Modulation of Human Hydrogen Sulfide Metabolism by Micronutrients, Preliminary Data

Background: Hydrogen sulfide (H2S) is a pivotal gasotransmitter networking with nitric oxide (NO) and carbon monoxide (CO) to regulate basic homeostatic functions. It is released by the alternative pathways of transulfuration by the enzymes Cystathionine Beta Synthase (CBS) and Cystathionine Gamma Lyase (CSE), and by Cysteine AminoTransferase (CAT)/ 3-Mercaptopyruvate Sulfur Transferase (3MPST). A non-enzymatic, intravascular release is also in place. We retrospectively investigated the possibility to modulate the endogenous H2S release and signaling in humans by a dietary manipulation with supplemented micronutrients (L-cystine, Taurine and pyridoxal 5-phopsphate/P5P). Methods: Patients referring for antiaging purposes underwent a 10-day supplementation. Blood was collected at baseline and after treatment and the metabolome was investigated by mass spectrometry to monitor the changes in the metabolites reporting on H2S metabolism and related pathways. Results: Data were available from 6 middle aged subjects (2 women). Micronutrients increased 3-mercaptopyruvate ( P = .03), reporting on the activity of CAT that provides the substrate for H2S release within mitochondria by 3MPST, decreased lanthionine ( P = .024), reporting the release of H2S from CBS, and had no significant effect of H2S release from CSE. This is compatible with a homeostatic balancing. We also recorded a strong increase of reporters of H2S-induced pathways including 5-MethylTHF ( P = .001) and SAME ( P = .022), reporting on methylation capacity, and of BH4 ( P = .021) and BH2 ( P = .028) reporting on nitric oxide metabolism. These activations may be explained by the concomitant induction of non-enzymatic release of H2S. Conclusions: Although the current evidences are weak and will need to be confirmed, the effect of micronutrients was compatible with an increase of the H2S endogenous release and signaling within the control of homeostatic mechanisms, further endorsing the role of feeding in health and disease. These effects might result in a H2S boosting effect in case of defective activity of pathologic origin, which should be checked in duly designed clinical trials.

Senescent Phenotype of Astrocytes Leads to Microglia Activation and Neuronal Death

Astrocyte, the most abundant cell type in the central nervous system, is increasingly recognized and is thought to depend on curial and diverse roles in maintaining brain homeostasis, the blood-brain barrier, ion homeostasis, secrete neurotrophic factors and regulate synaptic transmission which is essential to tune individual-to-network neuronal activity. Senescence in astrocytes has been discovered to be an important contributor to several age-related neurological diseases like Alzheimer's and Parkinson's disease. However, the latest research about astrocytes from aged subjects or aged astrocytes in vitro is not yet adequate to be well elucidated on their curial process in the regulation of brain function. In this study, an in vitro cell model of aged astrocytes was constructed by serial passaging until passage 20-25, and those passages within 1-5 were used as young astrocytes. Meanwhile, oxidative induced astrocyte senescence model was also constructed by H2O2 induction. Our results indicate that after serial passaging or oxidative stress-induced astrocytes, all showed manifest changes in several established markers of cellular senescence like P53, P21, the release of inflammatory cytokine IL-6 and SA-β-gal positive cells. Results also showed mitochondrial dysfunction in the oxidative stress-induced astrocyte senescence model and treatment of berberine could reverse these alterations. What’s more interests us is that those two types of senescent astrocytes’ conditioned medium co-cultured with neuronal cells could do impact on neuron apoptosis no matter in direct or indirect ways. This study may help us better understand the fundamental role of astrocyte senescence on the regulation of normal and pathological brain aging.

