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Deletion of Nrip1 Extends Female Mice Longevity, Increases Autophagy, and Delays Cell Senescence.

Wang J, Chen X, Osland J, Gerber SJ, Luan C, Delfino K, Goodwin L, Yuan R.

J Gerontol A Biol Sci Med Sci. 2018 Jun 14;73(7):882-892. doi: 10.1093/gerona/glx257.

PMID: 2934651

Abstract

Using age of female sexual maturation as a biomarker, we previously identified nuclear receptor interacting protein 1 (Nrip1) as a candidate gene that may regulate aging and longevity. In the current report, we found that the deletion of Nrip1 can significantly extend longevity of female mice (log-rank test, p = .0004). We also found that Nrip1 expression is altered differently in various tissues during aging and under diet restriction. Remarkably, Nrip1 expression is elevated with aging in visceral white adipose tissue (WAT), but significantly reduced after 4 months of diet restriction. However, in gastrocnemius muscle, Nrip1 expression is significantly upregulated after the diet restriction. In mouse embryonic fibroblasts, we found that the deletion of Nrip1 can suppress fibroblast proliferation, enhance autophagy under normal culture or amino acid starvation conditions, as well as delay oxidative and replicative senescence. Importantly, in WAT of old animals, the deletion of the Nrip could significantly upregulate autophagy and reduce the number of senescent cells. These results suggest that deleting Nrip1 can extend female longevity, but tissue-specific deletion may have varying effects on health span. The deletion of Nrip1 in WAT may delay senescence in WAT and extend health span.

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Caloric restriction counteracts chemotherapy-induced inflammation and increases response to therapy in a triple negative breast cancer model.

Simone BA, Palagani A, Strickland K, Ko K, Jin L, Lim MK, Dan TD, Sarich M, Monti DA, Cristofanilli M, Simone NL.

Cell Cycle. 2018 Jun 18. doi: 10.1080/15384101.2018.1471314. [Epub ahead of print]

PMID: 29912618

Abstract

Triple negative breast cancer (TNBC) is a heterogeneous disease that has no available targeted therapies. Previously, we have shown that caloric restriction (CR) can augment the effects of radiation therapy in a TNBC mouse model. To build upon this, we now present data regarding the combination of chemotherapy and CR in the same 4T1 model. Chemotherapy can induce inflammation that breeds resistance to therapy. We propose CR as a mechanism to decrease chemotherapy-induced inflammation and increase efficacy of therapy. 12-week old Balb/c mice were orthotopically injected with a syngeneic triple negative breast cancer cell line (4T1) and were treated in one of six cohorts: ad lib fed (AL), 30% reduction in calorie intake (CR), cisplatin or docetaxol alone or a combination CR+cisplatin/docetaxol. Mice in the cohorts receiving chemotherapy+CR had longer overall survival (12 +/- 2 days) as compared to the AL group. These mice also demonstrated less lung metastases at the final time point of in vivo imaging. In addition, downregulation of the IGF-1R and IRS signaling pathways were noted most significantly in those mice receiving combination therapy. Lastly, serum from these mice demonstrated an increase in inflammatory cytokines TNF-a and IL-1B in response to chemotherapy alone. This increase was dampened by the addition of CR. Taken together, these data suggest that while chemotherapy is effective in TNBC, it can cause inflammation, which can be a driver of resistance to therapy. This chemotherapy-induced inflammation can be reversed with the use of CR as a nontoxic adjunct to treatment.

KEYWORDS:

Diet; adipokines; breast cancer; chemotherapy; inflammation

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Age, calorie restriction, and age of calorie restriction onset reduce maturation of natural killer cells in C57Bl/6 mice.

Duriancik DM, Tippett JJ, Morris JL, Roman BE, Gardner EM.

Nutr Res. 2018 Jul;55:81-93. doi: 10.1016/j.nutres.2018.04.009. Epub 2018 Apr 21.

PMID: 29914631

Abstract

Calorie restriction (CR), also known as energy restriction, has been shown to have a deleterious impact on both adult and aged mouse survival during influenza virus infection. Natural killer (NK) cell phenotypic differences contribute to increased susceptibility of adult CR mice. We hypothesized NK cell phenotype from adult and aged C57Bl/6 mice fed NIH-31 diet ad libitum (AL) would be different from NK cell phenotype from adult and aged mice fed NIH-31/NIA fortified diet at 40% CR. We hypothesized NK cell phenotype from mice consuming 40% CR initiated at 20 months of age would not be different from 40% CR initiated at 3 months of age. We initiated the 40% restriction either at the standard 12 weeks of age or at 78 weeks of age. NK cells were isolated and quantified from various tissues using flow cytometry. Aged CR mice had significantly reduced levels of terminally mature (CD27-CD11b+) NK cells, increased expression of the immature marker CD127, and decreased expression of the mature marker DX5. Total number of NK cells among cells was significantly lower in the lung and spleen of old-onset aged CR mice compared to aged AL mice, while there was no significant difference between young-onset aged CR and aged AL mice. Old-onset aged CR mice had significantly less early mature (DX5+ and CD27+CD11b+) NK cells compared to young-onset aged CR and aged AL fed mice. Overall, we found that CR in aged mice is detrimental to maturation of NK cells, which is exacerbated when CR is initiated in old age.

KEYWORDS:

Aging; Calorie restriction; Cell maturation; Mice; Natural killer cell

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Carnitine acetyltransferase (Crat) in hunger-sensing AgRP neurons permits adaptation to calorie restriction.

Reichenbach A, Stark R, Mequinion M, Lockie SH, Lemus MB, Mynatt RL, Luquet S, Andrews ZB.

