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Caloric restriction is associated with preservation of muscle strength in experimental cancer cachexia.
Levolger S, van den Engel S, Ambagtsheer G, IJzermans JNM, de Bruin RWF.
Aging (Albany NY). 2018 Dec 26. doi: 10.18632/aging.101724. [Epub ahead of print]
PMID: 30591621
https://www.aging-us.com/article/101724/text
https://s3-us-west-1.amazonaws.com/paperchase-aging/pdf/fx3LzfzvtQWG2dYLd.pdf
Abstract
Caloric restriction increases lifespan and healthspan, and limits age-associated muscle wasting. In this study, we investigate the impact of 30% caloric restriction (CR) in a murine cancer cachexia model. Forty CD2F1 mice were allocated as C26 tumor-bearing (TB) + ad libitum food intake (dietary reference intake [DRI]), TB CR, non-TB (NTB) CR, or NTB matched intake (MI). TB groups were inoculated subcutaneously with 0.5x106 C26 cells 14 days after initiating CR. Bodyweight, food intake, and grip-strength were recorded periodically. Gastrocnemius (GCM) and tibialis anterior (TA) muscles were resected and weighed 3 weeks after tumor inoculation. mRNA expression of MuRF1, Atrogin-1, myogenin, and MyoD was determined. At tumor inoculation, the mean body weight of TB CR was 88.6% of initial body weight and remained stable until sacrifice. TB DRI showed wasting before sacrifice. TB groups experienced muscle wasting compared with NTB MI. Grip-strength change was less severe in TB CR. Expression of MuRF1, Atrogin-1, and MyoD was similar between TB DRI and both CR groups. Expression of myogenin was increased in CR groups. In conclusion, caloric restriction limits loss of muscle strength but has no impact on muscle mass despite significant loss of body weight in an experimental cancer-associated cachexia model.
KEYWORDS:
cachexia; caloric restriction; cancer; muscle wasting

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Impact of aging and caloric restriction on fibroblast growth factor 21 signaling in rat white adipose tissue.
Fujii N, Uta S, Kobayashi M, Sato T, Okita N, Higami Y.
Exp Gerontol. 2019 Jan 5. pii: S0531-5565(18)30595-3. doi: 10.1016/j.exger.2019.01.001. [Epub ahead of print]
PMID: 30620889
https://reader.elsevier.com/reader/sd/pii/S0531556518305953?token=6B14750AE2573337929C6748F48C62129068B457CB8CC7A00A49DA9E36254D935AA3BCCE4A922EF4C268E9CF975238E4
Abstract
Caloric restriction (CR) suppresses age-related pathophysiology and extends lifespan. We recently reported that metabolic remodeling of white adipose tissue (WAT) plays an important role in the beneficial actions of CR; however, the detailed molecular mechanisms of this remodeling remain to be established. In the present study, we aimed to identify CR-induced alterations in the expression of fibroblast growth factor 21 (FGF21), a regulator of lipid and glucose metabolism, and of its downstream signaling mediators in liver and WAT, across the lifespan of rats. We evaluated groups of rats that had been either fed ad libitum or calorie restricted from 3 months of age and were euthanized at 3.5, 9, or 24 months of age, under fed and fasted conditions. The expression of FGF21 mRNA and/or protein increased with age in liver and WAT. Interestingly, in the WAT of 9-month-old fed rats, CR further upregulated FGF21 expression and eliminated the aging-associated reductions in the expression of FGFR1 and beta-klotho (KLB; FGF21 receptor complex). It also enhanced the expression of FGF21 targets, including glucose transporter 1 and peroxisome proliferator-activated receptor (PPAR)γ coactivator-1α. The analysis of transcriptional regulators of Fgf21 suggested that aging and CR might upregulate Fgf21 expression via different mechanisms. In adipocytes in vitro, constitutive FGF21 overexpression upregulated the FGF21 receptor complex and FGF21 targets at the mRNA or protein level. Thus, both aging and CR induced FGF21 expression in rat WAT; however, only CR activated FGF21 signaling. Our results suggest that FGF21 signaling contributes to the CR-induced metabolic remodeling of WAT, likely activating glucose uptake and mitochondrial biogenesis.
KEYWORDS:
Caloric restriction; Fibroblast growth factor 21; Glucose transporter 1; White adipose tissue; β-Klotho

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Calorie restriction protects neural stem cells from age-related deficits in the subventricular zone.
Apple DM, Mahesula S, Fonseca RS, Zhu C, Kokovay E.
Aging (Albany NY). 2019 Jan 8. doi: 10.18632/aging.101731. [Epub ahead of print]
PMID: 30622221
https://s3-us-west-1.amazonaws.com/paperchase-aging/pdf/6jdEED4ZqLA7rst5u.pdf
Abstract
The brain can generate new neurons from neural stem cells throughout life. However, the capacity for neurogenesis declines with age, reducing the potential for learning and repair. We explored the effects of calorie restriction, an established anti-aging intervention, on neural stem cells in the subventricular zone of young and aged mice. Calorie restriction transiently enhanced proliferation of neural progenitor cells in young, but not aged mice. However, calorie restriction prevented the age-related loss of neurogenesis in the aged brain. Calorie-restricted mice showed enhanced olfactory memory compared with ad libitum-fed controls, suggesting that calorie restriction can produce functional improvements in the aged brain. Calorie restriction also mitigated the age-related activation of microglia and subsequent increase in pro-inflammatory cytokines. Likewise, calorie restriction prevented increases in senescent cells normally observed in the subventricular zone in aged mice, further protecting this neurogenic niche from pro-inflammatory signals. Together, these data suggest that calorie restriction protects the subventricular zone microenvironment from age-related inflammation, thereby preserving neurogenesis into old age.
KEYWORDS:
calorie restriction; inflammation; neural stem cell; neurogenesis; olfactory memory; subventricular zone

Effect of a hypocaloric, nutritionally complete, higher-protein meal plan on bone density and quality in older adults with obesity: a randomized trial.
Weaver AA, Houston DK, Shapses SA, Lyles MF, Henderson RM, Beavers DP, Baker AC, Beavers KM.
Am J Clin Nutr. 2019 Jan 9. doi: 10.1093/ajcn/nqy237. [Epub ahead of print]
PMID: 30624598
https://sci-hub.tw/10.1093/ajcn/nqy237
Abstract
BACKGROUND:
Dietary protein and micronutrients are important to the maintenance of bone health and may be an effective countermeasure to weight-loss-associated bone loss.
OBJECTIVES:
We aimed to determine the effect of a 6-mo hypocaloric, nutritionally complete, higher-protein meal plan on change in bone density and quality as compared with weight stability in older adults using a randomized post-test design. We hypothesized that participants randomly assigned to this meal plan would maintain similar bone density and quality to weight-stable controls, despite significant reductions in body mass.
METHODS:
Ninety-six older adults (aged 70.3 ± 3.7 y, 74% women, 27% African American) with obesity [body mass index (kg/m2): 35.4 ± 3.3] were randomly assigned to a 6-mo hypocaloric, nutritionally complete, higher-protein meal plan targeting ≥1.0 g protein · kg body weight-1 · d-1 [weight-loss (WL) group; n = 47] or to a weight-stability (WS) group targeting 0.8 g protein · kg body weight-1 · d-1, the current Recommended Dietary Allowance (n = 49). The primary outcome was total hip bone mineral density (BMD), with femoral neck BMD, lumbar spine BMD, and lumbar spine trabecular bone score (TBS) as secondary outcomes, all assessed at baseline and 3 and 6 mo with dual-energy X-ray absorptiometry.
RESULTS:
Baseline total hip, femoral neck, and lumbar spine BMDs were 1.016 ± 0.160, 0.941 ± 0.142, and 1.287 ± 0.246 g/cm2, respectively; lumbar TBS was 1.398 ± 0.109. Despite significant weight loss achieved in the WL group (6.6 ± 0.4 kg; 8.6% ± 0.4% of baseline weight), 6-mo regional BMD estimates were similar to those in the WS group (all P > 0.05). Lumbar spine TBS significantly increased at 6 mo in the WL group (mean: 1.421; 95% CI: 1.401, 1.441) compared with the WS group (1.390: 95% CI: 1.370, 1.409; P = 0.02).
CONCLUSIONS:
Older adults following a hypocaloric, nutritionally complete, higher-protein meal plan maintained similar bone density and quality to weight-stable controls. Our data suggest that adherence to this diet does not produce loss of hip and spine bone density in older adults and may improve bone quality.