“Forever young at the table”: metabolic effects of eating speed in obesity

Background Cardiometabolic diseases (CMD) are recognized as the main causes of morbidity and mortality in developed countries. In recent years eating speed (ES) has been of particular interest since some studies have associated it with the development of obesity and CMD. However, the different impact of the ES at which main meals are eaten on the risk of developing these diseases has not yet been identified. Thus, we aimed to investigate the effect of ES at the main meals (breakfast, lunch, and dinner) on the risk of developing cardiometabolic diseases (type 2 diabetes mellitus, dyslipidaemia and hypertension) in middle-aged Caucasian subjects with obesity. Methods For this purpose we carried out a cross-sectional, observational study. One hundred and eighty-seven middle-aged subjects aged 43.6 ± 16 years were enrolled of which anthropometric parameters and lifestyle habits were studied. A dietary interview was performed to collect information about meal duration and eating habits at the main meals. According to median value of meal duration, meals were classified in two groups: fast eating group (FEG) and slow eating group (SEG). Results The prevalence of dyslipidaemia was more than twice in FEG compared to SEG at lunch and dinner. For all main meals, FEG had a significantly higher risk of dyslipidaemia than SEG (p < 0.05) in unadjusted model. However, when the model was adjusted for age, BMI, physical activity, smoking and alcohol use and medication, the result remained significant for lunch and dinner (p < 0.05). Conclusion The results of our study suggest that fast eating increases at lunch and dinner increase the risk of developing dyslipidaemia in obesity.

Comparative Evaluation of Cognitive Function among Indian Obese and Non-Obese Middle-Aged Subjects

Background: Obesity has become one of the common problems encountered by people of the present day. This condition is often accompanied by cardiovascular problems like hypertension, hyperlipidemia, is chemic heart disease. Also, that the relationship between obesity and cognitive impairment plays an important role in the development of neurodegenerative disorders. But reports on the association between obesity and working memory lack scientific evidence. So, the present study planned to assess the influence of obesity on cognitive functions and compare among obese and non - obese individuals. Objective: This study evaluated the changes in cognitive functions comparative between samples of obese and non-obese individuals from India. Methods: Based on the Body Mass Index (BMI), the participants were classified into 2 groups. Cognitive screening was done using MINI MENTAL STATE EXAMINATION and the parameters like level of orientation, registration, recall, language, copy art skills were analyzed and scores were calculated. The data was statistically analyzed using SPSS version 23 and the independent sample t test was used to analyze the differences in cognitive functions. Results: The study reported that there was statistically significant decline in language, recall and copy art skills in obese individuals compared to non-obese group. Conclusion: The study concluded an innovative finding that obesity is associated with impaired cognitive performance pertaining to recall, language and copy art and overall decreased MMSE scores indicating that accelerated cognitive decline and neurodegenerative pathologies such as dementia in later life is influenced by changes in body weight. Interventions that target mid-life obesity may be helpful in reducing the cognitive risks associated with obesity.

Cellular Senescence and Senescence-Associated Secretory Phenotype Drive Multipotent Cardiac Stem/Progenitor Cell Dysfunction in Human Diabetic Cardiomyopathy Independently of Age