FASEB J. 2018 Jun 22:fj201800634R. doi: 10.1096/fj.201800634R. [Epub ahead of print]

PMID: 29932868

Abstract

Hunger-sensing agouti-related peptide (AgRP) neurons ensure survival by adapting metabolism and behavior to low caloric environments. This adaption is accomplished by consolidating food intake, suppressing energy expenditure, and maximizing fat storage (nutrient partitioning) for energy preservation. The intracellular mechanisms responsible are unknown. Here we report that AgRP carnitine acetyltransferase (Crat) knockout (KO) mice exhibited increased fatty acid utilization and greater fat loss after 9 d of calorie restriction (CR). No differences were seen in mice with ad libitum food intake. Eleven days ad libitum feeding after CR resulted in greater food intake, rebound weight gain, and adiposity in AgRP Crat KO mice compared with wild-type controls, as KO mice act to restore pre-CR fat mass. Collectively, this study highlights the importance of Crat in AgRP neurons to regulate nutrient partitioning and fat mass during chronically reduced caloric intake. The increased food intake, body weight gain, and adiposity in KO mice after CR also highlights the detrimental and persistent metabolic consequence of impaired substrate utilization associated with CR. This finding may have significant implications for postdieting weight management in patients with metabolic diseases.

KEYWORDS:

RER; body composition; feeding behavior; metabolic flexibility; rebound weight gain

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Glucose-Induced Transcriptional Hysteresis: Role in Obesity, Metabolic Memory, Diabetes, and Aging.

Mobbs CV.

Front Endocrinol (Lausanne). 2018 May 28;9:232. doi: 10.3389/fendo.2018.00232. eCollection 2018. Review.

PMID: 29892261 Free PMC Article

Abstract

During differentiation transient, inducers produce permanent changes in gene expression. A similar phenomenon, transcriptional hysteresis, produced by transient or prolonged exposure to glucose, leads to cumulative, persistent, and largely irreversible effects on glucose-regulated gene expression, and may drive key aspects of metabolic memory, obesity, diabetes, and aging, and explain the protective effects of dietary restriction during aging. The most relevant effects of glucose-induced transcriptional hysteresis are the persistent effects of elevated glucose on genes that control glucose metabolism itself. A key observation is that, as with the lac operon, glucose induces genes that promote glycolysis and inhibits gene expression of alternative metabolic pathways including the pentose pathway, beta oxidation, and the TCA cycle. A similar pattern of metabolic gene expression is observed during aging, suggesting that cumulative exposure to glucose during aging produces this metabolic shift. Conversely, dietary restriction, which increases lifespan and delays age-related impairments, produces the opposite metabolic profile, leading to a shift away from glycolysis and toward the use of alternative substrates, including lipid and ketone metabolisms. The effect of glucose on gene expression leads to a positive feedback loop that leads to metastable persistent expression of genes that promote glycolysis and inhibit alternative pathways, a phenomenon first observed in the regulation of the lac operon. On the other hand, this pattern of gene expression can also be inhibited by activation of peroxisome proliferator activating receptor transcription factors that promote beta oxidation and inhibit metabolism of glucose-derived carbon bonds in the TCA cycle. Several pathological consequences may arise from glucose-induced transcriptional hysteresis. First, elevated glucose induces glycolytic genes in pancreatic beta cells, which induces a semi-stable persistent increase in insulin secretion, which could drive obesity and insulin resistance, and also due to glucose toxicity could eventually lead to beta-cell decompensation and diabetes. Diabetic complications persist even after complete normalization of glucose, a phenomenon known as metabolic memory. This too can be explained by persistent bistable expression of glucose-induced glycolytic genes.

KEYWORDS:

aging; diabetes; glucose; metabolic memory; obesity; transcriptional hysteresis

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Food anticipatory activity on a calorie-restricted diet is independent of Sirt1.

Assali DR, Hsu CT, Gunapala KM, Aguayo A, McBurney M, Steele AD.

PLoS One. 2018 Jun 25;13(6):e0199586. doi: 10.1371/journal.pone.0199586. eCollection 2018.

PMID: 29940007

http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0199586&type=printable

Abstract

A number of studies have demonstrated that the Sirtuin family member, Sirt1, is a key integrator of growth, metabolism, and lifespan. Sirt1 directly interacts with and deacetylates key regulators of the circadian clock, positioning it to be an important link between feeding and circadian rhythms. In fact, one study suggests that Sirt1 is necessary for behavioral anticipation of limited daily food availability, a circadian process termed food anticipatory activity (FAA). In their study, mice overexpressing Sirt1 had enhanced FAA, while mice lacking Sirt1 had little to no FAA. Based on the supposition that Sirt1 was indeed required for FAA, we sought to use Sirt1 deletion to map the neural circuitry responsible for FAA. We began by inactivating Sirt1 using the cell-type specific Cre-driver lines proopiomelanocortin, but after observing no effect on body weight loss or FAA we then moved on to more broadly neuronal Cre drivers Ca2+/calmodulin-dependent protein kinase II and nestin. As neither of these neuronal deletions of Sirt1 had impaired FAA, we then tested 1) a broad postnatal tamoxifen-inducible deletion, 2) a complete, developmental knockout of Sirt1, and 3) a gene replacement, catalytically inactive, form of Sirt1; but all of these mice had FAA similar to controls. Therefore, our findings suggest that FAA is completely independent of Sirt1.

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Role of dietary amino acid balance in diet restriction-mediated lifespan extension, renoprotection, and muscle weakness in aged mice.

Yoshida S, Yamahara K, Kume S, Koya D, Yasuda-Yamahara M, Takeda N, Osawa N, Chin-Kanasaki M, Adachi Y, Nagao K, Maegawa H, Araki SI.

Aging Cell. 2018 Jun 25:e12796. doi: 10.1111/acel.12796. [Epub ahead of print]

PMID: 29943496

https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.12796

Abstract

Extending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)-induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age-related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age-dependent decrease in slow-twitch muscle fiber function but reduced absolute fast-twitch muscle fiber function. DR-induced fast-twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum-fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H2 S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet-restricted aged mice, which were accompanied by a recovery in H2 S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans-sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging.

