Al's CR updates

[AlPater]

Calorie restriction activates new adult born olfactory-bulb neurones in a ghrelin-dependent manner but acyl-ghrelin does not enhance sub-ventricular zone neurogenesis.
Ratcliff M, Rees D, McGrady S, Buntwal L, Hornsby AKE, Bayliss J, Kent BA, Bussey T, Saksida L, Beynon AL, Howell OW, Morgan AH, Sun Y, Andrews ZB, Wells T, Davies JS.
J Neuroendocrinol. 2019 Jun 10:e12755. doi: 10.1111/jne.12755. [Epub ahead of print]
PMID: 31179562
Abstract
The ageing and degenerating brain show deficits in neural stem/progenitor cell (NSPC) plasticity that are accompanied by impairments in olfactory discrimination. Emerging evidence suggests that the gut-hormone ghrelin plays an important role in protecting neurones, promoting synaptic plasticity and increasing hippocampal neurogenesis in the adult brain. Here, we studied the role of ghrelin in modulating adult sub-ventricular zone (SVZ) NSPCs that give rise to new olfactory bulb (OB) neurones. We characterised the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHSR), using an immuno-histochemical approach in GHSR-eGFP reporter mice to show that GHSR is expressed in several regions, including the OB, but not in the SVZ of the lateral ventricle. These data suggest that acyl-ghrelin does not mediate a direct effect on NSPC in the SVZ. Consistent with these findings, treatment with acyl-ghrelin or genetic silencing of GHSR did not alter NSPC proliferation within the SVZ. Similarly, using a BrdU pulse-chase approach we show that peripheral treatment of adult rats with acyl-ghrelin did not increase the number of new adult-born neurones in the granule cell layer (GCL) of the OB. These data demonstrate that acyl-ghrelin does not increase adult OB neurogenesis. Finally, we studied whether elevating ghrelin indirectly, via calorie restriction (CR), regulated the activity of new adult-born cells in the OB. Overnight CR induced c-Fos expression in new adult-born OB cells, but not in developmentally born cells, whilst neuronal activity was lost following re-feeding. These effects were absent in ghrelin-/- mice, suggesting that adult-born cells are uniquely sensitive to changes in ghrelin mediated by fasting and re-feeding. In summary, ghrelin does not promote neurogenesis in the SVZ and OB, however, new adult-born OB cells are activated by CR in a ghrelin-dependent manner.
KEYWORDS:
Calorie restriction; Ghrelin; Neurogenesis; Olfactory bulb; Sub-ventricular zone

[AlPater]

Acute but Not Chronic Calorie Restriction Defends against Stress-Related Anxiety and Despair in a GHS-R1a-Dependent Manner.
Lu Y, Niu M, Qiu X, Cao H, Xing B, Sun Y, Zhou Z, Zhou Y.
Neuroscience. 2019 Jun 8. pii: S0306-4522(19)30398-7. doi: 10.1016/j.neuroscience.2019.05.067. [Epub ahead of print]
PMID: 31185255
Abstract
Ghrelin is an important orexigenic brain-gut hormone that regulates feeding, metabolism and glucose homeostasis in human and rodents at multiple levels. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), which is widely expressed both inside and outside of the brain. Both acute and chronic calorie restriction (CR) were reported to increase endogenous ghrelin levels and lead to beneficial effects on brain functions, including anti-anxiety effects, anti-depressive effects, and memory improvement. However, the causal relationship and underlying mechanisms are not fully understood. Here, we introduced acute or chronic CR to both GHS-R1a KO (Ghsr-/-) mice and WT (Ghsr+/+) littermates, and investigated anxiety- and despair-related behaviors in the elevated plus maze (EPM), open field (OF) and forced swimming (FS) tests. We found that acute and chronic CR produced similar anxiolytic and anti-despair responses in Ghsr+/+ mice but opposite responses in Ghsr-/- mice. In particular, acute CR enhanced while chronic CR reduced anxiety- and despair-like behaviors in Ghsr-/- mice. Acute CR triggered anxiolytic and anti-despair responses in Ghsr+/+ mice. This effect was abolished by a GHS-R1a antagonist, suggesting a GHS-R1a dependent mechanism. Ad-libitum refeeding masked behavioral responses induced by acute CR in both Ghsr-/- and Ghsr+/+ mice. Altogether, our findings indicate that acute and chronic CR mitigate anxiety- and despair-like behaviors with different physiological mechanisms, with the former being dependent on endogenous ghrelin release and GHS-R1a signaling, while the latter may not be.
KEYWORDS:
GHS-R1a; anxiety; behaviors; calorie restriction; depression; ghrelin; mice; stress

[AlPater]

Mammary protein synthesis upon long-term nutritional restriction was attenuated by oxidative stress induced inhibition of v-ATPase/mTORC1 signaling.
Zhong H, Song Y, Wang P, Feng B, Zhang X, Che L, Lin Y, Xu S, Li J, Wu, Fang Z.
J Agric Food Chem. 2019 Jun 13. doi: 10.1021/acs.jafc.9b02170. [Epub ahead of print]
PMID: 31189310
Abstract
To determine how nutritional restriction compromised milk synthesis, sows were fed 100% (control) or 76% (restricted) of the recommended feed allowance from postpartum day (PD)-1 to PD-28. Compared with the control, more body reserves loss, increased plasma triglyceride and high-density lipoprotein cholesterol levels while decreased plasma methionine concentrations were observed in the restricted group at PD-21. The increased plasma malondialdehyde level while decreased plasma histidine, taurine concentrations and decreased glutathione peroxidase activity were observed at PD-28 when backfat loss further increased in the restricted group. In mammary glands, the vacuolar H+-adenosine triphosphatase (v-ATPase), as the upstream of mechanistic target of rapamycin (mTOR) signaling, showed decreased activity, while phosphorylation of mTOR, S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1, and β-casein abundance were all decreased following feed restriction. Altogether, long-term nutrition restriction could induce progressively aggravated oxidative stress and compromise mammary protein synthesis through repression of v-ATPase/mTORC1 signaling.

Calorie restriction with regular chow, but not a high-fat diet, delays onset of spontaneous osteoarthritis in the Hartley guinea pig model.
Radakovich LB, Marolf AJ, Culver LA, Santangelo KS.
Arthritis Res Ther. 2019 Jun 13;21(1):145. doi: 10.1186/s13075-019-1925-8.
PMID: 31196172
https://arthritis-research.biomedcentral.com/track/pdf/10.1186/s13075-019-1925-8
Abstract
BACKGROUND:
Obesity is a leading risk factor for osteoarthritis (OA). In contrast, calorie restriction (CR) may lessen OA due to improved systemic inflammatory status and reduced weight-bearing. The aim of this study was to determine how CR with regular chow versus a high-fat diet (HFD) alters OA progression using the Hartley guinea pig model of disease.
METHODS:
Twenty-four male guinea pigs were allocated to four groups at 2 months of age: (1) ad libitum regular chow (obese), (2) CR regular chow (lean), (3) ad libitum HFD, and (4) CR HFD. Animals in both HFD groups ate identical amounts and were combined into one HFD group for analyses. At 5 months, hind limbs were harvested for microcomputed tomography (microCT) and histopathologic evaluation of knee OA. Total body, gonad fat, and infrapatellar fat pad (IFP) masses were recorded. IFPs were collected for gene expression analysis. Immunohistochemistry for monocyte chemoattractant protein-1 (MCP-1) was performed on intact joints. Serum was utilized for protein C3 measurement. All data were compared using ordinary one-way ANOVA analyses with Tukey's post-hoc tests.
RESULTS:
Body mass in the lean and HFD groups were similar and lower than the obese group. Despite this, gonad fat pads in the HFD group were comparable to the obese group. MicroCT and histologic OA scores were similar in obese and HFD groups; both scores were significantly lower in the lean group. Obese and HFD groups displayed increased gene expression of pro-inflammatory and catabolic mediators in IFPs relative to lean animals. Consistent with this, immunohistochemistry for MCP-1 in knee joints demonstrated strong positive staining in obese and HFD groups but was minimally detected in lean animals. Serum protein C3 levels were also statistically higher.
CONCLUSIONS:
This study demonstrated that CR with a regular chow diet lessened knee OA in the Hartley guinea pig and was associated with decreased local and systemic inflammation compared to obese animals. HFD animals, although under CR conditions, had OA scores and inflammatory markers similar to obese animals. Thus, diet composition, and not solely body weight, may be a key factor in development of OA.
KEYWORDS:
Calorie restriction; Hartley guinea pig; High-fat diet; Obesity; Osteoarthritis

Cognitive Effects of Adding Caloric Restriction to Aerobic Exercise Training in Older Adults with Obesity.
Hugenschmidt CE, Leng X, Lyles M, Michael L, Dougherty A, Babcock P, Baker LD, Brinkley TE, Nicklas BJ.
Obesity (Silver Spring). 2019 Jun 14. doi: 10.1002/oby.22525. [Epub ahead of print]
PMID: 31199592
Abstract
OBJECTIVE:
This study examined the short- and long-term effects of adding caloric restriction to 5 months of aerobic exercise training on executive function in sedentary older adults with obesity.
METHODS:
Sedentary adults with obesity aged 65 to 79 years completed a randomized trial investigating the cardiorespiratory benefits of adding moderate (~ 250 kcal) or high (~ 600 kcal) caloric restriction to a 20-week aerobic exercise program. Approximately half (n = 88) completed a cognitive assessment battery at baseline, post intervention, and 18 to 24 months after intervention completion. The primary outcome was an executive function composite score.
RESULTS:
In the overall sample, the executive function composite increased 0.114 from baseline to postintervention (P = 0.01). Randomization to caloric restriction did not significantly alter executive function over aerobic exercise alone, nor were there between-group differences on any individual executive function test following the intervention or at long-term follow-up. Adding caloric restriction to exercise was associated with a modest increase in Mini-Mental State Examination score (P = 0.04). In the overall sample, increases from baseline at long-term follow-up were noted in digit symbol and word list recall performance as well.
CONCLUSIONS:
Adding caloric restriction to a 20-week aerobic exercise program does not worsen or improve executive function more than exercise alone assessed up to 24 months post randomization.

