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The effects of graded levels of calorie restriction XV: phase space attractors reveal distinct behavioral phenotypes.
Sun D, Liu F, Mitchell SE, Ma H, Derous D, Wang Y, Han JJD, Promislow DEL, Lusseau D, Douglas A, Speakman JR, Chen L.
J Gerontol A Biol Sci Med Sci. 2020 Mar 4. pii: glaa055. doi: 10.1093/gerona/glaa055. [Epub ahead of print]
PMID: 32128585
Abstract
Calorie restriction (CR) has a positive impact on health and lifespan. Previous work however does not reveal the whole underlying mechanism of behavioral phenotypes under CR. We propose a new approach based on phase space reconstruction (PSR) to analyze the behavioral responses of mice to graded CR. This involved reconstructing high-dimensional attractors which topologically represent the intrinsic dynamics of mice based on low-dimensional time series of movement counts observed during the 90 day time course of restriction. PSR together with correlation dimensions (CD), Kolmogorov entropy (KE) and multifractal spectra builds a map from internal attractors to the phenotype of mice and reveals the mice with increasing CR levels undergo significant changes from a normal to a new state. Features of the attractors (CD and KE) were significantly associated with gene expression profiles in the hypothalamus of the same individuals.
KEYWORDS:
attractors; calorie restriction; gene expression; phase space reconstruction

The hidden costs of dietary restriction: Implications for its evolutionary and mechanistic origins.
McCracken AW, Adams G, Hartshorne L, Tatar M, Simons MJP.
Sci Adv. 2020 Feb 21;6(8):eaay3047. doi: 10.1126/sciadv.aay3047. eCollection 2020 Feb.
PMID: 32128403
https://advances.sciencemag.org/content/advances/6/8/eaay3047.full.pdf
Abstract
Dietary restriction (DR) extends life span across taxa. Despite considerable research, universal mechanisms of DR have not been identified, limiting its translational potential. Guided by the conviction that DR evolved as an adaptive, pro-longevity physiological response to food scarcity, biomedical science has interpreted DR as an activator of pro-longevity molecular pathways. Current evolutionary theory predicts that organisms invest in their soma during DR, and thus when resource availability improves, should outcompete rich-fed controls in survival and/or reproduction. Testing this prediction in Drosophila melanogaster (N > 66,000 across 11 genotypes), our experiments revealed substantial, unexpected mortality costs when flies returned to a rich diet following DR. The physiological effects of DR should therefore not be interpreted as intrinsically pro-longevity, acting via somatic maintenance. We suggest DR could alternatively be considered an escape from costs incurred under nutrient-rich conditions, in addition to costs associated with DR.

Effect of Caloric Restriction on BMI, Gut Microbiota, and Blood Amino Acid Levels in Non-Obese Adults.
Zou H, Wang D, Ren H, Cai K, Chen P, Fang C, Shi Z, Zhang P, Wang J, Yang H, Zhong H.
Nutrients. 2020 Feb 27;12(3). pii: E631. doi: 10.3390/nu12030631.
PMID: 32120990
Abstract
Adequate calorie restriction (CR) as a healthy lifestyle is recommended not only for people with metabolic disorders but also for healthy adults. Previous studies have mainly focused on the beneficial metabolic effects of CR on obese subjects, while its effects on non-obese subjects are still scarce. Here, we conducted a three-week non-controlled CR intervention in 41 subjects, with approximately 40% fewer calories than the recommended daily energy intake. We measured BMI, and applied targeted metabolic profiling on fasting blood samples and shotgun metagenomic sequencing on fecal samples, before and after intervention. Subjects were stratified into two enterotypes according to their baseline microbial composition, including 28 enterotype Bacteroides (ETB) subjects and 13 enterotype Prevotella (ETP) subjects. CR decreased BMI in most subjects, and ETP subjects exhibited a significantly higher BMI loss ratio than the ETB subjects. Additionally, CR induced limited changes in gut microbial composition but substantial microbial-independent changes in blood AAs, including a significant increase in 3-methylhistidine, a biomarker of the skeletal muscle protein turnover. Finally, baseline abundances of seven microbial species, rather than baseline AA levels, could well predict CR-induced BMI loss. This non-controlled intervention study revealed associations between baseline gut microbiota and CR-induced BMI loss and provided evidence to accelerate the application of microbiome stratification in future personalized nutrition intervention.
KEYWORDS:
amino acids; body mass index; calorie restriction; enterotype; gut microbiota

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Changes in body weight, adherence, and appetite during 2 years of calorie restriction: the CALERIE 2 randomized clinical trial.
Dorling JL, Das SK, Racette SB, Apolzan JW, Zhang D, Pieper CF, Martin CK; CALERIE Study Group.
Eur J Clin Nutr. 2020 Mar 6. doi: 10.1038/s41430-020-0593-8. [Epub ahead of print]
PMID: 32144378
Abstract
BACKGROUND/OBJECTIVES:
The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE) study showed that individuals who are nonobese were able to undergo significant calorie restriction (CR), yet the time course changes in adherence, weight, and appetite are unknown. This analysis aimed to investigate the time course changes in adherence, body weight, and appetite during the CALERIE study.
SUBJECTS/METHODS:
Overall, 143 participants (body mass index: 21.9-28.0 kg/m2) were randomized to a CR group that aimed to achieve 25% CR for 2 years. Throughout the intervention, body weight was measured, and appetite was assessed through visual analogue scales. Algorithms were utilized with body weight measurements to calculate adherence percentile score. Participants targeted an adherence percentile score of 50, though being between 80 (lowest acceptable adherence) and 10 (highest acceptable adherence) was adequate. Polynomial regression analyses were used to assess time course changes.
RESULTS:
Polynomials indicated that adherence percentile score increased above 50 after approximately week 20, although adherence remained acceptable (adherence percentile score less than 80) (R2 = 0.89; P < 0.001). Weight loss occurred until approximately week 60 and then plateaued (R2 ≥ 0.92; P < 0.001). Hunger and thirst increased (R2 ≥ 0.30; P < 0.001), but the total increase in scale scores were <10 mm throughout the intervention.
CONCLUSIONS:
In individuals who are nonobese, adherence to 25% CR declines after 20 weeks, but 2 years of CR that stimulates a meaningful reduction in weight, promotes aging-related benefits and negligibly affects appetite is viable.

The Effects of Calorie Restriction and Exercise on Age-Related Alterations in Corpus Cavernosum.
Macit C, Ustundag UV, Dagdeviren OC, Mercanoglu G, Sener G.
Front Physiol. 2020 Feb 18;11:45. doi: 10.3389/fphys.2020.00045. eCollection 2020.
PMID: 32132927
Abstract
BACKGROUND:
Aging is an important risk factor for erectile dysfunction (ED). Both calorie restriction (CR) and physical exercise (PE) have been established as a non-medical method for the improvement of detrimental changes in aging. It is well documented that both CR and PE influence on sympathetic and parasympathetic systems; however, there are few studies on non-adrenergic non-cholinergic pathways. This study aims to investigate the NO-mediated mechanisms of CR and PE on corpus cavernosum in aged rats.
MATERIALS AND METHODS:
3 and 15 month-old rats were divided into five experimental groups: young rats fed ad libitum (Y-C), aged rats fed ad libitum (O-S), aged rats with CR (O-CR), aged rats with PE (O-PE), and aged rats with CR and PE (O-CR-PE). CR was applied to animals as a 40% reduction of daily food intake for 6 weeks. PE was moderate swimming at 30 min at 3 days/week. The effects of CR and PE were evaluated by histologic, biologic, and in-vitro tissue bath studies.
RESULTS:
The outcomes in CR and PE groups (characterized by decreased nitrosative damage together with increased antioxidant capacity) were improved in comparison to the O-S. Apoptotic biomarkers were also lower and both endothelial and smooth muscle cell' functions were preserved too. There was no statistical difference between apoptosis, antioxidant capacity, and nitrosative damage parameters. Contractile responses to phenylephrine and relaxation responses to carbachol were: O-CR > O-PE > O-CR-PE. In these groups, NOS protein levels determined by western-blot were: eNOS: O-CR = O-CR + PE > O-PE; iNOS: O-CR = O-PE > O-CR-PE; nNOS: O-PE > O-CR-PE > O-CR.
CONCLUSION:
In our study, both CR and PE prevented age-related changes in the corpus cavernosum of rats. Reducing nitrosative damage in the neurovascular structure was the main mechanism. CR and exercise restored the endothelial and smooth muscle cells in corpus cavernosum by decreasing apoptosis. The mechanism of enhancing functional response in corpus cavernosum with CR was the improvement of endothelial function via eNOS activation however it involves increases in the NO-cGMP signaling pathway by an endothelium-independent mechanism with PE. This might be a direct stimulation of smooth muscle cells by NO, which released from the cavernous nerve endings via nNOS activation.
KEYWORDS:
aging; calorie restriction; erectil dysfunction; nitric oxide; physical exercise