KEYWORDS:

H2S; amino acids; diet restriction; kidney aging; methionine; trans-sulfuration pathway

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Effect of the rs1862513 variant of resistin gene on insulin resistance and resistin levels after two hypocaloric diets with different fat distribution in subjects with obesity.

de Luis DA, Izaola O, Primo D, Aller R.

Eur Rev Med Pharmacol Sci. 2018 Jun;22(12):3865-3872. doi: 10.26355/eurrev_201806_15271.

PMID: 29949162

Abstract

OBJECTIVE:

Polymorphisms of a single nucleotide in resistin gene (RETN) have been associated with insulin resistance. We decide to investigate the role of this polymorphism on insulin resistance and resistin levels after two hypocaloric diets.

PATIENTS AND METHODS:

A sample of 361 obese non-diabetic Caucasian was enrolled. Biochemical evaluation and anthropometric data were measured at the start of the trial and repeated after 3 months of both diets (Diet P, Polyunsaturated vs. diet M, Monounsaturated).

RESULTS:

With both diets and in both genotype groups, BMI, weight, fat mass, waist circumference, systolic blood pressure, and diastolic blood pressure decreased. After diet P, insulin levels (GG vs. GC+CC genotypes) (-1.2±3.8 UI/L vs. -0.7±2.1 UI/L; p<0.05), HOMA-IR (-0.6±1.0 units vs. -0.4±0.9 units; p<0.05), total cholesterol (-10.5±20.1 mg/dl vs. -6.1±15.1 mg/dl; p<0.05) and LDL-total cholesterol (-8.6±10.1 mg/dl vs. -2.2±9.1 mg/dl; p<0.05) decreased in subjects with GG genotype. After diet M, insulin levels (-1.8±2.1 UI/L vs. -0.6±3.0 UI/L: p>0.05), HOMA-IR (-0.5±1.0 units vs. -0.3±1.1 units: p>0.05), total cholesterol (-9.5±13.1 mg/dl vs. -4.4±8.1 mg/dl; p<0.05) and LDL-total cholesterol (-8.1±6.1 mg/dl vs. -2.9±9.1 mg/dl; p<0.05) decreased, too.

CONCLUSIONS:

We suggest that GG genotype of RETN rs1862513 could be a predictor of the reduction of HOMA-IR, insulin, and LDL cholesterol secondary to two hypocaloric diet in obese subjects.

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Preconditioning with partial caloric restriction confers long-term protection against grey and white matter injury after transient focal ischemia.

Zhang J, Zhang W, Gao X, Zhao Y, Chen D, Xu N, Pu H, Stetler RA, Gao Y.

J Cereb Blood Flow Metab. 2018 Jan 1:271678X18785480. doi: 10.1177/0271678X18785480. [Epub ahead of print]

PMID: 29972653

Abstract

Caloric restriction (CR) has been extensively examined as a preventative strategy against aging and various diseases, but CR effects on cerebral ischemia are largely unknown. We subjected C57BL6/J mice to ad libitum food access (LF) or a diet restricted to 70% of ad libitum food access (RF) for two to four weeks followed by 60 min of transient focal ischemia (tFCI). RF for four weeks protected against subsequent tFCI-induced infarct. RF improved sensorimotor function after stroke in the foot fault and corner tests, as well as performance in the Morris water maze test. In addition, RF preserved ischemic white matter tract integrity assessed by histology and compound action potential. Sirt1 and Sirt3 were both upregulated in RF ischemic brain, but heterozygous deletion of Sirt1 or knockout of Sirt3 did not alter the protection induced by RF against ischemic injury. RF induced significant release of adiponectin, a hormone related to glucose metabolism. Knockout of adiponectin decreased RF-induced protection after tFCI. These data demonstrate the novel finding that white matter, as well as neurons, benefit from CR prior to cerebral ischemic injury, and that adiponectin may contribute to these protective effects.

KEYWORDS:

Adiponectin; caloric restriction; cerebral ischemia; sirtuin; stroke

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The effects of dietary restriction and administration of β-glucan from Euglena gracilis on the sperm characteristics and reproductive organs of rats.

Ak Sonat F, Alcay S, Toker MB, Peker S, Ustuner B.

Andrologia. 2018 Jul 10:e13088. doi: 10.1111/and.13088. [Epub ahead of print]

PMID: 29987855

https://sci-hub.tw/

Abstract

The aim of this study was to demonstrate the possible individual and/or synergistic effects of β-glucan and dietary restrictions on the reproductive parameters of rats. For this purpose, forty male Sprague-Dawley rats were randomly divided into four equal groups (n = 10 per group). The first group was the control, the second group was kept under dietary restriction (DR), the third group was kept under a dietary restriction and given β-glucan (DR + βG) and the fourth group was supplemented only with β-glucan (βG; 20 mg/kg) intragastrically for 14 days. Motility, vitality and morphology of spermatozoa, reproductive organ weights (testis, vesicula seminalis and epididymis) and seminiferous tubule diameters were evaluated in experimental rats. β-glucan had excellent effects on motility, live spermatozoa rate and the acrosome integrity when compared to the control group (p < 0.05). We also observed that β-glucan administration to rats having dietary restriction could improve sperm motility and acrosome integrity (p < 0.05). While the β-glucan improved seminiferous tubule diameter (p < 0.05), weights of the reproductive organs did not change positively as a result. This study demonstrated that β-glucan treatment significantly improved some spermatological characteristics in rats. Therefore, treatment with β-glucan could be used for its positive effects on motility, spermatozoa vitality rate and acrosome integrity for infertile men.

KEYWORDS:

dietary restriction; rat; spermatozoa; testis; β-glucan

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Involvement of autophagy in the beneficial effects of resveratrol in hepatic steatosis treatment. A comparison with energy restriction.

Milton-Laskibar I, Aguirre L, Etxeberria U, Milagro FI, Martínez JA, Portillo MP.