Age- and Experience-Related Plasticity of ATP-Mediated Signaling in the Neocortex.
Lalo U, Bogdanov A, Pankratov Y.
Front Cell Neurosci. 2019 May 29;13:242. doi: 10.3389/fncel.2019.00242. eCollection 2019.
PMID: 31191257
[pdf availed from PMID site.]
Abstract
There is growing recognition of the important role of interaction between neurons and glial cells for brain longevity. The extracellular ATP have been shown to bring significant contribution into bi-directional glia-neuron communications, in particular into astrocyte-driven modulation of synaptic plasticity. To elucidate a putative impact of brain aging on neuron-glia networks, we explored the aging-related plasticity of the purinoreceptors-mediated signaling in cortical neurons and astrocytes. We investigated the age- and experience-related alterations in purinergic components of neuronal synaptic currents and astroglial calcium signaling in the layer2/3 of neocortex of mice exposed to the mild caloric restriction (CR) and environmental enrichment (EE) which included ad libitum physical exercise. We observed the considerable age-related decline in the neuronal P2X receptor-mediated miniature spontaneous currents which originated from the release of ATP from both synapses and astrocytes. We also found out that purinergic astrocytic Ca2+-signaling underwent the substantial age-related decline but EE and CR rescued astroglial signaling, in particular mediated by P2X1, P2X1/5, and P2Y1 receptors. Our data showed that age-related attenuation in the astroglial calcium signaling caused a substantial decrease in the exocytosis of ATP leading to impairment of astroglia-derived purinergic modulation of excitatory synaptic currents and GABAergic tonic inhibitory currents. On a contrary, exposure to EE and CR, which enhanced purinergic astrocytic calcium signaling, up-regulated the excitatory and down-regulated the inhibitory currents in neurons of old mice, thus counterbalancing the impact of aging on synaptic signaling. Combined, our results strongly support the physiological importance of ATP-mediated signaling for glia-neuron interactions and brain function. Our data also show that P2 purinoreceptor-mediated communication between astrocytes and neurons in the neocortex undergoes remodeling during brain aging and decrease in the ATP release may contribute to the age-related impairment of synaptic transmission.
KEYWORDS:
AMPA receptor; GABA receptor A; ageing; calcium; diet; exercise; glia-neuron interaction; synaptic strength

[AlPater]

Diet restriction-induced healthy aging is mediated through the immune signaling component ZIP-2 in Caenorhabditis elegans.
Hahm JH, Jeong C, Nam HG.
Aging Cell. 2019 Jun 18:e12982. doi: 10.1111/acel.12982. [Epub ahead of print]
PMID: 31215146
https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.12982
Abstract
Dietary restriction (DR) robustly delays the aging process in all animals tested so far. DR slows aging by negatively regulating the target of rapamycin (TOR) and S6 kinase (S6K) signaling pathway and thus inhibiting translation. Translation inhibition in C. elegans is known to activate the innate immune signal ZIP-2. Here, we show that ZIP-2 is activated in response to DR and in feeding-defective eat-2 mutants. Importantly, ZIP-2 contributes to the improvements in longevity and healthy aging, including mitochondrial integrity and physical ability, mediated by DR in C. elegans. We further show that ZIP-2 is activated upon inhibition of TOR/S6K signaling. However, DR-mediated activation of ZIP-2 does not require the TOR/S6K effector PHA-4/FOXA. Furthermore, zip-2 was not activated or required for longevity in daf-2 mutants, which mimic a low nutrition status. Thus, DR appears to activate ZIP-2 independently of PHA-4/FOXA and DAF-2. The link between DR, aging, and immune activation provides practical insight into the DR-induced benefits on health span and longevity.
KEYWORDS:
C. elegans ; TOR/S6K; ZIP-2; dietary restriction; longevity; mitochondria

Effects of nutrient limitation on sperm and seminal fluid: a systematic review and meta-analysis.
Macartney EL, Crean AJ, Nakagawa S, Bonduriansky R.
Biol Rev Camb Philos Soc. 2019 Jun 19. doi: 10.1111/brv.12524. [Epub ahead of print]
PMID: 31215758
Abstract
Theory predicts that costly sexual traits should be reduced when individuals are in poor condition (i.e. traits should exhibit condition-dependent expression). It is therefore widely expected that male ejaculate traits, such as sperm and seminal fluid, will exhibit reduced quantity and quality when dietary nutrients are limited. However, reported patterns of ejaculate condition dependence are highly variable, and there has been no comprehensive synthesis of underlying sources of such variation in condition-dependent responses. In particular, it remains unclear whether all ejaculate traits are equally sensitive to nutrient intake, and whether such traits are particularly sensitive to certain dietary nutrients, respond more strongly to nutrients during specific life stages, or respond more strongly in some taxonomic groups. We systematically reviewed these potential sources of variation through a meta-analysis across 50 species of arthropods and vertebrates (from 71 papers and 348 effect sizes). We found that overall, ejaculate traits are moderately reduced when dietary nutrients are limited, but we also detected substantial variation in responses. Seminal fluid quantity was strongly and consistently condition dependent, while sperm quantity was moderately condition dependent. By contrast, aspects of sperm quality (particularly sperm viability and morphology) were less consistently reduced under nutrient limitation. Ejaculate traits tended to respond in a condition-dependent manner to a wide range of dietary manipulations, especially to caloric and protein restriction. Finally, while all major taxa for which sufficient data exist (i.e. arthropods, mammals, fish) showed condition dependence of ejaculate traits, we detected some taxonomic differences in the life stage that is most sensitive to nutrient limitation, and in the degree of condition dependence of specific ejaculate traits. Together, these biologically relevant factors accounted for nearly 20% of the total variance in ejaculate responses to nutrient limitation. Interestingly, body size showed considerably stronger condition-dependent responses compared to ejaculate traits, suggesting that ejaculate trait expression may be strongly canalised to protect important reproductive functions, or that the cost of producing an ejaculate is relatively low. Taken together, our findings show that condition-dependence of ejaculate traits is taxonomically widespread, but there are also many interesting, biologically relevant sources of variation that require further investigation. In particular, further research is needed to understand the differences in selective pressures that result in differential patterns of ejaculate condition dependence across taxa and ejaculate traits.
KEYWORDS:
body-size; condition dependence; diet; ejaculate; life history; nutrient limitation; post-copulatory; protein; semen; sperm

[AlPater]

The Effects of Graded Levels of Calorie Restriction: XIV. Global Metabolomics Screen Reveals Brown Adipose Tissue Changes in Amino Acids, Catecholamines, and Antioxidants After Short-Term Restriction in C57BL/6 Mice.
Green CL, Mitchell SE, Derous D, Wang Y, Chen L, Han JJ, Promislow DEL, Lusseau D, Douglas A, Speakman JR.
J Gerontol A Biol Sci Med Sci. 2019 Apr 9. pii: glz023. doi: 10.1093/gerona/glz023. [Epub ahead of print]
PMID: 31220223
https://watermark.silverchair.com/glz023.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAm8wggJrBgkqhkiG9w0BBwagggJcMIICWAIBADCCAlEGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMAqUNNgKS9qQ3Y7KfAgEQgIICIoSuh6PSe8tPce-uS6jxsGgmyB3zBYnWCl00LtvV8NOSuOeH0Jzy_PuqGHeDHhce4F4DmzODzaGmQnDaSUDxf9m6-faqkofNM93Z1r3Pi_uYnUf11qj1r-J5v3E-TOz0SmbtoMVzZzFFV9Qq-IHaZkvm787pXarVXXodAuWse_KIfEMb_jE-Uz6ZkmZkpoTQl3n6JW4oZr41dik-2AQ667G_vUPJUSI962nvJ12L_Kt_-3zExFcEQ6m1jmda8FrN3uLZz0RWj1hVnC6Dt6sddkdnRjnLfFfo_uICIV_8rlUB3g6cBqD4sTnmEjG9S9OOzJIiONtFcHo38HPxQ-aYibbnbXbLxMfxDKHriap6ODzanlAEiBBE5YzCRUKQLH0aebWElNjERLdAdjs2T_93KXOMKvGNSA7m7T5eR_BcJ6xZquwKwJfeSZJCreWFCzzNO-g_QVFYCpXcR4IRPhs6_VgrQooS3-ZleEV6hgWvngihkXnk05rjCatCs6hIgRW7Li-OO4b7dJJL_LC1MbqW6Ol-4Iiti0O9uRMzXCv58dbXAL3zFzJvuRsQj9tx0_HhOylM9KG_6zA2XtCvqBBbsifTIZu_EnDt-A-0FqFDZobMnl9PWSwQkfKv4O6gUXrVt3rIK0ALiSJG-rI1wqtCf-a4iJMZbxb1cxxvVXxyV-ACkD5ZRE8PDcLMxfoZ8RbusKYbb9DHjX5ujgpLQXDR57igJw
Abstract
Animals undergoing calorie restriction (CR) often lower their body temperature to conserve energy. Brown adipose tissue (BAT) is stimulated through norepinephrine when rapid heat production is needed, as it is highly metabolically active due to the uncoupling of the electron transport chain from ATP synthesis. To better understand how BAT metabolism changes with CR, we used metabolomics to identify 883 metabolites that were significantly differentially expressed in the BAT of C57BL/6 mice, fed graded CR (10%, 20%, 30%, and 40% CR relative to their individual baseline intake), compared with mice fed ad libitum (AL) for 12 hours a day. Pathway analysis revealed that graded CR had an impact on the TCA cycle and fatty acid degradation. In addition, an increase in nucleic acids and catecholamine pathways was seen with graded CR in the BAT metabolome. We saw increases in antioxidants with CR, suggesting a beneficial effect of mitochondrial uncoupling. Importantly, the instigator of BAT activation, norepinephrine, was increased with CR, whereas its precursors l-tyrosine and dopamine were decreased, indicating a shift of metabolites through the activation pathway. Several of these key changes were correlated with food anticipatory activity and body temperature, indicating BAT activation may be driven by responses to hunger.
KEYWORDS:
Diabetes; Dopamine; Obesity; Thermogenesis; Torpor