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The signaling pathways that mediate the anti-cancer effects of calorie restriction.
Lu Y, Tao F, Zhou MT, Tang KF.
Pharmacol Res. 2019 Jan 11. pii: S1043-6618(18)31466-X. doi: 10.1016/j.phrs.2019.01.021. [Epub ahead of print] Review.
PMID: 30641278
https://sci-hub.tw/10.1016/j.phrs.2019.01.021
Abstract
Caloric restriction (CR) can promote longevity and ameliorate aging-associated diseases, including cancer. Extensive research over recent decades has revealed that CR reduces IGF-1/PI3K/AKT signaling and increases sirtuin signaling. We recently found that CR also enhances ALDOA/DNA-PK/p53 signaling. In the present review, we summarize the molecular mechanisms underlying modulation of the IGF-1/PI3K/AKT pathway, sirtuin signaling, and the ALDOA/DNA-PK/p53 pathway by CR. We also summarize the evidence concerning the roles of these signaling pathways in carcinogenesis, and discuss how they are regulated by CR. Finally, we discuss the crosstalk between these signaling pathways.
KEYWORDS:
DNA damage; caloric restriction; cancer; signaling pathway

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Effect of Intermittent Compared With Continuous Energy Restricted Diet on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Noninferiority Trial.
Carter S, Clifton PM, Keogh JB.
JAMA Netw Open. 2018 Jul 6;1(3):e180756. doi: 10.1001/jamanetworkopen.2018.0756.
PMID: 30646030
[pdf availed from https://www.ncbi.nlm.nih.gov/pubmed/30646030 ]
Abstract
IMPORTANCE:
Intermittent energy restriction is an alternative weight loss method that is becoming popular; however, to date, there are no long-term clinical trials of intermittent energy restriction in patients with type 2 diabetes.
OBJECTIVE:
To compare the effects of intermittent energy restriction (2 days per week) with those of continuous energy restriction on glycemic control and weight loss in patients with type 2 diabetes during a 12-month period.
DESIGN, SETTING, AND PARTICIPANTS:
Adult participants (N = 137) with type 2 diabetes were randomized 1:1 to parallel diet groups (intermittent energy restriction [n = 70] or continuous energy restriction [n = 67]) between April 7, 2015, and September 7, 2017, at the University of South Australia. Medications likely to cause hypoglycemia were reduced at baseline according to the medication management protocol.
INTERVENTIONS:
An intermittent energy restriction diet (500-600 kcal/d) followed for 2 nonconsecutive days per week (participants followed their usual diet for the other 5 days) or a continuous energy restriction diet (1200-1500 kcal/d) followed for 7 days per week for 12 months.
MAIN OUTCOMES AND MEASURES:
The primary outcome was change in hemoglobin A1c (HbA1c) level, with equivalence prespecified by a 90% CI margin of ±0.5%. The secondary outcome was weight loss with equivalence set at ±2.5 kg (±1.75 kg for fat mass loss and ±0.75 kg for fat-free mass loss). All other outcomes were tested for superiority.
RESULTS:
Of the 137 randomized participants (77 women and 60 men; mean [SD] age, 61.0 [9.1] years; mean [SD] body mass index, 36.0 [5.8] [calculated as weight in kilograms divided by height in meters squared]; and mean [SD] HbA1c level, 7.3% [1.3%]), 97 completed the trial. Intention-to-treat analysis showed similar reductions in mean (SEM) HbA1c level between the continuous and intermittent energy restriction groups (-0.5% [0.2%] vs -0.3% [0.1%]; P = .65), with a between-group difference of 0.2% (90% CI, -0.2% to 0.5%) meeting the criteria for equivalence. Mean (SEM) weight change was similar between the continuous and intermittent energy restriction groups (-5.0 [0.8] kg vs -6.8 [0.8] kg; P = .25), but the between-group difference did not meet the criteria for equivalence (-1.8 kg; 90% CI, -3.7 to 0.07 kg), nor did the between-group difference in fat mass (-1.3 kg; 90% CI, -2.8 to 0.2 kg) or fat-free mass (-0.5 kg; 90% CI, -1.4 to 0.4 kg). There were no significant differences between groups in final step count, fasting glucose levels, lipid levels, or total medication effect score at 12 months. Effects did not differ using completers analysis. Hypoglycemic or hyperglycemic events in the first 2 weeks of treatment were similar between the continuous and intermittent energy restriction groups (mean number [SEM] of events, 3.2 [0.7] vs 4.9 [1.4]; P = .28), affecting 35% of participants (16 of 46) using sulfonylureas and/or insulin.
CONCLUSIONS AND RELEVANCE:
Intermittent energy restriction is an effective alternative diet strategy for the reduction of HbA1c and is comparable with continuous energy restriction in patients with type 2 diabetes.

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Calorie restriction for long-term remission of type 2 diabetes.
Taylor R.
Clin Med (Lond). 2019 Jan;19(1):37-42. doi: 10.7861/clinmedicine.19-1-37. Review.
PMID: 30651243
Abstract
Starting with a hypothesis which postulated a simple explanation arising from the basic cause of type 2 diabetes, a series of studies has introduced a paradigm shift in our understanding of the condition. Gradual accumulation of fat in the liver and pancreas leads eventually to beta cell dedifferentiation and loss of specialised function. The consequent hyperglycaemia can be returned to normal by removing the excess fat from liver and pancreas. At present this can be achieved only by substantial weight loss, and a simple practical and efficacious method for this has been developed and applied in a series of studies. For those people who used to have type 2 diabetes, the state of post-diabetes can be long term provided that weight regain is avoided. The implications for personal health and for national health economics are considerable.
KEYWORDS:
Type 2 diabetes; first phase insulin response; liver fat; pancreas fat; reversal of type 2 diabetes

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Effects of Lifestyle Intervention on Plasma Trimethylamine N-Oxide in Obese Adults.
Erickson ML, Malin SK, Wang Z, Brown JM, Hazen SL, Kirwan JP.
Nutrients. 2019 Jan 16;11(1). pii: E179. doi: 10.3390/nu11010179.
PMID: 30654453
https://www.mdpi.com/2072-6643/11/1/179/htm
Abstract
Accumulating evidence linking trimethylamine N-oxide (TMAO) to cardiovascular disease (CVD) risk has prompted interest in developing therapeutic strategies to reduce its production. We compared two lifestyle intervention approaches: hypocaloric versus eucaloric diet, combined with exercise, on TMAO levels in relation to CVD risk factors. Sixteen obese adults (66.1 ± 4.4 years, BMI (body mass index): 35.9 ± 5.3 kg/m², fasting glucose: 106 ± 16 mg/dL, 2-h PPG (postprandial glucose): 168 ± 37 mg/dL) were randomly assigned to 12 weeks of exercise (5 days/week, 80⁻85% HRmax (maximal heart rate)) plus either a hypocaloric (HYPO) (-500 kcal) or a eucaloric (EU) diet. Outcomes included plasma TMAO, glucose metabolism (oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamps for glucose disposal rates (GDR)), exercise capacity (VO2max, maximal oxygen consumption), abdominal adiposity (computed tomography scans), cholesterol, and triglycerides. Results showed that body composition (body weight, subcutaneous adiposity), insulin sensitivity, VO2max, and cholesterol all improved (p < 0.05). HYPO decreased the percentage change in TMAO compared to an increase after EU (HYPO: -31 ± 0.4% vs. EU: 32 ± 0.6%, p = 0.04). Absolute TMAO levels were not impacted (HYPO: p = 0.09 or EU: p = 0.53 group). The change in TMAO after intervention was inversely correlated with baseline visceral adipose tissue (r = -0.63, p = 0.009) and GDR (r = 0.58, p = 0.002). A hypocaloric diet and exercise approach appears to be effective in reducing TMAO. Larger trials are needed to support this observation.
KEYWORDS:
caloric restriction; cardiovascular disease risk factors; exercise; gut microbiome; lifestyle intervention; obesity; trimethylamine N-oxide

