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Cage bedding modifies metabolic and gut microbiota profiles in mouse studies applying dietary restriction.
Gregor A, Fragner L, Trajanoski S, Li W, Sun X, Weckwerth W, König J, Duszka K.
Sci Rep. 2020 Nov 30;10(1):20835. doi: 10.1038/s41598-020-77831-3.
PMID: 33257713
Abstract
Experiments involving food restriction are common practice in metabolic research. Under fasted conditions, mice supplement their diet with cage bedding. We aimed at identifying metabolic and microbiota-related parameters affected by the bedding type. We exposed mice housed with wooden, cellulose, or corncob cage beddings to ad libitum feeding, caloric restriction (CR), or over-night (ON) fasting. Additionally, two subgroups of the ON fast group were kept without any bedding or on a metal grid preventing coprophagy. Mice under CR supplemented their diet substantially with bedding; however, the amount varied depending on the kind of bedding. Bedding-related changes in body weight loss, fat loss, cecum size, stomach weight, fecal output, blood ghrelin levels as well as a response to glucose oral tolerance test were recorded. As fiber is fermented by the gut bacteria, the type of bedding affects gut bacteria and fecal metabolites composition of CR mice. CR wood and cellulose groups showed distinct cecal metabolite and microbiome profiles when compared to the CR corncob group. While all ad libitum fed animal groups share similar profiles. We show that restriction-related additional intake of bedding-derived fiber modulates multiple physiological parameters. Therefore, the previous rodent studies on CR, report the combined effect of CR and increased fiber consumption.

Middle age as a turning point in mouse cerebral cortex energy and redox metabolism: Modulation by every-other-day fasting.
Bayliak MM, Sorochynska OM, Kuzniak OV, Gospodaryov DV, Demianchuk OI, Vasylyk YV, Mosiichuk NM, Storey KB, Garaschuk O, Lushchak VI.
Exp Gerontol. 2020 Dec 5:111182. doi: 10.1016/j.exger.2020.111182. Online ahead of print.
PMID: 33290862
Abstract
Normal brain aging is accompanied by intensification of free radical processes and compromised bioenergetics. Caloric restriction is expected to counteract these changes but the underlying protective mechanisms remain poorly understood. The present work aimed to investigate the intensity of oxidative stress and energy metabolism in the cerebral cortex comparing mice of different ages as well as comparing mice given one of two regimens of food availability: ad libitum versus every-other-day fasting (EODF). Levels of oxidative stress markers, ketone bodies, glycolytic intermediates, mitochondrial respiration, and activities of antioxidant and glycolytic enzymes were assessed in cortex from 6-, 12- and 18-month old C57BL/6 J mice. The greatest increase in oxidative stress markers and the sharpest decline in key glycolytic enzyme activities was observed in mice upon the transition from young (6 months) to middle (12 months) age, with smaller changes occurring upon transition to old-age (18 months). Brain mitochondrial respiration showed no significant changes with age. A decrease in the activities of key glycolytic enzymes was accompanied by an increase in the activity of glucose-6-phosphate dehydrogenase suggesting that during normal brain aging glucose metabolism is altered to lower glycolytic activity and increase dependence on the pentose-phosphate pathway. Interestingly, levels of ketone bodies and antioxidant capacity showed a greater decrease in the brain cortex of females as compared with males. The EODF regimen further suppressed glycolytic enzyme activities in the cortex of old mice, and partially enhanced oxygen consumption and respiratory control in the cortex of middle aged and old males. Thus, in the mammalian cortex the major aging-induced metabolic changes are already seen in middle age and are slightly alleviated by an intermittent fasting mode of feeding.
Keywords: Aging; Antioxidant enzymes; Cerebral cortex; Glycolytic enzymes; Mitochondrial respiration; Pentose phosphate pathway.

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Does calorie restriction improve cognition?
Dias IR, Santos CS, Magalhães CODE, de Oliveira LRS, Peixoto MFD, De Sousa RAL, Cassilhas RC.
IBRO Rep. 2020 Jun 1;9:37-45. doi: 10.1016/j.ibror.2020.05.001. eCollection 2020 Dec.
PMID: 33336102 Free PMC article.]
Abstract
Calorie restriction (CR) has been considered the most effective non-pharmacological intervention to counteract aging-related diseases and improve longevity. This intervention has shown beneficial effects in the prevention and treatment of several chronic diseases and functional declines related to aging, such as Parkinson's, Alzheimer's, and neuroendocrine disorders. However, the effects of CR on cognition show controversial results since its effects vary according to intensity, duration, and the period of CR. This review focuses on the main studies published in the last ten years regarding the consequences of CR on cognition in different neurological diseases and conditions of experimental animals. Also, possible CR mimetics are discussed. These findings highlight the potential beneficial effects of CR of up to 40 % on cognition when started early in life in non human animals.
Keywords: Aging; Calorie intake; Cognitive function; Memory; Neurodegenative diseases.
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Nutrition to Prevent or Treat Cognitive Impairment in Older Adults: A GRADE Recommendation.
Buckinx F, Aubertin-Leheudre M.
J Prev Alzheimers Dis. 2021;8(1):110-116. doi: 10.14283/jpad.2020.40.
PMID: 33336232
Abstract
Aging is associated with cognitive declines leading to mild cognitive impairments or Alzheimer disease. Nutrition appear to protect from aging. Some dietary factors could either increase or protect against cognitive declines. This article aimed to provide GRADE recommendations related to nutrition aspects able to prevent or to treat cognitive impairments. A comprehensive literature review was performed using Medline database. The GRADE approach was used to classify quality of the existing evidence (systematic review or meta-analysis).The GRADE process led us to formulate seven key nutritional recommendations to manage cognitive declines, but did not allow us to do it for protein, vitamin B or antioxidants. Thus, 1) adherence to a Mediterranean diet (GRADE 1B); 2) high-level of consumption of mono- or poly- unsaturated fatty acids combined to a low consumption of saturated fatty acids (GRADE 1B); 3) high consumption of fruits and vegetables (GRADE 1B); 4) higher vitamin D intake (GRADE 1C) than the recommended daily allowance. In addition, a ketogenic diet, a low consumption of whole-fat dairy products or a caloric restriction are promising nutritional habits although the evidence does not yet support widespread uptake (GRADE 2C). In conclusion, nutrition is an important modifiable factor to prevent or protect against cognitive decline. Nevertheless, more studies are required to determine specific guidelines such as duration and amounts of nutrients to help older adult to maintain a healthy cognitive life.
Keywords: GRADE process; aging; cognitive impairment; diet guidelines.

Regulation of glucose homeostasis by calorie restriction and periodic fasting.
Mezhnina V, Kondratov R.
Aging (Albany NY). 2020 Dec 13. doi: 10.18632/aging.104217. Online ahead of print.
PMID: 33318315 No abstract available.
https://www.aging-us.com/article/104217/text

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Beyond calorie restriction: aging as a biological target for nutrient therapies.
Austad SN, Hoffman JM.
Curr Opin Biotechnol. 2020 Dec 23;70:56-60. doi: 10.1016/j.copbio.2020.11.008. Online ahead of print.
PMID: 33360494 Review.
Abstract
Arguably, the most important discovery in the biology of aging to date was that simply reducing food intake extended life and improved many aspects of health in a diversity of animal species. The conventional wisdom that emerged from first 50 years of rodent food restriction studies included (1) that the longevity impact of restriction was greater the longer restriction was imposed, and (2) that restricting calories rather than any specific macronutrient was critical to its health and longevity benefits. However these assumptions began to crumble as more and more restriction research was performed on other species besides laboratory rodents. Recent investigations of flies, rodents, monkeys, and increasingly humans, has begun to parse how calorie restriction, protein restriction, intermittent fasting, and the temporal pattern of eating all impact the health benefits of food restriction. Fly research continues to inform, as it has repeatedly shown that genotype, age, sex, duration, and tempo restriction all affect the health impact. Ultimately, optimizing human diets will require a personalized approach using omics approaches.

