as adjuvant anticancer strategies to be combined to standard cancer therapy (chemotherapeutic agents, ionizing radiation, and drugs with specific molecular target), whose major limiting factors are represented by toxicity against healthy cells but also limited efficacy easily circumvented by tumor cells. In fact, conventional cancer therapy is unable to distinguish normal and cancerous cells and thus causes toxic side effects including secondary malignancies, cardiovascular and respiratory complications, endocrinopathies, and other chronic conditions, that resemble and, in some cases, accelerate the age-related disorders and profoundly affect the quality of life. In this scenario, geroscience contributes to the understanding of the mechanisms of protection of normal cells against a cytotoxic agent and finding strategies focused on the preserving healthy cells while enhancing the efficacy of the treatment against malignant cells.


Aging; Calorie restriction; Fasting; Gerometabolites; Geroscience; Nutrient-sensing pathways; Sirtuins; Tumor metabolism

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Decreased food anticipatory activity of obese mice relates to hypothalamic c-Fos expression.

Luna-Illades C, Morales T, Miranda-Anaya M.

Physiol Behav. 2017 May 17. pii: S0031-9384(17)30148-8. doi: 10.1016/j.physbeh.2017.05.020. [Epub ahead of print]

PMID: 28527681


During daily Food Restriction (FR), obese Neotomodon alstoni mice present decreased Food Anticipatory Activity (FAA) compared to lean mice. Here, we investigated whether FOS expression in hypothalamic nuclei involved in food synchronization and anticipation parallels decreased FAA during daily FR of obese N. alstoni. Locomotor activity of lean and obese mice in ad libitum feeding conditions was monitored for at least two weeks. Then, a gradual restriction of food access was followed to establish a 5h period of daily food access. FR was maintained during at least two weeks before sacrifice of mice at the starting point of the feeding period. Obese mice subjected to FR displayed an overall reduction of FOS-positive (FOS+) hypothalamic neurons, while lean mice in a similar protocol exhibited an increase in FOS+ neurons within the arcuate and dorsomedial hypothalamic nuclei. These results are consistent with decreased FAA displayed by obese mice in comparison to lean mice. Furthermore, limbic system areas of lean mice, such as the cingulate cortex and the hippocampus, showed an increase in FOS during FR, while no responses were observed in obese mice. The daily food intake of obese mice was severely reduced during FR, compared to the ad libitum condition, whereas food intake in lean mice was not affected by FR. Current data suggests that decreased hypothalamic and limbic neuronal activation may contribute to the reduction of FAA in obese N. alstoni mice.


Arcuate; Dorsomedial; Food restriction; Neotomodon; Obesity; c-Fos

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Nutrition Across the Lifespan for Healthy Aging: Proceedings of a Workshop.

National Academies of Sciences, Engineering, and Medicine (US), Health and Medicine Division (US), Food and Nutrition Board (US), Food Forum (US).

Washington (DC): National Academies Press (US); 2017.

PMID: 28530787 Free Books & Documents



In September 2016, the National Academies of Sciences, Engineering, and Medicine convened a workshop to examine trends and patterns in aging and factors related to healthy aging in the United States, with a focus on nutrition, and how nutrition can sustain and promote healthy aging, not just in late adulthood, but beginning in pregnancy and early childhood and extending throughout the lifespan. Participants discussed the role of nutrition in the aging process at various stages in life, changes in organ systems over the lifespan and changes that occur with age related to cognitive, brain, and mental health, and explored opportunities to move forward in promoting healthy aging in the United States. This publication summarizes the presentations and discussions from the workshop.


... Rafael de Cabo, senior investigator, chief of the Translational

Gerontology Branch, and chief of the Experimental Gerontology Section in

the Aging, Metabolism, and Nutrition Unit, National Institute on Aging,

NIH, described several studies in which scientists have been able to alter

both the onset and the progression of aging in laboratory animals by restricting

daily total caloric intake. He discussed how efforts to identify the

underlying mechanisms have led to the identification of molecular targets

that can be activated or deactivated by pharmacological compounds to

produce the same effects, but without actual caloric restriction.

... There is also evidence to suggest that prebiotics may increase longevity

as well, Davis continued. She mentioned a review of dietary restriction and

the prebiotic high-amylose starch (HAS), which showed that the biological

effects of HAS are similar to those of dietary restriction (Keenan et al.,

2015). Because of this similarity, it has been hypothesized that HAS may

increase longevity in the same way that dietary restriction does.

... Caloric Restriction and Longevity

Can aging really be stopped? de Cabo asked. The short answer, he said,

is “no,” but in the laboratory, scientists have been able to alter both the

onset and the progression of aging through interventions. He explained that

over the past 500 years, the mean of the human lifespan has increased (i.e.,

people are living longer), and the sigmoidal shape of the survival curve has

squared as a result of nutrition, the health care system, and public health

(see Figure 4-8). He noted that this same shift has been replicated in the

laboratory in animals by restricting daily total caloric intake (without malnutrition).

Both mean and maximum lifespan have been shown to change

(Weindruch and Sohal, 1997; Weindruch et al., 1979, 1986). According to

de Cabo, caloric restriction has been shown to have an effect on lifespan in

every species tested. Also important, in his opinion, it is not just age-related

cancer but other age-related phenotypes, such as muscle structure and function

(Everitt et al., 1985), that can be affected by caloric restriction.

“But there’s always a catch,” de Cabo continued. Namely, these labtested

longevity interventions are lifelong interventions. It would be very

difficult, he said, to convince people to eat for the rest of their lives 30-50

percent fewer calories every day. However, he explained, a growing understanding

of some of the mechanisms that occur in response to caloric

restriction has led to the identification of molecular targets (e.g., SIRT1,

AMPK, mTOR, AKT/PKB) that potentially could be either activated or deactivated

by different pharmacological compounds (de Cabo et al., 2014).

He calls such compounds “caloric restriction mimetics.” The goal, he

explained, is to develop caloric restriction mimetics that have the same

longevity and other beneficial effects of caloric restriction, but without its

total reduction of caloric intake.

Caloric restriction mimetics have shown mixed results in the lab, however.

For example, de Cabo noted that the effects of rapamycin have been

shown to be substantially stronger in females than in males (Harrison et al.,

2009; Miller et al., 2014), while the effects of acarbose have been shown to

be strong in males but not in females (Harrison et al., 2014). After seeing

these results, he went back to the literature and found that, although caloric

restriction has been shown to have an effect on every species tested, there

are in fact cases in which caloric restriction has not worked. It appears, he

said, that many factors may influence the effects of caloric restriction, including

not just sex but also genetic background, diet composition, and age.

To test the effects of some of these factors, de Cabo and colleagues designed

an experiment with two common strains of mice, DBA and C57BL,

and two levels of caloric restriction, 20 percent and 40 percent (Mitchell

et al., 2016). Both strains showed reduced body weight over time at both

levels of caloric restriction compared with mice on unrestricted diets, with

the difference in body weight being dependent on both strain and sex. What

was shocking, de Cabo said, was variation in survival by strain and sex (see

Figure 4-9). For DBA females, there was no difference in survival between

the 20 percent and 40 percent calorie-restricted groups, and de Cabo interpreted

this result to mean that there was no added benefit for DBA females

to restricting their diet by 40 percent rather than 20 percent. The same was

true, more or less, with DBA males. In contrast, de Cabo reported, C57BL/6

females responded very differently to 20 percent versus 40 percent calorie

restriction, with the former being associated with longer lifespan and the

latter showing no difference from an unrestricted diet. In sum, he said, these

results indicate that the response to caloric restriction in mice depended on

strain (i.e., genetics), sex, and extent of caloric restriction.

In addition to caloric restriction mimetics, de Cabo mentioned several

other similar strategies that have been proposed as ways to elicit the same

effects as caloric restriction but without that form of restriction. These include

time-restricted feeding, which involves providing food for very short

periods of time; intermittent fasting, for example, eating one day, but not

the next; and restriction of amino acids, such as methionine.

Caloric Restriction and the Brain

With respect to phenotypic effects of caloric restriction other than

longevity, de Cabo remarked on the extensive mouse model work by Mark

Mattson and colleagues showing a connection between energy restriction

and the maintenance of optimal brain function and resistance to injury

and disease. In one study, he reported, Mattson and colleagues conducted

a 3-month experiment in which they treated wild type and db/db (prone

to diabetes) mice with either 40 percent caloric restriction or feeding every

other day, both with and without exercise (running) (Stranaham et al.,

2008, 2009). They found a drastic impact on dendritic spine density (in hippocampal

neurons), which de Cabo described as markers of memory formation,

and on BDNF levels in the hippocampus. Specifically, db/db mice

who overate (i.e., were fed an ad libitum diet) exhibited reduced dendritic

spine densities and BDNF levels compared with the control (normal-fed)

mice. In both db/db and wild type mice, dietary restriction and running led

to an increase in both dendritic spine densities and BDNF levels. In another

study cited by de Cabo, using a mouse model of Alzheimer’s disease (i.e., in

which the mice overexpress three proteins that have been associated with

Alzheimer’s), caloric restriction led to an improvement in learning and retention

of memory (Halagappa et al., 2007).

The Future of Caloric Restriction in Humans

In summary, de Cabo stated that the lifespan of most species studied

can be extended by caloric restriction. This awareness, he said, has led to

the identification of several underlying molecular pathways (e.g., IGF, sirtuins,

mTOR), which in turn has led to the search for molecules that can target

those pathways. To date, he noted, about 15 such molecules have been

identified. He reiterated that there are a growing number of nonmolecular

caloric restriction strategies as well (e.g., intermittent fasting, restricted

feeding). He recalled that when he started research in this area in 2000,

there was only one way to extend lifespan nongenetically, and that was

caloric restriction. With continued research on the mechanisms of caloric

restriction and the basic biology of aging, he predicts future success in the

translation of these results to humans.

Meanwhile, de Cabo suggested that many of these interventions could

also be translated to improve what he referred to as human “healthspan.”