Costs of exploratory behavior: the energy trade-off hypothesis and the allocation model tested under caloric restriction.
Peña-Villalobos I, Casanova-Maldonado I, Lois P, Palma V, Sabat P.
Sci Rep. 2020 Mar 5;10(1):4156. doi: 10.1038/s41598-020-61102-2.
PMID: 32139739
https://www.nature.com/articles/s41598-020-61102-2.pdf
Abstract
In order to maintain the energy balance, animals often exhibit several physiological adjustments when subjected to a decrease in resource availability. Specifically, some rodents show increases in behavioral activity in response to food restriction; a response regarded as a paradox because it would imply an investment in locomotor activity, despite the lack of trophic resources. Here, we aim to explore the possible existence of trade-offs between metabolic variables and behavioral responses when rodents are faced to stochastic deprivation of food and caloric restriction. Adult BALB/c mice were acclimatized for four weeks to four food treatments: two caloric regimens (ad libitum and 60% restriction) and two periodicities (continuous and stochastic). In these mice, we analyzed: exploratory behavior and home-cage behavior, basal metabolic rate, citrate synthase and cytochrome oxidase c enzyme activity (in liver and skeletal muscle), body temperature and non-shivering thermogenesis. Our results support the model of allocation, which indicates commitments between metabolic rates and exploratory behavior, in a caloric restricted environment. Specifically, we identify the role of thermogenesis as a pivotal budget item, modulating the reallocation of energy between behavior and basal metabolic rate. We conclude that brown adipose tissue and liver play a key role in the development of paradoxical responses when facing decreased dietary availability.

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Reduced caloric intake and periodic fasting independently contribute to metabolic effects of caloric restriction.
Velingkaar N, Mezhnina V, Poe A, Makwana K, Tulsian R, Kondratov RV.
Aging Cell. 2020 Mar 11:e13138. doi: 10.1111/acel.13138. [Epub ahead of print]
PMID: 32159926
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/acel.13138
Abstract
Caloric restriction (CR) has positive effects on health and longevity. CR in mammals implements time-restricted (TR) feeding, a short period of feeding followed by prolonged fasting. Periodic fasting, in the form of TR or mealtime, improves metabolism without reduction in caloric intake. In order to understand the relative contribution of reduced food intake and periodic fasting to the health benefits of CR, we compared physiological and metabolic changes induced by CR and TR (without reduced food intake) in mice. CR significantly reduced blood glucose and insulin around the clock, improved glucose tolerance, and increased insulin sensitivity (IS). TR reduced blood insulin and increased insulin sensitivity, but in contrast to CR, TR did not improve glucose homeostasis. Liver expression of circadian clock genes was affected by both diets while the mRNA expression of glucose metabolism genes was significantly induced by CR, and not by TR, which is in agreement with the minor effect of TR on glucose metabolism. Thus, periodic fasting contributes to some metabolic benefits of CR, but TR is metabolically different from CR. This difference might contribute to differential effects of CR and TR on longevity.
KEYWORDS:
caloric restriction; circadian rhythms; fasting; gene expression; glucose homeostasis; insulin sensitivity; longevity; metabolism

Strain-specificity in the hydrogen sulphide signalling network following dietary restriction in recombinant inbred mice.
Wilkie SE, Mulvey L, Sands WA, Marcu DE, Carter RN, Morton NM, Hine C, Mitchell JR, Selman C.
Geroscience. 2020 Mar 11. doi: 10.1007/s11357-020-00168-2. [Epub ahead of print]
PMID: 32162209
Abstract
Modulation of the ageing process by dietary restriction (DR) across multiple taxa is well established. While the exact mechanism through which DR acts remains elusive, the gasotransmitter hydrogen sulphide (H2S) may play an important role. We employed a comparative-type approach using females from three ILSXISS recombinant inbred mouse strains previously reported to show differential lifespan responses following 40% DR. Following long-term (10 months) 40% DR, strain TejJ89-reported to show lifespan extension under DR-exhibited elevated hepatic H2S production relative to its strain-specific ad libitum (AL) control. Strain TejJ48 (no reported lifespan effect following 40% DR) exhibited significantly reduced hepatic H2S production, while H2S production was unaffected by DR in strain TejJ114 (shortened lifespan reported following 40% DR). These differences in H2S production were reflected in highly divergent gene and protein expression profiles of the major H2S production and disposal enzymes across strains. Increased hepatic H2S production in TejJ89 mice was associated with elevation of the mitochondrial H2S-producing enzyme 3-mercaptopyruvate sulfurtransferase (MPST). Our findings further support the potential role of H2S in DR-induced longevity and indicate the presence of genotypic-specificity in the production and disposal of hepatic H2S in response to 40% DR in mice.
KEYWORDS:
3-mercaptopyruvate sulfurtransferase; Ageing; Caloric restriction; Dietary restriction; ILSXISS; Longevity; Sulphide

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Effects of aging and life-long moderate calorie restriction on IL-15 signaling in the rat white adipose tissue.
Giovannini S, Carter CS, Leeuwenburgh C, Flex A, Biscetti F, Morgan D, Laudisio A, Coraci D, Maccauro G, Zuccalà G, Caliandro P, Bernabei R, Marzetti E.
Eur Rev Med Pharmacol Sci. 2020 Mar;24(5):2738-2749. doi: 10.26355/eurrev_202003_20547.
PMID: 32196625
Abstract
OBJECTIVE:
Phosphorylation of insulin receptor substrate (IRS) 1 by tumor necrosis factor alpha (TNF-α) has been implicated as a factor contributing to insulin resistance. Administration of IL-15 reduces adipose tissue deposition in young rats and stimulates secretion of adiponectin, an insulin sensitizing hormone that inhibits the production and activity of TNF-α. We aimed at investigating the effects of age life-long moderate calorie restriction (CR) on IL-15 and TNF-α signaling in rat white adipose tissue (WAT).
MATERIALS AND METHODS:
Thirty-six 8-month-old, 18-month-old, and 29-month-old male Fischer344´Brown Norway F1 rats (6 per group) were either fed ad libitum (AL) or calorie restricted by 40%. The serum levels of IL-15 and IL-15 receptor α-chain (IL-15Rα) were increased by CR controls regardless of age. An opposite pattern was detected in WAT. In addition, CR reduced gene expression of TNF-α and cytosolic IRS1 serine phosphorylation in WAT, independently from age.
RESULTS:
IL-15 signaling in WAT is increased over the course of aging in AL rats compared with CR rodents. Protein levels of IL-15Rα are greater in WAT of AL than in CR rats independently from age. This adaptation was paralleled by increased IRS1 phosphorylation through TNF-α-mediated insulin resistance. Adiponectin decreased at old age in AL rats, while no changes were evident in CR rats across age groups.
CONCLUSIONS:
IL-15 signaling could therefore represent a potential target for interventions to counteract metabolic alterations and the deterioration of body composition during aging.

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Low costs of adaptation to dietary restriction.
Moger-Reischer RZ, Snider EV, McKenzie KL, Lennon JT.
Biol Lett. 2020 Mar;16(3):20200008. doi: 10.1098/rsbl.2020.0008. Epub 2020 Mar 25.
PMID: 32208792
Abstract
Dietary restriction (DR) is the most successful and widespread means of extending organismal lifespan. However, the evolutionary basis of life extension under DR remains uncertain. The traditional evolutionary explanation is that when organisms experience DR, they allocate endogenous resources to survival and postpone reproduction until conditions improve. However, this life-extension strategy should be maladaptive if DR continues for multiple generations due to trade-offs between longevity and reproduction. To test this prediction, we subjected the budding yeast Saccharomyces cerevisiae to 1800 generations of evolution on restricted versus non-restricted diets. Adaptation to a non-restricted diet improved reproductive fitness by 57%, but provided a much smaller (14%) advantage on a restricted diet. By contrast, adaptation to DR resulted in an approximately 35% increase in reproductive fitness on both restricted and non-restricted diets. Importantly, the life-extending effect of DR did not decrease following long-term evolution on the restricted diet. Thus, contrary to theoretical expectations, we found no evidence that the life-extending DR response became maladaptive during multigenerational DR. Together, our results suggest that the DR response has a low cost and that this phenomenon may have evolved as part of a generalist strategy that extends beyond the benefits of postponing reproduction.
KEYWORDS:
adaptation; experimental evolution; longevity; nutrition; yeast