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Skeletal muscle RBM3 expression is associated with extended lifespan in Ames dwarf and calorie restricted mice.
Hettinger ZR, Confides AL, Vanderklish PW, Sidhom S, Masternak MM, Dupont-Versteegden EE.
Exp Gerontol. 2020 Dec 29:111214. doi: 10.1016/j.exger.2020.111214. Online ahead of print.
PMID: 33385482
Abstract
RNA binding protein motif 3 (RBM3) is an RNA-binding and cold shock protein that protects myoblasts and promotes skeletal muscle hypertrophy by enhancing mRNA stability and translation. Muscle size is decreased during aging; however, it is typically delayed in models of extended lifespan such as the long-lived Ames Dwarf (df/df) mice and calorie restricted (CR) animals compared to age-match controls. In light of the protective and anabolic effects of RBM3 in muscle, we hypothesized that RBM3 expression is higher in long-lived animal models. Young and old df/df mice, and adult and old UM-HET3 CR mice were used to test this hypothesis. Gastrocnemius muscles were harvested and protein was isolated for RBM3 protein measurements. CR induced a 1.7 and 1.3-fold elevation in RBM3 protein abundance compared to adult and old male mice fed ad libitum (AL) diets, respectively; this effect was shared between males and females. Ames dwarfism induced a 4.6 and 2.7-fold elevation in RBM3 protein abundance in young and old df/df mice compared to normal control littermates, respectively. In contrast, there was an age-associated decrease in cold-inducible RNA-binding protein (CIRP), suggesting these effects are specific for RBM3. Lastly, there was an age-associated increase in RNA degradation marker decapping enzyme 2 (DCP2) in UM-HET3 mice that was mitigated by CR. These results show that muscle RBM3 expression is correlated with extended lifespan in both df/df and CR animals. Identifying how RBM3 exerts protective effects in muscle may yield new insights into healthy aging of skeletal muscle.
Keywords: Aging; Longevity; RBM3; RNA; RNA-binding proteins; Skeletal muscle.

Effect of Different Levels of Energy Diet Restriction on Energy Balance, Leptin and CL Development, Vascularization, and Function in South American Camelids.
Norambuena C, Hernandez F, Alfaro J, Silva G, Topp S, Ratto M.
Front Vet Sci. 2020 Dec 16;7:598147. doi: 10.3389/fvets.2020.598147. eCollection 2020.
PMID: 33392291 Free PMC article.
Abstract
The objective was to determine the effect of energy diet restriction on energy balance, systemic leptin and corpus luteum (CL) vascularization, development, and function in South American camelids. In experiment 1, adult llamas were randomly assigned to receive a diet of 70% of their maintenance energy requirements (MER) (Restricted group, n = 7) or fed ad libitum (Control group, n = 7) during 28 days. Body live weight (BLW) and body condition score (BCS) were recorded, blood samples were collected every 2 weeks to measure plasma leptin concentrations, and energy metabolites were quantified. In experiment 2, adult alpacas were randomly assigned to receive a diet of 40% MER for 21 days (Restricted group, n = 7) or fed ad libitum (Control group, n = 7). Then, ovulation was induced with gonadorelin acetate (day = 0), and trans-rectal ultrasonography (7.5 MHz) was performed using B and Doppler mode to record the diameter of the pre-ovulatory follicle, ovulation, CL diameter, and vascularization from Days 0 to 13. Blood samples were collected every 48 h from Days 1 to 13 to quantify plasma leptin and progesterone concentrations. In experiment 1, energy diet restriction of 70% MER did not affect plasma leptin concentration and metabolic parameters of the Restricted group. In experiment 2, the Restricted group had a lower BCS (p < 0.001), a smaller diameter of the CL on Days 5 and 7 (p < 0.05), and a smaller maximum diameter of the CL (10.2 ± 0.6 mm) than the Control group (12.1 ± 0.6 mm; p = 0.04). Low energy restriction of 70% MER for 28 days did not affect the energy balance of llamas (Experiment 1). Moderate energy restriction of 40% MER for 21 days negatively affected energy balance (BCS), and CL development but not its vascularization, leptin, and progesterone concentrations. These species must be submitted to longer periods or a higher level of energy restriction to impair ovarian function.
Keywords: alpaca; corpus luteum; diet restriction; leptin; llama; progesterone.

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Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis.
Palma C, La Rocca C, Gigantino V, Aquino G, Piccaro G, Di Silvestre D, Brambilla F, Rossi R, Bonacina F, Lepore MT, Audano M, Mitro N, Botti G, Bruzzaniti S, Fusco C, Procaccini C, De Rosa V, Galgani M, Alviggi C, Puca A, Grassi F, Rezzonico-Jost T, Norata GD, Mauri P, Netea MG, de Candia P, Matarese G.
Cell Metab. 2021 Jan 4:S1550-4131(20)30671-9. doi: 10.1016/j.cmet.2020.12.016. Online ahead of print.
PMID: 33421383
Abstract
There is a strong relationship between metabolic state and susceptibility to Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the basis for an exaggerated immuno-inflammatory response, which concurs with MTB pathogenesis. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB infection by reducing bacterial load, lung immunopathology, and generation of foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a metabolic shift toward glycolysis, and decreased both fatty acid oxidation and mTOR activity associated with induction of autophagy in immune cells. An integrated multi-omics approach revealed a specific CR-induced metabolomic, transcriptomic, and proteomic signature leading to reduced lung damage and protective remodeling of lung interstitial tightness able to limit MTB spreading. Our data propose CR as a feasible immunometabolic manipulation to control MTB infection, and this approach offers an unexpected strategy to boost immunity against MTB.
Keywords: T cells; adipose tissue; body weight; caloric restriction; immune response; immunometabolism; infection; tuberculosis.

Effects of dietary restriction on neuroinflammation in neurodegenerative diseases.
Fontana L, Ghezzi L, Cross AH, Piccio L.
J Exp Med. 2021 Feb 1;218(2):e20190086. doi: 10.1084/jem.20190086.
PMID: 33416892
Abstract
Recent and accumulating work in experimental animal models and humans shows that diet has a much more pervasive and prominent role than previously thought in modulating neuroinflammatory and neurodegenerative mechanisms leading to some of the most common chronic central nervous system (CNS) diseases. Chronic or intermittent food restriction has profound effects in shaping brain and peripheral metabolism, immunity, and gut microbiome biology. Interactions among calorie intake, meal frequency, diet quality, and the gut microbiome modulate specific metabolic and molecular pathways that regulate cellular, tissue, and organ homeostasis as well as inflammation during normal brain aging and CNS neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, among others. This review discusses these findings and their potential application to the prevention and treatment of CNS neuroinflammatory diseases and the promotion of healthy brain aging.

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Intermittent Energy Restriction Attenuates the Loss of Fat Free Mass in Resistance Trained Individuals. A Randomized Controlled Trial.
Campbell BI, Aguilar D, Colenso-Semple LM, Hartke K, Fleming AR, Fox CD, Longstrom JM, Rogers GE, Mathas DB, Wong V, Ford S, Gorman J.
J Funct Morphol Kinesiol. 2020 Mar 8;5(1):19. doi: 10.3390/jfmk5010019.
PMID: 33467235 Free PMC article.
Abstract
There is a lack of research into how lean, resistance trained (RT) individuals respond to intermittent energy restricted diets. Therefore, we investigated body composition changes in RT-individuals during continuous energy restriction or intermittent restriction. A total of 27 males and females (25 ± 6.1 years; 169 ± 9.4 cm; 80 ± 15.6 kg) were randomized to a ~25% caloric restricted diet Refeed (RF; n = 13) or Continuous group (CN; n = 14) in conjunction with 4-days/week resistance training for 7-weeks. RF implemented two consecutive days of elevated carbohydrate (CHO) intake, followed by 5-days of caloric restriction each week. CN adhered to a continuous 7-week caloric restriction. Body mass (BM), fat mass (FM), fat-free mass (FFM), dry fat-free mass (dFFM), and resting metabolic rate (RMR) were assessed pre/post-diet. Both groups significantly reduced BM (RF: baseline = 76.4 ± 15.6 kg, post-diet = 73.2 ± 13.8 kg, Δ3.2 kg; CN: baseline = 83.1 ± 15.4 kg, post-diet = 79.5 ± 15 kg, Δ3.6 kg) and FM (RF: baseline = 16.3 ± 4 kg, post-diet = 13.5 ± 3.6 kg, Δ2.8 kg; CN: baseline = 16.7 ± 4.5 kg, post-diet = 14.4 ± 4.9 kg, Δ2.3 kg) with no differences between groups. FFM (RF: baseline = 60.1 ± 13.8 kg, post-diet = 59.7 ± 13.0 kg, 0.4 kg; CN: baseline = 66.4 ± 15.2 kg, post-diet = 65.1 ± 15.2 kg, Δ1.3 kg p = 0.006), dFFM (RF: baseline = 18.7 ± 5.0 kg, post-diet = 18.5 ± 4.5 kg, Δ0.2 kg; CN: baseline =21.9 ± 5.7 kg, post-diet = 20.0 ± 5.7 kg, Δ1.9 kg), and RMR (RF: baseline = 1703 ± 294, post-diet = 1665 ± 270, Δ38 kcals; CN: baseline = 1867 ± 342, post-diet = 1789 ± 409, Δ78 kcals) were better maintained in the RF group. A 2-day carbohydrate refeed preserves FFM, dryFFM, and RMR during energy restriction compared to continuous energy restriction in RT-individuals.
Keywords: bodybuilding; diet; diet break; fat loss; nutrition; physique enhancement; refeed; resistance training; sports nutrition; weight loss.

