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Different effects of high-protein/low-carbohydrate versus standard hypocaloric diet on insulin resistance and lipid profile: role of rs16147 variant of neuropeptide Y.
Antonio de Luis D, Izaola O, Primo D, Aller R.
Diabetes Res Clin Pract. 2019 Aug 23:107825. doi: 10.1016/j.diabres.2019.107825. [Epub ahead of print]
PMID: 31449874
Abstract
BACKGROUND AND AIMS:
Few studies have assessed the effect of the NPY gene rs16147 variant on metabolic response following a dietary intervention. We evaluated the effect of rs16147 on body weight and biochemical changes after a high-protein/low-carbohydrate hypocaloric diet compared with a standard severe hypocaloric diet over 9 months.
MATERIALS AND METHODS:
A population of 270 obese individuals was enrolled. At baseline, participants were randomly allocated to one of two hypocaloric diets, high protein (Diet HP) or standard (Diet S), for a period of 9 months.
RESULTS:
After both diets, all genotypes showed decreased body mass index, weight, fat mass, waist circumference, and leptin levels. Participants with the minor allele (A) assigned to the HP diet showed decreases in total cholesterol (-6.5 ± 4.8 vs 10.1 ± 4.1 mg/dL; p < 0.05), LDL cholesterol (-5.9 ± 3.8 vs 9.6 ± 2.4 mg/dL; p < 0.05), triglycerides (-1.0 ± 4.8 vs 16.2 ± 4.1 mg/dL; p < 0.05), insulin (-0.5 ± 2.8 vs 1.7 ± 2.1 UI/L; p < 0.05), HOMA-IR (-0.2 ± 2.1 vs 0.5 ± 2.0 units; p < 0.05), and CRP (-0.3 ± 0.4 vs 1.3 ± 0.2 mg/dL; p < 0.05). Participants with the minor allele assigned to diet S also showed decreases in total cholesterol (-6.1 ± 4.1 vs 14.4 ± 3.1 mg/dL; p < 0.05), LDL-cholesterol (-3.1 ± 2.8 vs 15.0 ± 3.1 mg/dL; p < 0.05), triglycerides (-6.9 ± 4.1 vs 13.2 ± 4.0 mg/dL; p < 0.05), insulin (-0.3 ± 2.1 vs. -1.2 ± 0.2 UI/L: p < 0.05), HOMA-IR (-0.3 ± 2.1 vs. -1.6 ± 1.1 units: p < 0.05), and CRP (-0.4 ± 0.1 vs 1.1 ± 0.2 mg/dL; p < 0.05).
CONCLUSION:
In obese Caucasians, the presence of the A allele of the rs16147 genetic variant produces a better metabolic response that is secondary to weight loss with two different hypocaloric diets.
KEYWORDS:
NPY gene; SNP; hypocaloric diet; rs16147

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Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.
Stekovic S, Hofer SJ, Tripolt N, Aon MA, Royer P, Pein L, Stadler JT, Pendl T, Prietl B, Url J, Schroeder S, Tadic J, Eisenberg T, Magnes C, Stumpe M, Zuegner E, Bordag N, Riedl R, Schmidt A, Kolesnik E, Verheyen N, Springer A, Madl T, Sinner F, de Cabo R, Kroemer G, Obermayer-Pietsch B, Dengjel J, Sourij H, Pieber TR, Madeo F.
Cell Metab. 2019 Aug 20. pii: S1550-4131(19)30429-2. doi: 10.1016/j.cmet.2019.07.016. [Epub ahead of print]
PMID: 31471173
Abstract
Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.
KEYWORDS:
RCT; aging; body shape; caloric restriction; cardiovascular disease risk; clinical trial; fasting; fat distribution; intermittent fasting; triiodothyronine

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Time-restricted feeding plus resistance training in active females: a randomized trial.
Tinsley GM, Moore ML, Graybeal AJ, Paoli A, Kim Y, Gonzales JU, Harry JR, VanDusseldorp TA, Kennedy DN, Cruz MR.
Am J Clin Nutr. 2019 Jul 3. pii: nqz126. doi: 10.1093/ajcn/nqz126. [Epub ahead of print]
PMID: 31268131
Abstract
BACKGROUND:
A very limited amount of research has examined intermittent fasting (IF) programs, such as time-restricted feeding (TRF), in active populations.
OBJECTIVE:
Our objective was to examine the effects of TRF, with or without β-hydroxy β-methylbutyrate (HMB) supplementation, during resistance training (RT).
METHODS:
This study employed a randomized, placebo-controlled, reduced factorial design and was double-blind with respect to supplementation in TRF groups. Resistance-trained females were randomly assigned to a control diet (CD), TRF, or TRF plus 3 g/d HMB (TRFHMB). TRF groups consumed all calories between 1200 h and 2000 h, whereas the CD group ate regularly from breakfast until the end of the day. All groups completed 8 wk of supervised RT and consumed supplemental whey protein. Body composition, muscular performance, dietary intake, physical activity, and physiological variables were assessed. Data were analyzed prior to unblinding using mixed models and both intention-to-treat (ITT) and per protocol (PP) frameworks.
RESULTS:
Forty participants were included in ITT, and 24 were included in PP. Energy and protein intake (1.6 g/kg/d) did not differ between groups despite different feeding durations (TRF and TRFHMB: ∼7.5 h/d; CD: ∼13 h/d). Comparable fat-free mass (FFM) accretion (+2% to 3% relative to baseline) and skeletal muscle hypertrophy occurred in all groups. Differential effects on fat mass (CD: +2%; TRF: -2% to -4%; TRFHMB: -4% to -7%) were statistically significant in the PP analysis, but not ITT. Muscular performance improved without differences between groups. No changes in physiological variables occurred in any group, and minimal side effects were reported.
CONCLUSIONS:
IF, in the form of TRF, did not attenuate RT adaptations in resistance-trained females. Similar FFM accretion, skeletal muscle hypertrophy, and muscular performance improvements can be achieved with dramatically different feeding programs that contain similar energy and protein content during RT. Supplemental HMB during fasting periods of TRF did not definitively improve outcomes.
KEYWORDS:
body composition; energy restriction; fat loss; intermittent energy restriction; intermittent fasting; muscle mass; muscular strength; protein; resistance exercise; weight training

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Effects of caloric restriction on the expression of lipocalin-2 and its receptor in the brown adipose tissue of high-fat diet-fed mice.
Park KA, Jin Z, An HS, Lee JY, Jeong EA, Choi EB, Kim KE, Shin HJ, Lee JE, Roh GS.
Korean J Physiol Pharmacol. 2019 Sep;23(5):335-344. doi: 10.4196/kjpp.2019.23.5.335. Epub 2019 Aug 26.
PMID: 31496871
https://synapse.koreamed.org/Synapse/Data/PDFData/0067KJPP/kjpp-23-335.pdf
Abstract
Obesity causes inflammation and impairs thermogenic functions in brown adipose tissue (BAT). The adipokine lipocalin 2 (LCN2) has been implicated in inflammation and obesity. Herein, we investigated the protective effects of caloric restriction (CR) on LCN2-mediated inflammation and oxidative stress in the BAT of high-fat diet (HFD)-fed mice. Mice were fed a HFD for 20 weeks and then either continued on the HFD or subjected to CR for the next 12 weeks. CR led to the browning of the white fat-like phenotype in HFD-fed mice. Increased expressions of LCN2 and its receptor in the BAT of HFD-fed mice were significantly attenuated by CR. Additionally, HFD+CR-fed mice had fewer neutrophils and macrophages expressing LCN2 and iron-positive cells than HFD-fed mice. Further, oxidative stress and mitochondrial fission induced by a HFD were also significantly attenuated by CR. Our findings indicate that the protective effects of CR on inflammation and oxidative stress in the BAT of obese mice may be associated with regulation of LCN2.
KEYWORDS:
Brown adipose tissue; Caloric restriction; Lipocalin 2; Obesity