Rapamycin, for example, has been shown in mice to stop skin tumors

(Checkley et al., 2011) and the deposition of amyloid plaques (Caccamo et

al., 2010). Importantly, de Cabo said, some of these findings have already

been translated to humans. He cited one study in which administration of

an analogue of rapamycin led to an improved response to vaccination in

elderly individuals (i.e., via mTOR inhibition [Mannick et al., 2014]). In

other work, Brandhorst and colleagues (2015) showed that periodic shortterm

fasting can protect against carcinogenesis and other risk factors of


In conclusion, de Cabo believes that in the future, more tools will be

available with which to identify for whom, when, and how longevity interventions

can or should be applied. He emphasized the need to develop predictive

biomarkers for healthy aging and longevity for use in future work.




[The first below paper is not pdf-availed.]

Effects of Calorie Restriction and Fiber Type on Glucose Uptake and Abundance of Electron Transport Chain and Oxidative Phosphorylation Proteins in Single Fibers from Old Rats.

Wang H, Arias EB, Yu CS, Verkerke ARP, Cartee GD.

J Gerontol A Biol Sci Med Sci. 2017 May 22. doi: 10.1093/gerona/glx099. [Epub ahead of print]

PMID: 28531280


Calorie restriction (CR; reducing calorie intake by ~40% below ad libitum) can increase glucose uptake by insulin-stimulated muscle. Because skeletal muscle is comprised of multiple, heterogeneous fiber types, our primary aim was to determine in 23-26 months-old rats the effects of CR (initiated at 14 weeks-old) and fiber type on insulin-stimulated glucose uptake by single fibers of diverse fiber types. Isolated epitrochlearis muscles from AL and CR rats were incubated with [3H]-2-deoxyglucose ±insulin. Glucose uptake and fiber type were determined for single fibers dissected from the muscles. We also determined CR-effects on abundance of several key metabolic proteins in single fibers. CR resulted in: 1) significantly (P<0.05 to 0.001) greater glucose uptake by insulin-stimulated type I, IIA, IIB, IIBX and IIX fibers; 2) significantly (P<0.05 to 0.001) reduced abundance of several mitochondrial electron transport chain (ETC) and oxidative phosphorylation (OxPhos) proteins in type I, IIA and IIBX, but not IIB and IIX fibers; and 3) unaltered hexokinase II abundance in each fiber type. These results demonstrate that CR can enhance glucose uptake in each fiber type of rat skeletal muscle in the absence of upregulation of the abundance of hexokinase II or key mitochondrial ETC and OxPhos proteins.


glucose transport; hexokinase II; insulin resistance; insulin sensitivity; mitochondria


Study analysis shows cutting calories might slow biological aging

May 22, 2017 by Amara Omeokwe



Cut Calories, Lengthen Life Span?

May 22, 2017, at 9:00 a.m.

Cut Calories, Lengthen Life Span?

By Robert Preidt, HealthDay Reporter



Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis.

Belsky DW, Huffman KM, Pieper CF, Shalev I, Kraus WE.

J Gerontol A Biol Sci Med Sci. 2017 May 22. doi: 10.1093/gerona/glx096. [Epub ahead of print]

PMID: 28531269



Biological aging measures have been proposed as proxies for extension of healthy lifespan in trials of geroprotective therapies that aim to slow aging. Several methods to measure biological aging show promise; but it is not known if these methods are sensitive to changes caused by geroprotective therapy. We conducted analysis of two proposed methods to quantify biological aging using data from a recently concluded trial of an established geroprotector, caloric restriction. We obtained data from the National Institute on Aging CALERIE randomized trial through its public-access biobank (https://calerie.duke.edu/). The CALERIE trial randomized N=220 non-obese adults to 25% caloric restriction (n=145; 11.7% caloric restriction was achieved, on average) or to maintain current diet (n=75) for two years. We analyzed biomarker data collected at baseline, 12-, and 24-month follow-up assessments. We applied published biomarker algorithms to these data to calculate two biological age measures, Klemera-Doubal Method Biological Age and homeostatic dysregulation. Intent-to-treat analysis using mixed-effects growth models of within-person change over time tested if caloric restriction slowed increase in measures of biological aging across follow-up. Analyses of both measures indicated caloric restriction slowed biological aging. Weight loss did not account for the observed effects. Results suggest future directions for testing of geroprotective therapies in humans.

Keywords: caloric restriction, biological age, geroscience, geroprotector

Topic: aging obesity weight reduction diet adult biological markers follow-up proxy calorie restricted diet life span aging, biological biobanks

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Role of nutrition on anemia in elderly.

Bianchi VE.

Clin Nutr ESPEN. 2016 Feb;11:e1-e11. doi: 10.1016/j.clnesp.2015.09.003. Epub 2015 Dec 9. Review.

PMID: 28531420


Anemia in elderly population have a great incidence and is related to increased mortality risk. The incidence of nutrition in anemia is about one third of the total. Caloric and protein restriction, iron, vitamin B12, folic deficiency are the causes of nutritional anemia. Protein and energy malnutrition stimulate an increased cytokines production with induction of inflammation, immunodeficiency and anemia. Anorexia and obesity can be associated with anemia due to increased cytokines and hepdicin serum level. Macrophages activity is inhibited and a decrease in red blood cells (RBC), hemoglobin (Hb) concentration due to ineffective erythropoiesis is observed. An adequate energy and protein diet is necessary to reduce inflammation and increase iron absorption. A minimum of 1700 kcal/day and 1.7 gr/kg/day of protein intake are necessary to maintain anabolism in chronic patients to prevent and treat anemia. Iron supplementation by intravenous injection is safe and effective to correct severe iron deficiency. The supplementation of vitamins and oligomineral are useful to reduce oxidative stress and improve RBC longevity. Anemia in elderly could be prevented by an adequate nutrition, a simple and not expensive intervention, and associated to physical exercise reduce the incidence of mortality rate.


Anemia; Energy intake; Iron deficiency; Malnutrition; Protein; Vitamins supplementation


Time caloric restriction inhibits the neoplastic transformation of cirrhotic liver in rats treated with diethylnitrosamine.

Molina-Aguilar C, de Jesús Guerrero-Carrillo M, Espinosa-Aguirre JJ, Olguin-Reyes S, Castro-Belio T, Vázquez-Martínez O, Rivera-Zavala JB, Díaz-Muñoz M.

Carcinogenesis. 2017 May 23. doi: 10.1093/carcin/bgx052. [Epub ahead of print]

PMID: 28535183


Hepatocellular cancer is the most common type of primary liver cancer. Cirrhosis is the main risk factor that generates this malady. It has been proven that caloric restriction protocols and restricted feeding schedules are protective in experimental carcinogenic models. We tested the influence of a time-caloric restriction protocol (2 h of food access during the daytime for 18 weeks) in an experimental model of cirrhosis-hepatocarcinoma produced by weekly administration of diethylnitrosamine. Our results indicate that time-caloric restriction reduced hepatomegaly and prevented the increase in blood leukocytes promoted by diethylnitrosamine. Strikingly, time-caloric restriction preserved functional and histological characteristics of the liver in fibrotic areas compared to the cirrhotic areas of the Ad Libitum-fed group. Tumoural masses in the restricted group were well differentiated; consider a neoplastic or early stage of HCC. However, time-caloric restriction enhanced collagen deposits. With regard to the cancerous process, food restriction prevented systemic inflammation and an increase in carcinoembryonic antigen, and it favoured the occurrence of diffuse multinodular tumours. Histologically, it prevented hepatocyte inflammation response, the regenerative process, and neoplastic transformation. Time-caloric restriction stimulated circadian synchronization in fibrotic and cancerous liver sections, and it increased BMAL1 clock protein levels. We conclude that time-caloric restriction prevents fibrosis from progressing into cirrhosis, thus avoiding chronic inflammation and regenerative processes. It also prevents, probably through circadian entrainment and caloric restriction, the neoplastic transformation of tumoural lesions induced by diethylnitrosamine.

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Comparison of Intermittent Fasting Versus Caloric Restriction in Obese Subjects: A Two Year Follow-Up.

Aksungar FB, Sarıkaya M, Coskun A, Serteser M, Unsal I.

J Nutr Health Aging. 2017;21(6):681-685. doi: 10.1007/s12603-016-0786-y.

PMID: 28537332




Caloric restriction (CR) is proven to be effective in increasing life span and it is well known that, nutritional habits, sleeping pattern and meal frequency have profound effects on human health. In Ramadan some Muslims fast during the day-light hours for a month, providing us a unique model of intermittent fasting (IF) in humans. In the present study, we have investigated the effects of IF versus CR on the same non-diabetic obese subjects who were followed for two years according to the growth hormone (GH)/Insulin like growth factor (IGF)-1 axis and insulin resistance.


Single-arm Interventional Human Study.


23 female subjects (Body Mass Index (BMI) 29-39, aged between 28-42years).


Follow-up is designed as 12 months of CR, after which there was a month of IF and 11 months of CR again, to be totally 24 months. Subjects' daily diets were aligned as low calorie diet during CR and during the IF period, the same subjects fasted for 15 hours in a day for a month and there was no daily calorie restriction. Nutritional pattern was changed as 1 meal in the evening and a late supper before sleeping and no eating and drinking during the day light hours in the IF model. Subjects made brisk walking twice a day during the whole follow-up including both CR and IF periods. BMI, Blood glucose, insulin, TSH, GH, HbA1c, IGF-1, Homa-IR and urinary acetoacetate levels were monitored once in three months and twice in the fasting month.


While subjects lost 1250 ± 372g monthly during the CR, in the IF period, weight loss was decreased to 473 ± 146 g. BMI of all subjects decreased gradually and as the BMI decreased, glucose, HbA1c, insulin, Homa-IR and TSH levels were decreased. GH levels were at baseline at the beginning, increased in the first six months and stayed steady during the CR and IF period than began decreasing after the IF period, while IGF-I increased gradually during the CR period and beginning with the 7th day of IF period, it decreased and kept on decreasing till the end of the follow-up. Urinary acetoacetate levels were higher during the IF period suggesting a constant lipid catabolism.