Effects of Late-Life Caloric Restriction on Age-Related Alterations in the Rat Cortex and Hippocampus.
Tonini C, Segatto M, Martino F, Cigliano L, Nazzaro M, Barberio L, Mandalà M, Pallottini V.
Nutrients. 2021 Jan 15;13(1):E232. doi: 10.3390/nu13010232.
PMID: 33467406
Abstract
Background: A major problem of aging is the disruption of metabolic homeostasis. This is particularly relevant in the brain where it provokes neurodegeneration. Caloric restriction is a physiologic intervention known to delay the deleterious consequences of aging in several species ranging from yeast to mammals. To date, most studies on experimental models have started this dietary intervention from weaning, which is very difficult to be translated to human beings. Here, we study the effects of a more realistic dietary regimen in rats, starting at an advanced age and lasting for six months.
Methods: we analyzed in the cortex and hippocampus, the proteins involved in the energetic balance of the cells, cholesterol metabolism, oxidative stress response, inflammation, synaptic impairment, and brain trophism.
Results: our results suggest that caloric restriction in late life can revert only some age-related changes studied here.
Keywords: aging; caloric restriction; cholesterol; cortex; hippocampus; rats.

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Effects of Caloric Restriction Diet on Arterial Hypertension and Endothelial Dysfunction.
Di Daniele N, Marrone G, Di Lauro M, Di Daniele F, Palazzetti D, Guerriero C, Noce A.
Nutrients. 2021 Jan 19;13(1):E274. doi: 10.3390/nu13010274.
PMID: 33477912 Review.
Abstract
The most common manifestation of cardiovascular (CV) diseases is the presence of arterial hypertension (AH), which impacts on endothelial dysfunction. CV risk is associated with high values of systolic and diastolic blood pressure and depends on the presence of risk factors, both modifiable and not modifiable, such as overweight, obesity, physical exercise, smoking, age, family history, and gender. The main target organs affected by AH are the heart, brain, vessels, kidneys, and eye retina. AH onset can be counteracted or delayed by adopting a proper diet, characterized by a low saturated fat and sodium intake, a high fruit and vegetable intake, a moderate alcohol consumption, and achieving and maintaining over time the ideal body weight. In this review, we analyzed how a new nutritional approach, named caloric restriction diet (CRD), can provide a significant reduction in blood pressure values and an improvement of the endothelial dysfunction. In fact, CRD is able to counteract aging and delay the onset of CV and neurodegenerative diseases through the reduction of body fat mass, systolic and diastolic values, free radicals production, and oxidative stress. Currently, there are few studies on CRD effects in the long term, and it would be advisable to perform observational studies with longer follow-up.
Keywords: arterial hypertension; caloric restriction diet; endothelial dysfunction; intermittent fasting; organ damage

Caloric restriction reduces sympathetic activity similar to beta-blockers but conveys additional mitochondrio-protective effects in aged myocardium.
Niemann B, Li L, Simm A, Molenda N, Kockskämper J, Boening A, Rohrbach S.
Sci Rep. 2021 Jan 21;11(1):1931. doi: 10.1038/s41598-021-81438-7.
PMID: 33479375
Abstract
Increased activation of sympathetic nervous system contributes to congestive heart failure (CHF) progression, and inhibition of sympathetic overactivation by beta-blockers is successful in CHF patients. Similarly, caloric restriction (CR) reduces sympathetic activity but mediates additional effects. Here, we compared the cardiac effects of CR (- 40% kcal, 3 months) with beta-blocker therapy (BB), diuretic medication (DF) or control diet in 18-months-old Wistar rats. We continuously recorded blood pressure, heart rate, body temperature and activity with telemetric devices and analysed cardiac function, activated signalling cascades and markers of apoptosis and mitochondrial biogenesis. During our study, left ventricular (LV) systolic function improved markedly (CR), mildly (BB) or even deteriorated (DF; control). Diastolic function was preserved by CR and BB but impaired by DF. CR reduced blood pressure identical to DF and BB and heart rate identical to BB. Plasma noradrenaline was decreased by CR and BB but increased by DF. Only CR reduced LV oxidative damage and apoptosis, induced AMPK and Akt phosphorylation and increased mitochondrial biogenesis. Thus, additive to the reduction of sympathetic activity, CR achieves protective effects on mitochondria and improves LV function and ROS damage in aged hearts. CR mechanisms may provide additional therapeutic targets compared to traditional CHF therapy.

Maf1 limits RNA polymerase III-directed transcription to preserve genomic integrity and extend lifespan.
Noguchi C, Wang L, Shetty M, Mell JC, Sell C, Noguchi E.
Cell Cycle. 2021 Jan 21:1-9. doi: 10.1080/15384101.2021.1874697. Online ahead of print.
PMID: 33475456
Abstract
A key to longevity assurance is the nutrient-sensing mTOR pathway. Inhibition of mTOR extends lifespan in a variety of organisms. However, the downstream effectors of the mTOR pathway for lifespan regulation are elusive. In a recent report, we described the role of Maf1 as a critical lifespan regulator downstream of the mTOR pathway in fission yeast. Maf1 is the master negative regulator of RNA polymerase III-directed transcription (e.g. tRNAs and 5S rRNAs) and is regulated by mTOR-mediated phosphorylation. We demonstrated that Maf1 is required for lifespan extension under calorie restriction or when mTOR is inhibited. We also showed that Maf1 prevents DNA damage at tRNA genes, which appears to contribute to lifespan maintenance by Maf1. Here we highlight these observations and present additional results to discuss the role of the mTOR-Maf1-Pol III axis in promoting genomic integrity in the face of DNA replication-transcription conflicts in order to maintain normal lifespan.
Keywords: Maf1; RNA polymerase III; aging; genomic integrity; mTOR; replication fork.

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Ageing alters the lipid sensing process in the hypothalamus of Wistar rats. Effect of food restriction.
Rodríguez M, Pintado C, Torrillas-de la Cal R, Moltó E, Gallardo N, Andrés A, Arribas C.
Nutr Neurosci. 2021 Feb 5:1-15. doi: 10.1080/1028415X.2021.1872990. Online ahead of print.
PMID: 33544062
Abstract
Introduction: Lipids regulate a wide range of biological processes. The mechanisms by which fatty acids (FA) and its metabolites influence the hypothalamic regulation of energy homeostasis have been highly studied. However, the effect of ageing and food restriction (FR) on this process is unknown.
Methods: Herein, we analyzed the gene expression, protein and phosphorylation levels of hypothalamic enzymes and transcription factors related to lipid metabolism. Experiments were performed in male Wistar rats of 3-, 8- and 24-month-old Wistar rats fed ad libitum (AL), as ageing model. Besides, 5- and 21-month-old rats were subjected to a moderate FR protocol (equivalent to ≈ 80% of normal food intake) for three months before the sacrifice.
Results: Aged Wistar rats showed a situation of chronic lipid excess as a result of an increase in de novo FA synthesis and FA levels that reach the brain, contributing likely to the development of central leptin and insulin resistance. We observe a hypothalamic downregulation of AMP-activated protein kinase (AMPK) and stearoyl-CoA desaturase (SCD1) and an increase of carnitine palmitoyltransferase-1c (CPT1c) expression.
Discussion: Our results suggest an impairment in the physiological lipid sensing system of aged Wistar rats, which would alter the balance of the intracellular mobilization and trafficking of lipids between the mitochondria and the Endoplasmic Reticulum (ER) in the hypothalamus, leading probably to the development of neurolipotoxicity in aged rats. Lastly, FR can only partially restore this imbalance. Schematic representation of the fate of LCFA-CoA in the hypothalamus of young and old rats. Blood circulating LCFAs in young Wistar rats reach the hypothalamus, where they are esterified to LCFA-CoA. Into glial cells or neurons, LCFA-CoA are driven to mitochondria (CPT1a) or ER (CPT1c) where could be desaturated by SDC1 and, thereby, converted into structural and signaling unsaturated lipids as oleic acid, related with neuronal myelinization and differentiation. However, the excess of LCFA that reach to the hypothalamus in old animals, could generate an increase in LCFA-CoA, which together with an increase in CPT1c levels, could favor the capture of LCFA-CoA to the ER. The decrease in the levels of SCD1 in old rats would decrease FA unsaturation degree that could trigger lipotoxicity process and neurodegeneration, both related to the development of neurodegenerative diseases linked to age.
Keywords: Ageing; food-restriction; leptin-resistance; lipid sensing; lipotoxicity.