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Calorie Restriction Improves Physical Performance and Modulates the Antioxidant and Inflammatory Responses to Acute Exercise.
Capó X, Martorell M, Ferrer MD, Sureda A, Pons V, Domingo JC, Drobnic F, Martínez-Rodríguez A, Leyva-Vela B, Sarabia JM, Herranz-López M, Roche E, Tur JA, Pons A.
Nutrients. 2020 Mar 27;12(4). pii: E930. doi: 10.3390/nu12040930.
PMID: 32230858
Abstract
Our aim was to characterize the effects of calorie restriction on the anthropometric characteristics and physical performance of sportsmen and to evaluate the effects of calorie restriction and acute exercise on mitochondria energetics, oxidative stress, and inflammation. Twenty volunteer taekwondo practitioners undertook a calorie restriction of 30-40% on three alternate days a week for one month. Eleven volunteer sportsmen participated as controls. Both groups performed an energy efficiency test to evaluate physical performance, and samples were taken before and after exercise. The total weight of participants significantly decreased (5.9%) after calorie restriction, while the efficiency of work and the contributions of fat to obtain energy were enhanced by calorie restriction. No significant differences induced by acute exercise were observed in individual non-esterified fatty acid percentage or oxidative stress markers. Calorie restriction downregulated the basal gene expression of nitric oxide synthase, antioxidant enzymes, mitochondrial uncoupling proteins, and repairing stress proteins, but it enhanced the expression of sirtuins in peripheral blood mononuclear cells. In conclusion, one month of calorie restriction decreases body weight and increases physical performance, enhancing energy efficiency, moderating the antioxidant and inflammatory basal gene expression, and influencing its response to acute exercise.
KEYWORDS:
calorie restriction; exercise; fatty acids; oxidative stress; plasma

Caloric restriction triggers morphofunctional remodeling of astrocytes and enhances synaptic plasticity in the mouse hippocampus.
Popov A, Denisov P, Bychkov M, Brazhe A, Lyukmanova E, Shenkarev Z, Lazareva N, Verkhratsky A, Semyanov A.
Cell Death Dis. 2020 Mar 30;11(3):208. doi: 10.1038/s41419-020-2406-3.
PMID: 32231202
Abstract
Calorie-restricted (CR) diet has multiple beneficial effects on brain function. Here we report morphological and functional changes in hippocampal astrocytes in 3-months-old mice subjected to 1 month of the diet. Whole-cell patch-clamp recordings were performed in the CA1 stratum (str.) radiatum astrocytes of hippocampal slices. The cells were also loaded with fluorescent dye through the patch pipette. CR did not affect the number of astrocytic branches but increased the volume fraction (VF) of distal perisynaptic astrocytic leaflets. The astrocyte growth did not lead to a decrease in the cell input resistance, which may be attributed to a decrease in astrocyte coupling through the gap junctions. Western blotting revealed a decrease in the expression of Cx43 but not Cx30. Immunocytochemical analysis demonstrated a decrease in the density and size of Cx43 clusters. Cx30 cluster density did not change, while their size increased in the vicinity of astrocytic soma. CR shortened K+ and glutamate transporter currents in astrocytes in response to 5 × 50 Hz Schaffer collateral stimulation. However, no change in the expression of astrocytic glutamate transporter 1 (GLT-1) was observed, while the level of glutamine synthetase (GS) decreased. These findings suggest that enhanced enwrapping of synapses by the astrocytic leaflets reduces glutamate and K+ spillover. Reduced spillover led to a decreased contribution of extrasynaptic N2B containing N-methyl-D-aspartate receptors (NMDARs) to the tail of burst-induced EPSCs. The magnitude of long-term potentiation (LTP) in the glutamatergic CA3-CA1 synapses was significantly enhanced after CR. This enhancement was abolished by N2B-NMDARs antagonist. Our findings suggest that astrocytic morphofunctional remodeling is responsible for enhanced synaptic plasticity, which provides a basis for improved learning and memory reported after CR.

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Caloric restriction induces anabolic resistance to resistance exercise.
Murphy C, Koehler K.
Eur J Appl Physiol. 2020 Mar 31. doi: 10.1007/s00421-020-04354-0. [Epub ahead of print]
PMID: 32236752
https://sci-hub.tw/10.1007/s00421-020-04354-0
Abstract
PURPOSE:
Weight loss can result in the loss of muscle mass and bone mineral density. Resistance exercise is commonly prescribed to attenuate these effects. However, the anabolic endocrine response to resistance exercise during caloric restriction has not been characterized.
METHODS:
Participants underwent 3-day conditions of caloric restriction (15 kcal kg FFM-1) with post-exercise carbohydrate (CRC) and with post-exercise protein (CRP), and an energy balance control (40 kcal kg FFM-1) with post-exercise carbohydrate (CON). Serial blood draws were taken following five sets of five repetitions of the barbell back squat exercise on day 3 of each condition.
RESULTS:
In CRC and CRP, respectively, growth hormone peaked at 2.6 ± 0.4 and 2.5 ± 0.9 times the peak concentrations observed during CON. Despite this, insulin-like growth factor-1 concentrations declined 18.3 ± 3.4% in CRC and 27.2 ± 3.8% in CRP, which was greater than the 7.6 ± 3.6% decline in CON, over the subsequent 24 h. Sclerostin increased over the first 2 days of each intervention by 19.2 ± 5.6% in CRC, 21.8 ± 6.2% in CRP and 13.4 ± 5.9% in CON, but following the resistance exercise bout, these increases were attenuated and no longer significant.
CONCLUSION:
During caloric restriction, there is considerable endocrine anabolic resistance to a single bout of resistance exercise which persists in the presence of post-exercise whey protein supplementation. Alternative strategies to restore the sensitivity of insulin-like growth factor-1 to growth hormone need to be explored.
KEYWORDS:
Energy availability; Energy deficit; Growth hormone; Sclerostin; Strength training; Weightlifting

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The effect of caloric restriction on phosphate metabolism and uremic vascular calcification.
Vidal A, Ríos R, Pineda C, Lopez I, Rodríguez M, Aguilera-Tejero E, Raya AI.
Am J Physiol Renal Physiol. 2020 Apr 6. doi: 10.1152/ajprenal.00009.2020. [Epub ahead of print]
PMID: 32249611
Abstract
Caloric restriction (CR) is known to have multiple beneficial effects on health and longevity. To study the effect of CR on phosphate (P) metabolism and vascular calcification (VC), rats were fed normal or restricted calories (67% of normal). The P content of the diets was adjusted to provide equal P intake independent of the calories ingested. After 50 days of CR rats had negative P balance, lower plasma P, glucose, triglycerides and leptin, and higher adiponectin than rats fed normal calories. Uremia was induced by 5/6 nephrectomy (Nx). After Nx rats were treated with calcitriol (80 ng/kg ip every other day) and high P diets (1.2% and 1.8%). No differences in aortic calcium content were observed between rats that ate normal or restricted calories before Nx, neither in rats that received 1.2% P (11.5±1.7 vs 10.9 ± 2.1 mg/g tissue) nor in rats that received 1.8% P (12.5±2.3 vs 12.0±2.9 mg/g of tissue). However, mortality was significantly increased in rats subjected to CR prior to Nx, both in the 1.2% P groups (75% vs 25%, p=0.019) and in the 1.8% P groups (100% vs 45%, p<0.001). After stopping calcitriol administration and normalizing P intake, VC regressed rapidly but no significant differences in aortic calcium were detected between rats that ate normal or restricted calories during the regression phase (5.7 ± 2.7 and 5.2 ± 1.5 mg/g tissue). In conclusion, CR did not prevent or ameliorate VC and increased mortality in uremic rats.
KEYWORDS:
caloric restriction; rat; vascular calcification

Dietary restriction for prevention of contrast-induced acute kidney injury in patients undergoing percutaneous coronary angiography: a randomized controlled trial.
Grundmann F, Müller RU, Hoyer-Allo KJR, Späth MR, Passmann E, Becker I, Pfister R, Baldus S, Benzing T, Burst V.
Sci Rep. 2020 Mar 23;10(1):5202. doi: 10.1038/s41598-020-61895-2.
PMID: 32251303
Abstract
Short-term dietary restriction (DR) may prevent organ damage from ischemic or toxic insults in animals, but clear evidence in humans is missing. While especially intraarterial administration of contrast media represents a cause of hospital-acquired acute kidney injury (AKI), targeted preventive strategies are not available. This trial investigated the feasibility and effectiveness of pre-interventional DR for preventing AKI in patients undergoing percutaneous coronary intervention (PCI). Patients were randomized to receive a formula diet containing 60% of daily energy requirement (DR group) or ad-libitum food during the 4-day-interval before PCI. Primary endpoint was change of serum creatinine 48 h after PCI (Δcreatinine). Further analyses included incidence of AKI and safety evaluation. Δcreatinine post PCI in the DR group vs. the control group did not show any difference (DR: 0.03(-0.15,0.14)mg/dL vs. control: 0.09(-0.03,0.22)mg/dL;p = 0.797). Subgroup analyses revealed a significant beneficial impact of DR in patients that received ≤100 ml of contrast agent (DR n = 26: Δcreatinine -0.03(-0.20,0.08)mg/dL vs. control n = 24: Δcreatinine 0.10(-0.08,0.24)mg/dL; p = 0.041) and in patients with ≤2 risk factors for AKI (DR: n = 27; Δcreatinine -0.01(-0.18,0.07)mg/dL vs. control n = 31: Δcreatinine 0.09(-0.03,0.16)mg/dl; p = 0.030). Although the primary endpoint was not met, the results of this trial suggest a beneficial impact of DR in low-to-moderate risk patients.