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Brain region-specific effects of long-term caloric restriction on redox balance of the aging rat.
Moyse E, Arsenault M, Gaudreau P, Ferland G, Ramassamy C.
Mech Ageing Dev. 2019 Jan 16. pii: S0047-6374(18)30176-3. doi: 10.1016/j.mad.2019.01.002. [Epub ahead of print]
PMID: 30659860
https://sci-hub.tw/10.1016/j.mad.2019.01.002
Abstract
Caloric restriction (CR) is the most effective intervention to improve health span and extend lifespan in preclinical models. This anti-aging effect of CR is related to attenuation of oxidative damage in various tissues, with divergent results in the brain. We addressed how brain oxidoreductive balance would be modulated in male Sprague-Dawley (SD) rats submitted to a 40% CR from 8 to 19 months of age, by reference to ad libitum-fed (AL) rats at 2 and 19 months of age. Four brain structures were compared: hippocampus, striatum, parietal cortex, cerebellum. Our CR diet elicits significant prevention of oxidative damages with the upregulation of antioxidant defenses (levels of glutathione [GSH], mRNAs of clusterin and of three key antioxidant enzymes) as compared to age-matched AL controls, in a strikingly region-specific pattern. CR also prevented a drastic rise of the glial fibrillary acidic protein in the hippocampus of old AL rats. Besides, the CR effects at age 19 months mainly consist in improving endogenous defenses before the onset of age-related redox alterations. These effects are more prominent in the hippocampus.
KEYWORDS:
Clusterin; Glial Fibrillary Acidic Protein; Glutaredoxine-1; Glutathione; Superoxide dismutase-1; Thioredoxine-1

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Caloric restriction prevents the development of airway hyperresponsiveness in mice on a high fat diet.
Younas H, Vieira M, Gu C, Lee R, Shin MK, Berger S, Loube J, Nelson A, Bevans-Fonti S, Zhong Q, D'Alessio FR, McCormack MC, Hansel NN, Mitzner W, Polotsky VY.
Sci Rep. 2019 Jan 22;9(1):279. doi: 10.1038/s41598-018-36651-2.
PMID: 30670753
https://www.nature.com/articles/s41598-018-36651-2.pdf
Abstract
We have previously shown that high fat diet (HFD) for 2 weeks increases airway hyperresponsiveness (AHR) to methacholine challenge in C57BL/6J mice in association with an increase in IL-1β levels in lung tissue. We hypothesize that obesity increases AHR via the IL-1β mechanism, which can be prevented by caloric restriction and IL-1β blockade. In this study, we fed C57BL/6J mice for 8 weeks with several hypercaloric diets, including HFD, HFD supplemented with fructose, high trans-fat diet (HTFD) supplemented with fructose, either ad libitum or restricting their food intake to match body weight to the mice on a chow diet (CD). We also assessed the effect of the IL-1β receptor blocker anakinra. All mice showed the same total respiratory resistance at baseline. All obese mice showed higher AHR at 30 mg/ml of methacholine compared to CD and food restricted groups, regardless of the diet. Obese mice showed significant increases in lung IL-1 β mRNA expression, but not the protein, compared to CD and food restricted mice. Anakinra abolished an increase in AHR. We conclude that obesity leads to the airway hyperresponsiveness preventable by caloric restriction and IL-1β blockade.

Adaptive Physiological and Morphological Adjustments Mediated by Intestinal Stem Cells in Response to Food Availability in Mice.
Peña-Villalobos I, Casanova-Maldonado I, Lois P, Sabat P, Palma V.
Front Physiol. 2019 Jan 8;9:1821. doi: 10.3389/fphys.2018.01821. eCollection 2018.
PMID: 30670976
https://www.frontiersin.org/articles/10.3389/fphys.2018.01821/full
Abstract
Several studies have evaluated plastic changes in the morphology of the digestive tract in rodents subjected to caloric restriction or restricted availability. Nevertheless, studies that link these morphological responses to physiological consequences are scarce. In order to investigate short-term plastic responses in the intestine, we acclimated adult Mus musculus (BALB/c) males for 20 days to four distinctive treatments: two caloric regimens (ad libitum and 60% of calorie ingestion) and two levels of periodicity of the regimens (continuous and stochastic treatment). At the end of the treatment we analyzed the cell proliferation and cell death dynamics of small intestinal crypts in these animals. In addition, we measured organ masses and lengths, hydrolytic digestive enzyme activities, and energy output from feces. Finally, in order to explore the metabolic changes generated by these dietary conditions we assessed the catabolic activity (i.e., enzymes) of the liver. Our results show that individuals acclimated to a continuous and 60% regimen presented longer intestines in comparison to the other treatments. Indeed, their intestines grew with a rate of 0.22 cm/day, generating a significant caloric reduction in the content of their feces. Besides, both mass and intestinal lengths were predicted strongly by the stabilization coefficient of BrdU+ proliferating cells per crypt, the latter correlating positively with the activity of n-aminopeptidases. Interestingly, by using pharmacological inhibition of the kinase mammalian target of rapamycin complex 1 (mTORC1) by Rapamycin, we were able to recapitulate similar changes in the proliferation dynamics of intestinal stem cells. Based on our results, we propose that the impact of caloric restriction on macroscopic variation in morphology and functional changes in digestive n-aminopeptidases occurs through synchronization in the proliferation rate of stem and/or progenitor cells located in the small intestinal crypts and requires mTORC1 as a key mediator. Hence, we suggest that an excessive stem and progenitor activity could result in increased crypts branching and might therefore underlie the reported intestinal tissue expansion in response to short-term caloric restriction. Summarizing, we demonstrate for the first time that short-term caloric restriction induces changes in the level of cell proliferation dynamics explaining in part digestive tract plasticity in adaptive performance.
KEYWORDS:
caloric restriction; environmental stochasticity; intestinal crypts; jejunum; mTORC1; starvation

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Pilot Study of Novel Intermittent Fasting Effects on Metabolomic and Trimethylamine N-oxide Changes During 24-hour Water-Only Fasting in the FEELGOOD Trial.
Washburn RL, Cox JE, Muhlestein JB, May HT, Carlquist JF, Le VT, Anderson JL, Horne BD.
Nutrients. 2019 Jan 23;11(2). pii: E246. doi: 10.3390/nu11020246.
PMID: 30678028
https://www.mdpi.com/2072-6643/11/2/246/htm
Abstract
Intermittent fasting (IF) has been connected with health benefits such as weight loss, lower risk of coronary artery disease (CAD) and diabetes, increased longevity, and improved quality of life. However, the mechanisms of these IF benefits in humans require further investigation. This study sought to elucidate some of these mechanisms through secondary analyses of the Fasting and ExprEssion of Longevity Genes during fOOD abstinence (FEELGOOD) trial, in which apparently healthy participants were randomized in a Latin square design to a 24-h water-only fast and a 24-h ad libitum fed day. Two pathways were investigated, with trimethylamine N-oxide (TMAO) levels measured due to their association with elevated risk of CAD, along with conductance of a broad panel of metabolic analytes. Measurements were made at baseline, at the end of the fasting day, and at the end of the fed day. A fasting mean of 14.3 ng in TMAO was found versus the baseline mean of 27.1 ng with p = 0.019, although TMAO levels returned to baseline on refeeding. Further, acute alterations in levels of proline, tyrosine, galactitol, and urea plasma levels were observed along with changes in 24 other metabolites during the fasting period. These acute changes reveal short-term mechanisms which, with consistent repeated episodes of IF, may lead to improved health and reduced risk of CAD and diabetes.
KEYWORDS:
coronary artery disease; diabetes; intermittent energy restriction; intermittent fasting; metabolic analytes; trimethylamine N-oxide