The influence of diet upon liver function indices of healthy volunteers resident in a Phase I clinical trail.
Wei Y, Zhang H, Zhang S, Li H.
Am J Transl Res. 2019 May 15;11(5):3187-3194. eCollection 2019.
PMID: 31217888
Abstract
In order to avoid the occurrence of "abnormal liver biochemical tests" caused by diet in Phase I clinical trial, the effect of a low-calorie and low-carbohydrate diet on biochemical indices of liver function of healthy volunteers in a Phase I unit was investigated. A single-centered, non-randomized and parallel-controlled study was designed with 46 healthy subjects consuming two types of diet (24 in the experimental group and 22 in the control group). The diets comprised a balanced normal calorie diet for the control group and a low-calorie and low-carbohydrate diet for the experimental group. All subjects were required to reside on site for 15 consecutive days. Liver biochemical indices such as alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) were detected on Day-1 (baseline), Day 1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 12, Day 15 and Day 22 (follow-up). There was no significant difference in age, ethnicity, occupation and other demographic data between two groups with balanced baseline. There was no significant difference in ALP between two groups and ALP remained unchanged as a function of time. However, ALT level of the experimental group remained constant as a function of time while ALT level of the control group increased with time and the level was significantly higher than the experimental group after Day 2. The difference between two groups increased with time but decreased on Day 22 as follow-up. After controlling the baseline of AST, AST exhibited a similar trend as ALT. After Day 9, 5%-18% of the patients in the control group showed hepatocyte injury, while no hepatic injury was found in the experimental group. In summary, a low-calorie, low-carbohydrate diet can effectively avoid the occurrence of liver biochemical abnormalities caused by diet in Phase I clinical trials.
KEYWORDS:
Diet; Phase I clinical trial; healthy subjects; liver biochemical indices

[AlPater]

Sex differences in the response to dietary restriction in rodents.
Kane AE, Sinclair DA, Mitchell JR, Mitchell SJ.
Curr Opin Physiol. 2018 Dec;6:28-34. doi: 10.1016/j.cophys.2018.03.008. Epub 2018 Mar 27.
PMID: 31231711
https://sci-hub.tw/ [I had trouble using the doi, but the PMID, 31231711, worked.
Abstract
Dietary restriction (DR) remains the most reproducible and consistent laboratory intervention to extend lifespan and improve health in mammals. DR has been primarily characterized in males due to issues of cost, perceived heightened variability amongst females, and the misconception that the reproductive system is the only important difference between sexes in mammals. In reality, existing data point to clear sex differences in mammalian responses to DR. Here we discuss recent advances in our understanding of sex differences in the responses to DR in rodent models.

[AlPater]

Refeeding abolishes beneficial effects of severe calorie restriction from birth on adipose tissue and glucose homeostasis of adult rats.
Melo DS, Santos CS, Pereira LC, Mendes BF, Jesus LS, Pelaez JMN, Aguilar EC, Nascimento DR, Martins AS, Magalhães FC, Esteves EA, Capettini LDSA, Dias Peixoto MF.
Nutrition. 2019 May 6;66:87-93. doi: 10.1016/j.nut.2019.03.022. [Epub ahead of print]
PMID: 31247497
https://sci-hub.tw/10.1016/j.nut.2019.03.022
Abstract
OBJECTIVES:
Calorie restriction (CR) is an important intervention for reducing adiposity and improving glucose homeostasis. Recently we found that in rats, a severe calorie restriction (SCR) beginning at birth up to adult age promotes positive effects on cardiometabolic risk factors and heart. The aim of this study was to investigate the effects of this new model of SCR on adipose tissue and glucose homeostasis of rats and to evaluate the effects of refeeding.
METHODS:
From birth to 90 d of age, rats were divided into an ad libitum (AL) group, which had free access to food, and a CR50 group, which had food limited to 50% of that consumed by the AL group. From this moment, half of the CR50 animals had free access to food (the refeeding group [CR50-R]), and the other half continued 50% restricted for an additional 90-d period. Food intake was assessed daily and body weight weekly. In the final week of the SCR/refeeding protocol, oral glucose and intraperitoneal insulin tolerance tests were performed. Thereafter, rats were sacrificed and visceral fat was collected and used for histologic and Western blot analysis.
RESULTS:
Findings from this study revealed that SCR beginning at birth and up to adult life promoted a large decrease in visceral adiposity; improvement in glucose/insulin tolerance; and upregulation of adipose proliferating cell nuclear antigen, sirtuin 1, peroxisome proliferator-activated receptor-γ, and adiponectin. Refeeding abolished all of these effects. SCR from birth to adult age promoted beneficial effects on adipose tissue and glucose homeostasis; whereas refeeding abolished these effects.
KEYWORDS:
Adipocyte; Evere calorie restriction; Glucose homeostasis; Refeeding; SIRT1 signaling; Visceral fat

Anti-aging interventions affect lifespan variability in sex, strain, diet and drug dependent fashion.
Bartke A, Evans TR, Musters CJM.
Aging (Albany NY). 2019 Jun 24. doi: 10.18632/aging.102037. [Epub ahead of print]
PMID: 31235676
https://s3-us-west-1.amazonaws.com/paperchase-aging/pdf/jGgMw8AJFmP8582AD.pdf
Abstract
It was recently reported that socio-economic factors related differences in human life expectancy are associated with differences in the variance of age at death. To determine whether anti-aging interventions also alter the variance of longevity, we have analyzed data from mice subjected to treatment with drugs that affect aging or to calorie restriction and from long-lived mutant mice. The relationship of changes in longevity and in longevity variance was found to depend on sex and treatment and apparently also on strain. Increased longevity of male mice treated with effective anti-aging drugs was accompanied by reduced variance of age at death and apparent reduction of early life mortality. Life extension induced by growth-hormone related mutations and calorie restriction tended to increase longevity variance in females only. We conclude that impact of anti-aging interventions on the variance of age at death and distribution of individual lifespans in laboratory mice is treatment-dependent and sexually dimorphic.
KEYWORDS:
17 alpha estradiol; acarbose; calorie restriction; growth hormone; longevity; mice; rapamycin; variance

Measuring phenotypic flexibility by transcriptome time-course analyses during challenge tests before and after energy restriction.
van Bussel IPG, Fazelzadeh P, Frost GS, Rundle M, Afman LA.
FASEB J. 2019 Jun 25:fj201900148R. doi: 10.1096/fj.201900148R. [Epub ahead of print]
PMID: 31238007
Abstract
Metabolic challenge tests may be a valuable tool to magnify the effects of diet on health. The use of transcriptomics enables a more extensive characterization of the effects of diet. The question remains whether transcriptome time-course analyses during challenge tests will deliver more information on the effect of diet than a static fasting measurement. A dietary intervention known to improve health is energy restriction (ER). Seventy-two healthy, overweight men and women aged 50-65 were subjected to an oral glucose tolerance test (OGTT) and a mixed-meal test (MMT) before and after 12 wk of a 20% ER diet or control diet. Whole-genome gene expression of peripheral blood mononuclear cells was performed before and after the intervention. This was done during fasting, during the OGTT at 30, 60, and 120 min, and during the MMT at 60, 120, 240, and 360 min. Upon ER, the OGTT resulted in a faster and more pronounced down-regulation in gene expression of oxidative phosphorylation, cell adhesion, and DNA replication compared with the control. The MMT showed less-consistent effects. The OGTT combined with transcriptomics can be used to measure dynamic cellular adaptation upon an intervention that cannot be determined with a static fasting measurement.-Van Bussel, I. P. G., Fazelzadeh, P., Frost, G. S., Rundle, M., Afman, L. A., NutriTech Consortium. Measuring phenotypic flexibility by transcriptome time-course analyses during challenge tests before and after energy restriction.
KEYWORDS:
OGTT; PBMCs; mixed-meal test; whole-genome gene expression

Measuring phenotypic flexibility by transcriptome time-course analyses during challenge tests before and after energy restriction.
van Bussel IPG, Fazelzadeh P, Frost GS, Rundle M, Afman LA.
FASEB J. 2019 Jun 25:fj201900148R. doi: 10.1096/fj.201900148R. [Epub ahead of print]
PMID: 31238007
Abstract
Metabolic challenge tests may be a valuable tool to magnify the effects of diet on health. The use of transcriptomics enables a more extensive characterization of the effects of diet. The question remains whether transcriptome time-course analyses during challenge tests will deliver more information on the effect of diet than a static fasting measurement. A dietary intervention known to improve health is energy restriction (ER). Seventy-two healthy, overweight men and women aged 50-65 were subjected to an oral glucose tolerance test (OGTT) and a mixed-meal test (MMT) before and after 12 wk of a 20% ER diet or control diet. Whole-genome gene expression of peripheral blood mononuclear cells was performed before and after the intervention. This was done during fasting, during the OGTT at 30, 60, and 120 min, and during the MMT at 60, 120, 240, and 360 min. Upon ER, the OGTT resulted in a faster and more pronounced down-regulation in gene expression of oxidative phosphorylation, cell adhesion, and DNA replication compared with the control. The MMT showed less-consistent effects. The OGTT combined with transcriptomics can be used to measure dynamic cellular adaptation upon an intervention that cannot be determined with a static fasting measurement.
KEYWORDS:
OGTT; PBMCs; mixed-meal test; whole-genome gene expression