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Sustained mitochondrial biogenesis is essential to maintain caloric restriction-induced beige adipocytes.
Mooli RGR, Mukhi D, Watt M, Edmunds L, Xie B, Capooci J, Reslink M, Eze C, Mills A, Stolz DB, Jurczak M, Ramakrishnan SK.
Metabolism. 2020 Apr 7:154225. doi: 10.1016/j.metabol.2020.154225. [Epub ahead of print]
PMID: 32275973
Abstract
BACKGROUND:
Caloric restriction (CR) delays the onset of metabolic and age-related disorders. Recent studies have demonstrated that formation of beige adipocytes induced by CR is strongly associated with extracellular remodeling in adipose tissue, decrease in adipose tissue inflammation, and improved systemic metabolic homeostasis. However, beige adipocytes rapidly transition to white upon CR withdrawal through unclear mechanisms.
MATERIALS AND METHODS:
Six-week old C57BL6 mice were fed with 40% CR chow diet for 6 weeks. Subsequently, one group of mice was switched back to ad libitum chow diet, which was continued for additional 2 weeks. Adipose tissues were assessed histologically and biochemically for beige adipocytes.
RESULTS:
Beige adipocytes induced by CR rapidly transition to white adipocytes when CR is withdrawn independent of parkin-mediated mitophagy. We demonstrate that the involution of mitochondria during CR withdrawal is strongly linked with a decrease in mitochondrial biogenesis. We further demonstrate that beige-to-white fat transition upon β3-AR agonist-withdrawal could be attenuated by CR, partly via maintenance of mitochondrial biogenesis.
CONCLUSION:
In the model of CR, our study highlights the dominant role of mitochondrial biogenesis in the maintenance of beige adipocytes. We propose that loss of beige adipocytes upon β3-AR agonist withdrawal could be attenuated by CR.
KEYWORDS:
Beige adipocytes; Caloric restriction; Fission; Fusion; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy

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Four Weeks of Time-Restricted Feeding Combined with Resistance Training Does Not Differentially Influence Measures of Body Composition, Muscle Performance, Resting Energy Expenditure, and Blood Biomarkers.
Stratton MT, Tinsley GM, Alesi MG, Hester GM, Olmos AA, Serafini PR, Modjeski AS, Mangine GT, King K, Savage SN, Webb AT, VanDusseldorp TA.
Nutrients. 2020 Apr 17;12(4). pii: E1126. doi: 10.3390/nu12041126.
PMID: 32316561
Abstract
Recently, interest in time-restricted feeding (TRF) has increased from reports highlighting improvements in body composition and muscular performance measures. Twenty-six recreationally active males were randomly assigned to either TRF (n = 13; ~22.9 years; 82.0 kg; 178.1 cm; 8 h eating window, 25% caloric deficit, 1.8 g/kg/day protein) or normal diet (ND; n = 13; ~22.5 years; 83.3 kg; 177.5 cm; normal meal pattern; 25% caloric deficit, 1.8 g/kg/day protein) groups. Participants underwent 4-weeks of supervised full body resistance training. Changes in body composition (fat mass (FM), fat free mass (FFM), and body fat percentage (BF%)), skeletal muscle cross sectional area (CSA) and muscle thickness (MT) of the vastus lateralis (VL), rectus femoris, (RF), and biceps brachii (BB) muscles, resting energy expenditure (REE), muscular performance, blood biomarkers, and psychometric parameters were assessed. Significant (p < 0.05) decreases were noted in BM, FM, BF%, testosterone, adiponectin, and REE, along with significant increases in BP1RM, LP1RM, VJHT, VJPP, VLCSA, BBCSA, and BBMT in both groups. Plasma cortisol levels were significantly elevated at post (p = 0.018) only in ND. Additionally, FFM was maintained equally between groups. Thus, a TRF style of eating does not enhance reductions in FM over caloric restriction alone during a 4-week hypocaloric diet.
KEYWORDS:
body composition; caloric restriction; fasting; intermittent fasting; resistance training; time-restricted feeding

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Mitochondrial adaptations in liver and skeletal muscle to pro-longevity nutritional and genetic interventions: the crosstalk between calorie restriction and CYB5R3 overexpression in transgenic mice.
Rodríguez-López S, López-Bellón S, González-Reyes JA, Burón MI, de Cabo R, Villalba JM.
Geroscience. 2020 Apr 22. doi: 10.1007/s11357-020-00187-z. [Epub ahead of print]
PMID: 32323139
Abstract
Calorie restriction without malnutrition (CR) is considered as the most effective nongenetic nor pharmacological intervention that promotes healthy aging phenotypes and can extend lifespan in most model organisms. Lifelong CR leads to an increase of cytochrome b5 reductase-3 (CYB5R3) expression and activity. Overexpression of CYB5R3 confers some of the salutary effects of CR, although the mechanisms involved might be independent because key aspects of energy metabolism and lipid profiles of tissues go in opposite ways. It is thus important to study if some of the metabolic adaptations induced by CR are affected by CYB5R3 overexpression. CYB5R3 overexpression greatly preserved body and liver weight in mice under CR conditions. In liver, CR did not modify mitochondrial abundance, but lead to increased expression of mitofusin Mfn2 and TFAM, a transcription factor involved in mitochondrial biogenesis. These changes were prevented by CYB5R3 overexpression but resulted in a decreased expression of a different mitochondrial biogenesis-related transcription factor, Nrf1. In skeletal muscle, CR strongly increased mitochondrial mass, mitofusin Mfn1, and Nrf1. However, CYB5R3 mice on CR did not show increase in muscle mitochondrial mass, regardless of a clear increase in expression of TFAM and mitochondrial complexes in this tissue. Our results support that CYB5R3 overexpression significantly modifies the metabolic adaptations of mice to CR.
KEYWORDS:
Calorie restriction; Cytochrome b5 reductase; Liver; Mitochondria; Skeletal muscle

Calorie restriction improves aging-induced impairment of cognitive function in relation to deregulation of brain regional GABA system and corticosterone status.
Chakraborty A, Banerjee S, Mukherjee B, Poddar MK.
Mech Ageing Dev. 2020 Apr 24:111248. doi: 10.1016/j.mad.2020.111248. [Epub ahead of print]
PMID: 32339520
https://sci-hub.tw/http://www.sciencedirect.com/science/article/pii/S0047637420300440
Abstract
Aging is known to affect adversely the corticosterone status and the brain function including cognition. Calorie restricted (CR) diet has been found to reduce stress factors and improve brain aging. The objective of the present investigation is to study the effect of short-term CR diet without any food deprivation on aging-induced impairment of cognitive function in relation to the corticosterone status and the brain regional GABA system. The result showed that aging-induced deregulation of the brain regional GABA system, increase in plasma and adrenal corticosterone levels and cognitive impairment were attenuated with short-term CR diet supplementation for consecutive 1 and 2 months to the aged (18 and 24 months) rats. But in young rats (4 months) consumption of the same CR diet under similar conditions reversibly affected those above-mentioned parameters. These results, thus suggest that (a) aging down-regulates brain regional GABA system with an up-regulation of corticosterone status and impairment of cognitive function, (b) CR diet consumption improves this aging-induced deregulation of brain regional GABA system, corticosterone status, and cognitive function, (c) these attenuating effects of CR diet are greater with a longer period of consumption and (d) CR diet consumption is harmful to those above-mentioned parameters in young rats.
KEYWORDS:
Aging; Brain regional GABA; Calorie restriction; Cognitive function; Corticosterone