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Exercise degrades Bone in Caloric Restriction, despite Suppression of Marrow Adipose Tissue (MAT).
McGrath C, Sankaran JS, Misaghian-Xanthos N, Sen B, Xie Z, Styner MA, Zong X, Rubin J, Styner M.
J Bone Miner Res. 2019 Sep 11. doi: 10.1002/jbmr.3872. [Epub ahead of print]
PMID: 31509274
Abstract
Marrow adipose tissue (MAT) and its relevance to skeletal health during caloric restriction (CR) is unknown: it remains unclear whether exercise, which is anabolic to bone in a calorie-replete state, alters bone or MAT in CR. We hypothesized that response of bone and MAT to exercise in CR differs from the calorie-replete state. Ten-week-old female B6 mice fed a regular (RD) or 30% CR-diet were allocated to sedentary (RD CR, n = 10/group) or running exercise (RD-E, CR-E, n = 7/group). After 6 weeks, CR mice weighed 20% less than RD, p < 0.001; exercise did not affect weight. Femoral bone volume (BV) via 3D MRI was 20% lower in CR vs. RD (p < 0.0001). CR was associated with decreased bone by μCT: Tb. Th was 16% less in CR vs. RD, p < 0.003, Ct.Th was 5% less, p < 0.07. In CR-E Tb.Th was 40% less than RD-E, p < 0.0001. Exercise increased Tb.Th in RD (+23% RD-E vs. RD p < 0.003) but failed to do so in CR. Cortical porosity increased after exercise in CR (+28%, p = 0.04), suggesting exercise during CR is deleterious to bone. In terms of bone fat, metaphyseal MAT/ BV rose 159% in CR vs. RD, p = 0.003 via 3D MRI. Exercise decreased MAT/ BV by 52% in RD, p < 0.05 and also suppressed MAT in CR (-121%, p = 0.047). Histomorphometric analysis of adipocyte area correlated with MAT by MRI (R2  = 0.6233, p < 0.0001). With respect to bone, TRAP and Sost mRNA were reduced in CR. Intriguingly, the repressed Sost in CR rose with exercise and may underlie the failure of CR-bone quantity to increase in response to exercise. Notably, CD36, a marker of fatty acid uptake, rose 4088% in CR (p < 0.01 vs. RD) suggesting that basal increases in MAT during calorie restriction serve to supply local energy needs, and are depleted during exercise with a negative impact on bone. This article is protected by copyright. All rights reserved.
KEYWORDS:
Bone-fat interactions; Exercise; Marrow Adipose Tissue (MAT)

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This post today of Al's ("Exercise degrades Bone in Calorie Restriction") is very concerning. I'm assuming similar effects accrue to humans. The previous concerns among CR practitioners, if I recall correctly, were that CR could cause bone fragility. That exercise doesn't counterbalance the effect but instead makes matters worse is an even greater concern.

Informed comments and relevant research would be appreciated.

Edited by ras

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Dietary restriction in ILSXISS mice is associated with widespread changes in splicing regulatory factor expression levels.
Lee BP, Mulvey L, Barr G, Garratt J, Goodman E, Selman C, Harries LW.
Exp Gerontol. 2019 Sep 12:110736. doi: 10.1016/j.exger.2019.110736. [Epub ahead of print]
PMID: 3152172
Abstract
Dietary restriction (DR) represents one of the most reproducible interventions to extend lifespan and improve health outcomes in a wide range of species, but substantial variability in DR response has been observed, both between and within species. The mechanisms underlying this variation in effect are still not well characterised. Splicing regulatory factors have been implicated in the pathways linked with DR-induced longevity in C. elegans and are associated with lifespan itself in mice and humans. We used qRT-PCR to measure the expression levels of a panel of 20 age- and lifespan-associated splicing regulatory factors in brain, heart and kidney derived from three recombinant inbred strains of mice with variable lifespan responses to short-term (2 months) or long-term (10 months) 40% DR to determine their relationship to DR-induced longevity. We identified 3 patterns of association; i) splicing factors associated with DR alone, ii) splicing factors associated with strain alone or iii) splicing factors associated with both DR and strain. Tissue specific variation was noted in response to short term or long-term DR, with the majority of effects noted in brain following long term DR in the positive responder strain TejJ89. Association in heart and kidney were less evident, and occurred following short term DR. Splicing factors associated with both DR and strain may be mechanistically involved in strain-specific differences in response to DR. We provide here evidence concordant with a role for some splicing factors in the lifespan modulatory effects of DR across different mouse strains and in different tissues.
KEYWORDS:
Dietary restriction; Splicing factors

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Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension.
Yu D, Tomasiewicz JL, Yang SE, Miller BR, Wakai MH, Sherman DS, Cummings NE, Baar EL, Brinkman JA, Syed FA, Lamming DW.
Cell Rep. 2019 Oct 1;29(1):236-248.e3. doi: 10.1016/j.celrep.2019.08.084.
PMID: 31577953
https://www.cell.com/cell-reports/pdf/S2211-1247(19)31146-5.pdf
Abstract
Calorie restriction (CR) extends the healthspan and lifespan of diverse species. In mammals, a broadly conserved metabolic effect of CR is improved insulin sensitivity, which may mediate the beneficial effects of a CR diet. This model has been challenged by the identification of interventions that extend lifespan and healthspan yet promote insulin resistance. These include rapamycin, which extends mouse lifespan yet induces insulin resistance by disrupting mTORC2 (mechanistic target of rapamycin complex 2). Here, we induce insulin resistance by genetically disrupting adipose mTORC2 via tissue-specific deletion of the mTORC2 component Rictor (AQ-RKO). Loss of adipose mTORC2 blunts the metabolic adaptation to CR and prevents whole-body sensitization to insulin. Despite this, AQ-RKO mice subject to CR experience the same increase in fitness and lifespan on a CR diet as wild-type mice. We conclude that the CR-induced improvement in insulin sensitivity is dispensable for the effects of CR on fitness and longevity.
KEYWORDS:
Rictor; adipose; calorie restriction; fitness; frailty; healthspan; insulin sensitivity; lifespan; lipogenesis; mTORC2

