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1
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Finnell JE, Ferrario CR. Voluntary food restriction does not affect circulating corticosterone in obesity-prone or -resistant male and female rats. Physiol Behav 2025; 288:114729. [PMID: 39510225 DOI: 10.1016/j.physbeh.2024.114729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 10/09/2024] [Accepted: 11/03/2024] [Indexed: 11/15/2024]
Abstract
Food restriction in rodents can increase circulating corticosterone, which reflects activation of physiological stress responses. These responses affect a myriad of behaviors and physiological processes and can increase the risk of obesity. Most studies in this area have used experimenter-imposed restriction. However, rats will voluntarily restrict their food intake if they are returned to chow after a period of access to sugary, fatty "junk food" (JF) diet. Here we examine the effects of voluntary food restriction in obesity-prone and -resistant male and female rats on circulating corticosterone concentrations and determine whether corticosterone release in response to acute stress differs in groups with a history of JF consumption.
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Affiliation(s)
- Julie E Finnell
- Department of Pharmacology, University of Michigan, Ann Arbor MI 48109, USA; Pharmacology and Toxicology State University of New York at Buffalo, Buffalo NY 14203, USA
| | - Carrie R Ferrario
- Department of Pharmacology, University of Michigan, Ann Arbor MI 48109, USA; Psychology Department (Biopsychology Area), University of Michigan, Ann Arbor MI 48109, USA.
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2
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Staffeld A, Gill S, Zimmermann A, Böge N, Schuster K, Lang S, Kipp M, Palme R, Frintrop L. Establishment of a Murine Chronic Anorexia Nervosa Model. Cells 2023; 12:1710. [PMID: 37443744 PMCID: PMC10340390 DOI: 10.3390/cells12131710] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Anorexia nervosa (AN) is associated with hyperactivity, amenorrhea, and brain atrophy. The underlying pathophysiology is mostly unknown, and new targets for therapeutic interventions are needed. This study aimed to systematically establish a murine AN model with the parameter extent of starvation, animal age, and length of starvation for functional studies. The activity-based anorexia (ABA) model combines food restriction with running wheel access. Early adolescent and adolescent mice received 40% of their baseline food intake until a 20% or 25% weight reduction was reached (acute starvation). To mimic chronic starvation, body weight loss was maintained for another two weeks. Running activity was examined using wheel sensors, while amenorrhea was investigated by analysis of vaginal smears. Brain sections were used to analyze cerebral cortex volumes. Acute starvation did not lead to either AN-related symptoms, whereas chronic starvation led to hyperactivity and amenorrhea except in the adolescent cohort with 20% weight reduction. Only ABA mice with 25% weight reduction revealed a cortex volume reduction. The optimal parameters to mirror AN-related symptoms included a 25% weight reduction, early adolescent or adolescent mice, and chronic starvation. The ABA model enables functional analysis of the impact of chronic AN on the underlying hormonal, behavioral, and brain pathophysiology.
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Affiliation(s)
- Anna Staffeld
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Sadaf Gill
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Annelie Zimmermann
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Natalie Böge
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Katharina Schuster
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Stephan Lang
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Markus Kipp
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Rupert Palme
- Unit of Physiology, Pathophysiology and Experimental Endocrinology, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, A-1210 Vienna, Austria
| | - Linda Frintrop
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
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3
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Restricted cafeteria feeding and treadmill exercise improved body composition, metabolic profile and exploratory behavior in obese male rats. Sci Rep 2022; 12:19545. [PMID: 36379981 PMCID: PMC9666649 DOI: 10.1038/s41598-022-23464-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 10/31/2022] [Indexed: 11/16/2022] Open
Abstract
The aim of this study was to evaluate, in male Long-Evans rats, whether a restricted-cafeteria diet (CAFR), based on a 30% calorie restriction vs continuous ad libitum cafeteria (CAF) fed animals, administered alone or in combination with moderate treadmill exercise (12 m/min, 35 min, 5 days/week for 8 weeks), was able to ameliorate obesity and the associated risk factors induced by CAF feeding for 18 weeks and to examine the changes in circadian locomotor activity, hypothalamic-pituitary-adrenal (HPA) axis functionality, and stress response elicited by this dietary pattern. In addition to the expected increase in body weight and adiposity, and the development of metabolic dysregulations compatible with Metabolic Syndrome, CAF intake resulted in a sedentary profile assessed by the home-cage activity test, reduced baseline HPA axis activity through decreased corticosterone levels, and boosted exploratory behavior. Both CAFR alone and in combination with exercise reduced abdominal adiposity and hypercholesterolemia compared to CAF. Exercise increased baseline locomotor activity in the home-cage in all dietary groups, boosted exploratory behavior in STD and CAF, partially decreased anxiety-like behavior in CAF and CAFR, but did not affect HPA axis-related parameters.
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Tesic V, Ciric J, Jovanovic Macura I, Zogovic N, Milanovic D, Kanazir S, Perovic M. Corticosterone and Glucocorticoid Receptor in the Cortex of Rats during Aging-The Effects of Long-Term Food Restriction. Nutrients 2021; 13:nu13124526. [PMID: 34960078 PMCID: PMC8703853 DOI: 10.3390/nu13124526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 11/16/2022] Open
Abstract
Numerous beneficial effects of food restriction on aging and age-related pathologies are well documented. It is also well-established that both short- and long-term food restriction regimens induce elevated circulating levels of glucocorticoids, stress-induced hormones produced by adrenal glands that can also exert deleterious effects on the brain. In the present study, we examined the effect of long-term food restriction on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the cortex during aging, in 18- and 24-month-old rats. Corticosterone level was increased in the cortex of aged ad libitum-fed rats. Food restriction induced its further increase, accompanied with an increase in the level of 11β-hydroxysteroid dehydrogenase type 1. However, alterations in the level of GR phosphorylated at Ser232 were not detected in animals on food restriction, in line with unaltered CDK5 level, the decrease of Hsp90, and an increase in a negative regulator of GR function, FKBP51. Moreover, our data revealed that reduced food intake prevented age-related increase in the levels of NFκB, gfap, and bax, confirming its anti-inflammatory and anti-apoptotic effects. Along with an increase in the levels of c-fos, our study provides additional evidences that food restriction affects cortical responsiveness to glucocorticoids during aging.