Dietary Restriction and Neuroinflammation: A Potential Mechanistic Link.
Bok E, Jo M, Lee S, Lee BR, Kim J, Kim HJ.
Int J Mol Sci. 2019 Jan 22;20(3). pii: E464. doi: 10.3390/ijms20030464. Review.
PMID: 30678217
https://www.mdpi.com/1422-0067/20/3/464/htm
Abstract
Chronic neuroinflammation is a common feature of the aged brain, and its association with the major neurodegenerative changes involved in cognitive impairment and motor dysfunction is well established. One of the most potent antiaging interventions tested so far is dietary restriction (DR), which extends the lifespan in various organisms. Microglia and astrocytes are two major types of glial cells involved in the regulation of neuroinflammation. Accumulating evidence suggests that the age-related proinflammatory activation of astrocytes and microglia is attenuated under DR. However, the molecular mechanisms underlying DR-mediated regulation of neuroinflammation are not well understood. Here, we review the current understanding of the effects of DR on neuroinflammation and suggest an underlying mechanistic link between DR and neuroinflammation that may provide novel insights into the role of DR in aging and age-associated brain disorders.
KEYWORDS:
aging; astrocytes; dietary restriction; microglia; neuroinflammation

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Caloric Restriction Exacerbates Angiotensin II-Induced Abdominal Aortic Aneurysm in the Absence of p53.
Gao P, Zhang H, Zhang Q, Fang X, Wu H, Wang M, Lu Z, Wei X, Yang G, Yan Z, Liu D, Zhu Z.
Hypertension. 2019 Jan 28:HYPERTENSIONAHA11812086. doi: 10.1161/HYPERTENSIONAHA.118.12086. [Epub ahead of print]
PMID: 30686087
Abstract
p53-dependent vascular smooth muscle cell senescence is a key pathological process of abdominal aortic aneurysm (AAA). Caloric restriction (CR) is a nonpharmacological intervention that prevents AAA formation. However, whether p53 is indispensable to the protective role of CR remains unknown. In this study, we investigated the necessity of p53 in the beneficial role of CR in AAA formation and the underlying mechanisms. We subjected p53+/+ and p53-/- mice to 12 weeks of CR and then examined the incidence of Ang II (angiotensin II)-induced AAA formation. We found that both CR and p53 knockout reduced Ang II-induced AAA formation; however, CR markedly increased the incidence of AAA formation and exacerbated aortic elastin degradation in p53-/- mice, accompanied by increased vascular senescence, reactive oxygen species generation, and reduced energy production. Analysis of mitochondrial respiratory activity revealed that dysfunctional complex IV accounts for the abnormal mitochondrial respiration in p53-/- vascular smooth muscle cells treated by CR serum. Mechanistically, ablation of p53 almost totally blocked the protective role of CR by inhibiting SCO2 (cytochrome C oxidase assembly protein 2)-dependent mitochondrial complex IV activity. Overexpression of SCO2 restored the beneficial effect of CR on antagonizing Ang II-induced expression of AAA-related molecules and reactive oxygen species generation in p53-/- vascular smooth muscle cells. Together, our findings demonstrate that the existence of p53 in vascular smooth muscle cells is critical to the protective role of CR in Ang II-induced AAA formation by maintaining an appropriate mitochondrial function.
KEYWORDS:
angiotensin II; aortic aneurysm, abdominal; caloric restriction; mice; tumor suppressor protein p53

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Preoperative Protein or Methionine Restriction Preserves Wound Healing and Reduces Hyperglycemia.
Trocha K, Kip P, MacArthur MR, Mitchell SJ, Longchamp A, Treviño-Villarreal JH, Tao M, Bredella MA, De Amorim Bernstein K, Mitchell JR, Ozaki CK.
J Surg Res. 2019 Mar;235:216-222. doi: 10.1016/j.jss.2018.09.071. Epub 2018 Nov 17.
PMID: 30691797
https://sci-hub.tw/10.1016/j.jss.2018.09.071
Abstract
BACKGROUND:
Dietary restriction (DR), defined as reduced nutrient intake without malnutrition, is associated with longevity extension, improved glucose metabolism, and increased stress resistance, but also poor wound healing. Short-term preoperative DR followed by a return to normal feeding after surgery results in improved surgical outcomes in preclinical models. However, the effect of preoperative DR on wound healing and perioperative glucose homeostasis is currently unknown. Here, we tested the effects of two different preoperative DR regimens-protein restriction (PR) and methionine restriction (MR)-on wound healing and perioperative glucose homeostasis using an established murine model of wound healing in both nondiabetic and diabetic mice.
MATERIALS AND METHODS:
Surgical outcomes were tested using the McFarlane flap in nondiabetic and streptozotocin-induced diabetic mice. Short-term dietary preconditioning included 1 wk of PR or MR diet (1-2 wk) versus an isocaloric complete diet before surgery; all mice were returned to a complete diet postoperatively. Outcome measures of flap wound recovery included skin viability and laser Doppler imaging of flap perfusion and assessment of CD45+ cell infiltration. Glucose homeostasis was assessed by glucose tolerance testing and by perioperative glucose levels in the diabetic cohort.
RESULTS:
No significant differences were observed in percentage of viable skin, perfusion, or immune cell infiltration at 7-10 d after surgery in PR or MR mice compared with controls in healthy or diabetic mice. Preoperative glucose tolerance and postoperative glucose levels were however significantly improved by both PR and MR in diabetic mice.
CONCLUSIONS:
Short-term dietary preconditioning with PR or MR did not impair wound healing in nondiabetic or diabetic mice. However, both regimens reduced preoperative hyperglycemia in diabetic mice. Thus, brief preoperative dietary manipulations stand as strategies to potentially improve perioperative hyperglycemia with no deleterious effects on wound healing in mice.
KEYWORDS:
Dietary restriction; Metabolism; Methionine restriction; Protein restriction; Wound healing

Metabolic Implications of Diet and Energy Intake during Physical Inactivity.
Winn NC, Pettit-Mee R, Walsh LK, Restaino RM, Ready ST, Padilla J, Kanaley JA.
Med Sci Sports Exerc. 2019 Jan 25. doi: 10.1249/MSS.0000000000001892. [Epub ahead of print]
PMID: 30694977
Abstract
PURPOSE:
Physical inactivity is associated with disruptions in glucose metabolism and energy balance, whereas energy restriction may blunt these adverse manifestations. During hypocaloric feeding, higher-protein intake maintains lean mass which is an important component of metabolic health. This study determined whether mild energy restriction preserves glycemic control during physical inactivity and whether this preservation is more effectively achieved with a higher-protein diet.
METHODS:
Ten adults (24±1 year) consumed a control (64% carbohydrate, 20% fat, 16% protein) and higher-protein diet (50% carbohydrate, 20% fat, 30% protein) during two ten-day inactivity periods (>10,000→~5,000 steps/day) in a randomized cross-over design. Energy intake was decreased by ~400 kcal/d to account for reduced energy expenditure associated with inactivity. A subset of subjects (n=5) completed ten days of inactivity while consuming 35% excess of their basal energy requirements, which served as a positive control condition (overfeeding+inactivity).
RESULTS:
Daily steps were decreased from 12,154±308 to 4,275±269 steps/day (P<0.05) which was accompanied by reduced VO2max (-1.8±0.7 ml/kg/min, P<0.05), independent of diet conditions. No disruptions in fasting or postprandial glucose, insulin, and nonesterified fatty acids in response to 75-g of oral glucose were observed following inactivity for both diet conditions (P>0.05). Overfeeding+inactivity increased body weight, body fat, HOMA-IR, and 2-hour postprandial glucose and insulin concentrations (P<0.05), despite no changes in lipid concentrations.
CONCLUSIONS:
We show that independent of diet (normal vs. higher-protein), mild energy restriction preserves metabolic function during short-term inactivity in healthy subjects. That is, metabolic deterioration with inactivity only manifests in the setting of energy surplus.