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Mechanisms of Lifespan Regulation by Calorie Restriction and Intermittent Fasting in Model Organisms.
Hwangbo DS, Lee HY, Abozaid LS, Min KJ.
Nutrients. 2020 Apr 24;12(4). pii: E1194. doi: 10.3390/nu12041194. Review.
PMID: 32344591
Abstract
Genetic and pharmacological interventions have successfully extended healthspan and lifespan in animals, but their genetic interventions are not appropriate options for human applications and pharmacological intervention needs more solid clinical evidence. Consequently, dietary manipulations are the only practical and probable strategies to promote health and longevity in humans. Caloric restriction (CR), reduction of calorie intake to a level that does not compromise overall health, has been considered as being one of the most promising dietary interventions to extend lifespan in humans. Although it is straightforward, continuous reduction of calorie or food intake is not easy to practice in real lives of humans. Recently, fasting-related interventions such as intermittent fasting (IF) and time-restricted feeding (TRF) have emerged as alternatives of CR. Here, we review the history of CR and fasting-related strategies in animal models, discuss the molecular mechanisms underlying these interventions, and propose future directions that can fill the missing gaps in the current understanding of these dietary interventions. CR and fasting appear to extend lifespan by both partially overlapping common mechanisms such as the target of rapamycin (TOR) pathway and circadian clock, and distinct independent mechanisms that remain to be discovered. We propose that a systems approach combining global transcriptomic, metabolomic, and proteomic analyses followed by genetic perturbation studies targeting multiple candidate pathways will allow us to better understand how CR and fasting interact with each other to promote longevity.
KEYWORDS:
aging; calorie restriction; fasting; lifespan; longevity

Region-Specific Proteome Changes of the Intestinal Epithelium during Aging and Dietary Restriction.
Gebert N, Cheng CW, Kirkpatrick JM, Di Fraia D, Yun J, Schädel P, Pace S, Garside GB, Werz O, Rudolph KL, Jasper H, Yilmaz ÖH, Ori A.
Cell Rep. 2020 Apr 28;31(4):107565. doi: 10.1016/j.celrep.2020.107565.
PMID: 32348758
Abstract
The small intestine is responsible for nutrient absorption and one of the most important interfaces between the environment and the body. During aging, changes of the epithelium lead to food malabsorption and reduced barrier function, thus increasing disease risk. The drivers of these alterations remain poorly understood. Here, we compare the proteomes of intestinal crypts from mice across different anatomical regions and ages. We find that aging alters epithelial immunity, metabolism, and cell proliferation and is accompanied by region-dependent skewing in the cellular composition of the epithelium. Of note, short-term dietary restriction followed by refeeding partially restores the epithelium by promoting stem cell differentiation toward the secretory lineage. We identify Hmgcs2 (3-hydroxy-3-methylglutaryl-coenzyme A [CoA] synthetase 2), the rate-limiting enzyme for ketogenesis, as a modulator of stem cell differentiation that responds to dietary changes, and we provide an atlas of region- and age-dependent proteome changes of the small intestine.
KEYWORDS:
aging; dietary restriction; hmgcs2; intestine; ketone bodies; proteomics; stem cells

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice.
An HS, Lee JY, Choi EB, Jeong EA, Shin HJ, Kim KE, Park KA, Jin Z, Lee JE, Koh JS, Kwak W, Kim WH, Roh GS.
Sci Rep. 2020 Apr 28;10(1):7176. doi: 10.1038/s41598-020-64201-2.
PMID: 32346034
Abstract
Leptin-deficient and leptin-resistant mice manifest obesity, insulin resistance, and left ventricular hypertrophy (LVH); however, LVH's mechanisms are not fully understood. Cardiac iron dysregulation has been recently implicated in cardiomyopathy. Here we investigated the protective effects of caloric restriction on cardiac remodeling in impaired leptin signaling obese mice. RNA-seq analysis was performed to assess the differential gene expressions in the heart of wild-type and ob/ob mice. In particular, to investigate the roles of caloric restriction on iron homeostasis-related gene expressions, 10-week-old ob/ob and db/db mice were assigned to ad libitum or calorie-restricted diets for 12 weeks. Male ob/ob mice exhibited LVH, cardiac inflammation, and oxidative stress. Using RNA-seq analysis, we identified that an iron uptake-associated gene, transferrin receptor, was upregulated in obese ob/ob mice with LVH. Caloric restriction attenuated myocyte hypertrophy, cardiac inflammation, fibrosis, and oxidative stress in ob/ob and db/db mice. Furthermore, we found that caloric restriction reversed iron homeostasis-related lipocalin 2, divalent metal transporter 1, transferrin receptor, ferritin, ferroportin, and hepcidin expressions in the heart of ob/ob and db/db mice. These findings demonstrate that the cardioprotective effects of caloric restriction result from the cellular regulation of iron homeostasis, thereby decreasing oxidative stress, inflammation, and cardiac remodeling. We suggest that decreasing iron-mediated oxidative stress and inflammation offers new therapeutic approaches for obesity-induced cardiomyopathy.

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Effect of Caloric Restriction on the in vivo Functional Properties of Aging Microglia.
Olmedillas Del Moral M, Fröhlich N, Figarella K, Mojtahedi N, Garaschuk O.
Front Immunol. 2020 Apr 28;11:750. doi: 10.3389/fimmu.2020.00750. eCollection 2020.
PMID: 32411143
https://sci-hub.tw/10.3389/fimmu.2020.00750
Abstract
Throughout the lifespan, microglia, the primary innate immune cells of the brain, fulfill a plethora of homeostatic as well as active immune defense functions, and their aging-induced dysfunctionality is now considered as a key trigger of aging-related brain disorders. Recent evidence suggests that both organism's sex and age critically impact the functional state of microglia but in vivo determinants of such state(s) remain unclear. Therefore, we analyzed in vivo the sex-specific functional states of microglia in young adult, middle aged and old wild type mice by means of multicolor two-photon imaging, using the microglial Ca2 + signaling and directed process motility as main readouts. Our data revealed the sex-specific differences in microglial Ca2 + signaling at all ages tested, beginning with young adults. Furthermore, for both sexes it showed that during the lifespan the functional state of microglia changes at least twice. Already at middle age the cells are found in the reactive or immune alerted state, characterized by heightened Ca2 + signaling but normal process motility whereas old mice harbor senescent microglia with decreased Ca2 + signaling, and faster but disorganized directed movement of microglial processes. The 6-12 months long caloric restriction (70% of ad libitum food intake) counteracted these aging-induced changes shifting many but not all functional properties of microglia toward a younger phenotype. The improvement of Ca2 + signaling was more pronounced in males. Importantly, even short-term (6-week-long) caloric restriction beginning at old age strongly improved microglial process motility and induced a significant albeit weaker improvement of microglial Ca2 + signaling. Together, these data provide first sex-specific in vivo characterization of functional properties of microglia along the lifespan and identify caloric restriction as a potent, cost-effective, and clinically relevant tool for rejuvenation of microglia.
KEYWORDS:
aging; caloric restriction; in vivo Cacpsdummy2+ imaging; microglia; process motility; sex differences

Untangling Determinants of Enhanced Health and Lifespan through a Multi-omics Approach in Mice.
Aon MA, Bernier M, Mitchell SJ, Di Germanio C, Mattison JA, Ehrlich MR, Colman RJ, Anderson RM, de Cabo R.
Cell Metab. 2020 May 11. pii: S1550-4131(20)30235-7. doi: 10.1016/j.cmet.2020.04.018. [Epub ahead of print]
PMID: 32413334
https://sci-hub.tw/10.1016/j.cmet.2020.04.018
Abstract
The impact of chronic caloric restriction (CR) on health and survival is complex with poorly understood underlying molecular mechanisms. A recent study in mice addressing the diets used in nonhuman primate CR studies found that while diet composition did not impact longevity, fasting time and total calorie intake were determinant for increased survival. Here, integrated analysis of physiological and multi-omics data from ad libitum, meal-fed, or CR animals was used to gain insight into pathways associated with improved health and survival. We identified a potential involvement of the glycine-serine-threonine metabolic axis in longevity and related molecular mechanisms. Direct comparison of the different feeding strategies unveiled a pattern of shared pathways of improved health that included short-chain fatty acids and essential PUFA metabolism. These findings were recapitulated in the serum metabolome from nonhuman primates. We propose that the pathways identified might be targeted for their potential role in healthy aging.
KEYWORDS:
aging; calorie restriction; calories; dietary interventions; dietary restriction; fasting; meal fed; metabolism; metabolomics; time-restricted feeding