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Affiliation(s)
- Vesna Tesic
- Department of Neurobiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bul. despota Stefana 142, 11060 Belgrade, Serbia; (V.T.); (J.C.); (I.J.M.); (D.M.); (M.P.)
| | - Jelena Ciric
- Department of Neurobiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bul. despota Stefana 142, 11060 Belgrade, Serbia; (V.T.); (J.C.); (I.J.M.); (D.M.); (M.P.)
| | - Irena Jovanovic Macura
- Department of Neurobiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bul. despota Stefana 142, 11060 Belgrade, Serbia; (V.T.); (J.C.); (I.J.M.); (D.M.); (M.P.)
| | - Nevena Zogovic
- Department of Neurophysiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bul. despota Stefana 142, 11060 Belgrade, Serbia;
| | - Desanka Milanovic
- Department of Neurobiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bul. despota Stefana 142, 11060 Belgrade, Serbia; (V.T.); (J.C.); (I.J.M.); (D.M.); (M.P.)
| | - Selma Kanazir
- Department of Neurobiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bul. despota Stefana 142, 11060 Belgrade, Serbia; (V.T.); (J.C.); (I.J.M.); (D.M.); (M.P.)
- Correspondence:
| | - Milka Perovic
- Department of Neurobiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bul. despota Stefana 142, 11060 Belgrade, Serbia; (V.T.); (J.C.); (I.J.M.); (D.M.); (M.P.)
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Allen BD, Liao C, Shu J, Muglia LJ, Majzoub JA, Diaz V, Nelson JF. Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice. Aging Cell 2019; 18:e12944. [PMID: 30938024 PMCID: PMC6516174 DOI: 10.1111/acel.12944] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 01/26/2019] [Accepted: 02/18/2019] [Indexed: 11/30/2022] Open
Abstract
Calorie restriction (CR), which lengthens lifespan in many species, is associated with moderate hyperadrenocorticism and attenuated inflammation. Given the anti‐inflammatory action of glucocorticoids, we tested the hypothesis that the hyperadrenocorticism of CR contributes to its attenuated inflammatory response. We used a corticotropin‐releasing‐hormone knockout (CRHKO) mouse, which is glucocorticoid insufficient. There were four controls groups: CRHKO mice and wild‐type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL‐fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24‐hr plasma CORT levels of AL‐fed WT mice, (b) CR‐fed CRHKO mice given CORT to match the 24‐hr CORT levels of AL‐fed WT mice, and (c) CR‐fed CHRKO mice given CORT to match the 24‐hr CORT levels of CR‐fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT‐deficient CR‐fed CRHKO mice. Replacement of CORT in CR‐fed CRHKO mice to the elevated levels observed in CR‐fed WT mice, but not to the levels observed in AL‐fed WT mice, restored the anti‐inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti‐inflammatory action of CR, which may in turn contribute to its life‐extending actions.
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Affiliation(s)
- Brian D. Allen
- Department of Cellular and Integrative Physiology University of Texas Health Science Center at San Antonio San Antonio Texas
- Barshop Institute for Longevity and Aging Studies The University of Texas Health Science Center at San Antonio San Antonio Texas
- Geriatric Research, Education and Clinical Center and Research Service South Texas Veterans Health Care System San Antonio Texas
| | - Chen‐Yu Liao
- Department of Cellular and Integrative Physiology University of Texas Health Science Center at San Antonio San Antonio Texas
- Barshop Institute for Longevity and Aging Studies The University of Texas Health Science Center at San Antonio San Antonio Texas
| | - Jianhua Shu
- Department of Cellular and Integrative Physiology University of Texas Health Science Center at San Antonio San Antonio Texas
- Barshop Institute for Longevity and Aging Studies The University of Texas Health Science Center at San Antonio San Antonio Texas
- Geriatric Research, Education and Clinical Center and Research Service South Texas Veterans Health Care System San Antonio Texas
| | - Louis J. Muglia
- Department of Molecular Biology and Pharmacology Washington University School of Medicine St. Louis Missouri
| | - Joseph A. Majzoub
- Division of Endocrinology, Department of Medicine Boston Children’s Hospital, Harvard Medical School Boston Massachusetts
| | - Vivian Diaz
- Barshop Institute for Longevity and Aging Studies The University of Texas Health Science Center at San Antonio San Antonio Texas
| | - James F. Nelson
- Department of Cellular and Integrative Physiology University of Texas Health Science Center at San Antonio San Antonio Texas
- Barshop Institute for Longevity and Aging Studies The University of Texas Health Science Center at San Antonio San Antonio Texas
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Maliković J, Vuyyuru H, Koefeler H, Smidak R, Höger H, Kalaba P, Hussein AM, Lubec G, Korz V. Moderate differences in common feeding diets change lipid composition in the hippocampal dentate gyrus and affect spatial cognitive flexibility in male rats. Neurochem Int 2019; 128:215-221. [PMID: 31051212 DOI: 10.1016/j.neuint.2019.04.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/27/2019] [Accepted: 04/30/2019] [Indexed: 01/17/2023]
Abstract
There is growing evidence that lipids play a fundamental role in neuronal plasticity and learning and memory. Effects of nutrition on brain lipid composition and neuronal functioning are known, but the feeding interventions are often severe and may not reflect nutritional effects below clinical relevance. Therefore, we tested two commercially available rat feeding diets with only moderate differences in the food compositions, a standard diet (gross energy metabolizable 12.8 MJ/kg) and a energy reduced diet (gross energy metabolizable 8.9 MJ/kg) on possible effects upon dentate gyrus lipid composition, spatial learning and memory in a water maze and corticosterone release (blood serum concentrations) in adult male rats. Rats were fed with the standard diet up to an age of 8 weeks. One group was further fed with the standard and another with the energy reduced diet until an age of 5 months. We did not found differences in serum corticosterone levels. We found group differences in a variety of lipids in the hippocampal dentate gyrus.. Most of the lipid levels were lower in energy reduced diets, namely glycerophosphoethanolamines, sphingomyelins and hexosyceramides, whereas some ceramides (Cer18:0 and Cer24:1) and glycerophosphocholines (PC34:3 and PC36:2) were upregulated compared to the standard diet group. The performance in a common reference memory water maze task was not different between groups, however during reversal learning (platform in a different position) after the initial training, the standard diet fed rats learned better and spatial memory was improved compared to the energy reduced diet group. Thus, moderate differences in feeding diets have effects specifically upon spatial cognitive flexibility. Possible relations between differences in lipid composition and cognitive flexibility are discussed.