Calorie restriction and rapamycin administration induce stem cell self-renewal and consequent development and production in the mammary gland.
Kfir SH, Barash I.
Exp Cell Res. 2019 Jun 23. pii: S0014-4827(19)30317-9. doi: 10.1016/j.yexcr.2019.06.022. [Epub ahead of print]
PMID: 31242443
Abstract
Expansion of the mammary epithelial stem cell pool holds promise for consequent mammary gland development and production. Complementary analyses of bovine mammary implants maintained in de-epithelialized mouse mammary fat pad and endogenous mouse mammary gland were performed to elucidate the effect of calorie restriction (CR) on stem cell self-renewal. CR elevated propagation rate and non-adherent mammosphere generation in cultured bovine mammary cells. A corresponding decrease in progenitor-induced colony formation and differentiation marker expression was noted. In the mouse gland, CR enhanced the take rate of transplanted cells and outgrowths' fat pad occupancy. Downregulating mTOR activity by rapamycin administration reproduced CR's effects on stem cell self-renewal within a shorter period. Flow cytometry demonstrated a significant 1.5-fold increase in stem cell number and a corresponding decrease in luminal progenitor and differentiated cells. Consequent effects of rapamycin administration included enhanced ductlet generation in bovine implants and higher milk-protein gene expression in cultured mouse mammary cells. The stimulatory effect of CR on BST-1 expression in both bovine implants and mouse glands resembled that noted in the intestinal Paneth stem cell niche (Yilmaz et al., 2012). A putative niche may also exist in the mammary gland, conveying energy-status information to the insulated stem cells.
KEYWORDS:
Calorie restriction; Mammary gland; Rapamycin; Stem cell

[AlPater]

Caloric Restriction Alters Postprandial Responses of Essential Brain Metabolites in Young Adult Mice.
Yanckello LM, Young LEA, Hoffman JD, Mohney RP, Keaton MA, Abner E, Lin AL.
Front Nutr. 2019 Jun 12;6:90. doi: 10.3389/fnut.2019.00090. eCollection 2019.
PMID: 31249833
Abstract
Caloric restriction (CR) has been shown to extend longevity and protect brain function in aging. However, the effects of CR in young adult mice remain largely unexplored. In addition to the fundamental, long-term changes, recent studies demonstrate that CR has a significant impact on transient, postprandial metabolic flexibility and turnover compared to control groups. The goal of this study was to identify the brain metabolic changes at a transient (2 h) and steady (6 h) postprandial state in young mice (5-6 months of age) fed with CR or ad libitum (AL; free eating). Using metabolomics profiling, we show that CR mice had significantly higher levels of neurotransmitters (e.g., glutamate, N-acetylglutamate), neuronal integrity markers (e.g., NAA and NAAG), essential fatty acids (e.g., DHA and DPA), and biochemicals associated carnitine metabolism (related to reduced oxidative stress and inflammation) in the cerebral cortex and hippocampus at 2-h. These biochemicals remained at high levels at the 6-h postprandial time-point. The AL mice did not show the similar increases in essential fatty acid and carnitine metabolism until the 6-h time-point, and failed to show increases in neurotransmitters and neuronal integrity markers at any time-point. On the other hand, metabolites related to glucose utilization-glycolysis and pentose phosphate pathway (PPP)-were low in the CR mice throughout the 6-h period and significantly increased at the 6-h time-point in the AL mice. Our findings suggest that CR induces distinct postprandial responses in metabolites that are essential to maintain brain functions. CR mice produced higher levels of essential brain metabolites in a shorter period after a meal and sustained the levels for an extended period, while maintaining a lower level of glucose utilization. These early brain metabolism changes in the CR mice might play a critical role for neuroprotection in aging. Understanding the interplay between dietary intervention and postprandial metabolic responses from an early age may have profound implications for impeding brain aging and reducing risk for neurodegenerative disorders.
KEYWORDS:
aging; caloric restriction; metabolic plasticity; metabolomics; neurodegeneration; neurotransmitters; postprandial brain metabolism

Dietary restriction induces posttranscriptional regulation of longevity genes.
Rollins JA, Shaffer D, Snow SS, Kapahi P, Rogers AN.
Life Sci Alliance. 2019 Jun 28;2(4). pii: e201800281. doi: 10.26508/lsa.201800281. Print 2019 Aug.
PMID: 31253655
https://www.life-science-alliance.org/content/lsa/2/4/e201800281.full.pdf
Abstract
Dietary restriction (DR) increases life span through adaptive changes in gene expression. To understand more about these changes, we analyzed the transcriptome and translatome of Caenorhabditis elegans subjected to DR. Transcription of muscle regulatory and structural genes increased, whereas increased expression of amino acid metabolism and neuropeptide signaling genes was controlled at the level of translation. Evaluation of posttranscriptional regulation identified putative roles for RNA-binding proteins, RNA editing, miRNA, alternative splicing, and nonsense-mediated decay in response to nutrient limitation. Using RNA interference, we discovered several differentially expressed genes that regulate life span. We also found a compensatory role for translational regulation, which offsets dampened expression of a large subset of transcriptionally down-regulated genes. Furthermore, 3' UTR editing and intron retention increase under DR and correlate with diminished translation, whereas trans-spliced genes are refractory to reduced translation efficiency compared with messages with the native 5' UTR. Finally, we find that smg-6 and smg-7, which are genes governing selection and turnover of nonsense-mediated decay targets, are required for increased life span under DR.

Ghrelin receptor in AgRP neurons regulates metabolic adaptation to calorie restriction.
Wu CS, Bongmba OYN, Lee JH, Tuchaai E, Zhou Y, Li DP, Xue B, Chen Z, Sun Y.
J Neuroendocrinol. 2019 Jun 28:e12763. doi: 10.1111/jne.12763. [Epub ahead of print]
PMID: 31251830
Abstract
Ghrelin is a gut hormone that signals to the hypothalamus to stimulate growth hormone release, increase food intake and promote fat deposition. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons in the hypothalamus. Compelling evidence indicates that ghrelin serves as a survival hormone in maintaining blood glucose and body weight during nutritional deficiencies. Recent studies demonstrated that AgRP neurons are involved in metabolic and behavioral adaptation to energy deficit to improve survival. Here, we used a neuronal subtype-specific GHS-R knockout mouse (Agrp-Cre;Ghsrf/f ) to investigate the role of GHS-R in hypothalamic AgRP neurons in metabolic and behavioral adaptation to hypocaloric restricted feeding. We subjected the mice to a restricted feeding regimen of 40% mild calorie restriction (CR), with 1/4 food allotment given in the beginning of light cycle and 3/4 given at the beginning of dark cycle, to mimic normal mouse intake pattern. The CR-fed Agrp-Cre;Ghsrf/f mice exhibited reductions in body weight, fat mass and blood glucose. Metabolic profiling of these CR-fed Agrp-Cre;Ghsrf/f mice showed a trend toward reduced basal metabolic rate, significantly reduced core body temperature, and decreased expression of thermogenic genes in brown adipose tissue (BAT); this suggests a metabolic reset to a lower threshold. Significantly increased physical activity, a trend toward increased food anticipatory behavior, and altered fuel preferences were also observed in these mice. In addition, these CR-fed Agrp-Cre;Ghsrf/f mice exhibited a decreased counter-regulatory response, showing impaired hepatic glucose production. Lastly, hypothalamic gene expression in Agrp-Cre;Ghsrf/f mice revealed increased AgRP expression and decreased expression of genes in β-oxidation pathways. In summary, our data suggest that GHS-R in AgRP neurons is a key component of the neuro-circuitry involved in metabolic adaptation to calorie restriction.
KEYWORDS:
AgRP neurons; calorie restriction; ghrelin; glucose homeostasis; hepatic glucose production

[AlPater]

Physical activity plus energy restriction prevents 4T1.2 mammary tumor progression, MDSC accumulation, and an immunosuppressive tumor microenvironment.
Turbitt WJ, Xu Y, Sosnoski DM, Collins SD, Meng H, Mastro AM, Rogers CJ.
Cancer Prev Res (Phila). 2019 Jul 2. pii: canprevres.0233.2017. doi: 10.1158/1940-6207.CAPR-17-0233. [Epub ahead of print]
PMID: 31266827
Abstract
Physical activity and the prevention of weight gain decrease breast cancer incidence and improve survival. Unraveling the biological mechanisms underlying these cancer prevention effects is difficult because activity and dietary restriction are often linked. The goal of the current study was to determine whether physical activity (PA), preventing weight gain via energy restriction (ER), or the combination was most effective in delaying tumor growth, reducing metastatic progression, and improving survival in the 4T1.2 mammary tumor model. Furthermore, we determined if any of these interventions prevented the expansion of pro-tumor immunosuppressive cells and altered the tumor microenvironment (TME). Female BALB/c mice (n=7-20/group) were randomized to sedentary (SED) or physical activity wheel (PA) cages and fed ad libitum (AL) or 90% of control food intake (ER). After eight weeks on the interventions, mice were inoculated with 5x10^4 4T1.2luc cells into the 4th mammary fat pad and continued on their respective intervention. PA+ER significantly delayed primary tumor growth (final tumor volume, 0.193±0.042 vs. 0.369±0.049 cm3, p<0.001), reduced metastatic burden in the lungs (0.72±0.36 vs. 16.27±6.98, p=0.054) and increased survival (median survival, 68 vs 40 days, p=0.043) compared to SED+AL mice. PA+ER also reduced the expression level of metastatic and immunosuppressive genes and resulted in favorable changes in immune cell infiltrates in the tumor. These data suggest that both PA and ER are needed to reduce tumor growth, delay metastatic progression, and improve survival, and that this protection is associated with changes in immune-mediated mechanisms.