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Dietary restriction regimens for fighting kidney disease: Insights from rodent studies.
Singh G, Krishan P.
Exp Gerontol. 2019 Oct 5:110738. doi: 10.1016/j.exger.2019.110738. [Epub ahead of print] Review.
PMID: 31593758
Abstract
This review critically discusses the research findings on the effects of various dietary restriction regimens in rodent models of kidney disease. Long-term caloric restriction executed at both early and progressive stages of kidney disease was found to exert beneficial effects in rodents. Moreover, some studies have also demonstrated the efficacy of short-term caloric restriction in treating the kidney disease of variable aetiologies possibly by improving mitochondrial dysfunction, autophagy process and suppression of inflammation. However, the mechanisms underlying these short-term caloric restriction mediated protective effects in rodent models of kidney disease are not completely understood. Importantly, few available evidences have also suggested that carbohydrate restriction can exert beneficial effects in aging and experimentally induced renal injury models, but the mechanisms are not explored yet. Interestingly, the benefits of low protein diet in kidney disease models are extensively reported in literature. However, in most of these studies implementation of the low protein dietary regimen was found to associated with increased high carbohydrate and caloric intake (non-isocaloric). Thus, testing the effects of low protein diet under isocaloric conditions might further help to particularly understand the role of dietary protein content in pathology of kidney disease. Moreover, the direct evidences comparing the efficacy of various dietary restriction regimens in rodent models of kidney diseases are also scarce at present.
KEYWORDS:
Aging kidney disease; Autophagy; Carbohydrate restriction; Chronic renal failure; Diabetic nephropathy; Diet restriction; Low protein diet; Polycystic kidney disease

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Impact of energy turnover on fat balance in healthy young men during energy balance, caloric restriction and overfeeding.
Nas A, Büsing F, Hägele FA, Hasler M, Müller MJ, Bosy-Westphal A.
Br J Nutr. 2019 Oct 11:1-27. doi: 10.1017/S0007114519002551. [Epub ahead of print]
PMID: 31601285
Abstract
Body weight control is thought to be improved when physical activity and energy intake are both high (high energy turnover). The aim of this study was to investigate the short-term impact of energy turnover (ET) on fat balance during zero energy balance, caloric restriction and overfeeding. In a randomized crossover study, 9 healthy men (BMI: 23.0 ±2.1 kg/m2, 26.6 ±3.5 y) passed 3x3 days in a metabolic chamber: 3 levels of ET (low, medium and high; physical activity level = 1.3-1.4, 1.5-1.6 and 1.7-1.8) were performed at zero energy balance (EB), caloric restriction (CR), and overfeeding (OF) (100%, 75%, 125% of individual energy requirement). Different levels of ET were obtained by walking (4 km/h) on a treadmill (0, 165, 330 min). 24-h macronutrient oxidation and relative macronutrient balance (oxidation relative to intake) were calculated and free fatty acids, 24-h insulin and catecholamine secretion were analyzed as determinants of fat oxidation. During EB and OF, 24-h fat oxidation increased with higher ET. This resulted in a higher relative fat balance at medium ET (EB: +17%, OF: +14%) and high ET (EB: +23%, OF: +17%) compared to low ET (all p<0.05). In contrast, CR led to a stimulation of 24-h fat oxidation irrespective of ET (no differences in relative fat balance between ET levels, p>0.05). In conclusion, under highly controlled conditions a higher energy turnover improved relative fat balance in young healthy men during overfeeding and energy balance compared to a sedentary state.
KEYWORDS:
ClinicalTrials.gov as NCT03361566; energy expenditure; energy turnover; fat oxidation; metabolic chamber; physical activity

The Effectiveness of Intermittent Fasting to Reduce Body Mass Index and Glucose Metabolism: A Systematic Review and Meta-Analysis.
Cho Y, Hong N, Kim KW, Cho SJ, Lee M, Lee YH, Lee YH, Kang ES, Cha BS, Lee BW.
J Clin Med. 2019 Oct 9;8(10). pii: E1645. doi: 10.3390/jcm8101645.
PMID: 31601019
https://www.mdpi.com/2077-0383/8/10/1645/htm
Abstract
The effects of an intermittent fasting diet (IFD) in the general population are still controversial. In this study, we aimed to systematically evaluate the effectiveness of an IFD to reduce body mass index and glucose metabolism in the general population without diabetes mellitus. Cochrane, PubMed, and Embase databases were searched to identify randomized controlled trials and controlled clinical trials that compared an IFD with a regular diet or a continuous calorie restriction diet. The effectiveness of an IFD was estimated by the weighted mean difference (WMD) for several variables associated with glucometabolic parameters including body mass index (BMI) and fasting glucose. The pooled mean differences of outcomes were calculated using a random effects model. From 2814 studies identified through a literature search, we finally selected 12 articles (545 participants). Compared with a control diet, an IFD was associated with a significant decline in BMI (WMD, -0.75 kg/m2; 95% CI, -1.44 to -0.06), fasting glucose level (WMD, -4.16 mg/dL; 95% CI, -6.92 to -1.40), and homeostatic model assessment of insulin resistance (WMD, -0.54; 95% CI, -1.05 to -0.03). Fat mass (WMD, -0.98 kg; 95% CI, -2.32 to 0.36) tended to decrease in the IFD group with a significant increase in adiponectin (WMD, 1008.9 ng/mL; 95% CI, 140.5 to 1877.3) and a decrease in leptin (WMD, -0.51 ng/mL; 95% CI, -0.77 to -0.24) levels. An IFD may provide a significant metabolic benefit by improving glycemic control, insulin resistance, and adipokine concentration with a reduction of BMI in adults.
KEYWORDS:
body mass index; glucose metabolism; insulin resistance; intermittent fasting

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Impact of caloric restriction on peripheral nerve injury-induced neuropathic pain during aging in mice.
De Angelis F, Vacca V, Pavone F, Marinelli S.
Eur J Pain. 2019 Oct 14. doi: 10.1002/ejp.1493. [Epub ahead of print]
PMID: 31610068
Abstract
The incidence of peripheral neuropathy development and chronic pain is strongly associated with the arrival of senescence. The gradual physiological decline that begins after the mature stage produces myelin dysregulation and pathological changes in peripheral nervous system, attributed to reduction in myelin proteins expression and thinner myelin sheath. Moreover in elder subjects, when nerve damage occurs, the regenerative processes are seriously compromised and neuropathic pain (NeP) is maintained. We previously demonstrated that caloric restriction (CR) in adult (4 months) nerve-lesioned mice was able to facilitate remyelination and axons regeneration, to have anti-inflammatory action and to prevent NeP chronification. Here, we show CR therapeutic potential on nerve injury-induced neuropathy in mice at the beginning of the senescence (12 months). Long lasting decrease of hypersensitvity induced by peripheral nerve lesion and powerful reduction of pro-inflammatory circulating agents have been observed. Moreover, our results evidence that CR is able to counteract the aging-related delay in axonal regeneration, enhancing Schwann cells proliferation and accelerating recovery processes. Differently from adults, it does not affect fibres myelination. In light of a continuous growth in elderly population and correlated health problems, including metabolic disorders, the prevalence of neuropathy is enhancing, generating a significant public cost and social concern. In this context energy depletion by dietary restriction can be a therapeutic option in NeP.
KEYWORDS:
Aging; energy depletion; inflammation; nerve damage; nerve regeneration; neuropathic pain