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Affiliation(s)
- Jovana Maliković
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Harish Vuyyuru
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Harald Koefeler
- Center for Medical Research (ZMF), Medical University Graz, 8010, Graz, Austria
| | - Roman Smidak
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Harald Höger
- Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, Vienna, Austria
| | - Predrag Kalaba
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Ahmed M Hussein
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Gert Lubec
- Paracelsus Medical University, 5020, Salzburg, Austria.
| | - Volker Korz
- Paracelsus Medical University, 5020, Salzburg, Austria.
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7
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Maliković J, Feyissa DD, Hussein AM, Höger H, Lubec G, Korz V. Moderate Differences in Feeding Diets Largely Affect Motivation and Spatial Cognition in Adult and Aged but Less in Young Male Rats. Front Aging Neurosci 2018; 10:249. [PMID: 30158866 PMCID: PMC6104161 DOI: 10.3389/fnagi.2018.00249] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 07/30/2018] [Indexed: 01/03/2023] Open
Abstract
Nutrition can have significant effects on behavior and cognitive processes. Most of the studies related to this use extremely modified diets, such as high fat contents or the exclusion of distinct components needed for normal development and bodily homeostasis. Here we report significant effects of diets with moderate differences in compositions on food rewarded spatial learning in young (3–4 months), adult (6–7 months), and aged (17–18 months) rats. Young rats fed with a lower energy diet showed better performance only during aquisition of the spatial task when compared to rats fed with a standard diet. Adult rats (6–7 months) fed with a standard diet performed less well in the spatial learning task, than rats fed with lower energy diet. Aged rats fed with a lower energy diet (from 13 to 18 months of age) performed better during all training phases, as in a previous test when they were adult and fed with a standard diet. This difference could only be partly explained by lower motivation to search for food in the first test. Correspondingly, the variability of individual performance was significantly higher and increased over trials in adult rats fed with the standard diet as compared to adult rats fed with lower energy diet. Thus, moderate changes in feeding diets have large effects on motivation and cognition in elderly and less in young rats in a food rewarded spatial learning task. Therefore, nutrition effects upon food rewarded spatial learning and memory should be considered especially in aging studies.
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Affiliation(s)
- Jovana Maliković
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Daniel D Feyissa
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Ahmed M Hussein
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.,Department of Zoology, Faculty of Science, Al-Azhar University, Assiut, Egypt
| | - Harald Höger
- Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, Vienna, Austria
| | - Gert Lubec
- Department of Neuroproteomics, Paracelsus Medical University, Salzburg, Austria
| | - Volker Korz
- Center for Brain Research, Medical University of Vienna, Vienna, Austria
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Light LEO, Bartlett TQ, Poyas A, Nijland MJ, Huber HF, Li C, Keenan K, Nathanielsz PW. Maternal activity, anxiety, and protectiveness during moderate nutrient restriction in captive baboons (Papio sp.). J Med Primatol 2018; 47:10.1111/jmp.12350. [PMID: 29749628 PMCID: PMC6230519 DOI: 10.1111/jmp.12350] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND We hypothesized that maternal nutrient restriction (NR) would increase activity and behavioral indicators of anxiety (self-directed behaviors, SDBs) in captive baboons (Papio sp.) and result in more protective maternal styles. METHODS Our study included 19 adult female baboons. Seven females ate ad libitum (control group), and eight females ate 30% less (NR group) and were observed through pregnancy and lactation. RESULTS Control females engage in higher rates of SDB than NR females overall (P ≤ .018) and during the prenatal period (P ≤ .001) and engage in more aggressive behavior (P ≤ .033). Control females retrieved infants more than NR females during weeks 5-8 postpartum (P ≤ .019). CONCLUSIONS Lower SDB rates among prenatal NR females reduce energy expenditure and increase available resources for fetal development when nutritionally restricted. Higher infant retrieval rates by controls may indicate more infant independence rather than maternal style differences.