Background: Aging and Diabetes Mellitus (DM) independently and additively increase cardiovascular risk and a pathophysiological basis for this epidemiological link is currently the subject of intense investigations. Both aging and DM affect the biology and regenerative potential of tissue specific cardiac adult stem/progenitor cells (CSCs). In aged subjects over half of the CSCs are senescent with a senescence-associated secretory phenotype (SASP) that renders otherwise healthy CSCs to senescence, impairing their proliferative and differentiation potential. Although a link to organismal aging is clear, cells can undergo senescence, regardless of age. Yet, it is unclear whether the SASP is induced by Diabetes per se in CSCs and whether targeting senescent cells within the diabetic CSC compartment rescues their regenerative biology. Methods: In order to investigate the effects of DM on CSC senescence and to try separate those of aging from Diabetes on senescence events, we obtained peri-infarct/border zone biopsies from non-aged patients (50-64 years old) with DM type 2 (T2DM) and non-diabetic (NDM) patients with post-infarct cardiomyopathy undergoing surgical coronary revascularization. Results: Ischemic injury in DM is associated with a higher ROS production, as revealed by the exacerbated expression of 8-OH-deoxyguanosine, nitrotyrosine, and 4-hydroxinonenal targeting both cardiomyocytes as well as CSCs. The latter associated with an increased number of senescent and dysfunctional T2DM-hCSCs (isolated from atrial samples of T2DM and NDM patients with ischemic cardiomyopathy) identified by increased p16INK4a positive cells, reduced telomerase activity and telomere length, reduced proliferation, clonogenesis/spherogenesis and myogenic differentiation when compared to NDM-hCSCs in vitro. Importantly, T2DM-hCSCs show a defined SASP, as demonstrated by the increased secretion of MMP-3, PAI1, IL-6, IL-8, IL-1β and GM-CSF. A combination of two senolytics, Dasatinib and Quercetin, clears senescent T2DM-hCSCs in vitro restoring expansion and myogenic differentiation capacities of the diabetic hCSC pool. Conclusions: DM hampers human CSC biology, inducing a variety of hallmarks of senescence in non-aged subjects that contribute to the deficit of their regenerative potential. Clearance of senescent cells by senolytics abrogates the SASP and restores a fully proliferative- and differentiation- competent hCSC pool in T2DM.

Impact of a Carbohydrate Mouth Rinse on Corticomotor Excitability after Mental Fatigue in Healthy College-Aged Subjects

Mental Fatigue (MF) has been associated with reduced physical performance but the mechanisms underlying this result are unclear. A reduction in excitability of the corticomotor system is a way mental fatigue could negatively impact physical performance. Carbohydrate (CHO) mouth rinse (MR) has been shown to increase corticomotor excitability. PURPOSE: The purpose of this study was to determine if CHO MR impacts corticomotor excitability after MF. METHODS: Fifteen subjects (nine females, six males; age = 23 ± 1 years; height = 171 ± 2 cm; body mass = 69 ± 3 kg; BMI = 23.8 ± 0.7) completed two sessions under different MR conditions (Placebo (PLAC), 6.4% glucose (CHO)) separated by at least 48 h and applied in a double-blinded randomized fashion. Motor-evoked potential (MEP) of the left first dorsal interosseous (FDI) was determined by transcranial magnetic stimulation (TMS) before and after MF. Perceived MF was recorded before and after the MF task using a 100 mm visual analog scale (VAS). RESULTS: MF was greater following PLAC (+30.4 ± 4.0 mm) than CHO (+19.4 ± 3.9 mm) (p = 0.005). MEP was reduced more following PLAC (−16.6 ± 4.4%) than CHO (−3.7 ± 4.7%) (p < 0.001). CONCLUSIONS: CHO MR was successful at attenuating the reduction in corticomotor excitability after MF. Carbohydrate mouth rinse may be a valuable tool at combating the negative consequences of mental fatigue.

An Agent-Specific Stochastic Model of Generalized Reaching Task Difficulty

The ability of an agent to accomplish a trajectory during a certain motor task depends on the fit between external (environment) and internal (agent) constraints, also known as affordance. A model of difficulty for a generalized reaching motor task is proposed as an affordance-related measure, as perceived by a specific agent for a given environment and task. By extending the information-based Index of Difficulty of a trajectory, a stochastic model of difficulty is formulated based on the observed variability of spatial trajectories executed by a given agent during a repetitive motor task. The model is tested on an experimental walking dataset available in the literature, where the repetitive stride movement of differently aged subjects (14 “old” subjects aged 50–73; 20 “young” subjects aged 21–37) at multiple speed conditions (comfortable, ~30% faster, ~30% slower) is analyzed. Reduced trajectory variability in older as compared to younger adults results in a higher Index of Difficulty (slower: +24%, p < 0.0125; faster: +38%, p < 0.002) which is interpreted in this context as reduced affordance. The model overcomes the limits of existing difficulty measures by capturing the stochastic dependency of task difficulty on a subject’s age and average speed. This model provides a benchmarking tool for motor performance in biomechanics and ergonomics applications.