Two-meal caloric restriction induces 12-hour rhythms and improves glucose homeostasis.
Velingkaar N, Mezhnina V, Poe A, Kondratov RV.
FASEB J. 2021 Feb;35(2):e21342. doi: 10.1096/fj.202002470R.
PMID: 33543540
Abstract
Glucose metabolism is tightly regulated and disrupting glucose homeostasis is a hallmark of many diseases. Caloric restriction (CR), periodic fasting, and circadian rhythms are interlinked with glucose metabolism. Here, we directly investigated if CR depends on periodic fasting and circadian rhythms to improve glucose metabolism. CR was implemented as two-meals per day (2M-CR), provided at 12-hour intervals, and compared with one meal per day CR, mealtime (MT), and ad libitum (AL) feeding. The 2M-CR impacted the circadian rhythms in blood glucose, metabolic signaling, circadian clock, and glucose metabolism gene expression. 2M-CR significantly reduced around the clock blood glucose and improved glucose tolerance. Twenty-four-hour rhythms in mTOR signaling and gene expression observed under AL, MT, and CR, became 12-hour rhythms in 2M-CR. The 12-hour rhythms in behavior, gene expression, and signaling persisted in fasted mice, implicating some internal regulation. The study highlights that the reduction in caloric intake rather than meal frequency and duration of fasting is essential for metabolic reprograming and improvement in glucose metabolism and provides evidence on food-entrained molecular pacemaker, which can be uncoupled from the light-entrained circadian clock and rhythms.
Keywords: 12-hour rhythms; aging; circadian rhythms; diet; gene expression; glucose homeostasis; metabolism.

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Short-term dietary restriction ameliorates brain injury after cardiac arrest by modulation of mitochondrial biogenesis and energy metabolism in rats.
Zhou M, Yu T, Fang X, Ge Q, Song F, Huang Z, Jiang L, Wang P.
Ann Transl Med. 2021 Jan;9(1):8. doi: 10.21037/atm-20-3075.
PMID: 33553301 Free PMC article.
Abstract
Background: Dietary restriction (DR) is a well-known intervention that increases lifespan and resistance to multiple forms of acute stress, including ischemia reperfusion injury. However, the effect of DR on neurological injury after cardiac arrest (CA) remains unknown.
Methods: The effect of short-term DR (one week of 70% reduced daily diet) on neurological injury was investigated in rats using an asphyxial CA model. The survival curve was obtained using Kaplan-Meier survival analysis. Serum S-100β levels were detected by enzyme linked immunosorbent assay. Cellular apoptosis and neuronal damage were assessed by terminal deoxyribonucleotide transferase dUTP nick end labeling assay and Nissl staining. The oxidative stress was evaluated by immunohistochemical staining of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Mitochondrial biogenesis was examined by electron microscopy and mitochondrial DNA copy number determination. The protein expression was detected by western blot. The reactive oxygen species (ROS) and metabolite levels were measured by corresponding test kits.
Results: Short-term DR significantly improved 3-day survival, neurologic deficit scores (NDS) and decreased serum S-100β levels after CA. Short-term DR also significantly attenuated cellular apoptosis, neuronal damage and oxidative stress in the brain after CA. In addition, short-term DR increased mitochondrial biogenesis as well as brain PGC-1α and SIRT1 protein expression after CA. Moreover, short-term DR increased adenosine triphosphate, β-hydroxybutyrate, acetyl-CoA levels and nicotinamide adenine dinucleotide (NAD+)/reduced form of NAD+ (NADH) ratios as well as decreased serum lactate levels.
Conclusions: Reduction of oxidative stress, upregulation of mitochondrial biogenesis and increase of ketone body metabolism may play a crucial role in preserving neuronal function after CA under short-term DR.
Keywords: Cardiac arrest (CA); cardiopulmonary resuscitation (CPR); dietary restriction (DR); ketone body; oxidative stress.

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The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver.
Chimienti G, Picca A, Fracasso F, Russo F, Orlando A, Riezzo G, Leeuwenburgh C, Pesce V, Lezza AMS.
Int J Mol Sci. 2021 Feb 7;22(4):1665. doi: 10.3390/ijms22041665.
PMID: 33562258
Abstract
Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.
Keywords: age-sensitive efficacy of CR; aging; calorie restriction; mitochondrial biogenesis; mtDNA damage; rat liver.

Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice.
Ke Z, Firsanov D, Spencer B, Seluanov A, Gorbunova V.
NPJ Aging Mech Dis. 2020 Aug 14;6(1):9. doi: 10.1038/s41514-020-00047-2.
PMID: 33574237
Abstract
Calorie restriction (CR) improves health, reduces cancer incidence and extends lifespan in multiple organisms including mice. CR was shown to enhance base excision repair and nucleotide excision repair pathways of DNA repair, however, whether CR improves repair of DNA double-strand breaks has not been examined in in vivo system. Here we utilize non-homologous end joining (NHEJ) reporter mice to show that short-term CR strongly enhances DNA repair by NHEJ, which is associated with elevated levels of DNA-PK and SIRT6.

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Epigallocatechin Gallate During Dietary Restriction - Potential Mechanisms of Enhanced Liver Injury.
Shi Z, Zhu JX, Guo YM, Niu M, Zhang L, Tu C, Huang Y, Li PY, Zhao X, Zhang ZT, Bai ZF, Zhang GQ, Lu Y, Xiao XH, Wang JB.
Front Pharmacol. 2021 Jan 29;11:609378. doi: 10.3389/fphar.2020.609378. eCollection 2020.
PMID: 33584288 Free PMC article.
Abstract
Green tea extract (GTE) is popular in weight loss, and epigallocatechin gallate (EGCG) is considered as the main active component. However, GTE is the primary cause of herbal and dietary supplement-induced liver injury in the United States. Whether there is a greater risk of liver injury when EGCG is consumed during dieting for weight loss has not been previously reported. This study found for the first time that EGCG could induce enhanced lipid metabolism pathways, suggesting that EGCG had the so-called "fat burning" effect, although EGCG did not cause liver injury at doses of 400 or 800 mg/kg in normal mice. Intriguingly, we found that EGCG caused dose-dependent hepatotoxicity on mice under dietary restriction, suggesting the potential combination effects of dietary restriction and EGCG. The combination effect between EGCG and dietary restriction led to overactivation of linoleic acid and arachidonic acid oxidation pathways, significantly increasing the accumulation of pro-inflammatory lipid metabolites and thus mediating liver injury. We also found that the disruption of Lands' cycle and sphingomyelin-ceramides cycle and the high expression of taurine-conjugated bile acids were important metabolomic characteristics in EGCG-induced liver injury under dietary restriction. This original discovery suggests that people should not go on a diet while consuming EGCG for weight loss; otherwise the risk of liver injury will be significantly increased. This discovery provides new evidence for understanding the "drug-host" interaction hypothesis of drug hepatotoxicity and provides experimental reference for clinical safe use of green tea-related dietary supplements.
Keywords: combination effect; epigallocatechin gallate; green tea extract; hepatotoxicity; herbal and dietary supplements; lipid metabolism; metabolomics.

A neuronal blood marker is associated with mortality in old age
Stephan A. Kaeser, Benoit Lehallier[…]Mathias Jucker
Nature Aging 1, 218–225
Abstract
Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21–107 years of age) and correlate with changes in other plasma proteins linked to neural pathways. In centenarians (n = 135), plasma NfL levels are associated with mortality equally or better than previously described multi-item scales of cognitive or physical functioning, and this observation was replicated in an independent cohort of nonagenarians (n = 180). Plasma NfL levels also increase in aging mice (n = 114; 2–30 months of age), and dietary restriction, a paradigm that extends lifespan in mice, attenuates the age-related increase in plasma NfL levels. These observations suggest a contribution of nervous system functional deterioration to late-life mortality.