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Affiliation(s)
- Lydia E. O. Light
- Department of Anthropology, University of North Carolina Charlotte, 9201 University City Blvd, Charlotte, NC, 28223-0001, USA
- Department of Anthropology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA
| | - Thad Q. Bartlett
- Department of Anthropology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA
| | - Annica Poyas
- Department of Anthropology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA
| | - Mark J. Nijland
- Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX
| | - Hillary F. Huber
- Department of Animal Science, University of Wyoming, Laramie, WY, 82071, USA
| | - Cun Li
- Department of Animal Science, University of Wyoming, Laramie, WY, 82071, USA
| | - Kate Keenan
- Department of Psychiatry, University of Chicago, Chicago, IL
| | - Peter W. Nathanielsz
- Department of Animal Science, University of Wyoming, Laramie, WY, 82071, USA
- Southwest National Primate Research Center, San Antonio, TX, 78249, USA
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Tang D, Tao S, Chen Z, Koliesnik IO, Calmes PG, Hoerr V, Han B, Gebert N, Zörnig M, Löffler B, Morita Y, Rudolph KL. Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging. J Exp Med 2016; 213:535-53. [PMID: 26951333 PMCID: PMC4821645 DOI: 10.1084/jem.20151100] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 01/26/2016] [Indexed: 12/21/2022] Open
Abstract
Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways.
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Affiliation(s)
- Duozhuang Tang
- Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Si Tao
- Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Zhiyang Chen
- Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | | | | | - Verena Hoerr
- Institute of Medical Microbiology, Jena University Hospital, 07743 Jena, Germany
| | - Bing Han
- Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Nadja Gebert
- Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Martin Zörnig
- Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany
| | - Bettina Löffler
- Institute of Medical Microbiology, Jena University Hospital, 07743 Jena, Germany
| | - Yohei Morita
- Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Karl Lenhard Rudolph
- Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), 07745 Jena, Germany Faculty of Medicine, Friedrich Schiller University, 07743 Jena, Germany
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10
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Vasconcelos AR, Cabral-Costa JV, Mazucanti CH, Scavone C, Kawamoto EM. The Role of Steroid Hormones in the Modulation of Neuroinflammation by Dietary Interventions. Front Endocrinol (Lausanne) 2016; 7:9. [PMID: 26869995 PMCID: PMC4740355 DOI: 10.3389/fendo.2016.00009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 01/21/2016] [Indexed: 12/20/2022] Open
Abstract
Steroid hormones, such as sex hormones and glucocorticoids, have been demonstrated to play a role in different cellular processes in the central nervous system, ranging from neurodevelopment to neurodegeneration. Environmental factors, such as calorie intake or fasting frequency, may also impact on such processes, indicating the importance of external factors in the development and preservation of a healthy brain. The hypothalamic-pituitary-adrenal axis and glucocorticoid activity play a role in neurodegenerative processes, including in disorders such as in Alzheimer's and Parkinson's diseases. Sex hormones have also been shown to modulate cognitive functioning. Inflammation is a common feature in neurodegenerative disorders, and sex hormones/glucocorticoids can act to regulate inflammatory processes. Intermittent fasting can protect the brain against cognitive decline that is induced by an inflammatory stimulus. On the other hand, obesity increases susceptibility to inflammation, while metabolic syndromes, such as diabetes, are associated with neurodegeneration. Consequently, given that gonadal and/or adrenal steroids may significantly impact the pathophysiology of neurodegeneration, via their effect on inflammatory processes, this review focuses on how environmental factors, such as calorie intake and intermittent fasting, acting through their modulation of steroid hormones, impact on inflammation that contributes to cognitive and neurodegenerative processes.
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Affiliation(s)
- Andrea Rodrigues Vasconcelos
- Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
- Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
| | - João Victor Cabral-Costa
- Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
| | - Caio Henrique Mazucanti
- Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
| | - Cristoforo Scavone
- Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
| | - Elisa Mitiko Kawamoto
- Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
- *Correspondence: Elisa Mitiko Kawamoto,
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11
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Pereiro N, Moyano R, Blanco A, Lafuente A. Regulation of corticosterone secretion is modified by PFOS exposure at different levels of the hypothalamic-pituitary-adrenal axis in adult male rats. Toxicol Lett 2014; 230:252-62. [PMID: 24440345 DOI: 10.1016/j.toxlet.2014.01.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 11/25/2013] [Accepted: 01/02/2014] [Indexed: 01/29/2023]
Abstract
Perfluorooctane sulfonate (PFOS) is a fluorinated compound and a Persistent Organic Pollutant which can disrupt the endocrine system. This work was undertaken to evaluate the possible effects of PFOS exposure on the regulation of corticosterone secretion in adrenal and pituitary glands and at hypothalamic level in adult male rat, and to evaluate the possible morphological alterations induced by PFOS in this endocrine tissue. Adult male rats were orally treated with 0.5, 1.0, 3.0 and 6.0 mg of PFOS/kg/day for 28 days. Corticosterone, adrenocorticotropic hormone (ACTH) and corticotrophin-releasing hormone (CRH) secretion decreased in PFOS-treated rats. After PFOS exposure, relative expression of adrenocorticotropic hormone receptor (ACTHr) and proopiomelanocortin (POMC) genes was increased in adrenal and in pituitary glands, respectively; while relative expression of ACTHr and CRH genes decreased in hypothalamus with the doses of 0.5 and 1.0 mg/kg/day. PFOS treatment increased relative nitric oxide synthase 1 and 2 (NOS1 and NOS2) gene expression in the adrenal gland, and incremented superoxide dismutase activity. PFOS exposure induces a global inhibition of the hypothalamic-pituitary-adrenal (HPA) axis activity, and small morphological changes were observed in adrenal zona fasciculata cells.