Our results suggest that, CR affects metabolic parameters positively which will help especially pre-diabetic and insulin resistant patients without any pharmacological approach. In addition IF without calorie restriction can enhance health and cellular resistance to disease without losing weight and those effects may be attributed to different signalling pathways and circulating ketones during IF. Changes observed during IF are probably due to the changes in eating and sleeping pattern and thus changes in metabolic rhythm.


Fasting; calorie restriction; insulin resistance; intermittent fasting; low carbohydrate


When less may be more: calorie restriction and response to cancer therapy.

O'Flanagan CH, Smith LA, McDonell SB, Hursting SD.

BMC Med. 2017 May 24;15(1):106. doi: 10.1186/s12916-017-0873-x. Review.

PMID: 28539118



Calorie restriction (CR) extends lifespan and has been shown to reduce age-related diseases including cancer, diabetes, and cardiovascular and neurodegenerative diseases in experimental models. Recent translational studies have tested the potential of CR or CR mimetics as adjuvant therapies to enhance the efficacy of chemotherapy, radiation therapy, and novel immunotherapies. Chronic CR is challenging to employ in cancer patients, and therefore intermittent fasting, CR mimetic drugs, or alternative diets (such as a ketogenic diet), may be more suitable. Intermittent fasting has been shown to enhance treatment with both chemotherapy and radiation therapy. CR and fasting elicit different responses in normal and cancer cells, and reduce certain side effects of cytotoxic therapy. Findings from preclinical studies of CR mimetic drugs and other dietary interventions, such as the ketogenic diet, are promising for improving the efficacy of anticancer therapies and reducing the side effects of cytotoxic treatments. Current and future clinical studies will inform on which cancers, and at which stage of the cancer process, CR, fasting, or CR mimetic regimens will prove most effective.


Autophagy; Cachexia; Calorie restriction; Chemotherapy; Drug resistance; Fasting; Insulin-like growth factor 1; Ketogenic diet; Metabolism; Radiation therapy


Whole blood transcriptome analysis reveals potential competition in metabolic pathways between negative energy balance and response to inflammatory challenge.

Bouvier-Muller J, Allain C, Tabouret G, Enjalbert F, Portes D, Noirot C, Rupp R, Foucras G.

Sci Rep. 2017 May 24;7(1):2379. doi: 10.1038/s41598-017-02391-y.

PMID: 28539586



Negative Energy Balance (NEB) is considered to increase susceptibility to mastitis. The objective of this study was to improve our understanding of the underlying mechanisms by comparing transcriptomic profiles following NEB and a concomitant mammary inflammation. Accordingly, we performed RNA-seq analysis of blood cells in energy-restricted ewes and control-diet ewes at four different time points before and after intra mammary challenge with phlogogenic ligands. Blood leucocytes responded to NEB by shutting down lipid-generating processes, including cholesterol and fatty acid synthesis, probably under transcriptional control of SREBF 1. Furthermore, fatty acid oxidation was activated and glucose oxidation and transport inhibited in response to energy restriction. Among the differentially expressed genes (DEGs) in response to energy restriction, 64 genes were also differential in response to the inflammatory challenge. Opposite response included the activation of cholesterol and fatty acid synthesis during the inflammatory challenge. Moreover, activation of glucose oxidation and transport coupled with the increase of plasma glucose concentration in response to the inflammatory stimuli suggested a preferential utilization of glucose as the energy source during this stress. Leucocyte metabolism therefore undergoes strong metabolic changes during an inflammatory challenge, which could be in competition with those induced by energy restriction.


Diurnal rhythms of blood glucose, serum ghrelin, faecal IgA and faecal corticosterone in rats subjected to restricted feeding using the diet board.

Kasanen I, Inhilä K, Savontaus E, Voipio HM, Õkva K, Mering S, Kiviniemi V, Hau J, Laaksonen S, Nevalainen T.

Lab Anim. 2017 Jan 1:23677217709850. doi: 10.1177/0023677217709850. [Epub ahead of print]

PMID: 28541129


Laboratory rats are generally fed ad libitum, although this method is associated with obesity and an increased frequency of spontaneous tumours. It has been challenging looking for ways to limit feed consumption in group-housed rats without any setbacks to animal welfare and scientific results. The diet board, as a method of dietary restriction, was used in the present study. Diet board feeding allows group housing and should result in enhanced welfare compared with traditional methods of dietary restriction. With respect to animal model robustness and translatability of results it is important that the feeding regime does not affect diurnal rhythmicity of biological parameters. In the present study the effects of diet board feeding on diurnal rhythms of blood glucose, serum ghrelin, faecal immunoglobulin A (IgA) and faecal corticosterone were assessed. The diet board did not alter diurnal rhythms, and adds weight to the use of this method for dietary restriction which should benefit animal health and the validity of scientific results generated from the animals.


diurnal rhythms; rats; reduction; refinement; restricted feeding


Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner.

Sadagurski M, Cady G, Miller RA.

Aging Cell. 2017 May 20. doi: 10.1111/acel.12590. [Epub ahead of print]

PMID: 28544365


Aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF-1 signals. Early-life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM-HET3 mice in a sex-specific way: acarbose (ACA), 17-α-estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. In this study, we examined the effect of these anti-aging drugs on neuro-inflammation in hypothalamus and hippocampus. We found that age-associated hypothalamic inflammation is reduced in males but not in females at 12 months of age by ACA and 17αE2 and at 22 months of age in NDGA-treated mice. The three drugs blocked indices of hypothalamic reactive gliosis associated with aging, such as Iba-1-positive microglia and GFAP-positive astrocytes, as well as age-associated overproduction of TNF-α. This effect was not observed in drug-treated female mice or in the hippocampus of the drug-treated animals. On the other hand, caloric restriction (CR; an intervention that extends the lifespan in both sexes) significantly reduced hypothalamic microglia and TNF-α in both sexes at 12 months of age. Together, these results suggest that the extent of drug-induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long-lived nutrient restricted or mutant mice.


NDGA ; 17-α Estradiol; Acarbose; aging; hypothalamus; inflammation; longevity; sexual dimorphism


Efficacy and safety of very-low-calorie ketogenic diet: a double blind randomized crossover study.

Colica C, Merra G, Gasbarrini A, De Lorenzo A, Cioccoloni G, Gualtieri P, Perrone MA, Bernardini S, Bernardo V, Di Renzo L, Marchetti M.

Eur Rev Med Pharmacol Sci. 2017 May;21(9):2274-2289.

PMID: 28537652




To verify safety respect to weight loss, cardiometabolic diseases of short-term Very low-calorie ketogenic diets (VLCKDs, <800 kcal day-1).


Randomized cross-over trial with placebo. The study had no. 2 dietary treatment (DT), conducted in two arms: (1) VLCKD1 in which 50% of protein intake is replaced with synthetic amino acids; (2) VLCKD2 with placebo. The VLCKDs (<800 kcal day-1) were different in term of protein content and quality each arm lasted three weeks (wks). Between the two arms a 3-wks washout period was performed to avoid additive effects on DT to follow. At the baseline, at start and end of each arm, all the subjects were evaluated for their health and nutritional status, by anthropometric analysis, body composition (Dual X-ray Absorptiometry (DXA), Bioimpedentiometry, biochemical evaluation, and Peroxisome Proliferator-Activated Receptor γ (PPAR) γ expression by transcriptomic analysis.


After VLCKD1 were reduced: Body Mass Index (BMI) (Δ%=-11.1%, p=0.00), Total Body Water (TBW) (p<0.05); Android Fat Percentage (AFP) (Δ%=-1.8%, p=0.02); Android Fat Mass (AFM) (Δ%=-12.7%, p=0.00); Gynoid Fat Mass (GFM) (Δ%=-6.3%, p=0.01); Intermuscular Adipose Tissue (IMAT) (Δ%= -11.1%, p=0.00); Homeostasis Model Assessment of Insulin Re-sistance (HOMA-IR) (Δ%=-62.1%, p=0.01). After VLCKD1 a significant increase of uricemia, cre-atinine and aspartate aminotransferase (AST) (respectively Δ%=35%, p=0.01; Δ%=5.9%, p=0.02; Δ%=25.5%, p=0.03). After VLCKD2 were reduced: BMI (Δ%=-11.2%, p=0.00); AFM (Δ%=-14.3%, p=0.00); GFM (Δ%=-6.3%, p=0.00); Appendicular Skeletal Muscle Mass Index (ASMMI) (Δ%=-17.5%, p=0.00); HOMA-IR (Δ%=-59,4%, p=0.02). After VLCKD2, uricemia (Δ%=63.1%, p=0.03), and Vitamin D levels (Δ%=25.7%, p=0.02) were increased. No significant changes of car-diovascular disease (CVD) indexes were observed after DTs. No significant changes of PPARγ lev-el in any DTs.


21-days VLCKDs not impair nutritional state; not cause negative changes in global measurements of nutritional state including sarcopenia, bone mineral content, hepatic, renal and lipid profile.

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[The first below paper is not pdf-availed.]

Relationship between sleep pattern and efficacy of calorie-restricted Mediterranean diet in overweight/obese subjects.

Pagliai G, Dinu M, Casini A, Sofi F.

Int J Food Sci Nutr. 2017 May 25:1-7. doi: 10.1080/09637486.2017.1330405. [Epub ahead of print]

PMID: 28545315


The association between the sleep pattern and the effectiveness of a calorie-restricted Mediterranean diet in people with overweight/obesity has been investigated in this study. Four hundred and three subjects were provided with a calorie-restricted Mediterranean diet and followed for 9 months. Personal information, including sleep pattern, was obtained at the baseline. Body weight and composition were measured every 3 months. Poor sleepers reported to have significantly (p < .05) higher BMI and fat mass percentage than good sleepers. Among the good sleepers (6-8 h/day), women showed a greater reduction in fat mass than men after dieting (-3.6 vs. -2 kg, p = .05). Women who reported sleeping 6-8 or >8 h/day had an increased probability of losing fat mass than women who reported sleeping <6 h/day (OR = 4.47, 95% CI: 1.42-14.04, p = .010 and OR = 5.10, 95% CI: 1.15-22.70; p = .032, respectively). Our findings confirm that the normal sleep pattern is necessary to maintain body weight and optimal body composition.