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Gestational caloric restriction with micronutrients supplementation does not delay development and promotes feeding behavior benefits.
Stone V, Maurmann RM, Dal Magro BM, Crestani MS, Hozer RM, Klein CP, Matté C.
Nutr Neurosci. 2019 Oct 14:1-11. doi: 10.1080/1028415X.2019.1676972. [Epub ahead of print]
PMID: 31610769
Abstract
Introduction: Caloric restriction (CR) has been proven to promote a series of health benefits from yeast to primates. Nowadays, increasing rates of obesity certainly encourage researchers to evaluate CR effects and establish it as a therapeutic approach. Maternal obesity is also a concern, and studies in the developmental origins of health and disease (DOHaD) have shown the importance of interventions during pregnancy, especially those involving maternal nutrition. On the other hand, undernutrition during pregnancy leads to increased weight gain, disturbed feeding behavior and dysfunctional metabolism in adulthood. Methods: In this way, we utilized moderate CR (20% compared to control consumption) in pregnant Wistar rats as intervention, with malnutrition control by micronutrients supplementation. We assessed CR effects on offspring's developmental milestones, feeding behavior, exploratory behavior, and memory on adolescence (PND21) and adulthood (PND60). Results: We did not find alterations on litter size or birth weight, although CR pups were leaner at adult ages. Importantly, no delay in development was observed. Besides, female pups showed earlier suction reflex and male pups showed earlier response to the negative geotaxis. CR pups also showed less preference for palatable food (Froot Loops®) at adult age, which could be decisive on obesity tendency. Locomotor activity was increased by CR on PND60 and there was no effect on memory at all. Discussion: Our results on development and behavior demonstrate that gestational CR may be a helpful health strategy if malnutrition is well controlled, with potential clinical impact.
KEYWORDS:
Dietary restriction; behavior; developmental milestone; feeding behavior; intrauterine environment; malnutrition prevention; nutrition; pregnancy

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The Effect of Carbohydrate-Restricted Diets on the Skin Aging of Mice.
Okouchi R, Sakanoi Y, Tsuduki T.
J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S67-S71. doi: 10.3177/jnsv.65.S67.
PMID: 31619650
https://www.jstage.jst.go.jp/article/jnsv/65/Supplement/65_S67/_pdf/-char/en
Abstract
Low-carbohydrate, high-protein diets, known as carbohydrate-restricted diets, are in contrast to the carbohydrate-centric meals typical of the Japanese diet. Carbohydrate-restricted diets were reported to reduce visceral fat, owing to which they have attracted attention and been widely implemented. If, as proposed, carbohydrate-restricted diets are effective in delaying senescence, then Japanese diets have a hidden potential to evolve further. However, long-term carbohydrate restriction in mice was reported to have a negative effect on the cardiovascular system, with shortening of lifespan due to activation of mechanistic target of rapamycin (mTOR). As a result, the safety of long-term adherence to carbohydrate-restricted diets remains doubtful. Recently, we conducted a study using senescence-accelerated mouse-prone 8 (SAMP8) mice to examine the effects of a carbohydrate-restricted diet on aging and skin senescence, and to determine the effect of long-term carbohydrate restriction on the aging process in mice. Here, we discuss the safety of long-term carbohydrate restriction based on the findings obtained from animal studies.
KEYWORDS:
Japanese diet; SAMP8; carbohydrate restriction; senescence; staple food
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Carbohydrate-restricted diet promotes skin senescence in senescence-accelerated prone mice.
Wu Q, E S, Yamamoto K, Tsuduki T.
Biogerontology. 2018 Oct 3. doi: 10.1007/s10522-018-9777-1. [Epub ahead of print]
PMID: 30284122
https://www.crsociety.org/topic/11801-als-papers-citations-and-possibly-links-and-excerpts-or-my-synopses/?page=24&tab=comments#comment-29926

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Exercise training in ad libitum and food-restricted old rats: effects on metabolic and physiological parameters.
Corbianco S, Dini M, Bongioanni P, Carboncini MC, Cavallini G.
Biogerontology. 2019 Oct 22. doi: 10.1007/s10522-019-09844-z. [Epub ahead of print]
PMID: 31641969
https://sci-hub.tw/10.1007/s10522-019-09844-z
Abstract
Aging is accompanied by a decline in the healthy function of multiple organs, leading to increased incidence and mortality from diseases such as cancer and inflammatory, cardiovascular and neurodegenerative diseases. Dietary restriction is the most effective experimental intervention known to consistently slow the aging process and with positive effects on health span in different organisms, from invertebrates to mammals. Age is also associated with progressive decline in physical activity levels in a wide range of animal species: therefore, regular physical exercise could represent a safe intervention to antagonize aging. In this research we explore the effects of exercise training initiated in late middle aged rats fed with different lifelong dietary regimens: one group was fed ad libitum and the second group was subjected to every-other-day fasting. These two groups might represent examples of "normal" aging and "successful" aging. The study shows the effects of exercise and food restriction and their interaction on plasma levels of total antioxidant capacity, lactate, amino acids, and on products of protein oxidation in soleus and tibialis anterior muscles. In addition, we evaluated body composition measurement by bioelectrical impedance analysis and muscle strength by grasping test. Results show that late-onset exercise training has the potential to improve some metabolic and physiological parameters in rats with the same "chronological age" but different "biological age", without negative effects, and highlight the relevance of a personalised and selected exercise protocol, since the responsiveness to exercise may depend on the individual's "biological age".
KEYWORDS:
Aging; Dietary restriction; Exercise; Rat

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A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice.
Lévesque S, Le Naour J, Pietrocola F, Paillet J, Kremer M, Castoldi F, Baracco EE, Wang Y, Vacchelli E, Stoll G, Jolly A, De La Grange P, Zitvogel L, Kroemer G, Pol JG.
Oncoimmunology. 2019 Sep 7;8(11):e1657375. doi: 10.1080/2162402X.2019.1657375. eCollection 2019.
PMID: 31646107
https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2019.1657375?needAccess=true
Abstract
We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8+ T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents.
KEYWORDS:
Caloric restriction mimetics; chemotherapy; combination therapies; immune checkpoint blockers; tumor immune infiltrate

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Caloric restriction, longevity and aging: Recent contributions from human and non-human primate studies.
Pifferi F, Aujard F.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Dec 20;95:109702. doi: 10.1016/j.pnpbp.2019.109702. Epub 2019 Jul 17. Review.
PMID: 31325469
https://sci-hub.tw/10.1016/j.pnpbp.2019.109702
Abstract
The health benefits of chronic caloric restriction (CR) resulting in lifespan extension are well established in many species and has been recently demonstrated also in non-human primates, but its effects in humans remain to be proven on a long-term basis. CR might be a very efficient anti-aging strategy but its definition and limits must be well understood before envisaging to apply it to human. In this review, we first report and compare the recently issued CR studies in non-human primates and humans and then try to understand what an optimal caloric intake is. In a last part, we will discuss the pertinence of using CR as an anti-aging strategy with respect to the risks of frailty and obesity.
KEYWORDS:
Aging; Caloric restriction; Frailty; Healthspan; Lifespan; Obesity