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Affiliation(s)
- N Pereiro
- Laboratory of Toxicology, Faculty of Sciences, University of Vigo, Las Lagunas S/n, 32004 Ourense, Spain
| | - R Moyano
- Department of Pharmacology, Toxicology and Legal and Forensic Medicine, Veterinary Faculty, University of Córdoba, 14071, Córdoba, Spain
| | - A Blanco
- Department of Comparative Pathology, Faculty of Veterinary Medicine, University of Córdoba, 14071 Córdoba, Spain
| | - A Lafuente
- Laboratory of Toxicology, Faculty of Sciences, University of Vigo, Las Lagunas S/n, 32004 Ourense, Spain.
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12
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Proteomic analysis of plasma after 4 weeks of intermittent fasting in mice. MEDITERRANEAN JOURNAL OF NUTRITION AND METABOLISM 2013. [DOI: 10.1007/s12349-013-0136-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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13
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Yu XF, Wang YQ, Zou J, Dong J. A meta-analysis of the effects of energy intake on risk of digestive cancers. World J Gastroenterol 2012; 18:7362-7370. [PMID: 23326146 PMCID: PMC3544043 DOI: 10.3748/wjg.v18.i48.7362] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 10/04/2012] [Accepted: 11/13/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To quantitatively assess the relationship between energy intake and the incidence of digestive cancers in a meta-analysis of cohort studies.
METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded, and the bibliographies of retrieved articles. Studies were included if they reported relative risks (RRs) and corresponding 95% CIs of digestive cancers with respect to total energy intake. When RRs were not available in the published article, they were computed from the exposure distributions. Data were extracted independently by two investigators and discrepancies were resolved by discussion with a third investigator. We performed fixed-effects meta-analyses and meta-regressions to compute the summary RR for highest versus lowest category of energy intake and for per unit energy intake and digestive cancer incidence by giving each study-specific RR a weight that was proportional to its precision.
RESULTS: Nineteen studies consisting of 13 independent cohorts met the inclusion criteria. The studies included 995 577 participants and 5620 incident cases of digestive cancer with an average follow-up of 11.1 years. A significant inverse association was observed between energy intake and the incidence of digestive cancers. The RR of digestive cancers for the highest compared to the lowest caloric intake category was 0.90 (95% CI 0.81-0.98, P < 0.05). The RR for an increment of 239 kcal/d energy intake was 0.97 (95% CI 0.95-0.99, P < 0.05) in the fixed model. In subgroup analyses, we noted that energy intake was associated with a reduced risk of colorectal cancer (RR 0.90, 95% CI 0.81-0.99, P < 0.05) and an increased risk of gastric cancer (RR 1.19, 95% CI 1.08-1.31, P < 0.01). There appeared to be no association with esophageal (RR 0.96, 95% CI 0.86-1.07, P > 0.05) or pancreatic (RR 0.79, 95% CI 0.49-1.09, P > 0.05) cancer. Associations were also similar in studies from North America and Europe. The RR was 1.02 (95% CI 0.79-1.25, P > 0.05) when considering the six studies conducted in North America and 0.87 (95% CI 0.77-0.98, P < 0.05) for the five studies from Europe.
CONCLUSION: Our findings suggest that high energy intake may reduce the total digestive cancer incidence and has a preventive effect on colorectal cancer.
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14
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Abstract
Growth factors regulated by specific macronutrients have been shown to promote aging and accelerate mortality in the majority of the organisms studied. In particular, the enzymes activated by growth hormone, insulin, and insulin-like growth factor-1 in mammals and their orthologs in simple model organisms represent perhaps the best-understood proteins involved in the aging process. Dietary restriction, which reduces the level of insulin-like growth factor-1 and of other growth factors, has been associated with protection from diabetes, cancer, and cardiovascular diseases, and deficiencies in growth hormone signaling and insulin-like growth factor-1 are strongly associated with protection from cancer and diabetes in both mice and humans; however, their role in cardiac function and cardiovascular diseases is controversial. Here, we review the link between growth factors, cardiac function, and heart disease with focus on the cardioprotective and sensitizing effect of growth factors in both model organisms and humans.
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Affiliation(s)
- Luigi Fontana
- Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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15
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Xie X, Wen Y, Niu H, Shi D, Zhang Z. Re-feeding evokes reproductive overcompensation of food-restricted Brandt's voles. Physiol Behav 2012; 105:653-60. [DOI: 10.1016/j.physbeh.2011.09.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2011] [Revised: 09/14/2011] [Accepted: 09/30/2011] [Indexed: 11/29/2022]
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16
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Spindler SR. Caloric restriction: from soup to nuts. Ageing Res Rev 2010; 9:324-53. [PMID: 19853062 DOI: 10.1016/j.arr.2009.10.003] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2009] [Revised: 10/07/2009] [Accepted: 10/09/2009] [Indexed: 12/25/2022]
Abstract
Caloric restriction (CR), reduced protein, methionine, or tryptophan diets; and reduced insulin and/or IGFI intracellular signaling can extend mean and/or maximum lifespan and delay deleterious age-related physiological changes in animals. Mice and flies can shift readily between the control and CR physiological states, even at older ages. Many health benefits are induced by even brief periods of CR in flies, rodents, monkeys, and humans. In humans and nonhuman primates, CR produces most of the physiologic, hematologic, hormonal, and biochemical changes it produces in other animals. In primates, CR provides protection from type 2 diabetes, cardiovascular and cerebral vascular diseases, immunological decline, malignancy, hepatotoxicity, liver fibrosis and failure, sarcopenia, inflammation, and DNA damage. It also enhances muscle mitochondrial biogenesis, affords neuroprotection; and extends mean and maximum lifespan. CR rapidly induces antineoplastic effects in mice. Most claims of lifespan extension in rodents by drugs or nutrients are confounded by CR effects. Transcription factors and co-activators involved in the regulation of mitochondrial biogenesis and energy metabolism, including SirT1, PGC-1alpha, AMPK and TOR may be involved in the lifespan effects of CR. Paradoxically, low body weight in middle aged and elderly humans is associated with increased mortality. Thus, enhancement of human longevity may require pharmaceutical interventions.