Sleep; diet; obesity; overweight


Daytime restricted feeding modifies the daily regulation of fatty acid β-oxidation and the lipoprotein profile in rats.

Rivera-Zavala JB, Molina-Aguilar C, Pérez-Mendoza M, Olguín-Martínez M, Hernández-Muñoz R, Báez-Ruiz GA, Díaz-Muñoz M.

Br J Nutr. 2017 Apr;117(7):930-941. doi: 10.1017/S0007114517000800. Epub 2017 May 9.

PMID: 28482939



Daytime restricted feeding (2 h of food access from 12.00 to 14.00 hours for 3 weeks) is an experimental protocol that modifies the relationship between metabolic networks and the circadian molecular clock. The precise anatomical locus that controls the biochemical and physiological adaptations to optimise nutrient use is unknown. We explored the changes in liver oxidative lipid handling, such as β-oxidation and its regulation, as well as adaptations in the lipoprotein profile. It was found that daytime restricted feeding promoted an elevation of circulating ketone bodies before mealtime, an altered hepatic daily rhythmicity of 14CO2 production from radioactive palmitic acid, and an up-regulation of the fatty acid oxidation activators, the α-subunit of AMP-activated protein kinase (AMPK), the deacetylase silent mating type information regulation homolog 1, and the transcriptional factor PPARγ-1α coactivator. An increased localisation of phosphorylated α-subunit of AMPK in the periportal hepatocytes was also observed. Liver hepatic lipase C, important for lipoprotein transformation, showed a change of daily phase with a peak at the time of food access. In serum, there was an increase of LDL, which was responsible for a net elevation of circulating cholesterol. We conclude that our results indicate an enhanced fasting response in the liver during daily synchronisation to food access, which involves altered metabolic and cellular control of fatty acid oxidation as well a significant elevation of serum LDL. These adaptations could be part of the metabolic input that underlies the expression of the food-entrained oscillator.


β-Oxidation; AL ad libitum; AMPK AMP-activated protein kinase; BMAL1 brain and muscle Arnt-like protein 1; CPT-1α carnitine palmitoyltransferase 1α; CRY cryptochrome gene; DRF daytime restricted feeding; FAB food anticipatory behaviour; FAO fatty acid oxidation; FEO food-entrained oscillator; Fa 21 h fasting; KB ketone bodies; LIPC hepatic lipase; PEPCK phosphoenolpyruvate carboxykinase; PER period gene; PGC-1α PPARγ-1α coactivator; PP periportal; PV perivenous; Re refed after a 21-h fast; SIRT1 silent mating type information regulation homolog 1; pAMPKα phosphorylated AMP-activated protein kinase α; AMP-activated protein kinase; Food synchronisation; Liver zonation; PPARγ-1α coactivator

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PTEN, Longevity and Age-Related Diseases.

Tait IS, Li Y, Lu J.

Biomedicines. 2013 Dec 13;1(1):17-48. doi: 10.3390/biomedicines1010017. Review.

PMID: 28548055


Since the discovery of PTEN, this protein has been shown to be an effective suppressor of cancer and a contributor to longevity. This report will review, in depth, the associations between PTEN and other molecules, its mutations and regulations in order to present how PTEN can be used to increase longevity. This report will collect recent research of PTEN and use this to discuss PTEN's role in caloric restriction, antioxidative defense of DNA-damage and the role it plays in suppressing tumors. The report will also discuss that variety of ways that PTEN can be compromised, through mutations, complete loss of alleles and its main antagonist, the PI3K/AKT pathway.


DNA; PTEN; aging; caloric; damage; gene; longevity; restriction


Cardiac Telomere Length in Heart Development, Function, and Disease.

Booth SA, Charchar FJ.

Physiol Genomics. 2017 May 26:physiolgenomics.00024.2017. doi: 10.1152/physiolgenomics.00024.2017. [Epub ahead of print]

PMID: 28550088


Telomeres are repetitive nucleoprotein structures at chromosome ends and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise, can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, which need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury.

Copyright © 2017, Physiological Genomics.


ageing; cardiac; cardiovascular; heart; telomeres

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Neuroprotective effects of food restriction on autonomic innervation of the lacrimal gland in rat.

Nooh HZ, El-Saify NH, Eldien NMN.

Ann Anat. 2017 May 24. pii: S0940-9602(17)30052-3. doi: 10.1016/j.aanat.2017.05.001. [Epub ahead of print]

PMID: 28552639



Inflammatory mechanisms and oxidative stress play important roles in age-related lacrimal gland (LG) degeneration as well as neural degeneration. Research suggests that caloric restriction can prevent age-related LG dysfunction and increase the life span of neurons. In the present study, we hypothesized that caloric restriction prevents age-related LG dysfunction by ameliorating the influence of inflammatory/oxidative stress on autonomic neurons controlling lacrimal function. We evaluated the effects of food restriction (FR) on inflammatory/oxidative status and on autonomic neural/neuroglial cell populations in LGs from aging rats. A total of 45 female albino rats were divided into young adult, aged, and aged-FR groups. The FR group was subjected to a 50% reduction in food from 14-20 months of age. LG samples were collected for each group and subjected to biochemical, histological, and immunohistochemical studies. LGs from aged-FR rats, rather than those from aged rats, showed preservation of their cellular structures, organelles, and Schwan cell units. LG preservation was associated with a marked decrease in inflammatory markers, an increase in cellular antioxidants, and the up-regulation of choline acetyltransverase, tyrosine hydroxylase, neuron-specific enolase and S100. These findings strongly suggest that in aged rats, both oxidative and inflammatory stressors directly contribute to LG dysfunction by mediating the degeneration of autonomic neurons, and that FR can protect against these effects.


autonomic neurons; food restriction; inflammatory/oxidative stress; lacrimal gland

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[body fat and lean mass did not return to initial levels despite total weight doing so.]

Long-lasting effect of obesity on skeletal muscle transcriptome.

Messaoudi I, Handu M, Rais M, Sureshchandra S, Park BS, Fei SS, Wright H, White AE, Jain R, Cameron JL, Winters-Stone KM, Varlamov O.

BMC Genomics. 2017 May 25;18(1):411. doi: 10.1186/s12864-017-3799-y.

PMID: 28545403 Free PMC Article





Reduced physical activity and increased intake of calorically-dense diets are the main risk factors for obesity, glucose intolerance, and type 2 diabetes. Chronic overnutrition and hyperglycemia can alter gene expression, contributing to long-term obesity complications. While caloric restriction can reduce obesity and glucose intolerance, it is currently unknown whether it can effectively reprogram transcriptome to a pre-obesity level. The present study addressed this question by the preliminary examination of the transcriptional dynamics in skeletal muscle after exposure to overnutrition and following caloric restriction.


Six male rhesus macaques of 12-13 years of age consumed a high-fat western-style diet for 6 months and then were calorically restricted for 4 months without exercise. Skeletal muscle biopsies were subjected to longitudinal gene expression analysis using next-generation whole-genome RNA sequencing. In spite of significant weight loss and normalized insulin sensitivity, the majority of WSD-induced (n = 457) and WSD-suppressed (n = 47) genes remained significantly dysregulated after caloric restriction (FDR ≤0.05). The MetacoreTM pathway analysis reveals that western-style diet induced the sustained activation of the transforming growth factor-β gene network, associated with extracellular matrix remodeling, and the downregulation of genes involved in muscle structure development and nutritional processes.


Western-style diet, in the absence of exercise, induced skeletal muscle transcriptional programing, which persisted even after insulin resistance and glucose intolerance were completely reversed with caloric restriction.


Caloric restriction; High-fat diet; Insulin resistance; Obesity; Skeletal muscle


Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics.

Barger JL, Vann JM, Cray NL, Pugh TD, Mastaloudis A, Hester SN, Wood SM, Newton MA, Weindruch R, Prolla TA.

Aging Cell. 2017 May 26. doi: 10.1111/acel.12608. [Epub ahead of print]

PMID: 28556428


Caloric restriction (CR) without malnutrition has been shown to retard several aspects of the aging process and to extend lifespan in different species. There is strong interest in the identification of CR mimetics (CRMs), compounds that mimic the beneficial effects of CR on lifespan and healthspan without restriction of energy intake. Identification of CRMs in mammals is currently inefficient due to the lack of screening tools. We have performed whole-genome transcriptional profiling of CR in seven mouse strains (C3H/HeJ, CBA/J, DBA/2J, B6C3F1/J, 129S1/SvImJ, C57BL/6J, and BALB/cJ) in white adipose tissue (WAT), gastrocnemius muscle, heart, and brain neocortex. This analysis has identified tissue-specific panels of genes that change in expression in multiple mouse strains with CR. We validated a subset of genes with qPCR and used these to evaluate the potential CRMs bezafibrate, pioglitazone, metformin, resveratrol, quercetin, 2,4-dinitrophenol, and L-carnitine when fed to C57BL/6J 2-month-old mice for 3 months. Compounds were also evaluated for their ability to modulate previously characterized biomarkers of CR, including mitochondrial enzymes citrate synthase and SIRT3, plasma inflammatory cytokines TNF-α and IFN-γ, glycated hemoglobin (HbA1c) levels and adipocyte size. Pioglitazone, a PPAR-γ agonist, and L-carnitine, an amino acid involved in lipid metabolism, displayed the strongest effects on both the novel transcriptional markers of CR and the additional CR biomarkers tested. Our findings provide panels of tissue-specific transcriptional markers of CR that can be used to identify novel CRMs, and also represent the first comparative molecular analysis of several potential CRMs in multiple tissues in mammals.


aging; biomarkers; caloric restriction; gene expression; mouse


Extended calorie restriction suppresses overall and specific food cravings: a systematic review and a meta-analysis.

Kahathuduwa CN, Binks M, Martin CK, Dawson JA.

Obes Rev. 2017 May 30. doi: 10.1111/obr.12566. [Epub ahead of print] Review.

PMID: 28557246



Multiple studies have concluded that calorie restriction for at least 12 weeks is associated with reduced food cravings, while others have shown that calorie restriction may increase food cravings. We addressed this ambiguity in a systematic review and meta-analysis.