PGC-1a integrates a metabolism and growth network linked to caloric restriction.
Miller KN, Clark JP, Martin SA, Howell PR, Burhans MS, Haws SA, Johnson NB, Rhoads TW, Pavelec DM, Eliceiri KW, Roopra AS, Ntambi JM, Denu JM, Parks BW, Anderson RM.
Aging Cell. 2019 Jul 3:e12999. doi: 10.1111/acel.12999. [Epub ahead of print]
PMID: 31267675
https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.12999
Abstract
Deleterious changes in energy metabolism have been linked to aging and disease vulnerability, while activation of mitochondrial pathways has been linked to delayed aging by caloric restriction (CR). The basis for these associations is poorly understood, and the scope of impact of mitochondrial activation on cellular function has yet to be defined. Here, we show that mitochondrial regulator PGC-1a is induced by CR in multiple tissues, and at the cellular level, CR-like activation of PGC-1a impacts a network that integrates mitochondrial status with metabolism and growth parameters. Transcriptional profiling reveals that diverse functions, including immune pathways, growth, structure, and macromolecule homeostasis, are responsive to PGC-1a. Mechanistically, these changes in gene expression were linked to chromatin remodeling and RNA processing. Metabolic changes implicated in the transcriptional data were confirmed functionally including shifts in NAD metabolism, lipid metabolism, and membrane lipid composition. Delayed cellular proliferation, altered cytoskeleton, and attenuated growth signaling through post-transcriptional and post-translational mechanisms were also identified as outcomes of PGC-1a-directed mitochondrial activation. Furthermore, in vivo in tissues from a genetically heterogeneous mouse population, endogenous PGC-1a expression was correlated with this same metabolism and growth network. These data show that small changes in metabolism have broad consequences that arguably would profoundly alter cell function. We suggest that this PGC-1a sensitive network may be the basis for the association between mitochondrial function and aging where small deficiencies precipitate loss of function across a spectrum of cellular activities.
KEYWORDS:
NAD; PGC-1a; caloric restriction; lipid metabolism; longevity; mitochondria; redox metabolism

[AlPater]

Caloric Restriction Induces MicroRNAs to Improve Mitochondrial Proteostasis.
Zhang R, Wang X, Qu JH, Liu B, Zhang P, Zhang T, Fan PC, Wang XM, Xiao GY, Su Y, Xie Y, Liu Y, Pei JF, Zhang ZQ, Hao DL, Xu P, Chen HZ, Liu DP.
iScience. 2019 Jun 21;17:155-166. doi: 10.1016/j.isci.2019.06.028. [Epub ahead of print]
PMID: 31279933
https://www.cell.com/iscience/fulltext/S2589-0042(19)30211-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004219302111%3Fshowall%3Dtrue
Abstract
Both caloric restriction (CR) and mitochondrial proteostasis are linked to longevity, but how CR maintains mitochondrial proteostasis in mammals remains elusive. MicroRNAs (miRNAs) are well known for gene silencing in cytoplasm and have recently been identified in mitochondria, but knowledge regarding their influence on mitochondrial function is limited. Here, we report that CR increases miRNAs, which are required for the CR-induced activation of mitochondrial translation, in mouse liver. The ablation of miR-122, the most abundant miRNA induced by CR, or the retardation of miRNA biogenesis via Drosha knockdown significantly reduces the CR-induced activation of mitochondrial translation. Importantly, CR-induced miRNAs cause the overproduction of mtDNA-encoded proteins, which induces the mitochondrial unfolded protein response (UPRmt), and consequently improves mitochondrial proteostasis and function. These findings establish a physiological role of miRNA-enhanced mitochondrial function during CR and reveal miRNAs as critical mediators of CR in inducing UPRmt to improve mitochondrial proteostasis.
KEYWORDS:
Biological Sciences; Cell Biology; Functional Aspects of Cell Biology; Molecular Biology

[AlPater]

Gonadal hormones influence core body temperature during calorie restriction.
Cintron-Colon R, Shankar K, Sanchez-Alavez M, Conti B.
Temperature (Austin). 2019 Apr 26;6(2):158-168. doi: 10.1080/23328940.2019.1607653. eCollection 2019.
PMID: 31286026
https://sci-hub.tw/https://www.tandfonline.com/doi/full/10.1080/23328940.2019.1607653
Abstract
During calorie restriction (CR), endotherms adjust several physiological processes including the decrease of core body temperature (Tb) and reduction of energy expenditure. We recently found that CR-induced hypothermia is regulated in a sex-dependent manner in mice with lowered central insulin-like growth factor receptor signaling. Here, we describe the contribution of sex hormones to CR-induced hypothermia in wild type C57BL6 mice by measuring Tb of female and male mice following bilateral gonadectomy and hormonal replacement. Specifically, we evaluated the effects of progesterone (P4), 17-ß estradiol (E2), a combination of both (P4 + E2) in females and of 5-α dihydrotestosterone (5-α DHT) in males. Gonadectomy resulted in an earlier and stronger CR-induced hypothermia in both sexes. These effects were fully antagonized in females by E2 replacement, but not by P4, which had only minor and partial effects when used alone and did not prevent the action of E2 during CR when both hormones were given in combination. 5-α-DHT had only minor and transient effects on preventing the reduction of Tb during CR on gonadectomized male mice. These findings indicate that gonadal hormones contribute to sex-specific regulation of Tb and energy expenditure when nutrient availability is scarce. Abbreviations: AL: ad libitum; ANOVA: analysis of variance; CR: calorie restriction; E2: 17-ß estradiol; GNX: gonadectomy or gonadectomized; IGF-1R: insulin-like growth factor 1 receptor; POA: preoptic area; P4: progesterone; RM: repeated measures; SD: standard deviation; SEM: standard error of mean; Tb: core body temperature; WT: wildtype; 5-α DHT: 5-α dihydrotestosterone.
KEYWORDS:
Hypothermia; calorie restriction; estradiol; gonadal hormones; gonadectomy; temperature

[AlPater]

2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial
Prof William E Kraus, MD 
Manjushri Bhapkar, MS
Kim M Huffman, MD
Carl F Pieper, DrPh
Sai Krupa Das, PhD
Leanne M Redman, PhD
et al.
Published:July 11, 2019DOI:https://doi.org/10.1016/S2213-8587(19)30151-2
https://sci-hub.tw/10.1016/S2213-8587(19)30151-2
Summary
Background
For several cardiometabolic risk factors, values considered within normal range are associated with an increased risk of cardiovascular morbidity and mortality. We aimed to investigate the short-term and long-term effects of calorie restriction with adequate nutrition on these risk factors in healthy, lean, or slightly overweight young and middle-aged individuals.
Methods
CALERIE was a phase 2, multicentre, randomised controlled trial in young and middle-aged (21–50 years), healthy non-obese (BMI 22·0–27·9 kg/m 2) men and women done in three clinical centres in the USA. Participants were randomly assigned (2:1) to a 25% calorie restriction diet or an ad libitum control diet. Exploratory cardiometabolic risk factor responses to a prescribed 25% calorie restriction diet for 2 years were evaluated (systolic, diastolic, and mean blood pressure; plasma lipids; high-sensitivity C-reactive protein; metabolic syndrome score; and glucose homoeostasis measures of fasting insulin, glucose, insulin resistance, and 2-h glucose, area-under-the curve for glucose, and insulin from an oral glucose tolerance test) analysed in the intention-to-treat population.
Findings
From May 8, 2007, to Feb 26, 2010, of 238 participants that were assessed, 218 were randomly assigned to and started a 25% calorie restriction diet (n=143, 66%) or an ad libitum control diet (n=75, 34%). Individuals in the calorie restriction group achieved a mean reduction in calorie intake of 11·9% (SE 0·7; from 2467 kcal to 2170 kcal) versus 0·8% (1·0) in the control group, and a sustained mean weight reduction of 7·5 kg (SE 0·4) versus an increase of 0·1 kg (0·5) in the control group, of which 71% (mean change in fat mass 5·3 kg [SE 0·3] divided by mean change in weight 7·5 kg [0·4]) was fat mass loss. Calorie restriction caused a persistent and significant reduction from baseline to 2 years of all measured conventional cardiometabolic risk factors, including change scores for LDL-cholesterol (p<0·0001), total cholesterol to HDL-cholesterol ratio (p<0·0001), and systolic (p<0·0011) and diastolic (p<0·0001) blood pressure. In addition, calorie restriction resulted in a significant improvement at 2 years in C-reactive protein (p=0·012), insulin sensitivity index (p<0·0001), and metabolic syndrome score (p<0·0001) relative to control. A sensitivity analysis revealed the responses to be robust after controlling for relative weight loss changes.
Interpretation
2 years of moderate calorie restriction significantly reduced multiple cardiometabolic risk factors in young, non-obese adults. These findings suggest the potential for a substantial advantage for cardiovascular health of practicing moderate calorie restriction in young and middle-aged healthy individuals, and they offer promise for pronounced long-term population health benefits.