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Effects of intermittent fasting and energy-restricted diets on lipid profile: A systematic review and meta-analysis.
Meng H, Zhu L, Kord-Varkaneh H, O Santos H, Tinsley GM, Fu P.
Nutrition. 2020 Mar 12;77:110801. doi: 10.1016/j.nut.2020.110801. Online ahead of print.
PMID: 32428841
Abstract
Objectives: To the best of our knowledge, no systematic review and meta-analysis has evaluated the cholesterol-lowering effects of intermittent fasting (IF) and energy-restricted diets (ERD) compared with control groups. The aim of this review and meta-analysis was to summarize the effects of controlled clinical trials examining the influence of IF and ERD on lipid profiles.
Methods: A systematic review of four independent databases (PubMed/Medline, Scopus, Web of Science and Google Scholar) was performed to identify clinical trials reporting the effects of IF or ERD, relative to non-diet controls, on lipid profiles in humans. A random-effects model, employing the method of DerSimonian and Laird, was used to evaluate effect sizes, and results were expressed as weighted mean difference (WMD) and 95% confidence intervals (CIs). Heterogeneity between studies was calculated using Higgins I2, with values ≥50% considered to represent high heterogeneity. Subgroup analyses were performed to examine the influence of intervention type, baseline lipid concentrations, degree of energy deficit, sex, health status, and intervention duration.
Results: For the outcomes of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triacylglycerols (TG), there were 34, 33, 35, and 33 studies meeting all inclusion criteria, respectively. Overall, results from the random-effects model indicated that IF and ERD interventions resulted significant changes in TC (WMD, -6.93 mg/dL; 95% CI, -10.18 to -3.67; P < 0.001; I2 = 78.2%), LDL-C (WMD, -6.16 mg/dL; 95% CI, -8.42 to -3.90; P ˂ 0.001; I2 = 52%), and TG concentrations (WMD, -6.46 mg/dL; 95% CI, -10.64 to -2.27; P = 0.002; I2 = 61%). HDL-C concentrations did not change significantly after IF or ERD (WMD, 0.50 mg/dL; 95% CI, -0.69 to 1.70; P = 0.411; I2 = 80%). Subgroup analyses indicated potentially differential effects between subgroups for one or more lipid parameters in the majority of analyses.
Conclusions: Relative to a non-diet control, IF and ERD are effective for the improvement of circulating TC, LDL-C, and TG concentrations, but have no meaningful effects on HDL-C concentration. These effects are influenced by several factors that may inform clinical practice and future research. The present results suggest that these dietary practices are a means of enhancing the lipid profile in humans.
Keywords: Energy-restricted diet; High-density lipoprotein cholesterol; Intermittent fasting; Lipids; Low-density lipoprotein cholesterol; Meta-analysis; Triacylglycerols.

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AMPK-mediated formation of stress granules is required for dietary restriction-induced longevity in Caenorhabditis elegans.
Kuo CT, You GT, Jian YJ, Chen TS, Siao YC, Hsu AL, Ching TT.
Aging Cell. 2020 May 20:e13157. doi: 10.1111/acel.13157. Online ahead of print.
PMID: 32432401
Abstract
Stress granules (SGs) are nonmembranous organelles that are dynamically assembled and disassembled in response to various stressors. Under stressed conditions, polyadenylated mRNAs and translation factors are sequestrated in SGs to promote global repression of protein synthesis. It has been previously demonstrated that SG formation enhances cell survival and stress resistance. However, the physiological role of SGs in organismal aging and longevity regulation remains unclear. In this study, we used TIAR-1::GFP and GTBP-1::GFP as markers to monitor the formation of SGs in Caenorhabditis elegans. We found that, in addition to acute heat stress, SG formation could also be triggered by dietary changes, such as starvation and dietary restriction (DR). We found that HSF-1 is required for the SG formation in response to acute heat shock and starvation but not DR, whereas the AMPK-eEF2K signaling is required for starvation and DR-induced SG formation but not heat shock. Moreover, our data suggest that this AMPK-eEF2K pathway-mediated SG formation is required for lifespan extension by DR, but dispensable for the longevity by reduced insulin/IGF-1 signaling. Collectively, our findings unveil a novel role of SG formation in DR-induced longevity.
Keywords: AMPK; HSF-1; dietary restriction; heat shock; longevity; stress granule.

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Short-term caloric restriction induced bone loss in both axial and appendicular bones by increasing adiponectin.
Zhu J, Liu C, Jia J, Zhang C, Yuan W, Leng H, Xu Y, Song C.
Ann N Y Acad Sci. 2020 May 29. doi: 10.1111/nyas.14380. Online ahead of print.
PMID: 32469430
Abstract
Caloric restriction (CR) is well described and has received extensive attention for its multiple benefits, including longevity and stress resistance. However, some studies have shown that CR negatively influences bone, although a mechanism hasn't been provided. Adiponectin, an adipocyte-derived hormone, can affect bone metabolism by various pathways. To explore the role of adiponectin in short-term CR on bone, we tested the effect of short-term CR on limb bones (tibia and femur) and lumbar vertebral bodies of young C57BL/6 wild-type (WT) and adiponectin-deficient (Apn-/- ) mice. Two dietary regimes, ad libitum (AL) and CR (70% of the AL diet), were used. Dietary restriction led to increased serum adiponectin in WT mice, while bone mineral density, bone microarchitecture, and biomechanical outcomes of limb bone and vertebrae were decreased. In contrast, bone length, microarchitecture, and biomechanical outcomes were not impaired after CR in Apn-/- mice. Furthermore, CR increased adiponectin expression both in white adipose tissue and bone marrow adipose tissue in young WT mice. Histology analysis showed that expansion of bone marrow adipose tissue after CR in Apn-/- mice was impaired compared with WT mice. These results suggest that increased adiponectin induced by short-term CR may negatively influence bones.
Keywords: adiponectin; caloric restriction; longevity; osteoporosis; white adipose tissue.

Functional changes induced by caloric restriction in cardiac and skeletal muscle mitochondria.
Serna JDC, Caldeira da Silva CC, Kowaltowski AJ.
J Bioenerg Biomembr. 2020 May 27. doi: 10.1007/s10863-020-09838-4. Online ahead of print.
PMID: 32462240
Abstract
Caloric restriction (CR) is widely known to increase life span and resistance to different types of injuries in several organisms. We have previously shown that mitochondria from livers or brains of CR animals exhibit higher calcium uptake rates and lower sensitivity to calcium-induced mitochondrial permeability transition (mPT), an event related to the resilient phenotype exhibited by these organs. Given the importance of calcium in metabolic control and cell homeostasis, we aimed here to uncover possible changes in mitochondrial calcium handling, redox balance and bioenergetics in cardiac and skeletal muscle mitochondria in response to six months of CR. Unexpectedly, we found that CR does not alter the susceptibility to mPT in muscle (cardiac or skeletal), nor calcium uptake rates. Despite the lack in changes in calcium transport properties, CR consistently decreased respiration in the presence of ATP synthesis in heart and soleus muscle. In heart, such changes were accompanied by a decrease in respiration in the absence of ATP synthesis, lower maximal respiratory rates and a reduced rate of hydrogen peroxide release. Hydrogen peroxide release was unaltered by CR in skeletal muscle. No changes were observed in inner membrane potentials and respiratory control ratios. Together, these results highlight the tissue-specific bioenergetic and ion transport effects induced by CR, demonstrating that resilience against calcium-induced mPT is not present in all tissues.
Keywords: Bioenergetics; Caloric Restriction; Heart; Mitochondrial Permeability Transition; Reactive Oxygen Species; Soleus Muscle.

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Caloric restriction, resting metabolic rate and cognitive performance in Non-obese adults: A post-hoc analysis from CALERIE study.
Grigolon RB, Brietzke E, Trevizol AP, McIntyre RS, Mansur RB.
J Psychiatr Res. 2020 May 25;128:16-22. doi: 10.1016/j.jpsychires.2020.05.018. Online ahead of print.
PMID: 32485641
Abstract
Physical activity (PA) has been proposed as a determinant of cognitive function and is one component of energy balance (EB). EB is the difference between energy intake (EI) and the total daily energy expenditure (TDEE). TDEE is a combination of resting metabolic rate (RMR), thermic effect of food and PA. The potential role of each of these components on cognitive function has not yet been systemically investigated. We aim to evaluate the association between each component of EB on cognition, using baseline and longitudinal data from a clinical trial of caloric restriction (CR). This is a parallel-group, randomized clinical trial comparing two years of 25% CR with two years of ad libitum diet (AL), with 220 healthy volunteers of both sex, aged between 21 and 50 years and initial BMI ≥ 22 kg/m2 and <28 kg/m2. Body weight, fat mass (FM), fat-free mass (FFM), and bone mineral content were evaluated, as well as RMR, TDEE, cognitive performance and baseline energy intake. A 30 min/day of a moderate level on a minimum of 5 days/week was advised as PA measure. Longitudinal analysis demonstrated that the influence of CR in the improvement of cognitive performance was moderated by changes in RMR, suggesting that in individuals submitted to CR, the cognitive performance and the RMR improved proportionally, independently of changes in EI and body mass. EB and homeostasis are crucial to modulate the RMR. Moreover, RMR presents an important influence on cognitive function in individuals submitted to CR in a long term.
Keywords: Caloric restriction; Cognitive function; Cognitive performance; Energy balance; Resting metabolic rate.