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Potential effects of reduced red meat compared with increased fiber intake on glucose metabolism and liver fat content: a randomized and controlled dietary intervention study.
Willmann C, Heni M, Linder K, Wagner R, Stefan N, Machann J, Schulze MB, Joost HG, Häring HU, Fritsche A.
Am J Clin Nutr. 2019 Feb 5. doi: 10.1093/ajcn/nqy307. [Epub ahead of print]
PMID: 30721948
https://sci-hub.tw/10.1093/ajcn/nqy307
Abstract
BACKGROUND:
Epidemiological studies suggest that an increased red meat intake is associated with a higher risk of type 2 diabetes, whereas an increased fiber intake is associated with a lower risk.
OBJECTIVES:
We conducted an intervention study to investigate the effects of these nutritional factors on glucose and lipid metabolism, body-fat distribution, and liver fat content in subjects at increased risk of type 2 diabetes.
METHODS:
This prospective, randomized, and controlled dietary intervention study was performed over 6 mo. All groups decreased their daily caloric intake by 400 kcal. The "control" group (N = 40) only had this requirement. The "no red meat" group (N = 48) in addition aimed to avoid the intake of red meat, and the "fiber" group (N = 44) increased intake of fibers to 40 g/d. Anthropometric parameters and frequently sampled oral glucose tolerance tests were performed before and after intervention. Body-fat mass and distribution, liver fat, and liver iron content were assessed by MRI and single voxel proton magnetic resonance spectroscopy.
RESULTS:
Participants in all groups lost weight (mean 3.3 ± 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001). These changes did not differ between groups. Liver fat content decreased significantly (P < 0.001) with no differences between the groups. The decrease in liver fat correlated with the decrease in ferritin during intervention (r2 = 0.08, P = 0.0021). This association was confirmed in an independent lifestyle intervention study (Tuebingen Lifestyle Intervention Program, N = 229, P = 0.0084).
CONCLUSIONS:
Our data indicate that caloric restriction leads to a marked improvement in glucose metabolism and body-fat composition, including liver-fat content. The marked reduction in liver fat might be mediated via changes in ferritin levels. In the context of caloric restriction, there seems to be no additional beneficial impact of reduced red meat intake and increased fiber intake on the improvement in cardiometabolic risk parameters.

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Dietary Energy Restriction Ameliorates Cognitive Impairment in a Mouse Model of Traumatic Brain Injury.
Rubovitch V, Pharayra A, Har-Even M, Dvir O, Mattson MP, Pick CG.
J Mol Neurosci. 2019 Feb 8. doi: 10.1007/s12031-019-01271-6. [Epub ahead of print]
PMID: 30734244
https://sci-hub.tw/10.1007/s12031-019-01271-6
Abstract
Traumatic brain injury (TBI) is one of the most common causes of neurological damage in young people. It was previously reported that dietary restriction, by either intermittent fasting (IF) or daily caloric restriction (CR), could protect neurons against dysfunction and degeneration in animal models of stroke and Parkinson's disease. Recently, several studies have shown that the protein Sirtuin 1 (SIRT1) plays a significant role in the induced neuroprotection following dietary restriction. In the present study, we found a significant reduction of SIRT1 levels in the cortex and hippocampus in a mouse model of mild weight-drop closed head TBI. This reduction was prevented in mice maintained on IF (alternate day fasting) and CR initiated after the head trauma. Hippocampus-dependent learning and memory (measured using a novel object recognition test) was impaired 30 days post-injury in mice fed ad libitum, but not in mice in the IF and CR groups. These results suggest a clinical potential for IF and/or CR as an intervention to reduce brain damage and improve functional outcome in TBI patients.
KEYWORDS:
Axonal regeneration; Caloric restriction; Cognitive deficits; Intermittent fasting; Traumatic brain injury

Seafood intake and the development of obesity, insulin resistance and type 2 diabetes.
Liaset B, Øyen J, Jacques H, Kristiansen K, Madsen L.
Nutr Res Rev. 2019 Feb 7:1-22. doi: 10.1017/S0954422418000240. [Epub ahead of print]
PMID: 30728086
https://sci-hub.tw/10.1017/S0954422418000240
Abstract
We provide an overview of studies on seafood intake in relation to obesity, insulin resistance and type 2 diabetes. Overweight and obesity development is for most individuals the result of years of positive energy balance. Evidence from intervention trials and animal studies suggests that frequent intake of lean seafood, as compared with intake of terrestrial meats, reduces energy intake by 4-9 %, sufficient to prevent a positive energy balance and obesity. At equal energy intake, lean seafood reduces fasting and postprandial risk markers of insulin resistance, and improves insulin sensitivity in insulin-resistant adults. Energy restriction combined with intake of lean and fatty seafood seems to increase weight loss. Marine n-3 PUFA are probably of importance through n-3 PUFA-derived lipid mediators such as endocannabinoids and oxylipins, but other constituents of seafood such as the fish protein per se, trace elements or vitamins also seem to play a largely neglected role. A high intake of fatty seafood increases circulating levels of the insulin-sensitising hormone adiponectin. As compared with a high meat intake, high intake of seafood has been reported to reduce plasma levels of the hepatic acute-phase protein C-reactive protein level in some, but not all studies. More studies are needed to confirm the dietary effects on energy intake, obesity and insulin resistance. Future studies should be designed to elucidate the potential contribution of trace elements, vitamins and undesirables present in seafood, and we argue that stratification into responders and non-responders in randomised controlled trials may improve the understanding of health effects from intake of seafood.
KEYWORDS:
%E energy percent; AA arachidonic acid; CCK cholecystokinin; CRP C-reactive protein; GLP-1 glucagon-like peptide-1; HOMA-IR homeostasis model of assessment insulin resistance; POP persistent organic pollutant; RCT randomised controlled trial; T2D type 2 diabetes; Body-weight regulation; Fish; Glucose regulation; Marine PUFA; Obesity; Seafood; Type 2 diabetes
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Dietary fish as a major component of a weight-loss diet: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects.
Mori TA, Bao DQ, Burke V, Puddey IB, Watts GF, Beilin LJ.
Am J Clin Nutr. 1999 Nov;70(5):817-25.
PMID: 10539741
https://academic.oup.com/ajcn/article/70/5/817/4729086
Abstract
BACKGROUND:
Obesity in hypertensive patients is associated with dyslipidemia and insulin resistance, both of which are improved by weight control. n-3 Fatty acids have diverse effects on mechanisms underlying atherosclerosis, including a decrease in serum triacylglycerols and an increase in HDL(2) cholesterol.
OBJECTIVE:
The objective was to examine whether dietary fish enhances the effects of weight loss on serum lipids, glucose, and insulin in 69 overweight, treated hypertensive patients.
DESIGN:
Overweight patients being treated for hypertension were randomly assigned to either a daily fish meal (3.65 g n-3 fatty acids), a weight-loss regimen, the 2 regimens combined, or a control group for 16 wk.
RESULTS:
Sixty-three subjects completed the study. Weight decreased by a mean (+/-SEM) of 5.6 +/- 0.8 kg with energy restriction. Weight loss decreased fasting insulin (P = 0.003) and the area under the curve for insulin (P = 0.003) and glucose (P = 0.047) during an oral-glucose-tolerance test. The greatest decrease occurred in the fish + weight-loss group. There was no independent effect of fish on glucose or insulin. Fish increased HDL(2) cholesterol (P = 0.004) and decreased HDL(3) cholesterol (P = 0.026) without altering total, LDL, or HDL cholesterol. Weight loss had no effect on these variables. Fasting triacylglycerols fell significantly with fish consumption (29%) and weight loss (26%). The fish + weight-loss group showed the greatest improvement in lipids: triacylglycerols decreased by 38% (P < 0.001) and HDL(2) cholesterol increased by 24% (P = 0.04) compared with the control group.
CONCLUSIONS:
Incorporating a daily fish meal into a weight-loss regimen was more effective than either measure alone at improving glucose-insulin metabolism and dyslipidemia. Cardiovascular risk is likely to be substantially reduced in overweight hypertensive patients with a weight-loss program incorporating fish meals rich in n-3 fatty acids.