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17
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Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 2010; 31:89-98. [PMID: 20097433 DOI: 10.1016/j.tips.2009.11.004] [Citation(s) in RCA: 265] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2009] [Revised: 11/18/2009] [Accepted: 11/18/2009] [Indexed: 12/16/2022]
Abstract
An important discovery of recent years has been that lifestyle and environmental factors affect cancer initiation, promotion and progression, suggesting that many malignancies are preventable. Epidemiological studies strongly suggest that excessive adiposity, decreased physical activity, and unhealthy diets are key players in the pathogenesis and prognosis of many common cancers. In addition, calorie restriction (CR), without malnutrition, has been shown to be broadly effective in cancer prevention in laboratory strains of rodents. Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys. Whether the antitumorigenic effects of CR will apply to humans is unknown, but CR results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies. Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that might be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents.
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Affiliation(s)
- Valter D Longo
- The Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA.
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18
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Terzibasi E, Lefrançois C, Domenici P, Hartmann N, Graf M, Cellerino A. Effects of dietary restriction on mortality and age-related phenotypes in the short-lived fish Nothobranchius furzeri. Aging Cell 2009; 8:88-99. [PMID: 19302373 DOI: 10.1111/j.1474-9726.2009.00455.x] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The short-lived annual fish Nothobranchius furzeri shows extremely short captive life span and accelerated expression of age markers, making it an interesting model system to investigate the effects of experimental manipulations on longevity and age-related pathologies. Here, we tested the effects of dietary restriction (DR) on mortality and age-related markers in N. furzeri. DR was induced by every other day feeding and the treatment was performed both in an inbred laboratory line and a longer-lived wild-derived line. In the inbred laboratory line, DR reduced age-related risk and prolonged maximum life span. In the wild-derived line, DR induced early mortality, did not reduce general age-related risk and caused a small but significant extension of maximum life span. Analysis of age-dependent mortality revealed that DR reduced demographic rate of aging, but increased baseline mortality in the wild-derived strain. In both inbred- and wild-derived lines, DR prevented the expression of the age markers lipofuscin in the liver and Fluoro-Jade B (neurodegeneration) in the brain. DR also improved performance in a learning test based on conditioning (active avoidance in a shuttle box). Finally, DR induced a paradoxical up-regulation of glial fibrillary acidic protein in the brain.
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Affiliation(s)
- Eva Terzibasi
- Biology of Aging, Fritz Lipmann Institute for Age Research, Leibniz Institute, Jena 07745 Germany
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19
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Abstract
An epidemic of overweight/obesity and type 2 diabetes, caused by overeating nutrient-poor energy-dense foods and a sedentary lifestyle, is spreading rapidly throughout the world. Abdominal obesity represents a serious threat to health because it increases the risk of developing many chronic diseases, including cardiovascular disease and cancer. Calorie restriction (CR) with adequate nutrition improves cardiometabolic health, prevents tumorigenesis and increases life span in experimental animals. The purpose of this review is to evaluate the metabolic and clinical implications of CR with adequate nutrition in humans, within the context of data obtained in animal models. It is unlikely that information regarding the effect of CR on maximal life span in humans will become available in the foreseeable future. In young and middle-aged healthy individuals, however, CR causes many of the same cardiometabolic adaptations that occur in long-lived CR rodents, including decreased metabolic, hormonal and inflammatory risk factors for diabetes, hypertension, cardiovascular disease and cancer. Unraveling the mechanisms that link calorie intake and body composition with metabolism and aging will be a major step in understanding the age-dependency of a wide range of human diseases and will also contribute to improve the general quality of life at old ages.
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20
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Effect of aging on 24-hour pattern of stress hormones and leptin in rats. Life Sci 2008; 83:142-8. [PMID: 18593590 DOI: 10.1016/j.lfs.2008.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2007] [Revised: 05/22/2008] [Accepted: 06/05/2008] [Indexed: 10/21/2022]
Abstract
This work analyzes the 24-hour changes of hypothalamic-pituitary-adrenal (HPA) axis activity and leptin release in aged rats. Three- and 22-month-old male Wistar rats were killed at 6 time intervals during a 24-hour cycle (n=8-10 rats/group). Aging augmented plasma ACTH while it decreased plasma and adrenal gland corticosterone levels. Plasma and adrenal corticosterone levels attained high levels during all the scotophase, concomitantly with the maxima in ACTH levels, whereas in aged rats only a brief plasma corticosterone peak at the early scotophase and no time of day variations of adrenal corticosterone were observed. Aging augmented circulating leptin, with a significant interaction "agextime" in the factorial ANOVA, i.e. only in young rats time of day changes were significant, with the lowest values of leptin at the middle of the light period and higher values at night. When plasma leptin was expressed on body weight basis, the age-related differences became not significant but the daily pattern of plasma leptin found in young rats persisted. Plasma and adrenal corticosterone levels correlated significantly with plasma ACTH only in young rats. Likewise, plasma leptin correlated with plasma corticosterone only in young rats. These changes can be attributed to a disrupting effect of aging on the homeostatic mechanisms modulating HPA activity and leptin release.