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GWAS for Lifespan and Decline in Climbing Ability in Flies upon Dietary Restriction Reveal decima as a Mediator of Insulin-like Peptide Production.
Wilson KA, Beck JN, Nelson CS, Hilsabeck TA, Promislow D, Brem RB, Kapahi P.
Curr Biol. 2020 May 27:S0960-9822(20)30659-X. doi: 10.1016/j.cub.2020.05.020. Online ahead of print.
PMID: 32502405
https://www.cell.com/current-biology/pdf/S0960-9822(20)30659-X.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS096098222030659X%3Fshowall%3Dtrue
Abstract
Dietary restriction (DR) is the most robust means to extend lifespan and delay age-related diseases across species. An underlying assumption in the aging field is that DR enhances both lifespan and physical activity through similar mechanisms, but this has not been rigorously tested in different genetic backgrounds. Furthermore, nutrient response genes responsible for lifespan extension or age-related decline in functionality remain underexplored in natural populations. To address this, we measured nutrient-dependent changes in lifespan and age-related decline in climbing ability in the Drosophila Genetic Reference Panel fly strains. On average, DR extended lifespan and delayed decline in climbing ability, but there was a lack of correlation between these traits across individual strains, suggesting that distinct genetic factors modulate these traits independently and that genotype determines response to diet. Only 50% of strains showed positive response to DR for both lifespan and climbing ability, 14% showed a negative response for one trait but not both, and 35% showed no change in one or both traits. Through GWAS, we uncovered a number of genes previously not known to be diet responsive nor to influence lifespan or climbing ability. We validated decima as a gene that alters lifespan and daedalus as one that influences age-related decline in climbing ability. We found that decima influences insulin-like peptide transcription in the GABA receptor neurons downstream of short neuropeptide F precursor (sNPF) signaling. Modulating these genes produced independent effects on lifespan and physical activity decline, which suggests that these age-related traits can be regulated through distinct mechanisms.
Keywords: Drosophila melanogaster; GWAS; aging; dietary restriction; genetic variation; insulin-like peptides; lifespan; physical ability.

Perspective: Do Fasting, Caloric Restriction, and Diets Increase Sensitivity to Radiotherapy? A Literature Review.
Icard P, Ollivier L, Forgez P, Otz J, Alifano M, Fournel L, Loi M, Thariat J.
Adv Nutr. 2020 Jun 3:nmaa062. doi: 10.1093/advances/nmaa062. Online ahead of print.
PMID: 32492154
Abstract
Caloric starvation, as well as various diets, has been proposed to increase the oxidative DNA damage induced by radiotherapy (RT). However, some diets could have dual effects, sometimes promoting cancer growth, whereas proposing caloric restriction may appear counterproductive during RT considering that the maintenance of weight is a major factor for the success of this therapy. A systematic review was performed via a PubMed search on RT and fasting, or caloric restriction, ketogenic diet (>75% of fat-derived energy intake), protein starvation, amino acid restriction, as well as the Warburg effect. Twenty-six eligible original articles (17 preclinical studies and 9 clinical noncontrolled studies on low-carbohydrate, high-fat diets popularized as ketogenic diets, representing a total of 77 patients) were included. Preclinical experiments suggest that a short period of fasting prior to radiation, and/or transient caloric restriction during treatment course, can increase tumor responsiveness. These regimens promote accumulation of oxidative lesions and insufficient repair, subsequently leading to cancer cell death. Due to their more flexible metabolism, healthy cells should be less sensitive, shifting their metabolism to support survival and repair. Interestingly, these regimens might stimulate an acute anticancer immune response, and may be of particular interest in tumors with high glucose uptake on positron emission tomography scan, a phenotype associated with poor survival and resistance to RT. Preclinical studies with ketogenic diets yielded more conflicting results, perhaps because cancer cells can sometimes metabolize fatty acids and/or ketone bodies. Randomized trials are awaited to specify the role of each strategy according to the clinical setting, although more stringent definitions of proposed diet, nutritional status, and consensual criteria for tumor response assessment are needed. In conclusion, dietary interventions during RT could be a simple and medically economical and inexpensive method that may deserve to be tested to improve efficiency of radiation.
Keywords: Warburg effect; caloric restriction; fasting; immunity; ketogenic diet; radiotherapy.

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Early-adulthood caloric restriction is beneficial to improve renal redox status as future anti-aging strategy in rats.
Dağ AD, Yanar K, Atayik MC, Simsek B, Belce A, Çakatay U.
Arch Gerontol Geriatr. 2020 May 23;90:104116. doi: 10.1016/j.archger.2020.104116. Online ahead of print.
PMID: 32516639
Abstract
Aims: Caloric restriction (CR) is an experimental approach proposed to alleviate age-related oxidative damage. In the present study, we investigated the consequences of CR on renal redox homeostasis in rats at a specific time frame in early-adulthood.
Methods: Three groups of male Sprague-Dawley rats; young control at 6-month-old, 2-year-old subjected to 40% CR between 18th-24th months of age, and their non-CR controls were sacrificed, and numerous redox status biomarkers including protein oxidation, glycation, lipid peroxidation, glycation end products, thiol groups, and superoxide dismutase were assayed. It was also ensured that CR rats and their non-CR corresponding rats had similar body weights at the end of the study to decrease the confounding effects of different body weights on redox homeostasis and caloric restriction.
Results: After CR, the detrimental effects of the protein oxidation, glycation, and lipid peroxidation were significantly improved in the renal tissue CR rats when compared to their non-CR control group. However, there were no significant difference in thiol fractions between younger controls and both of the elderly groups.
Conclusion: Detrimental consequences of renal senescence on redox homeostasis are significantly improved via CR especially applied in early-adulthood.
Keywords: aging; caloric restriction; kidney; oxidative damage; redox homeostasis.

Caloric restriction attenuates C57BL/6 J mouse lung injury and extra-pulmonary toxicity induced by real ambient particulate matter exposure.
Li D, Chen S, Li Q, Chen L, Zhang H, Li H, Yu D, Zhang R, Niu Y, Lu S, Ye L, Zeng X, Dong G, Chen R, Aschner M, Zheng Y, Chen W.
Part Fibre Toxicol. 2020 Jun 5;17(1):22. doi: 10.1186/s12989-020-00354-2.
PMID: 32503629
Abstract
Background: Caloric restriction (CR) is known to improve health and extend lifespan in human beings. The effects of CR on adverse health outcomes in response to particulate matter (PM) exposure and the underlying mechanisms have yet to be defined.
Results: Male C57BL/6 J mice were fed with a CR diet or ad libitum (AL) and exposed to PM for 4 weeks in a real-ambient PM exposure system located at Shijiazhuang, China, with a daily mean concentration (95.77 μg/m3) of PM2.5. Compared to AL-fed mice, CR-fed mice showed attenuated PM-induced pulmonary injury and extra-pulmonary toxicity characterized by reduction in oxidative stress, DNA damage and inflammation. RNA sequence analysis revealed that several pulmonary pathways that were involved in production of reactive oxygen species (ROS), cytokine production, and inflammatory cell activation were inactivated, while those mediating antioxidant generation and DNA repair were activated in CR-fed mice upon PM exposure. In addition, transcriptome analysis of murine livers revealed that CR led to induction of xenobiotic metabolism and detoxification pathways, corroborated by increased levels of urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) and decreased cytotoxicity measured in an ex vivo assay.
Conclusion: These novel results demonstrate, for the first time, that CR in mice confers resistance against pulmonary injuries and extra-pulmonary toxicity induced by PM exposure. CR led to activation of xenobiotic metabolism and enhanced detoxification of PM-bound chemicals. These findings provide evidence that dietary intervention may afford therapeutic means to reduce the health risk associated with PM exposure.
Keywords: Caloric restriction; Extra-pulmonary toxicity; Particulate matter; Pulmonary injury; RNA sequencing; Xenobiotic metabolism.