Food Funct. 2018 Jul 11. doi: 10.1039/c8fo00930a. [Epub ahead of print]

PMID: 29993072

Abstract

Autophagy eliminates damaged cellular components. In the liver, it has been proposed that it mediates the breakdown of lipid droplets. This study aimed to compare the involvement of autophagy and the oxidative status in the effects of resveratrol and energy restriction as therapeutic tools for managing liver steatosis. In addition, potential additive or synergic effects were studied. Rats were fed a high-fat high-sucrose diet for 6 weeks and then divided into four experimental groups and fed a standard diet: a control group ©, a resveratrol-treated group (RSV, 30 mg kg-1 d-1), an energy restricted group (R, -15%), and an energy restricted group treated with resveratrol (RR). Liver triacylglycerols (TGs) were measured by Folch's method. TBARS, GSH, GSSG, GPx and SOD were assessed using commercial kits. The protein expression of beclin, atg5 and p62, as well as ratios of pSer555 ULK1/total ULK1, pSer757 ULK1/total ULK1 and LC3 II/I were determined by western blotting. Energy restriction increased the protein expression of beclin, atg5 and pSer757 ULK1/total ULK1 and LC3 II/I ratios, and reduced the protein expression of p62, thus indicating that it induced autophagy activation. The effects of resveratrol were similar but less marked than the hypocaloric diet. No differences were observed in oxidative stress determinants except for TBARS, which was decreased by energy restriction. In conclusion, resveratrol can reverse partially dietary-induced hepatic lipid accumulation, although less efficiently than energy restriction. The delipidating effect of energy restriction is mediated in part by the activation of autophagy; however, the involvement of this process in the effects of resveratrol is less clear.

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Calorie Restriction-Induced Increase in Skeletal Muscle Insulin Sensitivity Is Not Prevented by Overexpression of the p55α Subunit of Phosphoinositide 3-Kinase.

Martins VF, Tahvilian S, Kang JH, Svensson K, Hetrick B, Chick WS, Schenk S, McCurdy CE.

Front Physiol. 2018 Jun 27;9:789. doi: 10.3389/fphys.2018.00789. eCollection 2018.

PMID: 29997524

https://www.frontiersin.org/articles/10.3389/fphys.2018.00789/full

Abstract

Introduction: The Phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in skeletal muscle insulin-stimulated glucose uptake. While whole-body and tissue specific knockout (KO) of individual or combinations of the regulatory subunits of PI3K (p85α, p55α, and p50α or p85β); increase insulin sensitivity, no study has examined whether increasing the expression of the individual regulatory subunits would inhibit insulin action in vivo. Therefore, the objective of this study was to determine whether skeletal muscle-specific overexpression of the p55α regulatory subunit of PI3K impairs skeletal muscle insulin sensitivity, or prevents its enhancement by caloric restriction. Methods: We developed a novel "floxed" mouse that, through the Cre-LoxP approach, allows for tamoxifen (TMX)-inducible and skeletal muscle-specific overexpression of the p55α subunit of PI3K (referred to as, 'p55α-mOX'). Beginning at 10 weeks of age, p55α-mOX mice and their floxed littermates (referred to as wildtype [WT]) either continued with free access to food (ad libitum; AL), or were switched to a calorie restricted diet (CR; 60% of AL intake) for 20 days. We measured body composition, whole-body energy expenditure, oral glucose tolerance and ex vivo skeletal muscle insulin sensitivity in isolated soleus and extensor digitorum longus muscles using the 2-deoxy-glucose (2DOG) uptake method. Results: p55α mRNA and protein expression was increased ∼2 fold in muscle from p55α-mOX versus WT mice. There were no differences in energy expenditure, total activity, or food intake of AL-fed mice between genotypes. Body weight, fat and lean mass, tissue weights, and fasting glucose and insulin were comparable between p55α-mOX and WT mice on AL, and were decreased equally by CR. Interestingly, overexpression of p55α did not impair oral glucose tolerance or skeletal muscle insulin signaling or sensitivity, nor did it impact the ability of CR to enhance these parameters. Conclusion: Skeletal muscle-specific overexpression of p55α does not impact skeletal muscle insulin action, suggesting that p85α and/or p50α may be more important regulators of skeletal muscle insulin signaling and sensitivity.

KEYWORDS:

2-deoxyglucose; Cre-LoxP; Pik3r1; calorie restriction; glucose tolerance; insulin sensitivity

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Calorie restriction protects against apoptosis, mitochondrial oxidative stress and increased calcium signaling through inhibition of TRPV1 channel in the hippocampus and dorsal root ganglion of rats.

Gültekin F, Nazıroğlu M, Savaş HB, Çiğ B.

Metab Brain Dis. 2018 Jul 16. doi: 10.1007/s11011-018-0289-0. [Epub ahead of print]

PMID: 30014177

Abstract

The TRPV1 channel is activated in neurons by capsaicin, oxidative stress, acidic pH and heat factors, and these factors are attenuated by the antioxidant role of calorie restriction (CR). Hence, we investigated the hypothesis that the antioxidant roles of CR and food frequency (FF) may modulate TRPV1 activity and apoptosis through inhibition of mitochondrial oxidative stress in hippocampal (HIPPON) and dorsal root ganglion neurons (DRGN). We investigated the contribution of FF and CR to neuronal injury and apoptosis through inhibition of TRPV1 in rats. We assigned rats to control, FF and FF + CR groups. A fixed amount of food ad libitum was supplemented to the control and FF groups for 20 weeks, respectively. FF + CR group were fed the same amount of food as the control group but with 20% less calories during the same period. In major results, TRPV1 currents, intracellular Ca2+ levels, apoptosis, reactive oxygen species, mitochondrial depolarization, PARP-1 expression, caspase 3 and 9 activity and expression values were found to be increased in the HIPPON and DRGN following FF treatment, and these effects were decreased following FF + CR treatment. The FF-induced decrease in cell viability of HIPPO and DRGN, and vitamin E concentration of brain, glutathione peroxidase, vitamin A, and β-carotene values of the HIPPO, DRGN, plasma, liver and kidney were increased by FF + DR treatment, although lipid peroxidation levels in the same samples were decreased. In conclusion, CR reduces FF-induced increase of oxidative stress, apoptosis and Ca2+ entry through TRPV1 in the HIPPON and DRGN. Our findings may be relevant to the etiology and treatment of obesity following CR treatment.

