Alterations in oxidative, inflammatory and apoptotic events in short-lived and long-lived mice testes

Aged testes undergo profound histological and morphological alterations leading to a reduced functionality. Here, we investigated whether variations in longevity affect the development of local inflammatory processes, the oxidative state and the occurrence of apoptotic events in the testis. To this aim, well-established mouse models with delayed (growth hormone releasing hormone-knockout and Ames dwarf mice) or accelerated (growth hormone-transgenic mice) aging were used. We hereby show that the testes of short-lived mice show a significant increase in cyclooxygenase 2 expression, PGD2 production, lipid peroxidation, antioxidant enzymes expression, local macrophages and TUNEL-positive germ cells numbers, and the levels of both pro-caspase-3 and cleaved caspase-3. In contrast, although the expression of antioxidant enzymes remained unchanged in testes of long-lived mice, the remainder of the parameters assessed showed a significant reduction. This study provides novel evidence that longevity confers anti-inflammatory, anti-oxidant and anti-apoptotic capacities to the adult testis. Oppositely, short-lived mice suffer testicular inflammatory, oxidative and apoptotic processes.Fil: Matzkin, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Miquet, Johanna Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Fang, Yimin. Southern Illinois University. School Of Medicine; Estados UnidosFil: Hill, Cristal Monique. Southern Illinois University; Estados UnidosFil: Turyn, Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Calandra, Ricardo Saul. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bartke, Andrzej. Southern Illinois University; Estados UnidosFil: Frungieri, Monica Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin

The AGE Presents Introduction to Geroscience video lecture series.

The AGE Presents Introduction to Geroscience video lecture series is a collection of high-quality didactic video lectures and associated teaching materials focused on foundational topics in aging biology. The videos are made freely available on YouTube and are targeted toward an audience familiar with concepts learned in the first year of a college undergraduate biology/biomedical major. Members of the American Aging Association also receive the original lecture slides and lecture notes, with additional course materials to be developed in the future. We expect that these lectures will enhance understanding of geroscience among the general public while also providing tools that educators can use in the classroom for high school, undergraduate, and graduate level curricula

Duration of Rapamycin Treatment Has Differential Effects on Metabolism in Mice

SummaryThe evolutionarily conserved target of rapamycin (TOR) signaling controls growth, metabolism, and aging. In the first robust demonstration of pharmacologically-induced life extension in mammals, longevity was extended in mice treated with rapamycin, an inhibitor of mechanistic TOR (mTOR). However, detrimental metabolic effects of rapamycin treatment were also reported, presenting a paradox of improved survival despite metabolic impairment. How rapamycin extended lifespan in mice with such paradoxical effects was unclear. Here we show that detrimental effects of rapamycin treatment were only observed during the early stages of treatment. These effects were reversed or diminished in mice treated for 20 weeks, with better metabolic profiles, increased oxygen consumption and ketogenesis, and markedly enhanced insulin sensitivity. Thus, prolonged rapamycin treatment lead to beneficial metabolic alterations, consistent with life extension previously observed. Our findings provide a likely explanation of the “rapamycin paradox” and support the potential causal importance of these metabolic alterations in longevity

Do personality traits affect productivity?:Evidence from the lab

While survey data supports a strong relationship between personality and labor market outcomes, the exact mechanisms behind this association remain unexplored. In this paper, we take advantage of a controlled laboratory set-up to explore whether this relationship operates through productivity. Using a real-e ort task, we analyse the impact of the Big Five personality traits on performance. We nd that more neurotic subjects perform worse, and that more conscientious individuals perform better. These ndings are in line with previous survey studies and suggest that at least part of the e ect of personality on labor market outcomes operates through individual productivity. In addition, we nd evidence that gender and university major a ect the impact of the Big Five personality traits on performance

Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex

Background: Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR). Objective: We investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR. Methods: Using liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR. Results: We show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR. Conclusions: Our results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice

THE METABOLIC EFFECTS OF DIET-INDUCED OBESITY AND GROWTH HORMONE TREATMENT IN LONG-LIVED MICE WITH ALTERED INSULIN AND INSULIN-LIKE GROWTH FACTOR -1 SIGNALING