We searched for studies conducted on subjects with obesity, implemented calorie restriction for at least 12 weeks and measured food cravings pre-intervention and post-intervention. Our final eight studies mostly used the Food Craving Inventory. Other comparable methods were converted to a similar scale. We used the duration ≥12 weeks, but closest to 16 weeks for studies with multiple follow-ups and performed DerSimonian-Laird random-effects meta-analyses using the 'metafor' package in r software.


Despite heterogeneity across studies, we observed reductions in pooled effects for overall food cravings (-0.246 [-0.490, -0.001]) as well as cravings for sweet (-0.410 [-0.626, -0.194]), high-fat (-0.190 [-0.343, -0.037]), starchy (-0.288 [-0.517, -0.058]) and fast food (-0.340 [-0.633, -0.048]) in the meta-analysis. Baseline body weight, type of intervention, duration, sample size and percentage of female subjects explained the heterogeneity.


Calorie restriction is associated with reduced food cravings supporting a de-conditioning model of craving reductions. Our findings should ease the minds of clinicians concerned about increased cravings in patients undergoing calorie restriction interventions.


Calorie restriction; food craving inventory; food cravings; weight loss


The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan.

Minnerly J, Zhang J, Parker T, Kaul T, Jia K.

PLoS Genet. 2017 May 30;13(5):e1006764. doi: 10.1371/journal.pgen.1006764. [Epub ahead of print]

PMID: 28557996


Dietary restriction (DR) and reduced insulin growth factor (IGF) signaling extend lifespan in Caenorhabditis elegans and other eukaryotic organisms. Autophagy, an evolutionarily conserved lysosomal degradation pathway, has emerged as a central pathway regulated by various longevity signals including DR and IGF signaling in promoting longevity in a variety of eukaryotic organisms. However, the mechanism remains unclear. Here we show that the autophagy protein ATG-18 acts cell non-autonomously in neuronal and intestinal tissues to maintain C. elegans wildtype lifespan and to respond to DR and IGF-mediated longevity signaling. Moreover, ATG-18 activity in chemosensory neurons that are involved in food detection sufficiently mediates the effect of these longevity pathways. Additionally, ATG-18-mediated cell non-autonomous signaling depends on the release of neurotransmitters and neuropeptides. Interestingly, our data suggest that neuronal and intestinal ATG-18 acts in parallel and converges on unidentified neurons that secrete neuropeptides to regulate C. elegans lifespan through the transcription factor DAF-16/FOXO in response to reduced IGF signaling.

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Long-term dietary restriction up-regulates activity and expression of renal arginase II in aging mice.

Majaw T, Sharma R.

J Biosci. 2017 Jun;42(2):275-283.

PMID: 28569251



Arginase II is a mitochondrial enzyme that catalyses the hydrolysis of L-arginine into urea and ornithine. It is present in other extra-hepatic tissues that lack urea cycle. Therefore, it is plausible that arginase II has a physiological role other than urea cycle which includes polyamine, proline, glutamate synthesis and regulation of nitric oxide production. The high expression of arginase II in kidney, among extrahepatic tissues, might have an important role associated with kidney functions. The present study is aimed to determine the age-associated alteration in the activity and expression of arginase II in the kidney of mice of different ages. The effect of dietary restriction to modulate the agedependent changes of arginase II was also studied. Results showed that renal arginase II activity declines significantly with the progression of age (p less than 0.01 and p less than 0.001 in 6- and 18-month-old mice, respectively as compared to 2-month old mice) and is due to the reduction in its protein as well as the mRNA level (p less than 0.001 in both 6- and 18-month-old mice as compared to 2-month-old mice). Long-term dietary restriction for three months has significantly up-regulated arginase II activity and expression level in both 2- and 18-month-old mice (p less than 0.01 and p less than 0.001, respectively as compared to AL group). These findings clearly indicate that the reducing level of arginase II during aging might have an impact on the declining renal functions. This age-dependent down-regulation of arginase II in the kidney can be attenuated by dietary restriction which may help in the maintenance of such functions.

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The Effects of Graded Levels of Calorie Restriction: X. Transcriptomic Responses of Epididymal Adipose Tissue.

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

J Gerontol A Biol Sci Med Sci. 2017 May 27. doi: 10.1093/gerona/glx101. [Epub ahead of print]

PMID: 28575190


Calorie restriction (CR) leads to a remarkable decrease in adipose tissue mass and increases longevity in many taxa. Since the discovery of leptin, the secretory abilities of adipose tissue have gained prominence in the responses to CR. We quantified transcripts of epididymal white adipose tissue of male C57BL/6 mice exposed to graded levels of CR (0% to 40% CR) for three months. The numbers of differentially expressed genes (DEGs) involved in NF-κB, HIF1-α and p53 signalling increased with increasing levels of CR. These pathways were all significantly downregulated at 40% CR relative to 12h ad libitum feeding. In addition, graded CR had a substantial impact on DEGs associated with pathways involved in angiogenesis. Of the 497 genes differentially expressed with graded CR, 155 of these genes included a signal peptide motif. These putative signalling proteins were involved in the response to ketones, TGF-β signalling, negative regulation of insulin secretion and inflammation. This accords with the previously established effects of graded CR on glucose homeostasis in the same mice. Overall these data suggest reduced levels of adipose tissue under CR may contribute to the protective impact of CR in multiple ways linked to changes in a large population of secreted proteins.


Biology of ageing; Genetics; signalling

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High-Intensity Interval Training and Calorie Restriction Promote Remodeling of Glucose and Lipid Metabolism in Diet-Induced Obesity.

Davis RAH, Halbrooks JE, Watkins E, Fisher G, Hunter GR, Nagy TR, Plaisance EP.

Am J Physiol Endocrinol Metab. 2017 Jun 6:ajpendo.00445.2016. doi: 10.1152/ajpendo.00445.2016. [Epub ahead of print]

PMID: 28588097


Calorie restriction (CR) decreases adiposity, but the magnitude and defense of weight loss is less than predicted due to reductions in total daily energy expenditure (TEE). The purpose of the current investigation was to determine if high-intensity interval training (HIIT) would increase markers of sympathetic activation in white adipose tissue (WAT) and rescue CR-mediated reductions in EE to a greater extent than moderate-intensity aerobic exercise training (MIT). Thirty-two 5-wk old male C57BL/6J mice were placed on ad libitum HFD for 11 weeks followed by randomization to one of four groups (n = 8 per group) for an additional 15 weeks: 1) CON (remain on HFD); 2) CR (25% lower energy intake); 3) CR+HIIT (25% energy deficit created by 12.5% CR and 12.5% EE through HIIT); and 4) CR+MIT (25% energy deficit created by 12.5% CR and 12.5% EE through MIT). Markers of adipose thermogenesis (Ucp1, Prdm16, Dio2, Fgf21) were unchanged in either exercise group in inguinal or epididymal WAT while CR+HIIT decreased Ucp1 expression in retroperitoneal WAT and brown adipose tissue. HIIT rescued CR-mediated reductions in lean body mass (LBM) and resting energy expenditure (REE) and both were associated with improvements in glucose/insulin tolerance. Improvements in glucose metabolism in the CR+HIIT group appear to be linked to a molecular signature which enhances glucose and lipid storage in skeletal muscle. These findings suggest that negative energy balance abolishes exercise-mediated increases in markers of WAT thermogenesis but remodels skeletal muscle metabolic and thermogenic capacity which are linked to enhanced glucose metabolism.


Exercise training; brown adipose tissue; energy expenditure; glucose metabolism; weight loss


Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production.

Hine C, Kim HJ, Zhu Y, Harputlugil E, Longchamp A, Matos MS, Ramadoss P, Bauerle K, Brace L, Asara JM, Ozaki CK, Cheng SY, Singha S, Ahn KH, Kimmelman A, Fisher FM, Pissios P, Withers DJ, Selman C, Wang R, Yen K, Longo VD, Cohen P, Bartke A, Kopchick JJ, Miller R, Hollenberg AN, Mitchell JR.

Cell Metab. 2017 Jun 6;25(6):1320-1333.e5. doi: 10.1016/j.cmet.2017.05.003.

PMID: 28591635


Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.


FGF21; IGF-1; IRS-1; autophagy; cystathionine γ-lyase; growth hormone; hydrogen sulfide; hypopituitary dwarfism; longevity; thyroid hormone

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The association among chronotype, timing of food intake and food preferences depends on body mass status.

Muñoz JSG, Cañavate R, Hernández CM, Cara-Salmerón V, Morante JJH.

Eur J Clin Nutr. 2017 Jun;71(6):736-742. doi: 10.1038/ejcn.2016.182. Epub 2016 Sep 21.

PMID: 27650874




Previous studies have shown that individuals with circadian preferences for the evening (wake up later and reach maximum activity in the afternoon) have distorted dietary habits and misregulated body weight. Therefore, the present study was conducted to analyse the possible relationships between 'morningness' or 'eveningness' (chronotype), dietary habits and the level of obesity.


Among 400 participants, 171 subjects finished the follow-up period and were evaluated. Anthropometric, clinical and dietary parameters were analysed; the Horne-Östberg test was used to determine chronotype. A hypocaloric-behavioural intervention was performed in the overweight/obese subjects.


In normal-weight subjects, the morningness group ingested most of their energy and nutrients at breakfast and lunch, whereas the eveningness group showed a higher intake at dinner, corresponding with their chronotypes. A significant interaction was revealed between chronotype and body mass index regarding the energy and nutrients consumed at dinner (P<0.05 in all cases), as in the normal-weight subjects the evening food intake was higher in the eveningness group, but in the overweight subjects the situation was inverse. In addition, the food preferences were related to the chronotype, as the morningness subjects showed a higher intake of fruit (P<0.010).


The timing of food intake corresponded to the chronotype in the normal-weight subjects; however, the overweight/obese subjects showed intake patterns removed from their physiological rhythms. These findings may indicate a need to design specific diets based not only on the total energy expenditure but also on the chronotype, as an indicator of the biological rhythms.


Genetic Dissection of Nutrition-Induced Plasticity in Insulin/Insulin-Like Growth Factor Signaling and Median Life Span in a Drosophila Multiparent Population.

