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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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