KEYWORDS:

Apoptosis; Calorie restriction; Food frequency; Oxidative stress; TRPV1 channel

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Caloric restriction effects on liver mTOR signaling are time-of-day dependent.

Tulsian R, Velingkaar N, Kondratov R.

Aging (Albany NY). 2018 Jul 16. doi: 10.18632/aging.101498. [Epub ahead of print]

PMID: 30018180

http://www.aging-us.com/article/101498/text

Abstract

The regulation of mechanistic target of rapamycin (mTOR) signaling contributes to the metabolic effects of a calorie restriction (CR) diet. We assayed the effect of CR on the activity of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) in the liver of mice at six different times across the day. CR effects on mTORC1 and mTORC2 activities were time-of-day dependent. CR induced mTORC1 activity at one time, reduced at two times and has no effect during other times. CR induced mTORC2 activity at one time of the day and has no effects at other times. Circadian clocks are implemented in the regulation of mTOR signaling in mammals and mechanisms of CR. We assayed the effect of CR on mTOR signaling in the liver of mice deficient for circadian transcriptional regulators BMAL1 and CRYs. The CR induced suppression of mTORC1 activity was observed in both clock mutants, while up regulation of mTORC2 was observed in the liver of CRY deficient but not in the liver of BMAL1 deficient mice. Our finding revealed that CR has different time dependent effect on the activity of mTOR complexes 1 and 2 and suggest that circadian clock protein BMAL1 is involved in the up regulation of mTORC2 upon CR in mammals.

KEYWORDS:

aging; biological clocks; circadian clocks; glucose; insulin sensitivity; mTOR signaling pathway; metabolism; protein translation

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Stem Cell Rejuvenation and the Role of Autophagy in Age Retardation by Caloric Restriction: An Update.

Bi S, Wang H, Kuang W.

Mech Ageing Dev. 2018 Jul 18. pii: S0047-6374(18)30029-0. doi: 10.1016/j.mad.2018.07.005. [Epub ahead of print] Review.

PMID: 30031008

Abstract

Stem cells being pluripotent in nature can differentiate into a wide array of specific cells and asymmetrically divide to produce new ones but may undergo aging by themselves. Aging has both quantitative and qualitative effects on stem cells, and could eventually restrain them from replenishing into progenitor cells. Reactive oxygen species (ROS) accumulated in the aging cells could not only block the cell cycle but also affect autophagy by damaging the mitochondria. Autophagy could eliminate redundant production of ROS in aging stem cells and helps to maintain the proliferation capacity by restraining the expression of p16INK4a. Current studies showed that improving autophagy could restore the regenerative ability of aging stem cells. Therefore, it is important for an organism to maintain the appropriate autophagy. Caloric restriction (CR) was shown to retard the stem cell aging by a certain basic level of autophagy, suggesting that CR was an effective way to extend longevity in mammals. However, little is known about the underlying mechanisms. In this review, we tried to explore the molecular mechanisms on how CR induces appropriate autophagy to restore aging stem cell regenerative ability.

KEYWORDS:

Age retardation; Autophagy; Caloric Restriction; ROS; Stem Cell Aging

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Gene Expression of Sirtuin-1 and Endogenous Secretory Receptor for Advanced Glycation End Products in Healthy and Slightly Overweight Subjects after Caloric Restriction and Resveratrol Administration.

Roggerio A, Strunz CMC, Pacanaro AP, Leal DP, Takada JY, Avakian SD, Mansur AP.

Nutrients. 2018 Jul 21;10(7). pii: E937. doi: 10.3390/nu10070937.

PMID: 30037068

http://www.mdpi.com/2072-6643/10/7/937

Abstract

Sirtuin-1 (Sirt-1) and an endogenous secretory receptor for an advanced glycation end product (esRAGE) are associated with vascular protection. The purpose of this study was to examine the effects of resveratrol (RSV) and caloric restriction (CR) on gene expression of Sirt-1 and esRAGE on serum levels of Sirt1 and esRAGE in healthy and slightly overweight subjects. The study included 48 healthy subjects randomized to 30 days of RSV (500 mg/day) or CR (1000 cal/day). Waist circumference (p = 0.011), TC (p = 0.007), HDL (p = 0.031), non-HDL (p = 0.025), ApoA1 (p = 0.011), and ApoB (p = 0.037) decreased in the CR group. However, TC (p = 0.030), non-HDL (p = 0.010), ApoB (p = 0.034), and HOMA-IR (p = 0.038) increased in the RSV group. RSV and CR increased serum levels of Sirt-1, respectively, from 1.06 ± 0.71 ng/mL to 5.75 ± 2.98 ng/mL (p < 0.0001) and from 1.65 ± 1.81 ng/mL to 5.80 ± 2.23 ng/mL (p < 0.0001). esRAGE serum levels were similar in RSV (p = NS) and CR (p = NS) groups. Significant positive correlation was observed between gene expression changes of Sirt-1 and esRAGE in RSV (r = 0.86; p < 0.0001) and in CR (r = 0.71; p < 0.0001) groups, but not for the changes in serum concentrations. CR promoted increases in the gene expression of esRAGE (post/pre). Future long-term studies are needed to evaluate the impact of these outcomes on vascular health.

KEYWORDS:

Sirt-1; caloric restriction; esRAGE; resveratrol

 

Food deprivation disrupts normal holistic processing of domain-specific stimuli.

Zitron-Emanuel N, Ganel T.