Effects of Royal Jelly and Tocotrienol Rich Fraction in obesity treatment of calorie-restricted obese rats: a focus on white fat browning properties and thermogenic capacity.
Mesri Alamdari N, Irandoost P, Roshanravan N, Vafa M, Asghari Jafarabadi M, Alipour S, Roshangar L, Alivand M, Farsi F, Shidfar F.
Version 2. Nutr Metab (Lond). 2020 Jun 1;17:42. doi: 10.1186/s12986-020-00458-8. eCollection 2020.
PMID: 32508963 Free PMC article.
Abstract
Background: Obesity has reached an alarming rate worldwide. Promoting thermogenesis via increasing the function of brown adipose tissue (BAT) or white adipose tissue (WAT) browning has been proposed as a new protective approach against obesity. The goal of this study was to evaluate the effects of Royal Jelly (RJ) and tocotrienol rich fraction (TRF) on BAT activation and WAT browning during calorie restriction diet (CRD) in obesity model.
Methods: In this experimental study, 50 obese Wistar rats were randomly divided into 5 groups and then received one of the following treatments for a period of 8-week: High-fat diet (HFD), CRD, RJ + CRD, TRF + CRD, and RJ + TRF + CRD. Effects of RJ and TRF, individually and in combination on body weight and the expression of key thermoregulatory genes in WAT and BAT were examined by quantitative real-time (qRT-PCR). Also, morphological alterations were assessed by hematoxylin and eosin staining.
Results: RJ (- 67.21 g ±4.84 g) and RJ + TRF (- 73.29 g ±4.51 g) significantly reduced weight gain relative to the CRD group (- 40.70 g ±6.50 g, P < 0.001). In comparison with the CRD group, RJ and RJ + TRF remarkably enhanced the uncoupling protein1 (UCP1) expression in WAT (5.81, 4.72 fold, P < 0.001) and BAT (4.99, 4.75 fold, P < 0.001). The expression of PR domain containing 16(PRDM 16), cAMP response element-binding protein1 (CREB1), P38 mitogen-activated protein kinases (P38MAPK), and Bone morphogenetic protein8B (BMP8B) have significantly increased following RJ and RJ + TRF treatments (P < 0.001). However, the expression levels of CCAAT/enhancer-binding protein beta (CEBPβ) and Bone morphogenetic protein7 ( BMP7) did not remarkably change. Multilocular beige cells in WAT and compacted dense adipocytes were also observed in BAT of RJ and RJ + TRF received groups. TRF showed no substantial effects on the expression of the mentioned thermoregulatory genes and brown fat-like phenotype.
Conclusion: Our results suggest that, Royal Jelly promotes thermogenesis and browning of WAT, contributing to an increase in energy expenditure. Thus, Royal Jelly may give rise to a novel dietary choice to attenuate obesity.
Keywords: Brown adipose tissue; Calorie restriction; Obesity; Royal jelly; Tocotrienol rich fraction; White adipose tissue.

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The Role of Diet in Cancer Prevention and Chemotherapy Efficacy.
Mittelman SD.
Annu Rev Nutr. 2020 Jun 16. doi: 10.1146/annurev-nutr-013120-041149. Online ahead of print.
PMID: 32543948
https://sci-hub.tw/https://www.annualreviews.org/doi/10.1146/annurev-nutr-013120-041149
Abstract
Despite great advances in treatment, cancer remains a leading cause of death worldwide. Diet can greatly impact health, while caloric restriction and fasting have putative benefits for disease prevention and longevity. Strong epidemiological associations exist between obesity and cancer, whereas healthy diets can reduce cancer risk. However, less is known about how diet might impact cancer once it has been diagnosed and particularly how diet can impact cancer treatment. In the present review, we discuss the links between obesity, diet, and cancer. We explore potential mechanisms by which diet can improve cancer outcomes, including through hormonal, metabolic, and immune/inflammatory effects, and present the limited clinical research that has been published in this arena. Though data are sparse, diet intervention may reduce toxicity, improve chemotherapy efficacy, and lower the risk of long-term complications in cancer patients. Thus, it is important that we understand and expand the science of this important but complex adjunctive cancer treatment strategy.

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Calorie Restriction and Aging in Humans.
Flanagan EW, Most J, Mey JT, Redman LM.
Annu Rev Nutr. 2020 Jun 19. doi: 10.1146/annurev-nutr-122319-034601. Online ahead of print.
PMID: 32559388
https://www.annualreviews.org/doi/pdf/10.1146/annurev-nutr-122319-034601
Abstract
Calorie restriction (CR), the reduction of dietary intake below energy requirements while maintaining optimal nutrition, is the only known nutritional intervention with the potential to attenuate aging. Evidence from observational, preclinical, and clinical trials suggests the ability to increase life span by 1-5 years with an improvement in health span and quality of life lived. CR moderates intrinsic processes of aging through cellular and metabolic adaptations and reducing risk for the development of many cardiometabolic diseases. Yet, implementation of CR may require unique considerations for the elderly and other specific populations. The objectives of this review are to summarize the evidence for CR to modify primary and secondary aging; present caveats for implementation in special populations; describe newer, alternative approaches that have comparative effectiveness and fewer deleterious effects; and provide thoughts on the future of this important field of study.

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Combined effects of caloric restriction and fish oil attenuated anti-depressant and anxiolytic-like effects of fish oil: association with hippocampal BDNF concentrations.
Correa CR, Schena C, Lopes SC, Prediger RD, Silva EL, Venske DKR, Ribeiro LC, Moreira JD.
Behav Brain Res. 2020 Jun 16:112770. doi: 10.1016/j.bbr.2020.112770. Online ahead of print.
PMID: 32561388
Abstract
Omega-3-enriched fish oil (FO) and caloric restriction (CR) are nutritional therapeutic approaches that exert an important impact on brain function, behavior, memory, and neuroprotection. Here, we investigate the synergic effects of both therapeutic approaches combined (CR + FO) on behavior (memory, anxiety-like behavior, antidepressant-like behavior), as well as its association with hippocampal brain-derived neurotrophic factor (BDNF) concentrations. Adult male Wistar rats were divided into four dietary groups: Control group (C) - chow ad libitum; CR group - 30% CR, considering C group food intake; FO group - FO-enriched chow ad libitum; and CR + FO group - FO-enriched 30% CR chow. After 12 weeks of dietary treatment, behavioural analysis set was conducted, and hippocampal BDNF concentrations were measured. FO group presented anxiolytic-like and antidepressant-like behaviors as well as improved memory in the Morris' water maze. These effects were attenuated by the combined CR + FO treatment. FO group also presented higher BDNF concentrations. There was a positive association between the number of entries in the platform quadrant in the MWM and hippocampal BDNF concentrations (β = 0.39; R² = 0.15; p = 0.042) and an inverse association between forced swim immobility time and BDNF concentrations (β = -0.39; R² = 0.15; p = 0.041). Taken together, our data showed that the 12-week FO dietary treatment promoted anxiolytic-like and antidepressant-like behaviors as well as memory improvement, and these effects were associated with BDNF concentrations. Synergic effects of interventions attenuated FO-related behavioral responses and BDNF concentrations and probably reduced hippocampal neuroplasticity.
Keywords: Anxiolytic-like behavior; Caloric restriction; Wistar rats; antidepressant-like behavior; fish oil.

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Intermittent fasting promotes adult hippocampal neuronal differentiation by activating GSK-3β in 3xTg-AD mice.
Li W, Wu M, Zhang Y, Wei X, Zang J, Liu Y, Wang Y, Gong CX, Wei W.
J Neurochem. 2020 Jun 23. doi: 10.1111/jnc.15105. Online ahead of print.
PMID: 32578216
Abstract
Moderate dietary restriction can ameliorate age-related chronic diseases such as Alzheimer's disease (AD) by increasing the expression of neurotrophic factors and promoting neurogenesis in the brain. Glycogen synthase kinase-3β (GSK-3β) signaling is essential for the coordination of progenitor cell proliferation and differentiation during brain development. The mechanisms by which GSK-3β is involved in dietary restriction induced neurogenesis and cognitive improvement remain unclear. Six-month-old male 3xTg-AD and wild type mice were fed on alternate days (intermittent fasting, IF) or ad libitum (AL) for 3 months. GSK-3β activity was regulated by bilaterally infusing lentiviral vectors carrying siRNA targeting GSK-3β into the dentate gyrus region of the hippocampus. Intermittent fasting promoted neuronal differentiation and maturation in the dentate gyrus and ameliorated recognize dysfunction in 3xTg-AD mice. These effects were reversed by siRNA targeting GSK-3β. After intermittent fasting, the insulin and protein kinase A signaling pathways were inhibited, while the AMP-activated protein kinase and brain-derived neurotrophic factor pathways were activated. These findings suggest that intermittent fasting can promote neuronal differentiation and maturation in the hippocampus by activating GSK-3β, thus improving learning and memory.
Keywords: GSK-3β; Intermittent fasting; insulin pathway; neuronal differentiation.

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