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A Comparison of Dietary and Caloric Restriction Models on Body Composition, Physical Performance, and Metabolic Health in Young Mice.
Smith NJ, Caldwell JL, van der Merwe M, Sharma S, Butawan M, Puppa M, Bloomer RJ.
Nutrients. 2019 Feb 7;11(2). pii: E350. doi: 10.3390/nu11020350.
PMID: 30736418
[See https://www.mdpi.com/2072-6643/11/2/350 for pdf.]
Abstract
Time-restricted feeding (TRF), alternate day fasting (ADF), and the dietary restriction model known as the Daniel Fast (DF; a vegan/non-processed food diet plan) have garnered attention recently as nutritional interventions to combat obesity. We compared the effects of various dietary models on body composition, physical performance, and metabolic health in C57BL/6 mice. Sixty young C57BL/6 male mice were assigned a diet of TRF, ADF, DF, caloric restriction (CR), a high-fat Western diet (HF) fed ad libitum, or standard rodent chow for eight weeks. Their body composition, run time to exhaustion, fasting glucose, insulin, and glucose tolerance test area under the glucose curve (AUC) were determined. Compared to the HF group, all groups displayed significantly less weight and fat mass gain, as well as non-significant changes in fat-free mass. Additionally, although not statistically significant, all groups displayed greater run time to exhaustion relative to the HF group. Compared to the HF group, all groups demonstrated significantly lower fasting glucose, insulin, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as well as improved glucose tolerance, and the ADF group displayed the best fasting glucose and glucose tolerance results, with DF having the best HOMA-IR. All investigated fasting protocols may improve body composition, measures of insulin sensitivity, and physical performance compared to a high-fat Western diet. The DF and ADF protocols are most favorable with regards to insulin sensitivity and glucose tolerance. Since our selected dietary protocols have also been investigated in humans with success, it is plausible to consider that these dietary models could prove beneficial to men and women seeking improved body composition and metabolic health.
KEYWORDS:
body composition; diet; exercise; fasting; insulin

Effects of Caloric Restriction with Protein Supplementation on Plasma Protein Profiles in Middle-Aged Women with Metabolic Syndrome-A Preliminary Open Study.
Chang CY, Tung YT, Lin YK, Liao CC, Chiu CF, Tung TH, Shabrina A, Huang SY.
J Clin Med. 2019 Feb 6;8(2). pii: E195. doi: 10.3390/jcm8020195.
PMID: 30736312
[See https://www.mdpi.com/2077-0383/8/2/195 for pdf.]
Abstract
BACKGROUND:
Clinical studies have demonstrated that higher protein intake based on caloric restriction (CR) alleviates metabolic abnormalities. However, no study has examined the effects of plasma protein profiles on caloric restriction with protein supplementation (CRPS) in metabolic syndrome (MetS). Therefore, using a proteomic perspective, this pilot study investigated whether CRPS ameliorated metabolic abnormalities associated with MetS in middle-aged women.
METHODS:
Plasma samples of middle-aged women with MetS in CR (n = 7) and CRPS (n = 6) groups for a 12-week intervention were obtained and their protein profiles were analysed. Briefly, blood samples from qualified participants were drawn before and after the dietary treatment. Anthropometric, clinical, and biochemical variables were measured and correlated with plasma proteomics.
RESULTS:
In results, we found that body mass index, total body fat, and fasting blood glucose decreased significantly after the interventions but were not different between the CR and CRPS groups. After liquid chromatography⁻tandem mass spectrometry analysis, the relative plasma levels of alpha-2-macroglobulin (A2M), C4b-binding protein alpha chain (C4BPA), complement C1r subcomponent-like protein (C1RL), complement component C6 (C6), complement component C8 gamma chain (C8G), and vitamin K-dependent protein S (PROS) were significantly different between the CRPS and CR groups. These proteins are involved in inflammation, the immune system, and coagulation responses. Moreover, blood low-density lipoprotein cholesterol levels were significantly and positively correlated with C6 plasma levels in both groups.
CONCLUSIONS:
These findings suggest that CRPS improves inflammatory responses in middle-aged women with MetS. Specific plasma protein expression (i.e., A2M, C4BPA, C1RL, C6, C8G, and PROS) associated with the complement system was highly correlated with fasting blood glucose (FBG), blood lipids (BLs), and body fat.
KEYWORDS:
caloric restriction; metabolic syndrome; plasma proteomics; protein supplementation

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Neuronal SIRT1 Regulates Metabolic and Reproductive Function and the Response to Caloric Restriction.
Rickert E, Fernandez MO, Choi I, Gorman M, Olefsky JM, Webster NJG.
J Endocr Soc. 2018 Dec 24;3(2):427-445. doi: 10.1210/js.2018-00318. eCollection 2019 Feb 1.
PMID: 30746504
https://watermark.silverchair.com/js.2018-00318.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAkIwggI-BgkqhkiG9w0BBwagggIvMIICKwIBADCCAiQGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQM9UXXP1GwNo5vVZJDAgEQgIIB9d8qx_eK1fyqdKdCDW0lUpsftxiWGL0qUsGMWiGPQHaZpzS3H9IBIM63-T-mF1mm4_nRzAQ73u3F6zXhC8GR8W0zkmDwIFcmwjrn7e7ROboSiskPGViNzmC7KGvKCmfuOfIUZx57cjnK0F0uqZD23z5SE7eB2TB7JAGK0pjEHU7Xuq18SSt_X1aC80j-YLGnsFr2y_ybiGu3Wevh5_VdlmZYenpWr6-86sPjtuoxX3UebbHernlD7hkBEbLjeFgLw_YWNWBePNr6mXZKMS5q6nggm-nFctqB09T8SdYOvA597aykG-VW4zLG3BF3tWs55V2U0NuV5lxLxSx2_mFrhnDN82N7IJ-4TROAEulRRl3S423OabHiUNJzq9NKMAsyJiW9mV_6z5lolpB3OgVYlcD2h1SFxM6SgoiiUOYTxXHQDySMZSea2DEB-vPSZXxX7_DNW5R-BsRrH1PttKiFmHMlpeEH1z0FuGobgQ-KtOEEJRYS8k2WG62hfEmCe-7D6bcORJ8ys82VxS7hVpCaPOx3YC4q3Qrl2FHfETX1pFedbthme65udK1vMKweGA0jlW7_7mQjS1fyTxzfItfYEhksmKqbPW4ezLLJcyWPyE9OVbGuArUyxGdZ-CoZFuLzKtLFzMyqiyKdx4aygSODy3dm6KjcXg
Abstract
Sirt1 is an NAD-dependent, class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. In this study, we generated mice expressing an enzymatically inactive form (N-MUT) or wild-type (WT) SIRT1 (N-OX) in mature neurons. N-OX male and female mice had impaired glucose tolerance, and N-MUT female, but not male, mice had improved glucose tolerance compared with that of WT littermates. Furthermore, glucose tolerance was improved in all mice with caloric restriction (CR) but was greater in the N-OX mice, who had better glucose tolerance than their littermates. At the reproductive level, N-OX females had impaired estrous cycles, with increased cycle length and more time in estrus. LH and progesterone surges were absent on the evening of proestrus in the N-OX mice, suggesting a defect in spontaneous ovulation, which was confirmed by the ovarian histology revealing fewer corpora lutea. Despite this defect, the mice were still fertile when mated to WT mice on the day of proestrus, indicating that the mice could respond to normal pheromonal or environmental cues. When subjected to CR, the N-OX mice went into diestrus arrest earlier than their littermates. Together, these results suggested that the overexpression of SIRT1 rendered the mice more sensitive to the metabolic improvements and suppression of reproductive cycles by CR, which was independent of circadian rhythms.
KEYWORDS:
caloric restriction; fertility; glucose intolerance; neurons