[AlPater]

Calorie restriction in an obesogenic environment: reality or fiction?
Hu FB.
Lancet Diabetes Endocrinol. 2019 Jul 11. pii: S2213-8587(19)30196-2. doi: 10.1016/S2213-8587(19)30196-2. [Epub ahead of print] No abstract available.
PMID: 31303391
https://sci-hub.tw/10.1016/S2213-8587(19)30196-2
>>>>>>>>>>>>>>>>>>>
2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial.
Kraus WE, Bhapkar M, Huffman KM, Pieper CF, Krupa Das S, Redman LM, Villareal DT, Rochon J, Roberts SB, Ravussin E, Holloszy JO, Fontana L; CALERIE Investigators.
Lancet Diabetes Endocrinol. 2019 Jul 11. pii: S2213-8587(19)30151-2. doi: 10.1016/S2213-8587(19)30151-2. [Epub ahead of print]
PMID: 31303390
https://sci-hub.tw/10.1016/S2213-8587(19)30151-2
https://www.crsociety.org/topic/11800-als-cr-updates/?page=11&tab=comments#comment-24195

[AlPater]

ATGL-1 mediates the effect of dietary restriction and the insulin/IGF-1 signaling pathway on longevity in C. elegans.
Zaarur N, Desevin K, Mackenzie J, Lord A, Grishok A, Kandror KV.
Mol Metab. 2019 Jul 5. pii: S2212-8778(19)30482-X. doi: 10.1016/j.molmet.2019.07.001. [Epub ahead of print]
PMID: 31311719
Abstract
OBJECTIVE:
Animal lifespan is controlled through genetic pathways that are conserved from nematodes to humans. Lifespan-promoting conditions in nematodes include fasting and a reduction of insulin/IGF signaling. Here we aimed to investigate the input of the Caenorhabditis elegans homologue of the mammalian rate-limiting lipolytic enzyme Adipose Triglyceride Lipase, ATGL-1, in longevity control.
METHODS:
We used a combination of genetic and biochemical approaches to determine the role of ATGL-1 in accumulation of triglycerides and regulation of longevity.
RESULTS:
We found that expression of ATGL is increased in the insulin receptor homologue mutant daf-2 in a FoxO/DAF-16-dependent manner. ATGL-1 is also up-regulated by fasting and in the eat-2 loss-of-function mutant strain. Overexpression of ATGL-1 increases basal and maximal oxygen consumption rate and extends lifespan in C. elegans. Reduction of ATGL-1 function suppresses longevity of the long-lived mutants eat-2 and daf-2.
CONCLUSION:
Our results demonstrate that ATGL is required for extended lifespan downstream of both dietary restriction and reduced insulin/IGF signaling.
KEYWORDS:
ATGL-1; C. elegans; DAF-16; DAF-2; Dietary restriction; Longevity

[AlPater]

Caloric restriction, longevity and aging: Recent contributions from human and non-human primate studies.
Pifferi F, Aujard F.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jul 17:109702. doi: 10.1016/j.pnpbp.2019.109702. [Epub ahead of print] 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

[AlPater]

Differential Effects of Alternate-Day Fasting Versus Daily Calorie Restriction on Insulin Resistance.
Gabel K, Kroeger CM, Trepanowski JF, Hoddy KK, Cienfuegos S, Kalam F, Varady KA.
Obesity (Silver Spring). 2019 Jul 22. doi: 10.1002/oby.22564. [Epub ahead of print]
PMID: 31328895
Abstract
OBJECTIVE:
This study compared the effects of alternate-day fasting (ADF) with those of daily calorie restriction (CR) on body weight and glucoregulatory factors in adults with overweight or obesity and insulin resistance.
METHODS:
This secondary analysis examined the data of insulin-resistant individuals (n = 43) who participated in a 12-month study that compared ADF (25% energy needs on "fast days"; 125% energy needs on alternating "feast days") with CR (75% energy needs every day) and a control group regimen.
RESULTS:
In insulin-resistant participants, weight loss was not different between ADF (-8% ± 2%) and CR (-6% ± 1%) by month 12, relative to controls (P < 0.0001). Fat mass and BMI decreased (P < 0.05) similarly from ADF and CR. ADF produced greater decreases (P < 0.05) in fasting insulin (-52% ± 9%) and insulin resistance (-53% ± 9%) compared with CR (-14% ± 9%; -17% ± 11%) and the control regimen by month 12. Lean mass, visceral fat mass, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, blood pressure, C-reactive protein, tumor necrosis factor α, and interleukin 6 values remained unchanged.
CONCLUSIONS:
These findings suggest that ADF may produce greater reductions in fasting insulin and insulin resistance compared with CR in insulin-resistant participants despite similar decreases in body weight.

[AlPater]

Identification and Application of Gene Expression Signatures Associated with Lifespan Extension.
Tyshkovskiy A, Bozaykut P, Borodinova AA, Gerashchenko MV, Ables GP, Garratt M, Khaitovich P, Clish CB, Miller RA, Gladyshev VN.
Cell Metab. 2019 Jul 19. pii: S1550-4131(19)30372-9. doi: 10.1016/j.cmet.2019.06.018. [Epub ahead of print]
PMID: 31353263
Abstract
Several pharmacological, dietary, and genetic interventions that increase mammalian lifespan are known, but general principles of lifespan extension remain unclear. Here, we performed RNA sequencing (RNA-seq) analyses of mice subjected to 8 longevity interventions. We discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences. Expanding this analysis to 17 interventions with public data, we observed that many interventions induced similar gene expression changes. We identified hepatic gene signatures associated with lifespan extension across interventions, including upregulation of oxidative phosphorylation and drug metabolism, and showed that perturbed pathways may be shared across tissues. We further applied the discovered longevity signatures to identify new lifespan-extending candidates, such as chronic hypoxia, KU-0063794, and ascorbyl-palmitate. Finally, we developed GENtervention, an app that visualizes associations between gene expression changes and longevity. Overall, this study describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions.
KEYWORDS:
GENtervention; aging; caloric restriction; feminizing effect; gene expression; growth hormone; lifespan extension; lifespan-extending interventions; longevity; longevity signatures; rapamycin

Caloric restriction and redox homeostasis in various regions of aging male rat brain: Is caloric restriction still worth trying even after early-adulthood?: Redox homeostasis and caloric restriction in brain.
Yanar K, Simsek B, Çaylı N, Övül Bozkır H, Mengi M, Belce A, Aydin S, Çakatay U.
J Food Biochem. 2019 Mar;43(3):e12740. doi: 10.1111/jfbc.12740. Epub 2018 Dec 5.
PMID: 31353564
Abstract
Despite recent studies have shown that caloric restriction (CR) could improve some functional loss associated with brain aging, the biochemical effects of CR on brain aging are still not well understood on a quantifiable biochemical basis, including whether CR could be protective when started around middle adulthood, when age-related neurodegenerative diseases are thought to set in. Therefore, in the light of more than ever aging societies and increasing neurodegenerative diseases, we aimed to test the biochemical effects of CR on redox homeostasis in different parts of male Sprague-Dawley rat brain by using the biomarkers we consistently validated in our previous work (TOS, PCO, AOPP, AGEs, sRAGE, P-SH, LHPs, 4-HNE, TAS, Cu, Zn-SOD). Our results indicate that oxidative stress biomarkers are lower in CR group, implying a more favorable redox status that has been previously shown to be correlated with better neural function. PRACTICAL APPLICATIONS: We report that the beneficial effects of caloric restriction (CR) on various brain tissues result in significant improvements in biochemical markers, even though CR is not started in early adulthood. Hence, our select age group provides a sound redox status-related neurochemical understanding for many recent CR studies, where a functional loss was detected at this age.
KEYWORDS:
aging; brain lobes; caloric restriction; oxidative stress; redox homeostasis

[AlPater]

Effect of caloric restriction and rapamycin on ovarian aging in mice.
Garcia DN, Saccon TD, Pradiee J, Rincón JAA, Andrade KRS, Rovani MT, Mondadori RG, Cruz LAX, Barros CC, Masternak MM, Bartke A, Mason JB, Schneider A.
Geroscience. 2019 Jul 29. doi: 10.1007/s11357-019-00087-x. [Epub ahead of print]
PMID: 31359237
Abstract
Caloric restriction (CR) increases the preservation of the ovarian primordial follicular reserve, which can potentially delay menopause. Rapamycin also increases preservation on the ovarian reserve, with similar mechanism to CR. Therefore, the aim of our study was to evaluate the effects of rapamycin and CR on metabolism, ovarian reserve, and gene expression in mice. Thirty-six female mice were allocated into three groups: control, rapamycin-treated (4 mg/kg body weight every other day), and 30% CR. Caloric restricted females had lower body weight (P < 0.05) and increased insulin sensitivity (P = 0.003), while rapamycin injection did not change body weight (P > 0.05) and induced insulin resistance (P < 0.05). Both CR and rapamycin females displayed a higher number of primordial follicles (P = 0.02 and 0.04, respectively), fewer primary, secondary, and tertiary follicles (P < 0.05) and displayed increased ovarian Foxo3a gene expression (P < 0.05). Despite the divergent metabolic effects of the CR and rapamycin treatments, females from both groups displayed a similar increase in ovarian reserve, which was associated with higher expression of ovarian Foxo3a.
KEYWORDS:
FOXO3a; Ovarian reserve; Rapamycin; mTOR

[AlPater]

Life-Shortening Effect of Chronic Low-Dose-Rate Irradiation in Calorie-Restricted Mice.
Yamauchi K, Ono T, Ayabe Y, Hisamatsu S, Yoneya M, Tsutsumi Y, Komura JI.
Radiat Res. 2019 Aug 7. doi: 10.1667/RR15385.1. [Epub ahead of print]
PMID: 31390311
Abstract
Calorie restriction is known to influence several physiological processes and to alleviate the late effects of radiation exposure such as neoplasm induction and life shortening. However, earlier related studies were limited to acute radiation exposure. Therefore, in this study we examined the influence of chronic low-dose-rate irradiation on lifespan. Young male B6C3F1/Jcl mice were divided randomly into two groups, which were fed either a low-calorie (65 kcal/week) or high-calorie (95 kcal/week) diet. The latter is comparable to ad libitum feeding. The animals in the irradiated group were continuously exposed to gamma rays for 400 days at 20 mGy/day, resulting in a total dose of 8 Gy. Exposure and calorie restriction were initiated at 8 weeks of age and the diets were maintained for life. The life-shortening effects from chronic whole-body irradiation were compared between the groups. Body weights were reduced in calorie-restricted mice irrespective of radiation treatment. Radiation induced a shortened median lifespan in both groups, but to a greater extent in the calorie-restricted mice. These results suggest that calorie restriction may sensitize mice to chronic low-dose-rate radiation exposure to produce a life-shortening effect rather than alleviating the effects of radiation.