Myostatin dysfunction is associated with lower physical activity and reduced improvements in glucose tolerance in response to caloric restriction in Berlin high mice.
Kvedaras M, Minderis P, Krusnauskas R, Lionikas A, Ratkevicius A.
Exp Gerontol. 2019 Oct 22:110751. doi: 10.1016/j.exger.2019.110751. [Epub ahead of print]
PMID: 31654693
Abstract
Myostatin is an inhibitor of skeletal muscle growth and might be involved in adaptations to caloric restriction (CR). We compared responses to 12-week 30% CR in male mice of Berlin high strain with myostatin dysfunction (BEH) and wild-type myostatin (BEH+/+). BEH mice were heavier than BEH+/+ mice (58.8 ± 2.0 versus 53.1 ± 2.7 g, p < 0.001), had 1.8-fold greater hind limb muscle mass and were less (p < 0.05) physically active when fed ad libitum. After CR, BEH and BEH+/+ strains experienced similar weight loss (24.7 ± 5.7 versus 20.6 ± 6.5%, p > 0.05, respectively) and decreases (p < 0.001) in plasma IGF-1 and total cholesterol, but loss of hind limb muscle mass was greater (p < 0.001) in BEH mice than BEH+/+ mice. BEH mice had better (p < 0.001) glucose tolerance and showed smaller (p < 0.05) improvements of it than BEH+/+ mice after CR (1038.2 ± 174.7 versus 744.4 ± 95.8 glucose mM 120 min-1, p < 0.01 for BEH; 1365.8 ± 218.5 versus 831.5 ± 134.4 glucose mM 120 min-1, p < 0.001, for BEH+/+, respectively). In summary, myostatin dysfunction is associated with muscle hypertrophy and high glucose tolerance, but greater muscle wasting and smaller improvements in glucose tolerance in response to CR.
KEYWORDS:
Caloric restriction; Glucose tolerance; Myostatin, muscle fiber composition; Skeletal muscle

MicroRNA 16-5p is upregulated in calorie-restricted mice and modulates inflammatory cytokines of macrophages.
Yamada K, Takizawa S, Ohgaku Y, Asami T, Furuya K, Yamamoto K, Takahashi F, Hamajima C, Inaba C, Endo K, Matsui R, Kitamura H, Tanaka S.
Gene. 2019 Oct 22:144191. doi: 10.1016/j.gene.2019.144191. [Epub ahead of print]
PMID: 31654705
Abstract
Caloric restriction (CR) has long been known to increase median and maximal lifespans and to decrease mortality and morbidity in short-lived animal models, likely by altering fundamental biological processes that regulate aging and longevity. However, the detailed mechanisms of immunomodulation by CR remain unclear. In this study, we established a mouse model for CR and analyzed the changes of immune cells in these mice. The CR mice fed a calorie-restricted diet for 4 weeks had lower body weight and fat mass compared with control mice. The proportions of CD4+, CD8+, and naïve CD4+ T cells in spleen cells from CR mice were higher than those in of control mice. Additionally, the proportion of CD8+ T cells was significantly decreased and the mRNA expression of proinflammatory cytokines in the colon of CR mice was significantly decreased compared with those of control mice. To determine the effect of CR on microRNA (miRNA) expression, serum and tissues were collected from mice and the expression level of miRNA was analyzed by real-time RT-PCR. As a result, the expressions of miR-16-5p, miR-196b-5p, and miR-218-5p in serum from CR mice were higher than those in control mice. The expression of miR-16-5p increased in the spleen, thymus, colon, and stomach of CR mice compared with expression in control mice. Furthermore, RAW264 cells transfected with a miR-16-5p mimic significantly decreased the mRNA expression of IL-1β, IL-6, and TNF-α under LPS stimulation. These results suggested that miR-16-5p might be a critical factor involving the anti-inflammatory effects of calorie-restricted feeding.
KEYWORDS:
Caloric restriction; cellular immunology; cytokines; macrophages; microRNA

Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control.
Solon-Biet SM, Cogger VC, Pulpitel T, Wahl D, Clark X, Bagley E, Gregoriou GC, Senior AM, Wang QP, Brandon AE, Perks R, O'Sullivan J, Koay YC, Bell-Anderson K, Kebede M, Yau B, Atkinson C, Svineng G, Dodgson T, Wali JA, Piper MDW, Juricic P, Partridge L, Rose AJ, Raubenheimer D, Cooney GJ, Le Couteur DG, Simpson SJ.
Nat Metab. 2019 May;1(5):532-545. doi: 10.1038/s42255-019-0059-2. Epub 2019 Apr 29.
PMID: 31656947
https://sci-hub.tw/10.1038/s42255-019-0059-2
Abstract
Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA per se or hepatic mTOR activation, but rather due to a shift in the relative quantity of dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but, rather, a consequence of hyperphagia driven by AA imbalance.
KEYWORDS:
Nutrition; aging; appetite; branched chain amino acids; dietary balance; dietary restriction; lifespan; metabolic health; obesity; serotonin

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Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects.
Guerra BA, Brandão BB, Pinto SS, Salgueiro WG, De-Souza EA, Reis FCG, Batista TM, Cavalcante-Silva V, D'Almeida V, Castilho BA, Carneiro EM, Antebi A, Festuccia WT, Mori MA.
Mol Metab. 2019 Nov;29:124-135. doi: 10.1016/j.molmet.2019.08.017. Epub 2019 Aug 28.
PMID: 31668384
https://reader.elsevier.com/reader/sd/pii/S2212877819307422?token=12FD7D993B15C7B742AB3EF078EE2AC588BAA6435459E2D157FC7860A0EB6E3D56BB0B0BC1BBA971E530DB2D2A7359D1
Abstract
OBJECTIVE:
Dietary restriction (DR) improves health and prolongs lifespan in part by upregulating type III endoribonuclease DICER in adipose tissue. In this study, we aimed to specifically test which missing dietary component was responsible for DICER upregulation.
METHODS:
We performed a nutrient screen in mouse preadipocytes and validated the results in vivo using different kinds of dietary interventions in wild type or genetically modified mice and worms, also testing the requirement of DICER on the effects of the diets.
RESULTS:
We found that sulfur amino acid restriction (i.e., methionine or cysteine) is sufficient to increase Dicer mRNA expression in preadipocytes. Consistently, while DR increases DICER expression in adipose tissue of mice, this effect is blunted by supplementation of the diet with methionine, cysteine, or casein, but not with a lipid or carbohydrate source. Accordingly, dietary methionine or protein restriction mirrors the effects of DR. These changes are associated with alterations in serum adiponectin. We also found that DICER controls and is controlled by adiponectin. In mice, DICER plays a role in methionine restriction-induced upregulation of Ucp1 in adipose tissue. In C. elegans, DR and a model of methionine restriction also promote DICER expression in the intestine (an analog of the adipose tissue) and prolong lifespan in a DICER-dependent manner.
CONCLUSIONS:
We propose an evolutionary conserved mechanism in which dietary sulfur amino acid restriction upregulates DICER levels in adipose tissue leading to beneficial health effects.
KEYWORDS:
Adipose tissue; Aging; DICER; Dietary restriction; Methionine restriction; miRNAs