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Diets consisting of fewer calories improve cell performance
Date: February 12, 2019
Source: Fundação de Amparo à Pesquisa do Estado de São Paulo
Summary: Animal experiments have shown that caloric restriction causes cellular changes that can prevent diseases.
https://www.sciencedaily.com/releases/2019/02/190212120125.htm

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The association between dietary protein intake, energy intake and physical frailty- results from the Rotterdam Study.
Schoufour JD, Franco OH, Kiefte-de Jong JC, Trajanoska K, Stricker B, Brusselle G, Rivadeneira F, Lahousse L, Voortman T.
Br J Nutr. 2018 Nov 13:1-23. doi: 10.1017/S0007114518003367. [Epub ahead of print] No abstract available.
PMID: 30419973
https://sci-hub.tw/10.1017/S0007114518003367

Interaction of growth hormone and calorie restriction.
Masternak MM, Bartke A.
Expert Rev Endocrinol Metab. 2006 Nov;1(6):775-781. doi: 10.1586/17446651.1.6.775.
PMID: 30754151
https://sci-hub.tw/https://www.tandfonline.com/doi/full/10.1586/17446651.1.6.775
Abstract
Sustaining health and extending longevity have been perpetual goals of all human societies. For almost as long, there has been an ongoing effort to develop treatments that could prevent aging and, more importantly, make us live longer and more healthily. At present, there is one known intervention that delays aging, increases lifespan and prevents diseases in many animal species: calorie restriction. There are other physiological factors that are believed to have corresponding impacts on longevity and aging, including growth hormone and the insulin/insulin-like growth factor 1 signaling pathway. However, there is still much debate regarding the complex action of growth hormone on lifespan and aging.
KEYWORDS:
Ames dwarf; GHR-KO; calorie restriction; growth hormone; growth hormone receptor; knockout; longevity

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FEBRUARY 14, 2019
Uncovering a 'smoking gun' of biological aging clocks
by Harvard T.H. Chan School of Public Health
https://medicalxpress.com/news/2019-02-uncovering-gun-biological-aging-clocks.html
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Ribosomal DNA harbors an evolutionarily conserved clock of biological aging.
Wang M, Lemos B.
Genome Res. 2019 Feb 14. doi: 10.1101/gr.241745.118. [Epub ahead of print]
PMID: 30765617
https://sci-hub.tw/10.1101/gr.241745.118
Abstract
The ribosomal DNA (rDNA) is the most evolutionarily conserved segment of the genome and gives origin to the nucleolus, an energy intensive nuclear organelle and major hub influencing myriad molecular processes from cellular metabolism to epigenetic states of the genome. The rDNA/nucleolus has been directly and mechanistically implicated in aging and longevity in organisms as diverse as yeasts, Drosophila, and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity. Here, we introduce an age clock built exclusively with CpG methylation within the rDNA. The ribosomal clock is sufficient to accurately estimate individual age within species, is responsive to genetic and environmental interventions that modulate life-span, and operates across species as distant as humans, mice, and dogs. Further analyses revealed a significant excess of age-associated hypermethylation in the rDNA relative to other segments of the genome, and which forms the basis of the rDNA clock. Our observations identified an evolutionarily conserved marker of aging that is easily ascertained, grounded on nucleolar biology, and could serve as a universal marker to gauge individual age and response to interventions in humans as well as laboratory and wild organisms across a wide diversity of species.
[Calorie restriction (CR) has long been reported to extend lifespan and retard aging. For the C57BL/6 mice subjected to CR starting at 14 wk old, we observed lower rDNAm age compared to their
ad libitum (AL) controls (one-tailed t-test of the differences between rDNAm age and chronological age, P = 1.17 × 10−9) (Fig. 3A). The CR effect remained obvious when instead examining
the B6D2F1 strain mice (P = 0.002) (Supplemental Fig. S7A).]

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HSF1/HSP pathway in the hippocampus is involved in SIRT1-mediated caloric restriction-induced neuroprotection after surgery in aged mice.
Yao M, Zhao Z, Wei L, Zhou D, Xue Z, Ge S.
Exp Gerontol. 2019 Feb 14. pii: S0531-5565(18)30537-0. doi: 10.1016/j.exger.2019.02.011. [Epub ahead of print]
PMID: 30772489
Abstract
Postoperative cognitive dysfunction is common in the elderly. Endoplasmic reticulum stress (ER-stress) increases neuronal apoptosis after surgery, and chaperone molecules, such as heat shock proteins (HSPs), help reduce unfolded protein reactions, thereby promoting protein homeostasis. Mammal sirtuin1 (SIRT1)-mediated deacetylation of heat shock factor 1 (HSF1) upregulates HSF1 binding to the HSP70 promoter. Caloric restriction (CR) improves cognition in many neurodegenerative models. In this study, we evaluated whether CR improves impaired learning and memory after surgery by attenuating ER-stress in an SIRT1-dependent manner. Male 18-month-old C57BL/6J mice receiving a 12-week CR or an ad libitum (AL) diet pre-intervention were challenged with tibial open fracture surgery and anesthesia or no treatment. We found a significant protective effect of CR on memory in contextual fear conditioning test after surgery compared with the AL group. CR alleviated ER-stress and neuronal apoptosis in the hippocampus induced by surgery. CR increased HSP70 expression through the HSF1/HSP pathway in a SIRT1-mediated manner, and inhibition of SIRT1 in the hippocampus by lentivirus injection partially reduced the benefits of CR (increased HSP70, deacetylated HSF1, reduced ER-stress, and improved memory). Taken together, our results showed that CR alleviates memory impairment postoperatively via attenuation of ER-stress in the hippocampus in an SIRT1-dependent manner, and the SIRT1/HSF1/HSP70 pathway is involved in this process.
KEYWORDS:
Caloric restriction; HSF1; HSP70; Neuroprotection; SIRT1