Psychol Res. 2018 Jul 23. doi: 10.1007/s00426-018-1062-z. [Epub ahead of print]

PMID: 30039248

Abstract

Food deprivation has been shown to lead to a set of biological and psychological responses, including a decrease in perceptual thresholds, and an increase in attentional allocation for domain-specific, food-related stimuli. Here, we tested whether food deprivation could lead to a qualitative change in the way food is perceived. To this purpose, we tested the effect of food deprivation on a basic feature of human perception, the holistic processing of object shape. In three experiments, we examined the effect of food deprivation on participants' susceptibility to the height-width illusion, which served as a maker for holistic processing. In all experiments, food deprivation led to an abnormal, non-holistic processing of shape, which resulted in a total reduction of the illusion for food-related, but not for control stimuli. These results show that food deprivation alters the way food is perceived, and propose that motivational factors modulate people's resistance to perceptual distortions for domain-specific stimuli.

 

Regulation of metabolic health by essential dietary amino acids.

Green CL, Lamming DW.

Mech Ageing Dev. 2018 Jul 22. pii: S0047-6374(18)30079-4. doi: 10.1016/j.mad.2018.07.004. [Epub ahead of print] Review.

PMID: 30044947

Abstract

Although the beneficial effects of calorie restriction (CR) on health and aging were first observed a century ago, the specific macronutrients and molecular processes that mediate the effect of CR have been heavily debated. Recently, it has become clear that dietary protein plays a key role in regulating both metabolic health and longevity, and that both the quantity and quality - the specific amino acid composition - of dietary protein mediates metabolic health. Here, we discuss recent findings in model organisms ranging from yeast to mice and humans regarding the influence of dietary protein as well as specific amino acids on metabolic health, and the physiological and molecular mechanisms which may mediate these effects. We then discuss recent findings which suggest that the restriction of specific dietary amino acids may be a potent therapy to treat or prevent metabolic syndrome. Finally, we discuss the potential for dietary restriction of specific amino acids - or pharmaceuticals which harness these same mechanisms - to promote healthy aging.

KEYWORDS:

BCAAs; amino acids; diabetes; obesity; protein restriction

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Complementary intestinal mucosa and microbiota responses to caloric restriction.
Duszka K, Ellero-Simatos S, Ow GS, Defernez M, Paramalingam E, Tett A, Ying S, König J, Narbad A, Kuznetsov VA, Guillou H, Wahli W.
Sci Rep. 2018 Jul 27;8(1):11338. doi: 10.1038/s41598-018-29815-7.
PMID: 30054525
https://www.nature.com/articles/s41598-018-29815-7
Abstract
The intestine is key for nutrient absorption and for interactions between the microbiota and its host. Therefore, the intestinal response to caloric restriction (CR) is thought to be more complex than that of any other organ. Submitting mice to 25% CR during 14 days induced a polarization of duodenum mucosa cell gene expression characterised by upregulation, and downregulation of the metabolic and immune/inflammatory pathways, respectively. The HNF, PPAR, STAT, and IRF families of transcription factors, particularly the Pparα and Isgf3 genes, were identified as potentially critical players in these processes. The impact of CR on metabolic genes in intestinal mucosa was mimicked by inhibition of the mTOR pathway. Furthermore, multiple duodenum and faecal metabolites were altered in CR mice. These changes were dependent on microbiota and their magnitude corresponded to microbial density. Further experiments using mice with depleted gut bacteria and CR-specific microbiota transfer showed that the gene expression polarization observed in the mucosa of CR mice is independent of the microbiota and its metabolites. The holistic interdisciplinary approach that we applied allowed us to characterize various regulatory aspects of the host and microbiota response to CR.

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Diversity of Astroglial Effects on Aging- and Experience-Related Cortical Metaplasticity.
Lalo U, Bogdanov A, Pankratov Y.
Front Mol Neurosci. 2018 Jul 13;11:239. doi: 10.3389/fnmol.2018.00239. eCollection 2018.
PMID: 30057525
Abstract
Activity-dependent regulation of synaptic plasticity, or metaplasticity, plays a key role in the adaptation of neuronal networks to physiological and biochemical changes in aging brain. There is a growing evidence that experience-related alterations in the mechanisms of synaptic plasticity can underlie beneficial effects of physical exercise and caloric restriction (CR) on brain health and cognition. Astrocytes, which form neuro-vascular interface and can modulate synaptic plasticity by release of gliotransmitters, attract an increasing attention as important element of brain metaplasticity. We investigated the age- and experience-related alterations in astroglial calcium signaling and stimulus-dependence of long-term synaptic plasticity in the neocortex of mice exposed to the mild CR and environmental enrichment (EE) which included ad libitum physical exercise. We found out that astrocytic Ca2+-signaling underwent considerable age-related decline but EE and CR enhanced astroglial signaling, in particular mediated by noradrenaline (NA) and endocannabinoid receptors. The release of ATP and D-Serine from astrocytes followed the same trends of age-related declined and EE-induced increase. Our data also showed that astrocyte-derived ATP and D-Serine can have diverse effects on the threshold and magnitude of long-term changes in the strength of neocortical synapses; these effects were age-dependent. The CR- and EE-induced enhancement of astroglial Ca2+-signaling had more stronger effect on synaptic plasticity in the old (14-18 months) than in the young (2-5 months) wild-type (WT) mice. The effects of CR and EE on synaptic plasticity were significantly altered in both young and aged dnSNARE mice. Combined, our data suggest astrocyte-neuron interactions are important for dynamic regulation of cortical synaptic plasticity. This interaction can significantly decline with aging and thus contributes to the age-related cognitive impairment. On another hand, experience-related increase in the astroglial Ca2+-signaling can ameliorate the age-related decline.
KEYWORDS:
ATP release; BCM model; CB1 receptors; D-serine; caloric restriction; exocytosis; metaplasticy