AN ABSTRACT OF THE DISSERTATION OF Cristal M. Hill, for the Doctor of Philosophy degree in Molecular Biology, Microbiology, and Biochemistry, presented on January 22nd 2016, at Southern Illinois University Carbondale. THE METABOLIC EFFECTS OF DIET-INDUCED OBESITY AND GROWTH HORMONE TREATMENT IN LONG-LIVED MICE WITH ALTERED INSULIN AND INSULIN-LIKE GROWTH FACTOR -1 SIGNALING MAJOR PROFESSOR: Dr. Andrzej Bartke It is well established that high calorie diets providing mostly fat and simple carbohydrates as nutrients promote obesity and are associated with metabolic syndromes such as type 2 diabetes and cardiovascular disease. However, the effects of these types of diets in genetically long lived mice remain to be fully elucidated. The effects of high calorie diets have been reported to induce inflammation and alter longevity. However, when viewed in the context of the growth hormone (GH) pathway, these types of diets that have negative impact on IGF-1 and insulin signaling. To examine high calorie diet and GH-treatment effects in long-lived mice, we designed a three part study using hypopituitary Ames dwarf mice that have primary altered endocrine signaling and Pregnancy Associated Plasma Protein-A knockout mice that have normal endocrine signaling. Most importantly, together these studies investigate the detrimental effects of high energy feeding promoting obesity and influencing adipokine profiles that regulate or alter insulin/ IGF-1 signaling that may possibly impair glucose homeostasis in the context of the GH-axis. Longevity and aging are influenced by common intracellular signals of the insulin/insulin-like growth factor (IGF)-1 (IIS) pathway. Abnormally high levels of bioactive IGF-1 increase the development of various cancers and may contribute to metabolic diseases such as insulin resistance. Enhanced availability of IGF-1 is promoted by cleavage of IGF binding proteins (IGFBPs) by proteases, including the pregnancy associated plasma protein-A (PAPPA). In vitro, PAPPA is regulated by pro-inflammatory cytokines (PICs) such as interleukin (IL)-6 and tumor necrosis factor -a (TNF-a). Mice born with deficiency of the Papp-a gene [PAPP-A knockout (KO) mice] live ∼30–40 % longer than their normal littermates and have decreased bioactive IGF-1 on standard diets. In the first study, our objective was to elucidate how the effects of high-fat, high-sucrose diet (HFHS) promote obesity, induce metabolic dysfunction, and alter systemic cytokine levels in PAPP-A KO and normal mice. We show that PAPP-A KO mice fed HFHS diet for 10 weeks were more glucose tolerant and had enhanced insulin sensitivity compared to normal mice fed identical diet. PAPP-A KO mice fed HFHS diet had lower levels of pro-inflammatory cytokines (IL-2, IL-6, and TNF-α) compared to normal mice fed the same diet. Moreover, anti-inflammatory cytokine (IL-4 and adiponectin) levels were higher in PAPP-A KO mice fed HFHS diet compared to normal mice fed HFHS. Circulating PAPP-A levels were elevated in normal mice fed an HFHS diet compared to normal mice fed a standard, low-fat, low-sucrose (LFLS) diet. Indirect calorimetry, at 10 weeks of feeding HFHS diet, showed significantly increased oxygen consumption (VO2) in PAPP-A KO mice fed HFHS diet compared to normal mice fed the same diet. Furthermore, respiratory quotient (RQ) was significantly lower in PAPP-A KO mice fed HFHS diet compared to normal (N) mice fed HFHS diet indicating PAPP-A KO mice fed HFHS diet are able to rely on fat as their primary source of energy more so than normal controls. We conclude that PAPP-A KO mice are resistant to the HFHS diet induction of metabolic dysfunction associated with higher levels of anti-inflammatory cytokines and have a remarkably metabolically flexible phenotype and that some of the effects of HFHS diet in normal animals may be due to increased levels of PAPP-A. We continued our investigations of high calorie diet effects in long-lived endocrine disrupted Ames dwarf mice. Ames dwarf mice are hypopituitary, thus lacking the production of GH. GH stimulates the production of IGF-1; induces insulin resistance, alters inflammatory cytokine levels and can reduce life expectancy in both humans and mice. Disruption of GH signaling by reducing plasma GH levels significantly or deleting GH receptors extends health span and life span in mice as observed in Ames dwarfs. Metabolic stressors such as high-fat diet (HFD) may alter longevity through the GH signaling pathway. Our objective was to investigate the effects of HFD in Ames dwarf and control mice to elucidate the interactions on environmental (diet) and genetic mechanisms that regulate metabolism in aging processes. We show that Ames dwarf mice fed HFD for 12 weeks are sensitive to weight gain and increase in subcutaneous and visceral adiposity, yet are more insulin sensitive and have higher levels of adiponectin compared to control mice fed either standard diet (STD) or HFD. Interleukin 6 levels were lower in Ames dwarf mice fed HFD than control mice fed either STD or HFD. Energy expenditure was higher in Ames dwarf mice fed HFD than control mice fed STD or HFD. Moreover, we show that transplant of epididymal white adipose tissue (eWAT) from Ames dwarf mice fed HFD is able to improve insulin sensitivity in control mice fed the same diet. We conclude that Ames dwarf mice are resistant to the detrimental metabolic effects of HFD and the visceral adipose tissue of Ames dwarf mice can recuse metabolic dysfunction in control mice. In the third study, we investigated the effects of early-life GH-treatment in Ames dwarf mice starting at 1week of age. The focus of this study was to examine the metabolic effects of GH- treatment and HFD feeding during young age, which is the most critical time for biological maturation. In this study, one week old Ames dwarf and control mice were injected with either GH or saline for 6 weeks and fed STD. At 7 weeks of age, test for insulin sensitivity and calorimetric measurements were performed and the animals were subjected to diet switch from STD to HFD for 12 weeks post GH-treatment. With these preliminary data, we focus on the detrimental effects of GH-treatment during development and on the interaction of the effects of GH and diet. We first show that early-life-GH treatment in hypopituitary Ames dwarf mice induces a slight reduction of insulin sensitivity and decreased use of fatty acids as indicated by indirect calorimetry, thus promoting metabolic dysfunction. In addition, we show that the effects of early-life GH-treatment and high fat diet in Ames dwarf mice worsen insulin sensitivity and impair substrate utilization. We will continue to investigate the expression of genes that are associated with metabolism and longevity in these animals. Inhibition of proteases, such as PAPP-A, may be a therapeutic treatment to decrease the activity of biologically active IGF- to induce protection from metabolic dysfunction, including insulin resistance, in humans. Furthermore, it is not likely to inhibit GH/insulin/ IGF-1 signaling in healthy humans at young age, decreasing the activity of the insulin/ IGF-1 pathway at middle age may be beneficial in human therapies in the aims of protecting against metabolic dysfunction. Combined, these studies provide novel information on the interaction of the GH pathway and diets that induce obesity and metabolic dysfunction. Thus, mice with either primarily altered endocrine signaling or deletion of proteases that increase local IGF-1 signaling are protected from the detrimental effects of high calorie diets on metabolic function and energy expenditure