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21
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Fontana L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Exp Gerontol 2008; 44:41-5. [PMID: 18502597 DOI: 10.1016/j.exger.2008.04.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2008] [Accepted: 04/07/2008] [Indexed: 12/15/2022]
Abstract
Acute inflammation is usually a self-limited life preserving response, triggered by pathogens and/or traumatic injuries. This transient response normally leads to removal of harmful agents and to healing of the damaged tissues. In contrast, unchecked or chronic inflammation can lead to persistent tissue and organ damage by activated leukocytes, cytokines, or collagen deposition. Excessive energy intake and adiposity cause systemic inflammation, whereas calorie restriction without malnutrition exerts a potent anti-inflammatory effect. As individuals accumulate fat and their adipocytes enlarge, adipose tissue undergoes molecular and cellular alterations, macrophages accumulate, and inflammation ensues. Overweight/obese subjects have significantly higher plasma concentrations of C-reactive protein and several cytokines, including IL-6, IL-8, IL-18, and TNF-alpha. Experimental animals on a chronic CR regimen, instead, have low levels of circulating inflammatory cytokines, low blood lymphocyte levels, reduced production of inflammatory cytokines by the white blood cells in response to stimulation, and cortisol levels in the high normal range. Recent data demonstrate that CR exerts a powerful anti-inflammatory effect also in non-human primates and humans. Multiple metabolic and neuroendocrine mechanisms are responsible for the CR-mediated anti-inflammatory effects, including reduced adiposity and secretion of pro-inflammatory adipokines, enhanced glucocorticoid production, reduced plasma glucose and advanced glycation end-product concentrations, increased parasympathetic tone, and increased ghrelin production. Measuring tissue specific effects of CR using genomic, proteomic, and metabolomic techniques in humans will foster the understanding of the complex biological processes involved in the anti-inflammatory and anti-aging effects of CR.
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Affiliation(s)
- Luigi Fontana
- Division of Geriatrics and Nutritional Science, Center for Human Nutrition, Washington University School of Medicine, 4566 Scott Avenue, St. Louis, MO 63110, USA.
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22
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Yang H, Youm YH, Nakata C, Dixit VD. Chronic caloric restriction induces forestomach hypertrophy with enhanced ghrelin levels during aging. Peptides 2007; 28:1931-6. [PMID: 17875344 PMCID: PMC5682623 DOI: 10.1016/j.peptides.2007.07.030] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2007] [Revised: 07/26/2007] [Accepted: 07/26/2007] [Indexed: 12/22/2022]
Abstract
Caloric restriction (CR) is the only preventive intervention that has robust pro-longevity effects in experimental models. Various circulating hormones that regulate the state of negative energy balance may drive the multi-system beneficial effects of the CR phenomenon. Ghrelin, one such stomach-derived circulating peptide hormone stimulates food intake, promotes GH release and inhibits pro-inflammatory cytokines. We have recently demonstrated that ghrelin also reverses age-related thymic involution. Here, we report that chronic CR in aging mice results in reduction in body weight, and spleen size but remarkably, leads to a significant increase in the size and weight of stomach. The increased size of stomach was largely due to increased size of fundus (forestomach) and also smaller but statistically significant enlargement of antrum. The analysis of serial stomach sections revealed that chronic CR leads to a striking hypertrophy of lamina propria, stratum basale, stratum corneum and the stratified squamous epithelium of forestomach of the aged animals. We also report for the first time that chronic CR during aging significantly increases circulating ghrelin levels as well as total ghrelin production in the stomach and reverses age-related loss of ghrelin receptor expression in pituitary. Our data suggests that long-term CR-induced increased ghrelin production from hypertrophic stomach in mice may be an adaptive survival strategy in response to sustained negative energy balance that triggers heightened state of food seeking. Taken together, these data provide new insights into the underlying mechanism behind the salutary effects of chronic caloric restriction during aging process.
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Affiliation(s)
| | | | | | - Vishwa Deep Dixit
- Corresponding author. Tel.: +1 225 763 2719; fax: +1 225 763 0261. (V.D. Dixit)
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23
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Usa K, Singh RJ, Netzel BC, Liu Y, Raff H, Liang M. Renal interstitial corticosterone and 11-dehydrocorticosterone in conscious rats. Am J Physiol Renal Physiol 2007; 293:F186-92. [PMID: 17389675 DOI: 10.1152/ajprenal.00484.2006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Deficiencies in the conversion between active and inactive glucocorticoids in the kidney can lead to hypertension. However, the significance of glucocorticoid metabolism in specific kidney regions in vivo is not clear, possibly in part due to the difficulty in measuring glucocorticoid levels in kidney regions in vivo. We used microdialysis techniques to sample renal interstitial fluid from conscious rats. The levels of corticosterone (active) and 11-dehydrocorticosterone (inactive) were analyzed by liquid chromatography-tandem mass spectrometry. Direct infusion of the 11β-hydroxysteroid dehydrogenase (11β-HSD) inhibitor carbenoxolone into the renal medulla induced hypertension, and significantly increased corticosterone levels and the corticosterone/11-dehydrocorticosterone ratio, an index of 11β-HSD activity, in the renal medullary microdialysate, but not in urine or the plasma. Further characterization of conscious, untreated rats ( n = 13–16) indicated that corticosterone concentrations (ng/ml) were 0.8 ± 0.1, 1.0 ± 0.1, 66.7 ± 8.1, and 7.9 ± 1.1 in cortical microdialysate, medullary microdialysate, the plasma, and urine, respectively. The corticosterone/11-dehydrocorticosterone ratios were 0.8 ± 0.1, 0.6 ± 0.1, 10.6 ± 1.4, and 1.7 ± 0.1, respectively, in these 4 types of sample. The expression level of 11β-HSD1 was higher in the medulla than in the cortex, whereas 11β-HSD2 was most enriched in the outer medulla. Microdialysate levels of corticosterone were ∼1.6-fold higher in afternoons than in mornings, whereas plasma levels differed by 2.8-fold. These results demonstrated that corticosterone excess in the renal medulla might be sufficient to cause hypertension and provided the first characterization of renal interstitial glucocorticoids.