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Age-dependent effects of caloric restriction on mTOR and ubiquitin-proteasome pathways in skeletal muscles.
Chen CN, Liao YH, Tsai SC, Thompson LV.
Geroscience. 2019 Nov 1. doi: 10.1007/s11357-019-00109-8. [Epub ahead of print]
PMID: 31676964
https://sci-hub.tw/10.1007/s11357-019-00109-8
Abstract
In skeletal muscles, calorie restriction (CR) preserves muscle mass in middle-aged rats but not younger rats. The underlying mechanisms for this age-specific response are unknown. Skeletal muscle mass depends on several factors, with protein synthesis and degradation playing major roles. Therefore, the purpose of this study was to investigate whether CR affects younger and older animals differently on mTOR signaling and ubiquitin-proteasome pathway (UPP). Four-, 8-, and 16-month-old rats, with or without 40% CR for a duration of 14 weeks, were sacrificed after an overnight fasting. Total protein content and the phosphorylation level of AKT, mTOR, S6K, and 4EBP1 and protein content of key markers in the UPP (FOXO3a, atrogin, MuRF1, ubiquitinated proteins, proteasome subunits alpha 7 and beta 5) were determined. Unlike younger rats, CR decreased the content of phosphorylated mTOR, S6K, phosphorylated S6K, FOXO3a, and ubiquitinated proteins in middle-aged rats. In conclusion, CR-induced reduction of content/ phosphorylation levels of key proteins in mTOR signaling and the UPP occurred in the middle-aged rats but not younger rats. The age-dependent effects of CR on mTOR signaling and the UPP indirectly explained the age-related effects of CR on muscle mass of animals.
KEYWORDS:
Aging; Muscle mass; S6K; Sarcopenia

[Influence of rs670 variant of APOA1 gene on serum HDL response to an enriched-polyunsaturated vs. an enriched-monounsaturated fat hypocaloric diet].
de Luis Román DA, Izaola Jáuregui O, Primo D, Aller R.
Nutr Hosp. 2019 Nov 4. doi: 10.20960/nh.02390. [Epub ahead of print] Spanish.
PMID: 31682461
Abstract
BACKGROUND AND OBJECTIVES:
genetic variants of the APOA1 gene have been related to lipid profile in obese subjects. Our aim was to analyze the effects of the rs670 APOA1 gene polymorphism on metabolic changes secondary to an enriched-polyunsaturated fat vs. an enriched-monounsaturated fat hypocaloric diet.
METHODS:
360 Caucasian obese subjects were randomly allocated to two groups. One group received an enriched-polyunsaturated fat (diet P) and the other an enriched-monounsaturated fat hypocaloric diet (diet M) during 12 weeks. The effects on serum biomarkers related to lipid and carbohydrate metabolism were evaluated before and after the dietary intervention.
RESULTS:
after both diets, body mass index, weight, fat mass, waist circumference, systolic blood pressure, plasma leptin concentration, and waist circumference decreased in all patients. After 12 weeks of intervention with diet P, plasma insulin levels and HOMA-IR decreased in A-allele carriers: delta: -7.3 ± 2.2 IU/L (p = 0.01), and delta: -2.8 ± 0.5 units (p = 0.02), respectively. The same changes in delta were observed after diet M in A-allele carriers: insulin delta: -5.9 ± 1.2 IU/L (p = 0.01), and HOMA-IR delta: -2.1 ± 0.8 units (p = 0.02). In A-allele carriers, LDL-cholesterol decreased and HDL-cholesterol increased after the dietary intervention with diet P: delta: -12.1 ± 4.3 mg/dL (p = 0.01), and delta: 2.6 ± 0.7 mg/dL (p = 0.01), respectively. No differences in lipid profile were observed after diet M. These improvements were not observed in non-A-allele carriers after both interventions.
CONCLUSIONS:
our study showed the association of the rs670 ApoA1 polymorphism with insulin resistance changes as induced by both diets. An enriched-polyunsaturated fat diet produced an additional improvement of HDL-cholesterol and LDL-cholesterol in A-allele carriers.

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Effects of Two Types of Calorie Restriction on Methylation Levels of Adiponectin Receptor 1 (AdipoR1) and Leptin Receptor Overlapping Transcript (Leprot) in a MMTV-TGF-α Breast Cancer Mouse Model.
Cicekdal MB, Kazan BT, Tuna BG, Ozorhan U, Ekici ID, Zhu F, Suakar O, Kuskucu A, Bayrak OF, Arcaro K, Cleary MP, Dogan S.
Br J Nutr. 2019 Nov 5:1-23. doi: 10.1017/S0007114519002757. [Epub ahead of print]
PMID: 31685042
https://www.cambridge.org/core/services/aop-cambridge-core/content/view/C215E2A4605BEA1E839749FFE1611972/S0007114519002757a.pdf/div-class-title-effects-of-two-types-of-calorie-restriction-on-methylation-levels-of-adiponectin-receptor-1-span-class-italic-adipor1-span-and-leptin-receptor-overlapping-transcript-span-class-italic-leprot-span-in-a-mmtv-tgf-breast-cancer-mouse-model-div.pdf
Abstract
The role of adiponectin and leptin signaling pathways was suggested to play important roles in the protective effects of calorie restriction (CR) on mammary tumor (MT) development. To study the effects of CR on the methylation levels in AdipoR1 and Leprot genes using pyrosequencing method in mammary fat pad (MFP) tissue, mouse mammary tumor virus-transforming growth factor-alpha (MMTV-TGF-α) female mice were randomly assigned to ad libitum (AL), Chronic CR (CCR, 15% CR) or Intermittent CR (ICR, three weeks ALand one week 60% CR in cyclic periods) groups at 10 weeks of age until 82 weeks of age.The methylation levels of AdipoR1 in CCRgroupwas higher than in AL groupat week 49/50 (p<0.05), while the levels of methylation for AdipoR1 and Leprot genes were similar among the other groups. Also, the methylation levels at CpG2 and CpG3 regions of the promoter region of AdipoR1 gene in the CCR group were three times higher (p<0.05), while CpG1 island of Leprot methylation was significantlylowercompared to the other groups (p<0.05).Adiponectin and Leptin gene expression levels were consistent with the methylation levels. We also observed a change with the ageing in methylation levels of these genes.These results indicate that different types of CR modifymethylation levels of AdipoR1 andLeprotin different ways andCCR had a more significant effect on methylation levels of both genes.Epigenetic regulation of these genes may play important roles in the preventive effects of CR against MT development and ageing processes.