[AlPater]

Change in self-efficacy, eating behaviors and food cravings during two years of calorie restriction in humans without obesity.
Dorling J, Bhapkar M, Das SK, Racette SB, Apolzan JW, Fearnbach SN, Redman LM, Myers CA, Stewart TM, Martin CK; CALERIE Study Group.
Appetite. 2019 Aug 6:104397. doi: 10.1016/j.appet.2019.104397. [Epub ahead of print]
PMID: 31398376
Abstract
Calorie restriction (CR) enhances longevity in humans who are normal weight, overweight and obese. While dietary regimens can change self-efficacy, eating behaviors, and food cravings in individuals with obesity, the responses of these measures to prolonged CR in individuals who are exclusively not obese is unknown. The aim of this analysis was to test the effects of a two-year CR intervention on self-efficacy and eating attitudes and behaviors in humans without obesity by analyzing data from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE 2) study. Participants (n = 218, BMI range = 21.3-29.0 kg/m2) were randomized to a 25% CR group or an ad libitum (AL) group. Eating attitudes and behaviors and self-efficacy were assessed using validated questionnaires at baseline, 12, and 24 months. Dietary restraint and self-efficacy increased in the CR compared to the AL group (ES ≥ 0.32). Increased self-efficacy was negatively related to weight change (ρ < -0.24). In the CR group, males showed a reduction in cravings for carbohydrates and fats at month 24, whereas females did not. The CR group showed elevations in state hunger, which were transient, and disinhibited eating (ES ≥ 0.37). In individuals without obesity, dietary restraint and self-efficacy could be important in promoting long-term CR for individuals looking to use CR as a tool to improve longevity.
KEYWORDS:
Calorie restriction; Eating behaviors; Food cravings; Self-efficacy

Impact of energy turnover on the regulation of glucose homeostasis in healthy subjects.
Büsing F, Hägele FA, Nas A, Hasler M, Müller MJ, Bosy-Westphal A.
Nutr Diabetes. 2019 Aug 8;9(1):22. doi: 10.1038/s41387-019-0089-6.
PMID: 31395858
https://www.nature.com/articles/s41387-019-0089-6.pdf
Abstract
OBJECTIVE:
Sedentary lifestyle increases the risk of type 2 diabetes. The aim of this study was to investigate the impact of different levels of energy turnover (ET; low, medium, and high level of physical activity and the corresponding energy intake) on glucose metabolism at zero energy balance, caloric restriction, and overfeeding.
METHODS:
Sixteen healthy individuals (13 men, 3 women, 25.1 ± 3.9 years, BMI 24.0 ± 3.2 kg/m2) participated in a randomized crossover intervention under metabolic ward conditions. Subjects passed 3 × 3 intervention days. Three levels of physical activity (PAL: low 1.3, medium 1.6, and high 1.8 achieved by walking at 4 km/h for 0, 3 × 55, or 3 × 110 min) were compared under three levels of energy balance (zero energy balance (EB): 100% of energy requirement (Ereq); caloric restriction (CR): 75% Ereq, and overfeeding (OF): 125% Ereq). Continuous interstitial glucose monitoring, C-peptide excretion, and HOMA-IR, as well as postprandial glucose and insulin were measured.
RESULTS:
Daylong glycemia and insulin secretion did not increase with higher ET at all conditions of energy balance (EB, CR, and OF), despite a correspondingly higher CHO intake (Δ low vs. high ET: +86 to 135 g of CHO/d). At CR, daylong glycemia (p = 0.02) and insulin secretion (p = 0.04) were even reduced with high compared with low ET. HOMA-IR was impaired with OF and improved with CR, whereas ET had no effect on fasting insulin sensitivity. A higher ET led to lower postprandial glucose and insulin levels under conditions of CR and OF.
CONCLUSION:
Low-intensity physical activity can significantly improve postprandial glycemic response of healthy individuals, independent of energy balance.

[AlPater]

Short-term dietary restriction in old mice rejuvenates the aging-induced structural imbalance of gut microbiota.
Zeng T, Cui H, Tang D, Garside GB, Wang Y, Wu J, Tao Z, Zhang L, Tao S.
Biogerontology. 2019 Aug 10. doi: 10.1007/s10522-019-09830-5. [Epub ahead of print]
PMID: 31401701
Abstract
The world's aging population is growing rapidly. Incidences of multiple pathologies, such as abdominal obesity, cardiovascular and cerebrovascular diseases, type 2 diabetes, and malignant neoplasms, increase sharply with age. Aged individuals possess a significantly shifted composition of gut microbiota, which is suggested to play important roles in aging associated pathologies. Whether the existing shifted structural composition of microbiota in aged populations can be reverted non-pharmacologically has not been studied so far. Here, we show an intestinal flora imbalance in old C57BL/6J mice with a remarkable dominant proportion of microbes promoting lipid metabolism and inflammation. Intriguingly, short-term (2 months) dietary restriction was enough to significantly revert the imbalance of intestinal flora in aged mice toward a more balanced structural composition as shown in young mice. ... Our study provides the first evidence that short-term dietary restriction in old mice can restore the already dysfunctional aged gut microbiota, which may help ameliorate aging-related disorders plaguing the vast elderly population.
KEYWORDS:
Aging; Dietary restriction; Gut microbiota; Inflammation; Obesity; Rejuvenate

[AlPater]

Effects of Moderate Chronic Food Restriction on the Development of Postprandial Dyslipidemia with Ageing.
Fernández A, Mazuecos L, Pintado C, Rubio B, López V, de Solís AJ, Rodríguez M, Andrés A, Gallardo N.
Nutrients. 2019 Aug 10;11(8). pii: E1865. doi: 10.3390/nu11081865.
PMID: 31405194
https://www.mdpi.com/2072-6643/11/8/1865/htm
Abstract
Ageing is a major risk factor for the development of metabolic disorders linked to dyslipidemia, usually accompanied by increased adiposity. The goal of this work was to investigate whether avoiding an excessive increase in adiposity with ageing, via moderate chronic food restriction (FR), ameliorates postprandial dyslipidemia in a rat model of metabolic syndrome associated with ageing. Accordingly, we performed an oral lipid loading test (OLLT) in mature middle-aged (7 months) and middle-old-aged (24 months) Wistar rats fed ad libitum (AL) or under moderate FR for 3 months. Briefly, overnight fasted rats were orally administered a bolus of extra-virgin olive oil (1 mL/Kg of body weight) and blood samples were taken from the tail vein before fat load (t = 0) and 30, 60, 90, 120, 180, and 240 min after fat administration. Changes in serum lipids, glucose, insulin, and glucagon levels were measured at different time-points. Expression of liver and adipose tissue metabolic genes were also determined before (t = 0) and after the fat load (t = 240 min). Postprandial dyslipidemia progressively increased with ageing and this could be associated with hepatic ChREBP activity. Interestingly, moderate chronic FR reduced adiposity and avoided excessive postprandial hypertriglyceridemia in 7- and 24-month-old Wistar rats, strengthening the association between postprandial triglyceride levels and adiposity. The 24-month-old rats needed more insulin to maintain postprandial normoglycemia; nevertheless, hyperglycemia occurred at 240 min after fat administration. FR did not alter the fasted serum glucose levels but it markedly decreased glucagon excursion during the OLLT and the postprandial rise of glycemia in the 24-month-old rats, and FGF21 in the 7-month-old Wistar rats. Hence, our results pointed to an important role of FR in postprandial energy metabolism and insulin resistance in ageing. Lastly, our data support the idea that the vWAT might function as an ectopic site for fat deposition in 7-month-old and in 24-month-old Wistar rats that could increase their browning capacity in response to an acute fat load.
KEYWORDS:
ChREBP; adipose tissue; ageing; oral lipid loading test; postprandial hypertrigliceridemia; postprandial thermogenesis

Fasting and rapamycin: diabetes versus benevolent glucose intolerance.
Blagosklonny MV.
Cell Death Dis. 2019 Aug 13;10(8):607. doi: 10.1038/s41419-019-1822-8. Review.
PMID: 31406105
https://www.nature.com/articles/s41419-019-1822-8
Abstract
Rapamycin (Sirolimus) slows aging, extends life span, and prevents age-related diseases, including diabetic complications such as retinopathy. Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes. There is no indication that starvation (benevolent) pseudo-diabetes is detrimental. By contrast, it is associated with better health and life extension. In transplant patients, a weak association between rapamycin/everolimus use and hyperglycemia is mostly due to a drug interaction with calcineurin inhibitors. When it occurs in cancer patients, the hyperglycemia is mild and reversible. No hyperglycemic effects of rapamycin/everolimus have been detected in healthy people. For antiaging purposes, rapamycin/everolimus can be administrated intermittently (e.g., once a week) in combination with intermittent carbohydrate restriction, physical exercise, and metformin.