Stanley PD, Ng'oma E, O'Day S, King EG.

Genetics. 2017 Jun;206(2):587-602. doi: 10.1534/genetics.116.197780.

PMID: 28592498


The nutritional environments that organisms experience are inherently variable, requiring tight coordination of how resources are allocated to different functions relative to the total amount of resources available. A growing body of evidence supports the hypothesis that key endocrine pathways play a fundamental role in this coordination. In particular, the insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) pathways have been implicated in nutrition-dependent changes in metabolism and nutrient allocation. However, little is known about the genetic basis of standing variation in IIS/TOR or how diet-dependent changes in expression in this pathway influence phenotypes related to resource allocation. To characterize natural genetic variation in the IIS/TOR pathway, we used >250 recombinant inbred lines (RILs) derived from a multiparental mapping population, the Drosophila Synthetic Population Resource, to map transcript-level QTL of genes encoding 52 core IIS/TOR components in three different nutritional environments [dietary restriction (DR), control ©, and high sugar (HS)]. Nearly all genes, 87%, were significantly differentially expressed between diets, though not always in ways predicted by loss-of-function mutants. We identified cis (i.e., local) expression QTL (eQTL) for six genes, all of which are significant in multiple nutrient environments. Further, we identified trans (i.e., distant) eQTL for two genes, specific to a single nutrient environment. Our results are consistent with many small changes in the IIS/TOR pathways. A discriminant function analysis for the C and DR treatments identified a pattern of gene expression associated with the diet treatment. Mapping the composite discriminant function scores revealed a significant global eQTL within the DR diet. A correlation between the discriminant function scores and the median life span (r = 0.46) provides evidence that gene expression changes in response to diet are associated with longevity in these RILs.


Drosophila melanogaster; MPP; Multiparent Advanced Generation Inter-Cross (MAGIC); TOR signaling; diet; eQTLs; insulin signaling; life span; multiparental populations

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INDY-A New Link to Metabolic Regulation in Animals and Humans.

Rogina B.

Front Genet. 2017 May 24;8:66. doi: 10.3389/fgene.2017.00066. eCollection 2017. Review.

PMID: 28596784

Various ketogenic diets can differently support brain resistance against experimentally evoked seizures and seizure-induced elemental anomalies of hippocampal formation.

Chwiej J, Patulska A, Skoczen A, Matusiak K, Janeczko K, Ciarach M, Simon R, Setkowicz Z.

J Trace Elem Med Biol. 2017 Jul;42:50-58. doi: 10.1016/j.jtemb.2017.04.002. Epub 2017 Apr 10.

PMID: 28595792


In this paper the influence of two different ketogenic diets (KDs) on the seizure-evoked elemental anomalies of hippocampal formation was examined. To achieve this purpose normal and pilocarpine treated rats previously fed with one of the two high fat and carbohydrate restricted diets were compared with animals on standard laboratory diet. The ketogenic ratios of the examined KDs were equal to 5:1 (KD1) and 9:1 (KD2). KD1 and standard diet fed animals presented similar patterns of seizure-evoked elemental changes in hippocampal formation. Also the analysis of behavioral data recorded after pilocarpine injection did not show any significant differences in intensity and duration of seizures between KD1 and standard diet fed animals. Higher ketogenic ratio KD2 introduced in the normal hippocampal formation prolonged changes in the accumulation of P, K, Zn and Ca. Despite this, both the intensity and duration of seizures were significantly reduced in rats fed with KD2 which suggests that its saving action on the nerve tissue may protect brain from seizure propagation. Also seizure-evoked elemental anomalies in KD2 animals were different than those observed for rats both on KD1 and standard diets. The comparison of seizure experiencing and normal rats on KD2, did not show any statistically significant differences in elemental composition of CA1 and H hippocampal areas whilst in CA3 area only Zn level changed as a result of seizures. DG was the area mostly affected by seizures in KD2 fed rats but areal densities of all examined elements increased in this hippocampal region.


Epilepsy; Hippocampal formation; Ketogenic diet; Pilocarpine model of seizures; Synchrotron radiation; Topographic and quantitative elemental analysis; X-ray fluorescence microscopy

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Effect of physical activity and dietary restriction interventions on weight loss and the musculoskeletal function of overweight and obese older adults with knee osteoarthritis: a systematic review and mixed method data synthesis.

Alrushud AS, Rushton AB, Kanavaki AM, Greig CA.

BMJ Open. 2017 Jun 8;7(6):e014537. doi: 10.1136/bmjopen-2016-014537.

PMID: 28600365





Despite the clinical recommendation of exercise and diet for people with knee osteoarthritis (OA), there are no systematic reviews synthesising the effectiveness of combining physical activity and dietary restriction interventions on the musculoskeletal function of overweight and obese older adults with knee OA.


To evaluate the effectiveness of combined physical activity and dietary restriction programmes on body weight, body mass index (BMI) and the musculoskeletal function of overweight and obese older adults with knee OA.


A detailed search strategy was applied to key electronic databases (Ovid, Embase, Web of Science andCumulative Index to Nursing and Allied Health Literature (CINAHL)) for randomised controlled trials (RCTs) published in English prior to 15 January 2017.


Participants with BMI ≥25 kg/m2, aged ≥55 years of age and with radiographic evidence of knee OA.


Physical activity plus dietary restriction programmes with usual care or exercise as the comparators.


Primary outcome measures were body weight, BMI or musculoskeletal function. Secondary outcome measures were pain and quality of life.


One pilot and two definitive trials with n=794 participants were included. Two articles reporting additional data and outcome measures for one of the RCTs were identified. All included RCTs had an unclear risk of bias. Meta-analysis was only possible to evaluate mobility (6 min walk test) at 6 months and the pooled random effect 15.05 (95% CI -11.77 to 41.87) across two trials with n=155 participants did not support the combined intervention programme. Narrative synthesis showed clear differences in favour of a reduced body weight and an increased 6 min walk in the intervention group compared with control groups.


The quality of evidence of benefit of combining exercise and dietary interventions in older overweight/obese adults with knee OA is unclear.


CRD42015019088 and ISRCTN, ISRCTN12906938.


Exercise; diet; elderly; obesity; randomised controlled trials

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Effect of a High-Protein Diet versus Standard-Protein Diet on Weight Loss and Biomarkers of Metabolic Syndrome: A Randomized Clinical Trial.

Campos-Nonato I, Hernandez L, Barquera S.

Obes Facts. 2017 Jun 10;10(3):238-251. doi: 10.1159/000471485. [Epub ahead of print]

PMID: 28601864





Some studies have shown that protein-enriched diets can lead to greater weight loss and improvements in biomarkers of metabolic syndrome (MeS) than standard protein diets. Therefore, the aim of this study was to determine the effect of increased protein intake on weight loss in Mexican adults with MeS.


Randomized controlled trial in 118 adults aged 47.4 ± 11.5 years and meeting the established criteria for MeS were randomized to prescribed hypocaloric diets (500 kcal less than resting metabolic rate) providing either 0.8 g/kg body weight (standard protein diet (SPD)) or 1.34 g/kg body weight (higher protein diet (HPD)) for 6 months. Body weight, waist circumference, percent body fat by bioimpedance analysis, fasting blood glucose, fasting insulin, hemoglobin A1c, total cholesterol, high-density lipoprotein (HDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, triglycerides, C-reactive protein, creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase were measured at baseline, 3 months and at 6 months.


There were 105 subjects (51 for SPD and 54 for HPD) who completed the trial. Overall weight loss was 5.1 ± 3.6 kg in the SPD group compared to 7.0 ± 3.7 kg in the in HPD group. Both groups lost a significant percent of centimeters of waist circumference (SPD -6.5 ± 2.6 cm and HPD -8.8 ± 2.6 cm). There was no statistical difference Except for the varying weight losses the two groups did not show any further differences overall. However in the subgroup judged to be adherent more than 75% of the time with the prescribed diets, there was a significant difference in mean weight loss (SPD -5.8% vs. HPD -9.5%) after adjusting for baseline BMI. Both groups demonstrated significant decreases in waist circumference, glucose, insulin, triglycerides, and VLDL cholesterol, but there were no differences between the groups. There were no changes in blood tests for liver or renal function.


There were no significant differences in weight loss and biomarkers of MeS when the overall group was examined, but the participants with more adherence rate in the HPD group lost significantly more weight than adherent participants in the SPD group.


Diet; Metabolic syndrome; Protein intake; Weight loss

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Calorie Restriction in Rodents: Caveats to Consider.

Ingram DK, de Cabo R.

Ageing Res Rev. 2017 Jun 10. pii: S1568-1637(17)30126-5. doi: 10.1016/j.arr.2017.05.008. [Epub ahead of print] Review.

PMID: 28610949



The calorie restriction paradigm has provided one of the most widely used and most useful tools for investigating mechanisms of aging and longevity. By far, rodent models have been employed most often in these endeavors. Over decades of investigation, claims have been made that the paradigm produces the most robust demonstration that aging is malleable. In the current review of the rodent literature, we present arguments that question the robustness of the paradigm to increase lifespan and healthspan. Specifically, there are several questions to consider as follows: (1) At what age does CR no longer produce benefits? (2) Does CR attenuate cognitive decline? (3) Are there negative effects of CR, including effects on bone health, wound healing, and response to infection? (4) How important is schedule of feeding? (5) How long does CR need to be imposed to be effective? (6) How do genotype and gender influence CR? (7) What role does dietary composition play? Consideration of these questions produce many caveats that should guide future investigations to move the field forward.


chronic disease; diet restriction; fasting; healthspan; lifespan; longevity; low calorie diets; mortality; nutrition; protein restriction


Simple obesity and renal function.

Sikorska D, Grzymislawska M, Roszak M, Gulbicka P, Korybalska K, Witowski J.

J Physiol Pharmacol. 2017 Apr;68(2):175-180.