Long-lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high-fat diet on metabolic function and energy expenditure

Growth hormone (GH) signaling stimulates the production of IGF-1; however, increased GH signaling may induce insulin resistance and can reduce life expectancy in both mice and humans. Interestingly, disruption of GH signaling by reducing plasma GH levels significantly improves health span and extends lifespan in mice, as observed in Ames dwarf mice. In addition, these mice have increased adiposity, yet are more insulin sensitive compared to control mice. Metabolic stressors such as high-fat diet (HFD) promote obesity and may alter longevity through the GH signaling pathway. Therefore, our objective was to investigate the effects of a HFD (metabolic stressor) on genetic mechanisms that regulate metabolism during aging. We show that Ames dwarf mice fed HFD for 12 weeks had an increase in subcutaneous and visceral adiposity as a result of diet-induced obesity, yet are more insulin sensitive and have higher levels of adiponectin compared to control mice fed HFD. Furthermore, energy expenditure was higher in Ames dwarf mice fed HFD than in control mice fed HFD. Additionally, we show that transplant of epididymal white adipose tissue (eWAT) from Ames dwarf mice fed HFD into control mice fed HFD improves their insulin sensitivity. We conclude that Ames dwarf mice are resistant to the detrimental metabolic effects of HFD and that visceral adipose tissue of Ames dwarf mice improves insulin sensitivity in control mice fed HFD.Fil: Hill, Cristal M.. Southern Illinois University; Estados UnidosFil: Fang, Yimin. Southern Illinois University; Estados UnidosFil: Miquet, Johanna Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Sun, Liou Y.. University of Alabama at Birmingahm; Estados UnidosFil: Masternak, Michal M.. University of Central Florida; Estados UnidosFil: Bartke, Andrzej. Southern Illinois University; Estados Unido

The AGE Presents Introduction to Geroscience video lecture series.