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Does Calorie Restriction in Primates Increase Lifespan? Revisiting Studies on Macaques (Macaca mulatta) and Mouse Lemurs (Microcebus murinus).
Le Bourg E.
Bioessays. 2018 Aug 1:e1800111. doi: 10.1002/bies.201800111. [Epub ahead of print] Review.
PMID: 30067295
Abstract
The effects of calorie restriction have now been studied in two non-human primates, the macaque Macaca mulatta and the mouse lemur Microcebus murinus. The study on lemurs and one of the two studies on macaques have reported a lifespan increase. In this review, I argue that these results are better explained by a lifespan decrease in the control group because of a bad diet and/or overfeeding, rather than by a real lifespan increase in calorie-restricted animals. If these results can be readily translated to humans, it would mean that no beneficial effect of calorie restriction on lifespan can be expected in normal-weight or lean people, but that overweight and/or obese people could benefit to some extent from a decrease in excessive food intake.
KEYWORDS:
calorie restriction; human beings; non-human primates

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Dietary modulation of mitochondrial DNA damage: implications in aging and associated diseases.
Lam J, McKeague M.
J Nutr Biochem. 2018 Jul 7;63:1-10. doi: 10.1016/j.jnutbio.2018.07.003. [Epub ahead of print] Review.
PMID: 30071405
Abstract
Mammalian mitochondria contain small genomes [mitochondrial DNA (mtDNA)], which encode several of the proteins that are crucial for respiration. As such, maintaining the integrity of mtDNA is essential for healthy life. Nutritional strategies such as "Calorie Restriction" may play an important role in regulating mtDNA integrity and prolonging lifespan. In this review, we compare mtDNA with nuclear DNA damage and discuss how the resulting cell fates relate to human health. We provide a description of the mechanisms behind Calorie Restriction as an approach to induce mitochondrial processes contributing to a longer lifespan. We make connections between the current repertoire of studies to propose that how nutrition may mitigate mitochondrial dysfunction and potentially reduce DNA damage. Finally, we describe nutritional-based approaches to prevent mitochondrial dysfunction with a focus on mimetics of dietary and calorie restriction.
KEYWORDS:
Aging; DNA damage; Dietary restriction; Lifespan; Mitochondria

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Effect of exercise and/or reduced calorie dietary interventions on breast cancer-related endogenous sex hormones in healthy postmenopausal women.
de Roon M, May AM, McTiernan A, Scholten RJPM, Peeters PHM, Friedenreich CM, Monninkhof EM.
Breast Cancer Res. 2018 Aug 2;20(1):81. doi: 10.1186/s13058-018-1009-8. Review.
PMID: 30071893
Abstract
BACKGROUND:
Physical inactivity and being overweight are modifiable lifestyle risk factors that consistently have been associated with a higher risk of postmenopausal breast cancer in observational studies. One biologic hypothesis underlying this relationship may be via endogenous sex hormone levels. It is unclear if changes in dietary intake, physical activity, or both, are most effective in changing these hormone levels.
OBJECTIVE:
This systematic review and meta-analysis examines the effect of reduced caloric dietary intake and/or increased exercise levels on breast cancer-related endogenous sex hormones.
METHODS:
We conducted a systematic literature search in MEDLINE, Embase, and Cochrane's Central Register of Controlled Trials (CENTRAL) up to March 2017. Main outcome measures were breast cancer-related endogenous sex hormones. Randomized controlled trials (RCTs) reporting effects of reduced caloric intake and/or exercise interventions on endogenous sex hormones in healthy, physically inactive postmenopausal women were included. Studies including women using hormone therapy were excluded. The methodological quality of each study was assessed by the Cochrane's risk of bias tool.
RESULTS:
From the 2599 articles retrieved, seven articles from six RCTs were included in this meta-analysis. These trials investigated 1588 healthy postmenopausal women with a mean age ranging from 58 to 61 years. A combined intervention of reduced caloric intake and exercise, with durations ranging from 16 to 52 weeks, compared with a control group (without an intervention to achieve weight loss) resulted in the largest beneficial effects on estrone treatment effect ratio (TER) = 0.90 (95% confidence interval (CI) = 0.83-0.97), total estradiol TER = 0.82 (0.75-0.90), free estradiol TER = 0.73 (0.66-0.81), free testosterone TER = 0.86 (0.79-0.93), and sex hormone biding globulin (SHBG) TER = 1.23 (1.15-1.31). A reduced caloric intake without an exercise intervention resulted in significant effects compared with control on total estradiol TER = 0.86 (0.77-0.95), free estradiol TER = 0.77 (0.69-0.84), free testosterone TER = 0.91 (0.84-0.98), and SHBG TER = 1.20 (1.06-1.36). Exercise without dietary change, versus control, resulted in borderline significant effects on androstenedione TER = 0.97 (0.94-1.00), total estradiol TER = 0. 97 (0.94-1.00), and free testosterone TER = 0. 0.97 (0.95-1.00).
CONCLUSIONS AND RELEVANCE:
This meta-analysis of six RCTs demonstrated that there are beneficial effects of exercise, reduced caloric dietary intake or, preferably, a combination of exercise and diet on breast cancer-related endogenous sex hormones in physically inactive postmenopausal women.
KEYWORDS:
Breast cancer; Caloric restriction; Exercise; Postmenopausal women; Prevention; Sex hormones; Weight loss