PMID: 28614766


Increasing evidence accumulate to suggest that obesity increases the risk of chronic kidney disease independently of dyslipidemia, diabetes, and hypertension. This so-called obesity-related glomerulopathy is characterized at early stages by glomerular hypertrophy with or without secondary focal segmental glomerulosclerosis. Since, however, kidney biopsies are usually not performed at this phase, an early diagnosis of the disease is often difficult. Here, we review new developments in the pathophysiology of obesity-associated kidney dysfunction and discuss the potential of appropriate monitoring of glomerular filtration rate and albuminuria for early detection of the disease. We also present the benefits conferred by even moderate dietary restriction on the course of the disease.

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<b>Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1<sup>Δ/-</sup>mice</b>.

Wu H, van Thiel BS, Bautista-Nino PK, Reiling E, Durik M, Leijten FPJ, Ridwan Y, Brandt RMC, van Steeg H, Dollé MET, Vermeij WP, Hoeijmakers JHJ, Essers J, van der Pluijm I, Danser AHJ, Roks AJM.

Clin Sci (Lond). 2017 Jun 15. pii: CS20170026. doi: 10.1042/CS20170026. [Epub ahead of print]

PMID: 28620011


DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model ( Ercc1∆/- mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system . Ercc1∆/- mice showed increased blood pressure and decreased aortic relaxations to acetylcholine in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1d/- DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II vasoconstrictions, which were increased in Ercc1∆/- mice. Ercc1∆/- mutants showed a loss of Angiotensin II type 2 receptor-mediated counterregulation of Angiotensin II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of renin-angiotensin system blockade with respect to endothelial function improvement. In summary, dietary restriction effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang type 1 receptor blockade is ineffective.


Aging; cardiovascular disease; dietary restriction; genetic association; renin-angiotensin system


The effect of caloric restriction on the forelimb skeletal muscle fibers of the hypertrophic myostatin null mice.

Elashry MI, Matsakas A, Wenisch S, Arnhold S, Patel K.

Acta Histochem. 2017 Jun 13. pii: S0065-1281(17)30128-9. doi: 10.1016/j.acthis.2017.06.002. [Epub ahead of print]

PMID: 28622884


Skeletal muscle mass loss has a broad impact on body performance and physical activity. Muscle wasting occurs due to genetic mutation as in muscular dystrophy, age-related muscle loss (sarcopenia) as well as in chronic wasting disorders as in cancer cachexia. Food restriction reduces muscle mass underpinned by increased muscle protein break down. However the influence of dietary restriction on the morphometry and phenotype of forelimb muscles in a genetically modified myostatin null mice are not fully characterized. The effect of a five week dietary limitation on five anatomically and structurally different forelimb muscles was examined. C57/BL6 wild type (Mstn+/+) and myostatin null (Mstn-/-) mice were either given a standard rodent normal daily diet ad libitum (ND) or 60% food restriction (FR) for a 5 week period. M. triceps brachii Caput laterale (T.lateral), M. triceps brachii Caput longum (T.long), M. triceps brachii Caput mediale (T.medial), M. extensor carpi ulnaris (ECU) and M. flexor carpi ulnaris (FCU) were dissected, weighted and processed for immunohistochemistry. Muscle mass, fibers cross sectional areas (CSA) and myosin heavy chain types IIB, IIX, IIA and type I were analyzed. We provide evidence that caloric restriction results in muscle specific weight reduction with the fast myofibers being more prone to atrophy. We show that slow fibers are less liable to dietary restriction induced muscle atrophy. The effect of dietary restriction was more pronounced in Mstn-/- muscles to implicate the oxidative fibers compared to Mstn+/+. Furthermore, peripherally located myofibers are more susceptible to dietary induced reduction compared to deep fibers. We additionally report that dietary restriction alters the glycolytic phenotype of the Mstn-/- into the oxidative form in a muscle dependent manner. In summary our study shows that calorie restriction alters muscle fiber profile of forelimb muscles of Myostatin null mice.


Food restriction; Myosin heavy chain; Myostatin; Skeletal muscle

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Lifelong dietary intervention does not affect hematopoietic stem cell function.

Lazare S, Ausema A, Reijne AC, van Dijk G, van Os R, de Haan G.

Exp Hematol. 2017 Jun 15. pii: S0301-472X(17)30232-1. doi: 10.1016/j.exphem.2017.06.002. [Epub ahead of print]

PMID: 28625745


Hematopoietic stem cells (HSC) undergo a profound functional decline during normal aging. As caloric or dietary restriction has been shown to delay multiple aspects of the aging process in many species, we here decided to explore the consequences of lifelong caloric restriction or, reversely, lifelong excess caloric intake for HSC numbers and function. Although caloric restriction prevented age-dependent increase in bone marrow cellularity, caloric restriction was not able to prevent functional decline of aged long-term hematopoietic stem cell functioning. In addition, a lifelong high fat diet did not affect stem cell functioning either. We conclude that lifelong caloric interventions fail to prevent or induce loss of age-associated hematopoietic stem cell functioning.


Protein restriction does not affect body temperature pattern in female mice.

Kato GA, Shichijo H, Takahashi T, Shinohara A, Morita T, Koshimoto C.

Exp Anim. 2017 Jun 13. doi: 10.1538/expanim.17-0035. [Epub ahead of print]

PMID: 28626157


Daily torpor is a physiological adaptation in mammals and birds characterized by a controlled reduction of metabolic rate and body temperature during the resting phase of circadian rhythms. In laboratory mice, daily torpor is induced by dietary caloric restriction. However, it is not known which nutrients are related to daily torpor expression. To determine whether dietary protein is a key factor in inducing daily torpor in mice, we fed mice a protein-restricted (PR) diet that included only one-quarter of the amount of protein but the same caloric level as a control © diet. We assigned six non-pregnant female ICR mice to each group and recorded their body weights and core body temperatures for 4 weeks. Body weights in the C group increased, but those in the PR group remained steady or decreased. Mice in both groups did not show daily torpor, but most mice in a food-restricted group (n=6) supplied with 80% of the calories given to the C group exhibited decreased body weights and frequently displayed daily torpor. This suggests that protein restriction is not a trigger of daily torpor; torpid animals can conserve their internal energy, but torpor may not play a significant role in conserving internal protein. Thus, opportunistic daily torpor in mice may function in energy conservation rather than protein saving.


core body temperature; daily torpor; female mice; isocaloric; protein restriction

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Microbiota in anorexia nervosa: The triangle between bacterial species, metabolites and psychological tests.

Borgo F, Riva A, Benetti A, Casiraghi MC, Bertelli S, Garbossa S, Anselmetti S, Scarone S, Pontiroli AE, Morace G, Borghi E.

PLoS One. 2017 Jun 21;12(6):e0179739. doi: 10.1371/journal.pone.0179739. eCollection 2017.

PMID: 28636668


Anorexia nervosa (AN) is a psychiatric disease with devastating physical consequences, with a pathophysiological mechanism still to be elucidated. Metagenomic studies on anorexia nervosa have revealed profound gut microbiome perturbations as a possible environmental factor involved in the disease. In this study we performed a comprehensive analysis integrating data on gut microbiota with clinical, anthropometric and psychological traits to gain new insight in the pathophysiology of AN. Fifteen AN women were compared with fifteen age-, sex- and ethnicity-matched healthy controls. AN diet was characterized by a significant lower energy intake, but macronutrient analysis highlighted a restriction only in fats and carbohydrates consumption. Next generation sequencing showed that AN intestinal microbiota was significantly affected at every taxonomic level, showing a significant increase of Enterobacteriaceae, and of the archeon Methanobrevibacter smithii compared with healthy controls. On the contrary, the genera Roseburia, Ruminococcus and Clostridium, were depleted, in line with the observed reduction in AN of total short chain fatty acids, butyrate, and propionate. Butyrate concentrations inversely correlated with anxiety levels, whereas propionate directly correlated with insulin levels and with the relative abundance of Roseburia inulinivorans, a known propionate producer. BMI represented the best predictive value for gut dysbiosis and metabolic alterations, showing a negative correlation with Bacteroides uniformis (microbiota), with alanine aminotransferase (liver function), and with psychopathological scores (obsession-compulsion, anxiety, and depression), and a positive correlation with white blood cells count. In conclusion, our findings corroborate the hypothesis that the gut dysbiosis could take part in the AN neurobiology, in particular in sustaining the persistence of alterations that eventually result in relapses after renourishment and psychological therapy, but causality still needs to be proven.


Effects of mild calorie restriction on lipid metabolism and inflammation in liver and adipose tissue.

Park CY, Park S, Kim MS, Kim HK, Han SN.

Biochem Biophys Res Commun. 2017 Jun 16. pii: S0006-291X(17)31221-4. doi: 10.1016/j.bbrc.2017.06.090. [Epub ahead of print]

PMID: 28630003




Calorie restriction (CR) has been reported to improve lipid metabolism and to decrease inflammatory diseases. However, most existing CR models use 30-50% calorie reduction, which is hard to achieve in humans. We investigated the effects of mild CR on lipid metabolism and inflammatory responses. Male C57BL/6 mice were fed control diet (10% kcal fat, Control) or high fat diet (60% kcal fat, HFD) ad libitum or reduced amount of control diet to achieve 15% CR for 16 wks. Body weights, white adipose tissue weights, liver triacylglycerol levels, and serum fetuin-A levels were lower in CR than in the Control. Serum adiponectin levels were higher in CR and lower in HFD compared with the Control. Liver and adipose tissue Mcp-1 mRNA levels were significantly lower in CR compared with the Control. Adipose tissue mRNA levels of Mcp-1, Il-6, Tnf-α and Socs3 were significantly higher in HFD than in the Control and CR, and levels of these negatively correlated with serum adiponectin levels. CR group had the lowest leptin levels and the highest liver Lepr expression, and Lepr mRNA levels positively correlated with liver Socs3 mRNA levels. Our findings showed that mild CR lowered adiposity which resulted in higher adiponectin and lower fetuin-A levels, and might have contributed to alleviation of inflammatory status in the liver and adipose tissue. Furthermore, mild CR might have affected leptin sensitivity by up-regulating Lepr expression.


Adiponectin; Fetuin-A; Liver triacylglycerol; Mild calorie restriction; Peripheral leptin sensitivity; Pro-inflammatory cytokine

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Caloric Restriction Protects Livers from Ischemia/Reperfusion Damage by Preventing Ca<sup>2+</sup>-Induced Mitochondrial Permeability Transition.