[AlPater]

Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis.
Matai L, Sarkar GC, Chamoli M, Malik Y, Kumar SS, Rautela U, Jana NR, Chakraborty K, Mukhopadhyay A.
Proc Natl Acad Sci U S A. 2019 Aug 14. pii: 201900055. doi: 10.1073/pnas.1900055116. [Epub ahead of print]
PMID: 31413197
https://www.pnas.org/content/early/2019/08/13/1900055116
Abstract
Unfolded protein response (UPR) of the endoplasmic reticulum (UPRER) helps maintain proteostasis in the cell. The ability to mount an effective UPRER to external stress (iUPRER) decreases with age and is linked to the pathophysiology of multiple age-related disorders. Here, we show that a transient pharmacological ER stress, imposed early in development on Caenorhabditis elegans, enhances proteostasis, prevents iUPRER decline with age, and increases adult life span. Importantly, dietary restriction (DR), that has a conserved positive effect on life span, employs this mechanism of ER hormesis for longevity assurance. We found that only the IRE-1-XBP-1 branch of UPRER is required for the longevity effects, resulting in increased ER-associated degradation (ERAD) gene expression and degradation of ER resident proteins during DR. Further, both ER hormesis and DR protect against polyglutamine aggregation in an IRE-1-dependent manner. We show that the DR-specific FOXA transcription factor PHA-4 transcriptionally regulates the genes required for ER homeostasis and is required for ER preconditioning-induced life span extension. Finally, we show that ER hormesis improves proteostasis and viability in a mammalian cellular model of neurodegenerative disease. Together, our study identifies a mechanism by which DR offers its benefits and opens the possibility of using ER-targeted pharmacological interventions to mimic the prolongevity effects of DR.
KEYWORDS:
aging; dietary restriction; endoplasmic reticulum; hormesis; life span

Impact of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeys.
Natarajan N, Vujic A, Das J, Wang AC, Phu KK, Kiehm SH, Ricci-Blair EM, Zhu AY, Vaughan KL, Colman RJ, Mattison JA, Lee RT.
JCI Insight. 2019 Aug 15. pii: 128685. doi: 10.1172/jci.insight.128685. [Epub ahead of print]
PMID: 31415241
https://insight.jci.org/articles/view/128685/pdf
Abstract
Calorie restriction (CR) improved healthspan in two longitudinal studies in nonhuman primates (NHPs), yet only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Here, analysis of left ventricle samples showed that CR did not reduce cardiac fibrosis relative to controls. However, there was a 5.9-fold increase of total fibrosis in UW hearts, compared to NIA. Diet composition was a prominent difference between the studies; therefore, we used the NHP diets to characterize diet-associated molecular and functional changes in the hearts of mice. Consistent with the findings from the NHP samples, mice fed UW or a modified NIA diet with increased sucrose and fat developed greater cardiac fibrosis compared to the NIA diet, and transcriptomics analysis revealed diet-induced activation of myocardial oxidative phosphorylation and cardiac muscle contraction pathways.
KEYWORDS:
Aging; Cardiology; Cardiovascular disease; Fibrosis

[AlPater]

Effects of long-term intermittent versus chronic calorie restriction on oxidative stress in a mouse cancer model.
Cicekdal MB, Tuna BG, Charehsaz M, Cleary MP, Aydin A, Dogan S.
IUBMB Life. 2019 Aug 19. doi: 10.1002/iub.2145. [Epub ahead of print]
PMID: 31424629
https://sci-hub.tw/10.1002/iub.2145
Abstract
Calorie restriction (CR) is one of the most effective methods to prevent many diseases including cancer in preclinical models. However, the molecular mechanism of how CR prevents cancer is unclear. The aim of this study was to understand the role of oxidative stress (OS) in the preventive effects of different types of CR in aging mouse mammary tumor virus-transforming growth factor-alpha (MMTV-TGF-α) female mice. Mice were enrolled in ad libitum (AL), chronic CR (CCR, 15% CR) or intermittent CR [ICR, 3 weeks AL (ICR-Refeed, ICR-RF) and 1 week 60% CR (ICR-Restriction, ICR-R) in cyclic periods] groups started at the age of 10 weeks and continued until 81/82 weeks of age. Blood samples were collected to measure malondialdehyde (MDA), glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) levels. There was no significant difference for MDA levels among the dietary groups although the chronic calorie restriction (CCR) group had lower MDA levels compared to intermittent calorie restriction (ICR) and AL group at different time points. There was also no change in MDA levels of CCR group with aging. On the other hand, the CCR group had higher CAT and SOD activity compared to ICR-R, ICR-RF, and AL groups. Moreover, GSH level was higher in CCR compared to ICR group at week 49/50 (p < .05). CAT and SOD activities were also positively correlated (p < .05). Here, for the first time, the long-term (72 weeks) effects of different types of CR on OS parameters were reported. In conclusion, moderate that is, 15%, CCR is more likely to be protective compared to the same overall calorie deficit implemented by ICR against OS that may play role in the preventive effects of CR.
KEYWORDS:
MMTV-TGF-α mice; breast cancer; energy restriction; intermittent calorie restriction; mammary tumor; oxidative stress

[AlPater]

When Fasting Gets Tough, the Tough Immune Cells Get Going-or Die.
Buono R, Longo VD.
Cell. 2019 Aug 22;178(5):1038-1040. doi: 10.1016/j.cell.2019.07.052.
PMID: 31442398
Abstract
Cycles of fasting reduce autoimmunity and activate lymphocyte-dependent killing of cancer cells, but the mechanisms remain poorly understood. Three studies in this issue of Cell begin to reveal the drastic and complex effects of fasting and severe calorie restriction on the levels and localization of different immune cells and the mechanisms responsible for them.
>>>>>>>>>>>>>>>
Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses.
Nagai M, Noguchi R, Takahashi D, Morikawa T, Koshida K, Komiyama S, Ishihara N, Yamada T, Kawamura YI, Muroi K, Hattori K, Kobayashi N, Fujimura Y, Hirota M, Matsumoto R, Aoki R, Tamura-Nakano M, Sugiyama M, Katakai T, Sato S, Takubo K, Dohi T, Hase K.
Cell. 2019 Aug 22;178(5):1072-1087.e14. doi: 10.1016/j.cell.2019.07.047.
PMID: 31442401
https://sci-hub.tw/10.1016/j.cell.2019.07.047
Abstract
Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis.
KEYWORDS:
B cell; CXCL13; IgA; Immunometabolism; Peyer's patch; bone marrow; fasting; mTOR signaling; mucosal immunity; nutritional signals; stroma cell
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Dietary Intake Regulates the Circulating Inflammatory Monocyte Pool.
Jordan S, Tung N, Casanova-Acebes M, Chang C, Cantoni C, Zhang D, Wirtz TH, Naik S, Rose SA, Brocker CN, Gainullina A, Hornburg D, Horng S, Maier BB, Cravedi P, LeRoith D, Gonzalez FJ, Meissner F, Ochando J, Rahman A, Chipuk JE, Artyomov MN, Frenette PS, Piccio L, Berres ML, Gallagher EJ, Merad M.
Cell. 2019 Aug 22;178(5):1102-1114.e17. doi: 10.1016/j.cell.2019.07.050.
PMID: 31442403
https://www.cell.com/cell/pdf/S0092-8674(19)30850-5.pdf
Abstract
Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
KEYWORDS:
AMPK; CCL2; Caloric restriction; PPARα; fasting; inflammation; inflammatory disease; liver; metabolism; monocyte
>>>>>>>>>>>>>>>>>>>.
The Bone Marrow Protects and Optimizes Immunological Memory during Dietary Restriction.
Collins N, Han SJ, Enamorado M, Link VM, Huang B, Moseman EA, Kishton RJ, Shannon JP, Dixit D, Schwab SR, Hickman HD, Restifo NP, McGavern DB, Schwartzberg PL, Belkaid Y.
Cell. 2019 Aug 22;178(5):1088-1101.e15. doi: 10.1016/j.cell.2019.07.049.
PMID: 31442402
https://www.crsociety.org/topic/17090-memory-t-cells-shelter-in-bone-marrow-with-restricted-diets/?tab=comments#comment-32510
https://www.cell.com/cell/pdf/S0092-8674(19)30849-9.pdf
Abstract
Mammals evolved in the face of fluctuating food availability. How the immune system adapts to transient nutritional stress remains poorly understood. Here, we show that memory T cells collapsed in secondary lymphoid organs in the context of dietary restriction (DR) but dramatically accumulated within the bone marrow (BM), where they adopted a state associated with energy conservation. This response was coordinated by glucocorticoids and associated with a profound remodeling of the BM compartment, which included an increase in T cell homing factors, erythropoiesis, and adipogenesis. Adipocytes, as well as CXCR4-CXCL12 and S1P-S1P1R interactions, contributed to enhanced T cell accumulation in BM during DR. Memory T cell homing to BM during DR was associated with enhanced protection against infections and tumors. Together, this work uncovers a fundamental host strategy to sustain and optimize immunological memory during nutritional challenges that involved a temporal and spatial reorganization of the memory pool within "safe haven" compartments.