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Undernutrition induces major alterations in the lipid droplets of white and brown adipose tissues in wistar rats.
Rodríguez-Rivera C, Santín Moreda L, Alguacil LF, Escrivá F, Álvarez C, González-Martín C.
Tissue Cell. 2021 Feb 12;71:101500. doi: 10.1016/j.tice.2021.101500. Online ahead of print.
PMID: 33640739
Abstract
Several studies have shown a relationship between the distribution of fat mass around the organism, metabolic disorders, and an increased risk of morbidity and mortality. It has been demonstrated that in obese animals there is a big rise in the white fat deposits due to hyperplasia and hypertrophy of the adipocytes. Studies related to weight and health have been more popular regarding obesity rather than extreme caquexia or calorico-proteic deficiencies, but these states are interesting from the point of view of the preferential atrophy of certain organs that may help us in the understanding of undernourishment. Moreover, the discovery of beige adipose tissue has instigated thoughts around the roles played by the different cells in the adipose tissue as well as its adaptability in pathological states. In our study we carried out morphometric, morphological, and quantitative measurements of the adipose tissue in an animal model based on a 40-50% diet restriction in comparison to control animals. We have found a decrease in the size of white adipocytes together with a variation in the lipid droplet size of brown adipocytes in undernourished animals, what may be considered as possible transformations between the types of adipose tissues, and that could be caused by an adaptive phenomenon to the undernourished state.
Keywords: Adipose tissue; Browning; Undernourishment; Whitening.

Reduced High-Dose Radiation-Induced Residual Genotoxic Damage by Induction of Radioadaptive Response and Prophylactic Mild Dietary Restriction in Mice.
Wang B, Tanaka K, Katsube T, Maruyama K, Ninomiya Y, Varès G, Liu C, Hirakawa H, Murakami M, Fardous Z, Sultana N, Fujita K, Fujimori A, Nakajima T, Nenoi M.
Dose Response. 2021 Feb 11;19(1):1559325820982166. doi: 10.1177/1559325820982166. eCollection 2021 Jan-Mar.
PMID: 33628149 Free PMC article.
Abstract
Radioadaptive response (RAR) describes a phenomenon in a variety of in vitro and in vivo systems that a low-dose of priming ionizing radiation (IR) reduces detrimental effects of a subsequent challenge IR at higher doses. Among in vivo investigations, studies using the mouse RAR model (Yonezawa Effect) showed that RAR could significantly extenuate high-dose IR-induced detrimental effects such as decrease of hematopoietic stem cells and progenitor cells, acute radiation hematopoietic syndrome, genotoxicity and genomic instability. Meanwhile, it has been demonstrated that diet intervention has a great impact on health, and dietary restriction shows beneficial effects on numerous diseases in animal models. In this work, by using the mouse RAR model and mild dietary restriction (MDR), we confirmed that combination of RAR and MDR could more efficiently reduce radiogenotoxic damage without significant change of the RAR phenotype. These findings suggested that MDR may share some common pathways with RAR to activate mechanisms consequently resulting in suppression of genotoxicity. As MDR could also increase resistance to chemotherapy and radiotherapy in normal cells, we propose that combination of MDR, RAR, and other cancer treatments (i.e., chemotherapy and radiotherapy) represent a potential strategy to increase the treatment efficacy and prevent IR risk in humans.
Keywords: adaptive response; dietary restriction; ionizing radiation; mice; radiogenotoxicity.

Caloric restriction impairs regulatory T-cells within the tumor microenvironment after radiation and primes effector T-cells.
Manukian G, Kivolowitz C, DeAngelis T, Shastri A, Savage JE, Camphausen K, Rodeck U, Zarif J, Simone NL.
Int J Radiat Oncol Biol Phys. 2021 Feb 26:S0360-3016(21)00207-8. doi: 10.1016/j.ijrobp.2021.02.029. Online ahead of print.
PMID: 33647370
Abstract
Outcomes for triple negative breast cancer (TNBC) are poor and may be improved by increasing CD8+ tumor infiltrating lymphocytes (TIL) to augment anti-tumor immunity. Radiation (RT) can promote immunogenic cell death with increased anti-tumor T-cell activity but also stimulates suppressive regulatory T-cells (Tregs). Since metabolic alterations affect immune homeostasis and prior studies show caloric restriction (CR) combined with RT improves preclinical TNBC outcomes, we hypothesized that CR augments RT, in part, by altering intratumoral immunity. Using an in vivo model of TNBC, mice were treated with ad libitum (AL) diet, radiation, a CR diet, or CR+RT, and demonstrated an immune suppressive environment with a significant increase in CD4+CD25+Foxp3+ Tregs after RT but not CR-fed mice. CD8:Treg ratio in CR+RT TIL increased 4 fold compared with AL+RT mice. In vivo CD8 depletion was performed to assess the role of effector T-cells in mitigating the effects of CR and it was found that in mice undergoing CR, depletion of CD8 T-cells resulted in increased tumor progression and decreased median survival compared with isotype control treated mice. In addition, PD-1 expression on CD3+CD8+ T-cells within the tumor microenvironment was significantly increased in CR+RT versus AL+RT treated mice as per immunofluorescence. Serum from breast cancer patients undergoing RT alone or CR and RT was collected pre- and post-intervention and a cytokine array demonstrated that patients treated with CR+RT had notable decreases in immunosuppressive cytokines such as IL-2Rγ, IL-10Rβ, and TGF-β2 and 3, compared with patients receiving RT alone. In conclusion, combining CR with RT decreases intratumoral Tregs, increases CD8:Treg and increases PD-1 expression via a process dependent on CD8 T-cells in a TNBC model. Breast cancer patients undergoing CR concurrently with RT experience also had significant reduction in immunosuppressive cytokine levels compared with those receiving RT alone.

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Protective Effects of Voluntary Exercise on Hepatic Fat Accumulation Induced by Dietary Restriction in Zucker Fatty Rats.
Kurosaka Y, Machida S, Shiroya Y, Yamauchi H, Minato K.
Int J Mol Sci. 2021 Feb 18;22(4):2014. doi: 10.3390/ijms22042014.
PMID: 33670590
Abstract
Weight control based on dietary restriction (DR) alone can cause lipid metabolic failure and progression to fatty liver. This study aimed to investigate the effect of exercise on preventing DR-induced hepatic fat accumulation in Zucker fatty (ZF) rats by focusing on the relationship between adipose tissue lipolysis and hepatic fat uptake. Six-week-old male ZF rats were randomly assigned to obese, DR, or DR with exercise (DR + Ex) groups. The DR and DR + Ex groups were fed a restricted diet, with the latter also undergoing voluntary exercise. After 6 weeks, hepatic fat accumulation was observed in the DR group, whereas intrahepatic fat was markedly reduced in the DR + Ex group. Compared with the obese (Ob) group, the DR group exhibited 2.09-fold expression of hepatic fatty acid translocase (FAT)/CD36 proteins (p < 0.01) and 0.14-fold expression of hepatic fatty acid-binding protein (FABP)1 (p < 0.01). There were no significant differences between the DR + Ex group and the Ob group. FAT/CD36 and hepatic triglyceride (TG) expression levels were strongly positively correlated (r = 0.81, p < 0.001), whereas there was a strong negative correlation between FABP1 and hepatic TG expression levels (r = -0.65, p < 0.001). Our results suggest that hepatic fat accumulation induced by DR in ZF rats might be prevented through exercise-induced modifications in FAT/CD36 and FABP1 expression.
Keywords: CD36; FABP1; diet restriction; exercise; fatty liver; hepatocyte ultrastructure; obesity.