Menezes-Filho SL, Amigo I, Prado FM, Ferreira NC, Koike MK, Pinto IFD, Miyamoto S, Montero EFS, Medeiros MHG, Kowaltowski AJ.

Free Radic Biol Med. 2017 Jun 19. pii: S0891-5849(17)30646-9. doi: 10.1016/j.freeradbiomed.2017.06.013. [Epub ahead of print]

PMID: 28642067


Caloric restriction (CR) promotes lifespan extension and protects against many pathological conditions, including ischemia/reperfusion injury to the brain, heart and kidney. In the liver, ischemia/reperfusion damage is related to excessive mitochondrial Ca2+ accumulation, leading to the mitochondrial permeability transition. Indeed, liver mitochondria isolated from animals maintained on CR for 4 months were protected against permeability transition and capable of taking up Ca2+ at faster rates and in larger quantities. These changes were not related to modifications in mitochondrial respiratory activity, but rather to a higher proportion of ATP relative to ADP in CR liver mitochondria. Accordingly, both depletion of mitochondrial adenine nucleotides and loading mitochondria with exogenous ATP abolished the differences between CR and ad libitum (AL) fed groups. The prevention against permeability transition promoted by CR strongly protected against in vivo liver damage induced by ischemia/reperfusion. Overall, our results show that CR strongly protects the liver against ischemia/reperfusion and uncover a mechanism for this protection, through a yet undescribed diet-induced change in liver mitochondrial Ca2+ handling related to elevated intramitochondrial ATP.


ATP; Ca(2+); Calorie Restriction; Ischemic Protection; Liver; Mitochondria

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Late-onset dementia: a mosaic of prototypical pathologies modifiable by diet and lifestyle.

Mattson MP.

NPJ Aging Mech Dis. 2015;1. pii: 15003. doi: 10.1038/npjamd.2015.3. Epub 2015 Sep 28.

PMID: 28642821



Idiopathic late-onset dementia (ILOD) describes impairments of memory, reasoning and/or social abilities in the elderly that compromise their daily functioning. Dementia occurs in several major prototypical neurodegenerative disorders that are currently defined by neuropathological criteria, most notably Alzheimer's disease (AD), Lewy body dementia, frontotemporal dementia (FTD) and hippocampal sclerosis of aging (HSA). However, people who die with ILOD commonly exhibit mixed pathologies that vary within and between brain regions. Indeed, many patients diagnosed with probable AD exhibit only modest amounts of disease-defining amyloid β-peptide plaques and p-Tau tangles, and may have features of FTD (TDP-43 inclusions), Parkinson's disease (α-synuclein accumulation), HSA and vascular lesions. Here I argue that this 'mosaic neuropathological landscape' is the result of commonalities in aging-related processes that render neurons vulnerable to the entire spectrum of ILODs. In this view, all ILODs involve deficits in neuronal energy metabolism, neurotrophic signaling and adaptive cellular stress responses, and associated dysregulation of neuronal calcium handling and autophagy. While this mosaic of neuropathologies and underlying mechanisms poses major hurdles for development of disease-specific therapeutic interventions, it also suggests that certain interventions would be beneficial for all ILODs. Indeed, emerging evidence suggests that the brain can be protected against ILOD by lifelong intermittent physiological challenges including exercise, energy restriction and intellectual endeavors; these interventions enhance cellular stress resistance and facilitate neuroplasticity. There is also therapeutic potential for interventions that bolster neuronal bioenergetics and/or activate one or more adaptive cellular stress response pathways in brain cells. A wider appreciation that all ILODs share age-related cellular and molecular alterations upstream of aggregated protein lesions, and that these upstream events can be mitigated, may lead to implementation of novel intervention strategies aimed at reversing the rising tide of ILODs.

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Aging and Caloric Restriction Research: A Biological Perspective With Translational Potential.

Balasubramanian P, Howell PR, Anderson RM.

EBioMedicine. 2017 Jun 19. pii: S2352-3964(17)30250-5. doi: 10.1016/j.ebiom.2017.06.015. [Epub ahead of print] Review.

PMID: 28648985


Aging as a research pursuit is fairly new compared with traditional lines of medical research. A growing field of investigators is focused on understanding how changes in tissue biology, physiology, and systemic homeostasis, conspire to create increased vulnerability to disease as a function of age. Aging research as a discipline is necessarily broad; in part because aging itself is multi-faceted and in part because different model systems are employed to define the underlying biology. In this review we outline aspects of aging research that are likely to uncover the pivotal events leading to age-related disease vulnerability. We focus on studies of human aging and discuss the value of research on caloric restriction, an intervention with proven efficacy in delaying aging. We propose that studies such as these will deliver target factors and processes that create vulnerability in human aging, an advance that would potentially be transformative in clinical care.


Aging; Caloric restriction; Humans; Metabolism; Nonhuman primates


Both overlapping and independent mechanisms determine how diet and insulin-ligand knockouts extend lifespan of <i>Drosophila melanogaster</i>.

Zandveld J, van den Heuvel J, Zwaan BJ, Piper MDW.

NPJ Aging Mech Dis. 2017 Feb 20;3:4. doi: 10.1038/s41514-017-0004-0. eCollection 2017.

PMID: 28649422


Lifespan in many organisms, including Drosophila melanogaster, can be increased by reduced insulin-IGF-like signaling (IIS) or by changes in diet. Most studies testing whether IIS is involved in diet-mediated lifespan extension employ only a few diets, but recent data shows that a broad range of nutritional environments is required. Here, we present lifespan data of long-lived Drosophila, lacking three of the eight insulin-like peptides [Drosophila insulin-like peptides 2,3,5 (dilp2-3,5)] on nine different diets that surround the optimum for lifespan. Their nutritional content was varied by manipulating sugar and yeast concentrations independently, and thus incorporated changes in both diet restriction and nutrient balance. The mutants were substantially longer-lived than controls on every diet, but the effects on the lifespan response to sugar and yeast differed. Our data illustrates how a greater coverage of diet balance (DB) and restriction can unify differing interpretations of how IIS might be involved in the response of lifespan to diet.

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Influence of expression of UCP3, PLIN1 and PPARG2 on the oxidation of substrates after hypocaloric dietary intervention.

Cortes de Oliveira C, Nicoletti CF, Pinhel MAS, de Oliveira BAP, Quinhoneiro DCG, Noronha NY, Fassini PG, Marchini JS, da Silva Júnior WA, Salgado Júnior W, Nonino CB.

Clin Nutr. 2017 Jun 15. pii: S0261-5614(17)30223-6. doi: 10.1016/j.clnu.2017.06.012. [Epub ahead of print]

PMID: 28651828



In addition to environmental and psychosocial factors, it is known that genetic factors can also influence the regulation of energy metabolism, body composition and determination of excess weight. The objective of this study was to evaluate the influence of UCP3, PLIN1 and PPARG2 genes on the substrates oxidation in women with grade III obesity after hypocaloric dietary intervention.


This is a longitudinal study with 21 women, divided into two groups: Intervention Group (G1): 11 obese women (Body Mass Index (BMI) ≥40 kg/m2), and Control Group (G2): 10 eutrophic women (BMI between 18.5 kg/m2 and 24.9 kg/m2). Weight (kg), height (m), BMI (kg/m2), substrate oxidation (by Indirect Calorimetry) and abdominal subcutaneous adipose tissue were collected before and after the intervention. For the dietary intervention, the patients were hospitalized for 6 weeks receiving 1200 kcal/day.


There was a significant weight loss (8.4 ± 4.3 kg - 5.2 ± 1.8%) and reduction of UCP3 expression after hypocaloric dietary intervention. There was a positive correlation between carbohydrate oxidation and UCP3 (r = 0.609; p = 0.04), PLIN1 (r = 0.882; p = 0.00) and PPARG2 (r = 0.791; p = 0.00) expression before dietary intervention and with UCP3 (r = 0.682; p = 0.02) and PLIN1 (r = 0.745; p = 0.00) genes after 6 weeks of intervention. There was a negative correlation between lipid oxidation and PLIN1 (r = -0.755; p = 0.00) and PPARG2 (r = 0.664; p = 0.02) expression before dietary intervention and negative correlation with PLIN1 (r = 0.730; p = 0.02) expression after 6 weeks of hypocaloric diet.


Hypocaloric diet reduces UCP3 expression in individuals with obesity and the UCP3, PLIN1 and PPARG2 expression correlate positively with carbohydrate oxidation and negatively with lipid oxidation.


Gene expression; Hypocaloric diet intervention; Obesity; Oxidation of substrate; Weight loss

Edited by AlPater
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Interventions to slow cardiovascular aging: Dietary restriction, drugs and novel molecules.

Heiss C, Spyridopoulos I, Haendeler J.

Exp Gerontol. 2017 Jun 25. pii: S0531-5565(17)30293-0. doi: 10.1016/j.exger.2017.06.015. [Epub ahead of print] Review.

PMID: 28658611


Cardiovascular aging is a highly dynamic process. Despite the fact that cardiovascular function and structure change with age, they can still be modulated even in aged humans. The most prominent approaches to improve age-dependent vascular changes include dietary restriction and pharmacologic agents interacting with signaling pathways implicated in this context. These include inhibition of TOR, glycolysis, and GH/IGF-1, activation of sirtuins, and AMPK, as well as modulators of inflammation, epigenetic pathways, and telomeres. Promising nutritional approaches include Mediterranean diet and novel dietary bioactives including flavanols, anthocyanins, and lignins. Many plant bioactives improve cardiovascular parameters implied in vascular healthy aging including endothelial function, arterial stiffness, blood pressure, cholesterol, and glycemic control. However, the mechanism of action of most bioactives is not established and it remains to be elucidated whether they act as dietary restriction mimetics or via other modes of action. Even more importantly, whether these interventions can slow or even reverses components of cardiovascular aging itself and can increase healthspan or longevity in humans needs to be determined.


Bioactives; Cardiovascular aging; Dietary restriction; Interventions

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