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Affiliation(s)
- Kristie Usa
- Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
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24
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Abstract
To investigate whether mice genetically unaltered by many generations of laboratory selection exhibit similar hormonal and demographic responses to caloric restriction (CR) as laboratory rodents, we performed CR on cohorts of genetically heterogeneous male mice which were grandoffspring of wild-caught ancestors. Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups, although a maximum likelihood fitted Gompertz mortality model indicated a significantly shallower slope and higher intercept for the CR group. This result was due to higher mortality in CR animals early in life, but lower mortality late in life. A subset of animals may have exhibited the standard demographic response to CR in that the longest-lived 8.1% of our animals were all from the CR group. Despite the lack of a robust mean longevity difference between groups, we did note a strong anticancer effect of CR as seen in laboratory rodents. Three plausible interpretations of our results are the following: (1) animals not selected under laboratory conditions do not show the typical CR effect; (2) because wild-derived animals eat less when fed AL, our restriction regime was too severe to see the CR effect; or (3) there is genetic variation for the CR effect in wild populations; variants that respond to CR with extended life are inadvertently selected for under conditions of laboratory domestication.
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Affiliation(s)
- James M. Harper
- Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA
| | - Charles W. Leathers
- Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164, USA
| | - Steven N. Austad
- Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA
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Ikeno Y, Hubbard GB, Lee S, Richardson A, Strong R, Diaz V, Nelson JF. Housing density does not influence the longevity effect of calorie restriction. J Gerontol A Biol Sci Med Sci 2006; 60:1510-7. [PMID: 16424282 DOI: 10.1093/gerona/60.12.1510] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
This study examined the effect of housing density on the longevity-extending and disease-delaying actions of calorie restriction (CR). Singly or multiply housed (four per cage) mice were either fed ad libitum (AL) or were on CR beginning at 2 months. All CR mice were fed 40% less food than were multiply housed AL mice. CR increased median longevity by 19%, and housing density had no effect on this increase. CR also reduced neoplastic lesions in both housing groups, but lymphoma, the most common neoplasm, was reduced more in singly than in multiply housed mice. Singly housed AL mice ate 40% more food than did multiply housed AL mice, but weighed the same and lived as long as multiply housed AL mice. These results indicate that CR can extend life span as effectively in multiply as in singly housed mice, even though housing density can differentially affect the cancer-reducing effect of CR.
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Affiliation(s)
- Yuji Ikeno
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care Systems, San Antonio, TX, USA
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26
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Newton IG, Forbes ME, Legault C, Johnson JE, Brunso-Bechtold JK, Riddle DR. Caloric restriction does not reverse aging-related changes in hippocampal BDNF. Neurobiol Aging 2005; 26:683-8. [PMID: 15708443 DOI: 10.1016/j.neurobiolaging.2004.06.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2003] [Revised: 05/26/2004] [Accepted: 06/16/2004] [Indexed: 11/20/2022]
Abstract
Caloric restriction (CR) can attenuate the aging-related decline in learning and memory in rats. Understanding the mechanisms underlying this effect could lead to therapies for human memory impairment. We tested the hypotheses that aging is associated with a decline in hippocampal brain-derived neurotrophic factor (BDNF), a growth factor that enhances learning and memory, and that CR increases hippocampal BDNF. We compared BDNF protein levels in hippocampal subregions of young, middle-aged and old rats fed CR or ad libitum (AL) diets. Mean BDNF levels in the dentate gyrus and CA3 did not differ with diet but increased with age. In CA1, BDNF levels were slightly higher in CR than AL rats at middle and old age but did not change across lifespan. These data suggest that mnemonic impairments with age do not reflect a decrease in hippocampal BDNF. Furthermore, if CRs attenuation of aging-related memory changes is mediated by BDNF, then it must be through a small, CA1-specific increase and does not involve reversal of an aging-related decline in BDNF.
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Affiliation(s)
- Isabel G Newton
- Department of Neurobiology, Medical Center Boulevard, Winston-Salem, NC 27157-1010, USA.
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Li D, Sun F, Wang K. Protein profile of aging and its retardation by caloric restriction in neural retina. Biochem Biophys Res Commun 2004; 318:253-8. [PMID: 15110781 DOI: 10.1016/j.bbrc.2004.04.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2004] [Indexed: 11/19/2022]
Abstract
Aging is a slow, gradual deterioration process of an organism. The only experimental intervention, which can reliably retard aging and age-related degenerative diseases, is dietary caloric restriction (CR). To gain insight into the mechanism of CR intervention, we have investigated the protein profile of aging and its retardation by CR in the neural retina of Brown Norway (BN) rats using the comprehensive proteomic approach. We found that the intensities of 18 proteins decreased significantly with age. CR intervention can completely prevent seven of them, and partially protect eight of them, from such age-related declines. The major protein targets protected by CR intervention appear to be glycolytic enzymes and molecular chaperones. These data are the first to suggest that CR may retard the age-related degeneration of retina by maintaining sufficient glucose metabolism, by ensuring proper protein folding, and/or by preventing protein denaturation in the neural retina.
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Affiliation(s)
- Dayu Li
- Department of Ophthalmology, College of Physicians and Surgeons of Columbia University, New York, NY, USA
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