Increased 1,25(OH)(2)-Vitamin D Concentrations after Energy Restriction Are Associated with Changes in Skeletal Muscle Phenotype.
Vidal A, Rios R, Pineda C, Lopez I, Raya AI, Aguilera-Tejero E, Rivero JL.
Nutrients. 2021 Feb 12;13(2):607. doi: 10.3390/nu13020607.
PMID: 33673262
Abstract
The influence of energy restriction (ER) on muscle is controversial, and the mechanisms are not well understood. To study the effect of ER on skeletal muscle phenotype and the influence of vitamin D, rats (n = 34) were fed a control diet or an ER diet. Muscle mass, muscle somatic index (MSI), fiber-type composition, fiber size, and metabolic activity were studied in tibialis cranialis (TC) and soleus (SOL) muscles. Plasma vitamin D metabolites and renal expression of enzymes involved in vitamin D metabolism were measured. In the ER group, muscle weight was unchanged in TC and decreased by 12% in SOL, but MSI increased in both muscles (p < 0.0001) by 55% and 36%, respectively. Histomorphometric studies showed 14% increase in the percentage of type IIA fibers and 13% reduction in type IIX fibers in TC of ER rats. Decreased size of type I fibers and reduced oxidative activity was identified in SOL of ER rats. An increase in plasma 1,25(OH)2-vitamin D (169.7 ± 6.8 vs. 85.4 ± 11.5 pg/mL, p < 0.0001) with kidney up-regulation of CYP27b1 and down-regulation of CYP24a1 was observed in ER rats. Plasma vitamin D correlated with MSI in both muscles (p < 0.001), with the percentages of type IIA and type IIX fibers in TC and with the oxidative profile in SOL. In conclusion, ER preserves skeletal muscle mass, improves contractile phenotype in phasic muscles (TC), and reduces energy expenditure in antigravity muscles (SOL). These beneficial effects are closely related to the increases in vitamin D secondary to ER.
Keywords: energy restriction; muscle; rat; vitamin D.

The role of central corticotrophin-releasing factor receptor signalling in plasma glucose maintenance through ghrelin secretion in calorie-restricted mice.
Kimura R, Kondo D, Takemi S, Fujishiro M, Tsukahara S, Sakai T, Sakata I.
J Neuroendocrinol. 2021 Mar;33(3):e12961. doi: 10.1111/jne.12961.
PMID: 33675127
Abstract
Under severe calorie restriction (CR), the ghrelin-growth hormone axis in mice is involved in the maintenance of plasma glucose levels. Ghrelin, a stomach-derived acylated peptide, is up-regulated by the sympathetic nerve in the negative energy status. Central corticotrophin-releasing factor receptor (CRF-R) signalling stimulates the sympathetic tone. The present study aimed to examine the effect of central CRF-R signalling on the maintenance of plasma glucose concentrations in severe calorie-restricted mice with the involvement of ghrelin. Intracerebroventricular injections of urocorin-1 and urocorin-2, which are natural ligands for CRF-R1 and CRF-R2, elevated plasma ghrelin concentrations and ghrelin elevation with an i.c.v. injection of urocorin-1 was cancelled by atenolol (β1 adrenergic receptor antagonist) administration. We then established a mice model of 60% CR and found that the administration of [d-Lys3]-GHRP-6 (a ghrelin receptor antagonist) in mice under 60% CR reduced the plasma glucose concentration more compared to the vehicle mice. Similarly, the atenolol injection in mice under 60% CR significantly reduced the plasma glucose concentration, which was rescued by the co-administration of ghrelin. An i.c.v. injection of the alpha helical CRH, a non-selective corticotrophin-releasing factor receptor antagonist, in mice under 60% CR significantly reduced the plasma glucose concentration, although the co-administration of α-helical CRH with ghrelin maintained plasma glucose levels. These results suggest that central CRF-R signalling is involved in the maintenance of plasma glucose levels in mice under severe CR via the sympathetic-ghrelin pathway.
Keywords: calorie restriction; corticotrophin-releasing factor receptor; ghrelin; glucose; sympathetic nerve.

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Calorie restriction and SIRT1 overexpression induce different gene expression profiles in white adipose tissue in association with metabolic improvement.
Pardo R, Velilla M, Herrero L, Cervela L, Ribeiro ML, Simó R, Villena JA.
Mol Nutr Food Res. 2021 Mar 9:e2000672. doi: 10.1002/mnfr.202000672. Online ahead of print.
PMID: 33686759
Abstract
Introduction: Calorie restriction (CR) exerts multiple effects on health, including the amelioration of systemic insulin resistance. Although the precise mechanisms by which CR improves glucose homeostasis remain poorly defined, SIRT1 has been suggested to act as a central mediator of the cellular responses to CR. Here, we aimed at identifying the mechanisms by which CR and SIRT1 modulate white adipose tissue (WAT) function, a key tissue in the control of glucose homeostasis.
Material and methods: A gene expression profiling study using DNA microarrays was conducted in WAT of control and SIRT1 transgenic mice fed ad libitum and mice subjected to 40% CR.
Results: Gene expression profiling revealed a relatively low degree of overlap between the transcriptional programs regulated by SIRT1 and CR. Gene networks related to extracellular matrix appeared commonly down-regulated by SIRT1/CR, whereas mitochondrial biogenesis was enhanced exclusively by CR. Moreover, WAT inflammation was reduced by CR and SIRT1, although their anti-inflammatory effects appeared to be achieved by regulating different gene networks related to the immune system.
Concluding remarks: In WAT, SIRT1 does not mediate most of the effects of CR on gene expression. Still, gene networks differentially regulated by SIRT1 and CR converge to reduce WAT inflammation.
Keywords: Sirt1; adipose tissue; calorie restriction; gene expression; glucose homeostasis.

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The effect of calorie intake, fasting, and dietary composition on metabolic health and gut microbiota in mice.
Zhang Z, Chen X, Loh YJ, Yang X, Zhang C.
BMC Biol. 2021 Mar 19;19(1):51. doi: 10.1186/s12915-021-00987-5.
PMID: 33740961
Abstract
Background: Calorie restriction (CR) and intermittent fasting (IF) can promote metabolic health through a process that is partially mediated by gut microbiota modulation. To compare the effects of CR and IF with different dietary structures on metabolic health and the gut microbiota, we performed an experiment in which mice were subjected to a CR or IF regimen and an additional IF control (IFCtrl) group whose total energy intake was not different from that of the CR group was included. Each regimen was included for normal chow and high-fat diet.
Results: We showed that in normal-chow mice, the IFCtrl regimen had similar positive effects on glucose and lipid metabolism as the CR regimen, but the IF regimen showed almost no influence compared to the outcomes observed in the ad libitum group. IF also resulted in improvements, but the effects were less marked than those associate with CR and IFCtrl when the mice were fed a high-fat diet. Moreover, CR created a stable and unique gut microbial community, while the gut microbiota shaped by IF exhibited dynamic changes in fasting-refeeding cycles. At the end of each cycle, the gut microbiota of the IFCtrl mice was similar to that of the CR mice, and the gut microbiota of the IF mice was similar to that of the ad libitum group. When the abundance of Lactobacillus murinus OTU2 was high, the corresponding metabolic phenotype was improved regardless of eating pattern and dietary structure, which might be one of the key bacterial groups in the gut microbiota that is positively correlated with metabolic amelioration.
Conclusion: There are interactions among the amount of food intake, the diet structure, and the fasting time on metabolic health. The structure and composition of gut microbiota modified by dietary regimens might contribute to the beneficial effects on the host metabolism.
Keywords: Calorie restriction; Gut microbiota; High-fat diet; Intermittent fasting; Lactobacillus murinus.

Dietary restriction transforms the mammalian protein persulfidome in a tissue-specific and cystathionine gamma-lyase-dependent manner.
Bithi N, Link C, Henderson YO, Kim S, Yang J, Li L, Wang R, Willard B, Hine C.
Nat Commun. 2021 Mar 19;12(1):1745. doi: 10.1038/s41467-021-22001-w.
PMID: 33741971
Abstract
Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

Effects of calorie restricted low carbohydrate high fat ketogenic vs. non-ketogenic diet on strength, body-composition, hormonal and lipid profile in trained middle-aged men.
Vidić V, Ilić V, Toskić L, Janković N, Ugarković D.
Clin Nutr. 2021 Feb 26;40(4):1495-1502. doi: 10.1016/j.clnu.2021.02.028. Online ahead of print.
PMID: 33743284
Abstract
Background & aims: The aim of this paper was to investigate and compare the effects of two iso-energetic hypo-caloric ketogenic hyper-ketonemic and non-ketogenic low carbohydrate high fat high cholesterol diets on body-composition, muscle strength and hormonal profile in experienced resistance-trained middle-aged men.
Methods: Twenty non-competitive experienced resistance-trained middle-aged men were on the supervised calorie maintenance western diet and resistance-training regimen for 4 weeks and then divided into ketogenic and non-ketogenic groups for 8 weeks period. Keto bodies (β-hydroxybutyrate) levels were measured weekly, testosterone and insulin biweekly, strength and body-composition monthly, lipid profile and blood sugar level at the beginning and at the end of the study.
Results: Both groups lost a similar amount of lean body mass and fat tissue (from F = 248.665, p < 0.001 to F = 21.943, p = 0.001), but preserved maximal upper and lower body strength (from F = 1.772, p = 0.238 to F = 0.595, p = 0.577). Basal testosterone and free testosterone increased (from F = 37.267, p = 0.001 to F = 16.261, p = 0.005) and insulin levels decreased significantly in both groups (F = 27.609, p = 0.001; F = 54.256, p < 0.001, respectively). No differences in lipid profile and blood sugar level were found (from F = 4.174, p = 0.058, to F = 0.065, p = 0.802).
Conclusions: Ketogenic diet with sustained hyper-ketonemia above 1 mol/l has the same impact as low carbohydrate non-ketogenic diet on muscle strength, body-composition, and hormonal and lipid profile in hypo-caloric dietary conditions in strength-trained middle-aged men.
Keywords: Body-composition; Insulin; Ketogenic diet; Middle-aged men; Resistance-training; Testosterone.