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Caloric restriction modulates the monoaminergic and glutamatergic systems in the hippocampus, and attenuates age-dependent spatial memory decline.
Rojic-Becker D, Portero-Tresserra M, Martí-Nicolovius M, Vale-Martínez A, Guillazo-Blanch G.
Neurobiol Learn Mem. 2019 Nov 6:107107. doi: 10.1016/j.nlm.2019.107107. [Epub ahead of print]
PMID: 31705980
Abstract
The beneficial effects of caloric restriction (CR) on health and life expectancy are well documented, although its ability to slow down age-dependent cognitive decline and the underlying biochemical changes remains unclear. Therefore, the aim of this study was to investigate the effects of CR on spatial memory in aged Wistar rats, as well as on monoaminergic and glutamatergic neurotransmission in the hippocampus (HPC). As such, animals maintained on different dietary regimes were trained in the Morris Water Maze (MWM): old rats (24-27 months) maintained on a 30% CR diet from four months of age, old rats (24-27 months) with unrestricted access to food (Ad Libitum); and adult rats (3-4 months) with Ad Libitum access to food. As well as their performance in the spatial memory task, monoamine levels, and NMDA and AMPA receptor subunit expression in the HPC were also assessed in these rats, as was the plasma corticosterone as a measure of the pituitary-adrenal response to stress. Accordingly, it appears that CR attenuates the spatial memory decline in aged rats and the age-associated decrease in the serotonin metabolite 5-HIAA, as well as the expression of the GluA1 and GluA2 AMPA receptor subunits in the HPC. In addition, CR augments the noradrenaline in this structure, although it did not modify the age-associated increase in plasma corticosterone levels. These findings support the positive effect of CR on spatial memory, suggesting that enhancing monoaminergic and glutamatergic neurotransmission in the HPC may help improve learning and memory in aged animals.
KEYWORDS:
Aging; Morris water maze; corticosterone; dietary intervention; glutamatergic receptors; monoamines metabolites

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Dietary restriction in old age does not extend life.
Kriebs A.
Nat Rev Endocrinol. 2019 Nov 13. doi: 10.1038/s41574-019-0295-2. [Epub ahead of print] No abstract available.
PMID: 31723228
https://sci-hub.tw/10.1038/s41574-019-0295-2
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The diet and the damage done
Stephen J. Simpson & David G. Le Couteur 
Nature Metabolism volume 1, pages1030–1031(2019) doi:s42255-019-0121-0
Lifespan is increased and ageing is delayed by lifelong dietary restriction. A study in Nature Metabolism shows that these benefits are reduced when dietary restriction is started in old age, owing to the development of an inflexible nutritional memory within white adipose tissue.
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A nutritional memory effect counteracts the benefits of dietary restriction in old mice
Oliver Hahn, Lisa F. Drews, An Nguyen, Takashi Tatsuta, Lisonia Gkioni, Oliver Hendrich, Qifeng Zhang, Thomas Langer, Scott Pletcher, Michael J. O. Wakelam, Andreas Beyer, Sebastian Grönke & Linda Partridge 
Nature Metabolism volume 1, pages 1059–1073 (2019)
Abstract
Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at old age remains elusive. Here, we report results of a late-life DR-switch experiment using 800 mice. Female mice aged 24 months were switched from an ad libitum (AL) diet to DR or vice versa. Strikingly, the switch from DR to AL acutely increases mortality, whereas the switch from AL to DR causes only a weak and gradual increase in survival, suggesting the body has a memory of earlier nutrition. RNA sequencing in liver and brown and white adipose tissue (BAT and WAT, respectively) demonstrates a largely refractory transcriptional and metabolic response in fat tissue to DR after an AL diet, particularly in WAT, and a proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Our results provide evidence for a ‘nutritional memory’ as a limiting factor for DR-induced longevity and metabolic remodelling of WAT in mammals.

Effect of Systemic Inflammation on Rat Attentional Function and Neuroinflammation: Possible Protective Role for Food Restriction.
Yegla B, Foster T.
Front Aging Neurosci. 2019 Oct 25;11:296. doi: 10.3389/fnagi.2019.00296. eCollection 2019.
PMID: 31708767
Abstract
Background: Aging is characterized by subtle cognitive decline, which correlates with increased peripheral inflammation. Acute activation of the peripheral immune system, via lipopolysaccharide (LPS) injection, elicits deficits in hippocampal-dependent spatial memory. Little is known concerning the effect of chronic inflammation on prefrontal cortex (PFC)-dependent vigilance. We examined the impact of repeated LPS injections in young and middle-age rats on the 5-choice serial reaction time task (5-CSRTT), expecting repeated LPS treatment to induce attentional deficits with greater disruption in middle-age. Methods: Male Fischer-344 rats, 4- and 12-months-old, were food restricted and trained on the 5-CSRTT. Once rats reached criterion, they were injected with LPS (1 mg/kg, i.p.) weekly for 4 weeks and testing started 48 h after each injection. To examine the possibility that mild food restriction inherent to the behavioral task influenced inflammation markers, a second group of food-restricted or ad-lib-fed rats was assessed for cytokine changes 48 h after one injection. Results: Performing LPS-treated rats exhibited a sickness response, manifesting as reduced initiated and completed trials during the first week but recovered by the second week of testing. After the first week, LPS-treated rats continued to exhibit longer response latencies, despite no change in food retrieval latency, suggestive of LPS-induced cognitive slowing. Similarly, LPS-induced impairment of attention was observed as increased omissions with heightened cognitive demand and increased age. Repeated LPS-treatment increased the level of PFC IL-1α, and PFC IL-6 was marginally higher in middle-age rats. No effect of age or treatment was observed for plasma cytokines in performing rats. Histological examination of microglia indicated increased colocalization of Iba1+ and CD68+ cells from middle-age relative to young rats. Examination of food restriction demonstrated an attenuation of age- and LPS-related increases in plasma cytokine levels. Conclusions: Systemic inflammation, induced through LPS treatment, impaired attentional function, which was independent of sickness and exacerbated by increased cognitive demand and increased age. Additional studies revealed that food restriction, associated with the task, attenuated markers of neuroinflammation and plasma cytokines. The results emphasize the need for improved methods for modeling low-level chronic systemic inflammation to effectively examine its impact on attention during aging.
KEYWORDS:
aging; attention; caloric restriction; lipopolysaccharide; systemic inflammation

Caloric restriction maintains stem cells through niche and regulates stem cell aging.
Maharajan N, Vijayakumar K, Jang CH, Cho GW.
J Mol Med (Berl). 2019 Nov 12. doi: 10.1007/s00109-019-01846-1. [Epub ahead of print] Review.
PMID: 31713638
https://sci-hub.tw/10.1007/s00109-019-01846-1
Abstract
The functional loss of adult stem cells is a major cause of aging and age-related diseases. Changes in the stem cell niche, increased energy metabolic rate, and accumulation of cell damage severely affect the function and regenerative capacity of stem cells. Reducing the cellular damage and maintaining a pristine stem cell niche by regulating the energy metabolic pathways could be ideal for the proper functioning of stem cells and tissue homeostasis. Numerous studies point out that caloric restriction (CR) has beneficiary effects on stem cell maintenance and tissue regeneration. Recent researches indicate the preventive nature of calorie restriction in stem cells by modulating the stem cell niche through the reduction of energy metabolism and eventually decrease stem cell damage. In this review, we have focused on the general stimuli of stem cell aging, particularly the energy metabolism as an intrinsic influence and stem cell niche as an extrinsic influence in different adult stem cells. Further, we discussed the mechanism behind CR in different adult stem cells and their niche. Finally, we conclude on how CR can enhance the stem cell function and tissue homeostasis through the stem cells niche.
KEYWORDS:
Aging; Caloric restriction; Energy metabolism; Longevity; Stem cell niche; Stem cells