The AGE Presents Introduction to Geroscience video lecture series is a collection of high-quality didactic video lectures and associated teaching materials focused on foundational topics in aging biology. The videos are made freely available on YouTube and are targeted toward an audience familiar with concepts learned in the first year of a college undergraduate biology/biomedical major. Members of the American Aging Association also receive the original lecture slides and lecture notes, with additional course materials to be developed in the future. We expect that these lectures will enhance understanding of geroscience among the general public while also providing tools that educators can use in the classroom for high school, undergraduate, and graduate level curricula

Female Papp-A Knockout Mice Are Resistant To Metabolic Dysfunction Induced By High-Fat/High-Sucrose Feeding At Middle Age

Longevity and aging are influenced by common intracellular signals of the insulin/insulin-like growth factor (IGF)-1 pathway. Abnormally high levels of bioactive IGF-1 increase the development of various cancers and may contribute to metabolic diseases such as insulin resistance. Enhanced availability of IGF-1 is promoted by cleavage of IGF binding proteins (IGFBPs) by proteases, including the pregnancy-associated plasma protein-A (PAPPA). In vitro, PAPP-A is regulated by pro-inflammatory cytokines (PICs) such as interleukin (IL)-6 and tumor necrosis factor (TNF). Mice born with deficiency of the Papp-a gene (PAPP-A knockout (KO) mice) live ∼30–40 % longer than their normal littermates and have decreased bioactive IGF-1 on standard diets. Our objective was to elucidate how the effects of high-fat, high-sucrose diet (HFHS) promote obesity, induce metabolic dysfunction, and alter systemic cytokine expression in PAPP-A KO and normal mice. PAPP-A KO mice fed HFHS diet for 10 weeks were more glucose tolerant and had enhanced insulin sensitivity compared to normal mice fed HFHS diet. PAPP-A KO mice fed HFHS diet had lower levels of pro-inflammatory cytokines (IL-2, IL-6, and TNF-α) compared to normal mice fed the same diet. However, anti-inflammatory cytokine levels (IL-4 and adiponectin) were higher in PAPP-A KO mice fed HFHS diet compared to normal mice fed HFHS. Circulating PAPP-A levels were elevated in normal mice fed an HFHS diet compared to normal mice fed a standard, low-fat, low-sucrose (LFLS) diet. Indirect calorimetry showed, at 10 weeks of feeding HFHS diet, significantly increased oxygen consumption (VO2) in PAPP-A KO mice fed HFHS diet compared to normal mice fed the same diet. Furthermore, respiratory quotient (RQ) was significantly lower in PAPP-A KO mice fed HFHS diet compared to normal (N) mice fed HFHS diet indicating PAPP-A KO mice fed HFHS diet are able to rely on fat as their primary source of energy more so than normal controls. We conclude that PAPP-A KO mice are resistant to the HFHS diet induction of metabolic dysfunction associated with higher levels of anti-inflammatory cytokines and a remarkably metabolic flexible phenotype and that some of the effects of HFHS diet in normal animals may be due to increased levels of PAPP-A

Long-Lived Hypopituitary Ames Dwarf Mice Are Resistant To The Detrimental Effects Of High-Fat Diet On Metabolic Function And Energy Expenditure

Growth hormone (GH) signaling stimulates the production of IGF-1; however, increased GH signaling may induce insulin resistance and can reduce life expectancy in both mice and humans. Interestingly, disruption of GH signaling by reducing plasma GH levels significantly improves health span and extends lifespan in mice, as observed in Ames dwarf mice. In addition, these mice have increased adiposity, yet are more insulin sensitive compared to control mice. Metabolic stressors such as high-fat diet (HFD) promote obesity and may alter longevity through the GH signaling pathway. Therefore, our objective was to investigate the effects of a HFD (metabolic stressor) on genetic mechanisms that regulate metabolism during aging. We show that Ames dwarf mice fed HFD for 12 weeks had an increase in subcutaneous and visceral adiposity as a result of diet-induced obesity, yet are more insulin sensitive and have higher levels of adiponectin compared to control mice fed HFD. Furthermore, energy expenditure was higher in Ames dwarf mice fed HFD than in control mice fed HFD. Additionally, we show that transplant of epididymal white adipose tissue (eWAT) from Ames dwarf mice fed HFD into control mice fed HFD improves their insulin sensitivity. We conclude that Ames dwarf mice are resistant to the detrimental metabolic effects of HFD and that visceral adipose tissue of Ames dwarf mice improves insulin sensitivity in control mice fed HFD