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Calorie restriction prevents age-related changes in the intestinal microbiota.
Kurup K, Matyi S, Giles CB, Wren JD, Jones K, Ericsson A, Raftery D, Wang L, Promislow D, Richardson A, Unnikrishnan A.
Aging (Albany NY). 2021 Mar 10;13(5):6298-6329. doi: 10.18632/aging.202753. Epub 2021 Mar 10.
PMID: 33744869
Abstract
The effect of calorie restriction (CR) on the microbiome, fecal metabolome, and colon transcriptome of adult and old male mice was compared. Life-long CR increased microbial diversity and the Bacteroidetes/Firmicutes ratio and prevented the age-related changes in the microbiota, shifting it to a younger microbial and fecal metabolite profile in both C57BL/6JN and B6D2F1 mice. Old mice fed CR were enriched in the Rikenellaceae, S24-7 and Bacteroides families. The changes in the microbiome that occur with age and CR were initiated in the cecum and further modified in the colon. Short-term CR in adult mice had a minor effect on the microbiome but a major effect on the transcriptome of the colon mucosa. These data suggest that CR has a major impact on the physiological status of the gastrointestinal system, maintaining it in a more youthful state, which in turn could result in a more diverse and youthful microbiome.
Keywords: aging; calorie restriction; metabolome; microbiome; transcriptome.

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Cardioprotective effects of severe calorie restriction from birth in adult ovariectomized rats.
Rodrigues CM, Domingues TE, de Sousa Santos C, Costa-Pereira LV, Mendes BF, Dos Santos JM, Costa KB, Silva G, Cantuária VL, Rocha-Vieira E, Peixoto MFD, Honorato-Sampaio K.
Life Sci. 2021 Mar 24:119411. doi: 10.1016/j.lfs.2021.119411. Online ahead of print.
PMID: 33774029
Abstract
Aims: Menopause is a female condition induced by a reduction of ovarian hormone and is related to an increase in cardiovascular diseases in women. We have shown that severe calorie restriction (SCR) from birth reduces the cardiometabolic risk in adult male Wistar rats. In this study, we investigated the effects of SCR from birth to adulthood on cardiovascular function of ovariectomized rats.
Main methods: From birth to adulthood, rats were daily fed ad libitum (control group - C) or with 50% of the amount consumed by the control group (calorie-restricted group - R). At 90 days, half of the rats in each group underwent bilateral ovariectomy (OVX), totaling 4 groups: C-Sham, C-OVX, R-Sham, R-OVX. Systolic blood pressure (SBP), heart rate (HR) and, double product (DP) index were recorded by tail-cuff plethysmography. Cardiac function was analyzed by the Langendorff technique and cardiomyocyte diameter was accessed by histologic analysis. Additionally, cardiac SERCA2 content and redox status were evaluated.
Key findings: C-OVX rats exhibited reduced cardiac function and cardiac non-enzymatic total antioxidant capacity (TAC). R-Sham animals showed reduced SBP, DP, HR, improved cardiac function, reduced cardiac protein carbonyl derivatives and increased TAC, catalase, and superoxide dismutase activities. R-OVX rats maintained reduced SBP, DP, HR, and increased contractility and relaxation indexes. R-Sham and R-OVX rats exhibited preserved heart mass and reduced cardiomyocyte diameter. Cardiac SERCA2 content did not differ between the groups.
Significance: Taken together, our findings show cardioprotective effects of SCR from birth in adult ovariectomized rats.

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DNMT3.1 controls trade-offs between growth, reproduction, and life span under starved conditions in Daphnia magna.
Nguyen ND, Matsuura T, Kato Y, Watanabe H.
Sci Rep. 2021 Apr 1;11(1):7326. doi: 10.1038/s41598-021-86578-4.
PMID: 33795753
Abstract
The cladoceran crustacean Daphnia has long been a model of energy allocation studies due to its important position in the trophic cascade of freshwater ecosystems. However, the loci for controlling energy allocation between life history traits still remain unknown. Here, we report CRISPR/Cas-mediated target mutagenesis of DNA methyltransferase 3.1 (DNMT3.1) that is upregulated in response to caloric restriction in Daphnia magna. The resulting biallelic mutant is viable and did not show any change in growth rate, reproduction, and longevity under nutrient rich conditions. In contrast, under starved conditions, the growth rate of this DNMT3.1 mutant was increased but its reproduction was reciprocally reduced compared to the wild type when the growth and reproduction activities competed during a period from instar 4 to 8. The life span of this mutant was significantly shorter than that of the wild type. We also compared transcriptomes between DNMT3.1 mutant and wild type under nutrient-rich and starved conditions. Consistent with the DNMT3.1 mutant phenotypes, the starved condition led to changes in the transcriptomes of the mutant including differential expression of vitellogenin genes. In addition, we found upregulation of the I am not dead yet (INDY) ortholog, which has been known to shorten the life span in Drosophila, explaining the shorter life span of the DNMT3.1 mutant. These results establish DNMT3.1 as a key regulator for life span and energy allocation between growth and reproduction during caloric restriction. Our findings reveal how energy allocation is implemented by selective expression of a DNMT3 ortholog that is widely distributed among animals. We also infer a previously unidentified adaptation of Daphnia that invests more energy for reproduction than growth under starved conditions.

Calorie Restriction Suppresses the Progression of Radiation-Induced Intestinal Tumours in C3B6F1 Apc (Min/+) Mice.
Morioka T, Yamazaki S, Yanagihara H, Sunaoshi M, Kaminishi M, Kakinuma S.
Anticancer Res. 2021 Mar;41(3):1365-1375. doi: 10.21873/anticanres.14894.
PMID: 33788728
Abstract
Background/aim: Progress in cancer treatment and diagnosis has made second cancer after medical radiation exposure a particular concern among childhood cancer survivors. Calorie restriction (CR) is a broadly effective cancer prevention strategy, although its effects on radiation-induced intestinal tumours are unclear. Here we examined the cancer-preventative efficacy of a CR diet at different starting ages on radiation induction of intestinal tumours in mice.
Materials and methods: Male C3B6F1 ApcMin/+ mice were irradiated with 0 or 2 Gy of X-rays at 2 weeks of age. After an interval of 2, 8 or 18 weeks, mice were fed with a non-CR (95 kcal/week/mouse) or CR (65 kcal/week/mouse) diet. Intestinal tumours were evaluated for number, size distribution and malignancy.
Results: CR suppressed the size and progression of both spontaneous and radiation-induced intestinal tumours depending on age at starting of CR. CR diets were effective even administered to adult mice.
Conclusion: CR was effective for suppression of tumour progression, which was accelerated by radiation exposure. Use of CR might be a useful cancer-prevention strategy for radiation-induced tumours of the intestinal tract.
Keywords: Calorie restriction; cancer prevention; radiation carcinogenesis.

Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal.
Zhang B, Jun H, Wu J, Liu J, Shawn Xu XZ.
Nat Aging. 2021 Mar;1(3):255-268. doi: 10.1038/s43587-021-00039-1. Epub 2021 Mar 15.
PMID: 33796867
Abstract
The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of C. elegans under DR but not those fed ad libitum, revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC. This olfactory circuit signals the gut to suppress DR-mediated longevity via octopamine, the mammalian homolog of norepinephrine, by regulating the energy sensor AMPK through a Gq-PLCβ-CaMKK-dependent mechanism. In mouse primary cells, we find that norepinephrine signaling regulates AMPK through a similar mechanism. Our results identify a brain-gut axis that regulates DR-mediated longevity by relaying olfactory information about food abundance from the brain to the gut.