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Long-term effects of increased protein intake after weight loss on intrahepatic lipid content and implications for insulin sensitivity - a PREVIEW study.
Drummen M, Dorenbos E, Vreugdenhil AC, Raben A, Fogelholm M, Westerterp-Plantenga MS, Adam T.
Am J Physiol Endocrinol Metab. 2018 Aug 7. doi: 10.1152/ajpendo.00162.2018. [Epub ahead of print]
PMID: 30086649
Abstract
AIMS:
To assess the effects of a weight maintenance period comprising two diets differing in protein intake, after weight loss, on intrahepatic lipid content and implications for insulin sensitivity.
MATERIALS AND METHODS:
A total of 25 participants (BMI: 31.1±3.5 kg/m2; intrahepatic lipid (IHL): 8.7±8.3%; fasting glucose: 6.4±0.6 mmol/l; HOMA-IR: 3.7±1.6; Matsuda index: 3.4±2.9) started an 8-week low energy diet followed by a 2-year weight maintenance period with either high protein (HP) or medium protein (MP) dietary guidelines. At baseline, after 6 months and after 2 years, IHL, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were determined by magnetic resonance spectroscopy/imaging. Glucose and insulin concentrations, determined during an oral glucose challenge, were used to assess the HOMA-IR and Matsuda insulin sensitivity index (ISI). Protein intake was measured with 24-h urinary nitrogen excretion.
RESULTS:
Protein intake, BMI, IHL, VAT, SAT, HOMA-IR and ISI did not change differently between the groups during the intervention. In the whole group, BMI, IHL, VAT, SAT, HOMA-IR, and ISI were favourably changed at 6 months and 2 years compared to baseline (p<0.05). Mixed model analysis showed that independent of BMI, protein intake (g·d-1) at 6 months was inversely related to IHL (coefficient:-0.04; p<0.05) and VAT (coefficient:-0.01; p<0.05). Overall, IHL was positively related to HOMA-IR (coefficient: 0.10; p<0.01) and inversely related to ISI (coefficient: -0.17; p<0.01), independent of BMI.
CONCLUSIONS:
A 2-year medium- to high-protein energy restricted diet reduced IHL and VAT. Independently of changes in BMI, IHL was inversely related to insulin sensitivity.
KEYWORDS:
body composition; insulin sensitivity; intrahepatic lipid content; protein intake; weight loss

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Anti-Aging Approach for Ocular Disorders: from Dry Eye to Retinitis Pigmentosa and Myopia.
Tsubota K.
Nippon Ganka Gakkai Zasshi. 2017 Mar;121(3):232-48. Japanese.
PMID: 30088407
Abstract
More than 90% of ocular diseases, such as glaucoma, age-related macular degeneration, and dry eye, are age-related with the incidence increasing with age. Furthermore, although retinitis pigmentosa and myopia may be associated with hereditary factors, they are also considered age-related diseases since they progress with aging. Thus, instead of targeting individual diseases, a new approach aimed at targeting aging itself is being examined. The most established current anti-aging approach is calorie restriction, considered to induce various gene expressions such as anti-oxidative enzymes contributing to life extension. At first, we confirmed that conditions under increased oxidative stresses, including genetically modified animals, such as Sod-1 knockout mice (KO), Mev1 transgenic mice, and Nrf-2 KO mice, and smoking induces a decrease in tear secretion resulting in dry eye. Recently, we found that dietary supplements containing lactoferrin or lactic acid bacteria suppress oxidative stress in the lacrimal glands, these results need to be considered in association with the current advances in the microbiome research. It is now possible to promote the clinical use of those supplements to increase tear secretion. Calorie restriction (CR) activates longevity gene sirtuins. We also have shown that agents activating sirtuins, such as resveratrol or nicotinamide mononucleotide (NMN) have retinal protective effects. Particularly, NMN is promising since we have confirmed its therapeutic effect against retinitis pigmentosa. Ketone bodies are considered another mechanistic target of CR. We developed eye drops containing ketone bodies, and confirmed a therapeutic effect similar to that of CR. Now we are expanding our investigations to include new therapies for dry eye and neuroprotection for the retina and the optic nerve. Other pathways such as endoplasmic reticulum (ER) stress, inhibition of hypoxia-inducible factor (HIF), and inhibition of the insulin-like growth factor (IGF) are also considered to be targets for the anti-aging approach. Taken together, the new strategy "anti-aging" is one approach in dealing with ocular diseases. The anti-aging approach is promising as the next generation of preventive medicine focusing on aging for the current era with increased health care expenditures.

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Caloric restriction inhibits mammary tumorigenesis in MMTV-ErbB2 transgenic mice through the suppression of ER and ErbB2 pathways and inhibition of epithelial cell stemness in premalignant mammary tissues.
Ma Z, Parris AB, Howard EW, Shi Y, Yang S, Jiang Y, Kong L, Yang X.
Carcinogenesis. 2018 Aug 9. doi: 10.1093/carcin/bgy096. [Epub ahead of print]
PMID: 30107476
Abstract
Caloric intake influences the onset of many diseases, including cancer. In particular, caloric restriction (CR) has been reported to suppress mammary tumorigenesis in various models. However, the underlying cancer preventive mechanisms have not been fully explored. To this end, we aimed to characterize the anticancer mechanisms of CR using MMTV-ErbB2 transgenic mice, a well-established spontaneous ErbB2-overexpressing mammary tumor model, by focusing on cellular and molecular changes in premalignant tissues. In MMTV-ErbB2 mice with 30% CR beginning at 8 weeks of age, mammary tumor development was dramatically inhibited, as exhibited by reduced tumor incidence and increased tumor latency. Morphogenic mammary gland analyses in 15- and 20-week-old mice indicated that CR significantly decreased mammary epithelial cell (MEC) density and proliferative index. To understand the underlying mechanisms, we analyzed the effects of CR on mammary stem/progenitor cells. Results from fluorescence-activated cell sorting analyses showed that CR modified mammary tissue hierarchy dynamics, as evidenced by decreased luminal cells (CD24highCD49flow), putative mammary reconstituting unit subpopulation (CD24highCD49fhigh) and luminal progenitor cells (CD61highCD49fhigh). Mammosphere and colony-forming cell assays demonstrated that CR significantly inhibited mammary stem cell self-renewal and progenitor cell numbers. Molecular analyses indicated that CR concurrently inhibited estrogen receptor (ER) and ErbB2 signaling. These molecular changes were accompanied by decreased mRNA levels of ER-targeted genes and epidermal growth factor receptor/ErbB2 family members and ligands, suggesting ER-ErbB2 signaling cross-talk. Collectively, our data demonstrate that CR significantly impacts ER and ErbB2 signaling, which induces profound changes in MEC reprogramming, and mammary stem/progenitor cell inhibition is a critical mechanism of CR-mediated breast cancer prevention.

Edited by AlPater

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