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Protein Quantity and Source, Fasting-Mimicking Diets, and Longevity.
Brandhorst S, Longo VD.
Adv Nutr. 2019 Nov 1;10(Supplement_4):S340-S350. doi: 10.1093/advances/nmz079.
PMID: 31728501
https://watermark.silverchair.com/nmz079.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAnwwggJ4BgkqhkiG9w0BBwagggJpMIICZQIBADCCAl4GCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMps5khtXw3tCoJlxzAgEQgIICLxhKUFunrZg7cDkKKq3LMq_F0WUA9XA3Hvj8x2J9Qi-eDga0wlQUhWbbxwr3fCnxkeLm6a9gBSwdoGX6E-um8G7Erw7BcBZpuLC-XFCCIyz1eUTzfEVeZ7LZh_CMLewHhzaJwIU7naiIQ77eazQeBH1Z1gnxU75BLeRNWpg_fAdFCFrXJrnxAAHvv0tB1BgHJeIAX5FeLEFXySM-MBgQ8CfUjvhskZjdxxRvmWSAb5rz-_GEB6T5IGj6IuftEFT0R7hR0yeFcjE1EkVgSgWIcGe3VjnCSX0SLXX43rGJux5tTfNxeD687QQuIFT0i7Gikopbb3npTj0BeoA9cREddgr6NA434CIDZq_mRiklUVMA86o_g8kI-gKsSO6Tb9Km7kZNccmsbfwIEuqpKCAXpylfOBvKmcNEWoptnnbEhnHttAsqa6OeoVwzcs50PO5Kg_YZxPwx2fddcgztDvE_8xTqv2h_DDo5-xe-2WbM3BLi5RMOnKngp-mYnQoWQBxfjSOeFA21bTXstK-cYL4HMeAzmAq3GeDasg8xwpe37JxTxmKiWOlkMrVUEaWdvZJT91qTQTfxquoLDFA61akB6cNS5uvuiK8qUGcTU7gUmkK-CF_9YqOLt8jxFJn_EZFHtM2osl24pR3YlQM4cwU8Lfo3Ua0TevE2fmnq4ZKpeHOZA1lFbRkbZms2s06-zuYi6z_N_7TWj1Krgt1t2S4iJVxs0MKxW6nkJrodFjafRC4
Abstract
Dietary modifications, including caloric restriction, dietary restriction, various intervals of fasting, and even limiting the time when food is consumed can have a pronounced impact on longevity. In addition, dietary modifications are powerful interventions to delay, prevent, or treat many aging-related diseases such as cancer and diabetes. Restricting amino acid and protein intake generally decreases aging-related comorbidities and thereby increases health and longevity. However, chronic dietary interventions are likely not feasible for most people due to low adherence to dietary protocols or resistance to drastic changes to lifestyle, and might even cause detrimental effects, possibly by negatively affecting the immune system and wound healing. The periodic use of low-protein, low-calorie fasting-mimicking diets (FMDs) has the potential to promote health benefits, while minimizing the burden of chronic restriction. Protein restriction and FMDs together have the potential to play an important complementary role in medicine by promoting disease prevention and treatment, and by delaying the aging process at least in part by stimulating stem cell-based regeneration in periods of normal food intake after periodic FMD cycles. The aim of this narrative review is to summarize research on the impact of protein restriction on health and longevity in model organisms and to discuss the implementation of an FMD in mice and in human clinical trials and its effects on biomarkers of healthy aging. Taking into account the importance of sex on aging and diet, we include this information in all discussed studies. Whereas for some model organisms of aging, such as rodents, many studies are available, results are more limited for primates and/or humans.
KEYWORDS:
fasting-mimicking diet; healthspan; longevity; protein intake; protein source

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Influence of sleep restriction on weight loss outcomes associated with caloric restriction.
Wang X, Sparks JR, Bowyer KP, Youngstedt SD.
Sleep. 2018 May 1;41(5). doi: 10.1093/sleep/zsy027.
PMID: 29438540
Abstract
STUDY OBJECTIVES:
To examine the effects of moderate sleep restriction (SR) on body weight, body composition, and metabolic variables in individuals undergoing caloric restriction (CR).
METHODS:
Overweight or obese adults were randomized to an 8 week caloric restriction (CR) regimen alone (n = 15) or combined with sleep restriction (CR + SR) (n = 21). All participants were instructed to restrict daily calorie intake to 95 per cent of their measured resting metabolic rate. Participants in the CR + SR group were also instructed to reduce time in bed on five nights and to sleep ad libitum on the other two nights each week.
RESULTS:
The CR + SR group reduced sleep by 57 ± 36 min per day during SR days and increased sleep by 59 ± 38 min per day during ad libitum sleep days, resulting in a sleep reduction of 169 ± 75 min per week. The CR and CR + SR groups lost similar amounts of weight, lean mass, and fat mass. However, the proportion of total mass lost as fat was significantly greater (p = 0.016) in the CR group. This proportion was greater than body fat percentage at baseline for the CR (p = 0.0035), but not the CR + SR group. Resting respiratory quotient was reduced (p = 0.033) only in CR, and fasting leptin concentration was reduced only in CR + SR (p = 0.029).
CONCLUSIONS:
Approximately 1 hr of SR on five nights a week led to less proportion of fat mass loss in individuals undergoing hypocaloric weight loss, despite similar weight loss. SR may adversely affect changes in body composition and "catch-up" sleep may not completely reverse it.

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Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration.
Zivanovic J, Kouroussis E, Kohl JB, Adhikari B, Bursac B, Schott-Roux S, Petrovic D, Miljkovic JL, Thomas-Lopez D, Jung Y, Miler M, Mitchell S, Milosevic V, Gomes JE, Benhar M, Gonzales-Zorn B, Ivanovic-Burmazovic I, Torregrossa R, Mitchell JR, Whiteman M, Schwarz G, Snyder SH, Paul BD, Carroll KS, Filipovic MR.
Cell Metab. 2019 Nov 13. pii: S1550-4131(19)30562-5. doi: 10.1016/j.cmet.2019.10.007. [Epub ahead of print]
PMID: 31735592
https://sci-hub.tw/10.1016/j.cmet.2019.10.007
Abstract
Life on Earth emerged in a hydrogen sulfide (H2S)-rich environment eons ago and with it protein persulfidation mediated by H2S evolved as a signaling mechanism. Protein persulfidation (S-sulfhydration) is a post-translational modification of reactive cysteine residues, which modulate protein structure and/or function. Persulfides are difficult to label and study due to their reactivity and similarity with cysteine. Here, we report a facile strategy for chemoselective persulfide bioconjugation using dimedone-based probes, to achieve highly selective, rapid, and robust persulfide labeling in biological samples with broad utility. Using this method, we show persulfidation is an evolutionarily conserved modification and waves of persulfidation are employed by cells to resolve sulfenylation and prevent irreversible cysteine overoxidation preserving protein function. We report an age-associated decline in persulfidation that is conserved across evolutionary boundaries. Accordingly, dietary or pharmacological interventions to increase persulfidation associate with increased longevity and improved capacity to cope with stress stimuli.
KEYWORDS:
aging; calorie restriction; hydrogen peroxide; hydrogen sulfide; protein persulfidation; redox signaling; sulfenylation; sulfinylation; sulfonylation
"Lifespan Extension by Dietary Restriction Is Caused by
Increased Protein Persulfidation"

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