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LONG-TERM CHRONIC CALORIC RESTRICTION ALTERS miRNA PROFILES IN THE BRAIN OF AGEING MICE.
Ozorhan U, Tuna BG, Cicekdal MB, Kuskucu A, Bayrak OF, Yilmaz B, Demirel PB, Cleary MP, Dogan S.
Br J Nutr. 2021 Apr 7:1-32. doi: 10.1017/S0007114521001239. Online ahead of print.
PMID: 33823947
Abstract
Calorie restriction (CR) has been shown to be one of the most effective methods in alleviating the effects of ageing and age-related diseases such as increasing longevity and preventing dementia, and Alzheimer's Disease. Although the protective effects of CR have been reported, the exact molecular mechanism still needs to be clarified. This study aims to determine differentially expressed (DE) miRNAs and altered gene pathways due to long-term chronic (CCR) and intermittent (ICR) CR in the brain of mice to understand the preventive roles of miRNAs in long-term CR. Ten weeks old mice were enrolled into three different dietary groups; ad-libitum, CCR or ICR, and fed until 82 weeks old mice. miRNAs were analyzed using GeneChip 4.1 microarray and the target of DE miRNAs was determined using miRNA target databases. Out of a total 3,163 analyzed miRNAs, 55 of them were differentially expressed either by different CR protocols or by ageing. Brain samples from the CCR group had increased expression levels of mmu-miR-713 while decreasing expression levels of mmu-miR-184-3p and mmu-miR-351-5p compared to the other dietary groups. Also, current results indicated that CCR showed better preventive effects than that of ICR. Thus, CCR may perform its protective effects by modulating these specific miRNAs since they are shown to play roles in neurogenesis, chromatin, and histone regulation. In conclusion, these three miRNAs could be potential targets for neurodegenerative and ageing-related diseases and may play important roles in the protective effects of CR in the brain.
Keywords: Ageing; Brain; Intermittent Calorie Restriction; Neurodegeneration; Neurogenesis; miRNA.

Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy.
Eriau E, Paillet J, Kroemer G, Pol JG.
Cancers (Basel). 2021 Mar 12;13(6):1260. doi: 10.3390/cancers13061260.
PMID: 33809187 Review.
Abstract
Caloric restriction and fasting have been known for a long time for their health- and life-span promoting effects, with coherent observations in multiple model organisms as well as epidemiological and clinical studies. This holds particularly true for cancer. The health-promoting effects of caloric restriction and fasting are mediated at least partly through their cellular effects-chiefly autophagy induction-rather than reduced calorie intake per se. Interestingly, caloric restriction has a differential impact on cancer and healthy cells, due to the atypical metabolic profile of malignant tumors. Caloric restriction mimetics are non-toxic compounds able to mimic the biochemical and physiological effects of caloric restriction including autophagy induction. Caloric restriction and its mimetics induce autophagy to improve the efficacy of some cancer treatments that induce immunogenic cell death (ICD), a type of cellular demise that eventually elicits adaptive antitumor immunity. Caloric restriction and its mimetics also enhance the therapeutic efficacy of chemo-immunotherapies combining ICD-inducing agents with immune checkpoint inhibitors targeting PD-1. Collectively, preclinical data encourage the application of caloric restriction and its mimetics as an adjuvant to immunotherapies. This recommendation is subject to confirmation in additional experimental settings and in clinical trials. In this work, we review the preclinical and clinical evidence in favor of such therapeutic interventions before listing ongoing clinical trials that will shed some light on this subject.
Keywords: caloric restriction; caloric restriction mimetics; cancer immunotherapy; fasting; metabolism.

Long-Term Caloric Restriction Attenuates beta-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice.
Müller L, Power Guerra N, Stenzel J, Rühlmann C, Lindner T, Krause BJ, Vollmar B, Teipel S, Kuhla A.
Nutrients. 2021 Mar 18;13(3):985. doi: 10.3390/nu13030985.
PMID: 33803798
Abstract
Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer's disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism-a hallmark of AD-and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology.
Keywords: APPswe/PS1delta9; [18F]FDG-PET/CT; amyloid β; autophagy; caloric restriction; iba1.

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Caloric restriction or cafeteria diet from birth to adulthood increases the sensitivity to ephedrine in anxiety and locomotion in Wistar rats.
Rocha-Gomes A, Teixeira AE, Lima DS, Rocha LS, da Silva AA, Lessa MR, Pinto NAD, Stuckert-Seixas SR, Riul TR.
Physiol Behav. 2021 Apr 15:113430. doi: 10.1016/j.physbeh.2021.113430. Online ahead of print.
PMID: 33865851
Abstract
Introduction: Obesity and undernutrition, consequences of malnutrition, have been linked to the development of mental illnesses. Both states have been linked to increased sensitivity to some drugs, but there are few data for this association considering drugs with noradrenergic-dopaminergic action.
Objective: To evaluate the nutritional status of animals treated with either a caloric restriction (CR) or cafeteria (CAF) diet from birth and their behavior after ephedrine application.
Methods: During the lactation period, 12 litters of Wistar rats (dam + 8 pups) were fed one of three diets: control (n=4), CR (n=4), and CAF (n=4). After weaning, the males were placed in individual boxes and received the same diet as their respective dams. Nutritional assessments were performed after weaning and in adulthood. In adulthood, males received either saline or ephedrine (20 mg/kg) and underwent behavioral tests including the elevated plus-maze, open-field, and food intake tests.
Results: The CR group exhibited higher serum high-density lipoprotein (HDL) levels and lower food and caloric intake, weight gain, and fat mass than the control group. The CAF group exhibited lower food intake and higher fat caloric intake, fat mass, and serum low-density lipoprotein (LDL), triglyceride, total cholesterol, and hepatic lipid levels than the control group. These results indicated that the CR and CAF groups had developed undernutrition and obesity, respectively. In the elevated plus-maze and open-field tests, the CR and CAF groups showed lower anxiety-like behaviors than the control group after ephedrine application. This result indicates that the animal's nutritional status (undernutrition or obesity) can enhance ephedrine sensitivity.
Conclusion: The CR group exhibited undernutrition, whereas the CAF group exhibited obesity. Ephedrine altered anxiety and locomotion in animals that received the CR and CAF diets in manner different than that observed in animals receiving the standard diet.
Keywords: elevated plus-maze; ephedrine; obesity; open-field; sensitivity; undernutrition.

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Effects of caloric restriction on monoaminergic neurotransmission, peripheral hormones, and olfactory memory in aged rats.
Rojic-Becker D, Portero-Tresserra M, Martí-Nicolovius M, Vale-Martínez A, Guillazo-Blanch G.
Behav Brain Res. 2021 Apr 27:113328. doi: 10.1016/j.bbr.2021.113328. Online ahead of print.
PMID: 33930470
Abstract
Aging is associated with a reduced ability to identify and discriminate scents, and olfactory dysfunction has been linked to preclinical stages of neurodegenerative diseases in humans. Moreover, emerging evidence suggests that smell-driven behaviors are regulated by hormones like insulin or leptin, and by metabolic parameters like glucose, which in turn may influence monoaminergic neurotransmission in brain areas related to cognition. Several studies have suggested that dietary interventions like caloric restriction (CR) can mitigate the age-induced decline in memory by modifying metabolic parameters and brain monoaminergic levels. The present study explored the effects of CR on age-dependent olfactory memory deficits, as well as their relationship with peripheral leptin, insulin and glucose levels, and brain monoamines. To this end, aged rats (24-months-old) fed on a CR diet or with ad libitum access to food, and adult rats (3-4 months), were trained in an odor discrimination task (ODT). The peripheral plasma levels of insulin, leptin, and glucose, and of monoamines and metabolites/precursors in brain areas related to olfactory learning and memory processes, such as the striatum and frontal cortex (FC), were determined. The data obtained indicated that CR attenuated the age-dependent decline in olfactory sensitivity in old animals fed ad libitum, which was correlated with the performance in ODT retention trial, as well as with leptin plasma levels. CR enhanced dopamine levels in the striatum, while it attenuated the age-related decline in serotonin levels in the striatum and FC. Such findings support a positive effect of CR on age-dependent olfactory sensitivity decline and dysfunctions in brain monoamine levels.
Keywords: Aging; IGF-1; frontal cortex; leptin; odor-reward association; striatum.
 

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