SAHMRI research reveals why high-protein diets are bad for you
Clare Peddie, Science Reporter, The Advertiser
February 14, 2019
https://www.adelaidenow.com.au/news/south-australia/sahmri-research-reveals-why-highprotein-diets-are-bad-for-you/news-story/9277b39a4ad84b5f1ce38b6ddfaf001f?nk=db94ec9b47b2d84b4dda8cee105fbb26-1550338206
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Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan.
Xie J, de Souza Alves V, von der Haar T, O'Keefe L, Lenchine RV, Jensen KB, Liu R, Coldwell MJ, Wang X, Proud CG.
Curr Biol. 2019 Feb 4. pii: S0960-9822(19)30031-4. doi: 10.1016/j.cub.2019.01.029. [Epub ahead of print]
PMID: 30773367
https://www.cell.com/action/showPdf?pii=S0960-9822(19)30031-4
Xie et al. report that eukaryotic elongation factor 2 kinase (eEF2K), which impairs the rate of elongation, decreases misreading or termination readthrough errors and promotes the correct recognition of start codons in mRNAs. Depletion of the eEF2K ortholog or other factors implicated in translation fidelity in C. elegans decreases lifespan.
Highlights
•eEF2 kinase enhances the accuracy of protein synthesis under a range of conditions
•mTORC1 inhibition improves translation accuracy by activating eEF2K
•eEF2K assists correct start codon selection during translation initiation
•Impairing translation fidelity reduces lifespan in C. elegans
Summary
Maintaining accuracy during protein synthesis is crucial to avoid producing misfolded and/or non-functional proteins. The target of rapamycin complex 1 (TORC1) pathway and the activity of the protein synthesis machinery are known to negatively regulate lifespan in many organisms, although the precise mechanisms involved remain unclear. Mammalian TORC1 signaling accelerates the elongation stage of protein synthesis by inactivating eukaryotic elongation factor 2 kinase (eEF2K), which, when active, phosphorylates and inhibits eEF2, which mediates the movement of ribosomes along mRNAs, thereby slowing down the rate of elongation. We show that eEF2K enhances the accuracy of protein synthesis under a range of conditions and in several cell types. For example, our data reveal it links mammalian (m)TORC1 signaling to the accuracy of translation. Activation of eEF2K decreases misreading or termination readthrough errors during elongation, whereas knocking down or knocking out eEF2K increases their frequency. eEF2K also promotes the correct recognition of start codons in mRNAs. Reduced translational fidelity is known to correlate with shorter lifespan. Consistent with this, deletion of the eEF2K ortholog or other factors implicated in translation fidelity in Caenorhabditis elegans decreases lifespan, and eEF2K is required for lifespan extension induced by nutrient restriction. Our data uncover a novel mechanism linking nutrient supply, mTORC1 signaling, and the elongation stage of protein synthesis, which enhances the accuracy of protein synthesis. Our data also indicate that modulating translation elongation and its fidelity affects lifespan.
KEYWORDS:
Caenorhabditis elegans; caloric restriction; eEF2; eEF2K; elongation; lifespan; mTOR; tRNA; translation fidelity

ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians' Perspective.
Vitale G, Pellegrino G, Vollery M, Hofland LJ.
Front Endocrinol (Lausanne). 2019 Feb 1;10:27. doi: 10.3389/fendo.2019.00027. eCollection 2019. Review.
PMID: 30774624
https://www.frontiersin.org/articles/10.3389/fendo.2019.00027/full
Abstract
Human aging is currently defined as a physiological decline of biological functions in the body with a continual adaptation to internal and external damaging. The endocrine system plays a major role in orchestrating cellular interactions, metabolism, growth, and aging. Several in vivo studies from worms to mice showed that downregulated activity of the GH/IGF-1/insulin pathway could be beneficial for the extension of human life span, whereas results are contradictory in humans. In the present review, we discuss the potential role of the IGF-1 system in modulation of longevity, hypothesizing that the endocrine and metabolic adaptation observed in centenarians and in mammals during caloric restriction may be a physiological strategy for extending lifespan through a slower cell growing/metabolism, a better physiologic reserve capacity, a shift of cellular metabolism from cell proliferation to repair activities and a decrease in accumulation of senescent cells. Therefore, understanding of the link between IGF-1/insulin system and longevity may have future clinical applications in promoting healthy aging and in Rehabilitation Medicine.
KEYWORDS:
IGF-1; aging; caloric restriction; centenarians; insulin; longevity; rehabilitation medicine

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Nrf2/ARE Pathway Modulation by Dietary Energy Regulation in Neurological Disorders.
Vasconcelos AR, Dos Santos NB, Scavone C, Munhoz CD.
Front Pharmacol. 2019 Feb 4;10:33. doi: 10.3389/fphar.2019.00033. eCollection 2019. Review.
PMID: 30778297
https://www.frontiersin.org/articles/10.3389/fphar.2019.00033/full
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of an array of enzymes with important detoxifying and antioxidant functions. Current findings support the role of high levels of oxidative stress in the pathogenesis of neurological disorders. Given the central role played by Nrf2 in counteracting oxidative damage, a number of studies have targeted the modulation of this transcription factor in order to confer neuroprotection. Nrf2 activity is tightly regulated by oxidative stress and energy-based stimuli. Thus, many dietary interventions based on energy intake regulation, such as dietary energy restriction (DER) or high-fat diet (HFD), modulate Nrf2 with consequences for a variety of cellular processes that affect brain health. DER, by either restricting calorie intake or meal frequency, activates Nrf2 thereby triggering its protective effects, whilst HFD inhibit this pathway, thereby exacerbating oxidative stress. Consequently, DER protocols can be valuable strategies in the management of central nervous system (CNS) disorders. Herein, we review current knowledge of the role of Nrf2 signaling in neurological diseases, namely Alzheimer's disease, Parkinson's disease, multiple sclerosis and cerebral ischemia, as well as the potential of energy intake regulation in the management of Nrf2 signaling.
KEYWORDS:
Alzheimer’s disease; Nrf2; Parkinson’s disease; aging; cerebral ischemia; dietary energy restriction; high-fat diet; multiple sclerosis

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Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restriction.
Kim DH, Park MH, Ha S, Bang EJ, Lee Y, Lee AK, Lee J, Yu BP, Chung HY.
Aging (Albany NY). 2019 Feb 27. doi: 10.18632/aging.101838. [Epub ahead of print]
PMID: 30811347
https://s3-us-west-1.amazonaws.com/paperchase-aging/pdf/dtSBxbPMkjbGFt4Zo.pdf
Abstract
β-Hydroxybutyrate (HB) is a ketone body used as an energy source that has shown anti-inflammatory effects similar to calorie restriction (CR); Here, PGC-1α, an abundantly expressed co-factor in the kidney, was reported to interact with both FoxO1 and NF-κB although the definitive interactive mechanism has not yet been reported. In this study, we investigated whether renal aging-related inflammation is modulated by HB. We compared aged rats administered with HB to calorie restricted rats and examined the modulation of FoxO1 and the NF-κB pathway through interactions with PGC-1α. We found that in aged rats treated with HB, pro-inflammatory signaling changes were reversed and showed effects comparable to CR. As FoxO1 and its target genes catalase/MnSOD were upregulated by HB treatment and PGC-1α selectively interacted with FoxO1, not with NF-κB, and ameliorated the renal inflammatory response. These findings were further confirmed using FoxO1 overexpression and siRNA transfection in vitro. Our findings suggest that HB suppressed aging-related inflammation as a CR mimetic by enabling the co-activation and selective interaction between FoxO1 and PGC-1α. This study demonstrates the potential therapeutic role of HB as a CR mimetic, which ameliorates inflammation by a novel mechanism where FoxO1 outcompetes NF-κB by interacting with PGC-1α in aging kidneys.
KEYWORDS:
FoxO1; aging kidney; calorie restriction; inflammation; β-hydroxybutyrate

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Maternal age alters offspring lifespan, fitness, and lifespan extension under caloric restriction.
Bock MJ, Jarvis GC, Corey EL, Stone EE, Gribble KE.
Sci Rep. 2019 Feb 28;9(1):3138. doi: 10.1038/s41598-019-40011-z.
PMID: 30816287
https://www.nature.com/articles/s41598-019-40011-z
Abstract
Maternal age has a negative effect on offspring lifespan in a range of taxa and is hypothesized to influence the evolution of aging. However, the mechanisms of maternal age effects are unknown, and it remains unclear if maternal age alters offspring response to therapeutic interventions to aging. Here, we evaluate maternal age effects on offspring lifespan, reproduction, and the response to caloric restriction, and investigate maternal investment as a source of maternal age effects using the rotifer, Brachionus manjavacas, an aquatic invertebrate. We found that offspring lifespan and fecundity decline with increasing maternal age. Caloric restriction increases lifespan in all offspring, but the magnitude of lifespan extension is greater in the offspring from older mothers. The trade-off between reproduction and lifespan extension under low food conditions expected by life history theory is observed in young-mother offspring, but not in old-mother offspring. Age-related changes in maternal resource allocation to reproduction do not drive changes in offspring fitness or plasticity under caloric restriction in B. manjavacas. Our results suggest that the declines in reproduction in old-mother offspring negate the evolutionary fitness benefits of lifespan extension under caloric restriction.

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