Impact of Caloric Restriction on Molecular and Functional Networks in Rhesus Monkeys

Caloric restriction (CR) delays aging and the onset of age-related disease in diverse species. Several diseases of aging including diabetes, cancer, and neurodegeneration, have an established metabolic component. Although the mechanisms of CR remain unknown, numerous factors implicated in longevity regulation by CR converge on regulation of metabolism. The reprograming of metabolism with CR is tissue specific, but mitochondrial activation and changes in redox metabolism are among the shared features. Changes in non-coding miRNA and in processing of transcripts are contributing mechanisms in integrating metabolic and growth pathways. Our studies in simple cell culture shows that small changes in metabolic status can precipitate large-scale multi-modal functional changes across cellular processes. We propose that modest failures in metabolic integrity with age broadly impact homeostasis and adaptation, creating shared vulnerability to diseases and conditions despite differences in their etiology, and that CR harnesses this same axis to promote health and enhanced longevity.

Metabolomic Fingerprint of Mecp2-Deficient Mouse Cortex: Evidence for a Pronounced Multi-Facetted Metabolic Component in Rett Syndrome

Using unsupervised metabolomics, we defined the complex metabolic conditions in the cortex of a mouse model of Rett syndrome (RTT). RTT, which represents a cause of mental and cognitive disabilities in females, results in profound cognitive impairment with autistic features, motor disabilities, seizures, gastrointestinal problems, and cardiorespiratory irregularities. Typical RTT originates from mutations in the X-chromosomal methyl-CpG-binding-protein-2 (Mecp2) gene, which encodes a transcriptional modulator. It then causes a deregulation of several target genes and metabolic alterations in the nervous system and peripheral organs. We identified 101 significantly deregulated metabolites in the Mecp2-deficient cortex of adult male mice; 68 were increased and 33 were decreased compared to wildtypes. Pathway analysis identified 31 mostly upregulated metabolic pathways, in particular carbohydrate and amino acid metabolism, key metabolic mitochondrial/extramitochondrial pathways, and lipid metabolism. In contrast, neurotransmitter-signaling is dampened. This metabolic fingerprint of the Mecp2-deficient cortex of severely symptomatic mice provides further mechanistic insights into the complex RTT pathogenesis. The deregulated pathways that were identified—in particular the markedly affected amino acid and carbohydrate metabolism—confirm a complex and multifaceted metabolic component in RTT, which in turn signifies putative therapeutic targets. Furthermore, the deregulated key metabolites provide a choice of potential biomarkers for a more detailed rating of disease severity and disease progression.

Effect of Leptin Treatment in a Mouse Model of Tdp-43 Proteinopathy

Amyotrophic Lateral Sclerosis (ALS) is an irreversible neurodegenerative disease with no known cure. Recent studies suggest a strong metabolic component in ALS pathogenesis and have shown an inverse relationship between leptin levels and ALS progression, although the effects of leptin as a treatment have not yet been studied. Therefore, we aim to examine whether the acute treatment with leptin has beneficial effects on brain pathology and cognitive function in the transgenic TDP43A315T line of ALS. Mice were treated intranasally (IN) with 0.03mg/kg of leptin or vehicle (VH) daily for 7 days. Data showed a progressive decline in body weight and motor coordination in TDP43A315T mice. Moreover, Lep-treated TDP43A315T mice showed an earlier disease onset, along with an improvement in motor performance. Altered levels of some of the adipokines and metabolic proteins studied were found in TDP43A315T mice, which were differently expressed among Lep-treated and VH-treated animals. Furthermore, some correlations were found among the serum levels of this proteins in WT and TDP43A315T mice. As far as we know, this is the first pilot study to provide evidence of the therapeutic effect of leptin treatment in a mice model of ALS, although further studies are needed to expound on the underlying mechanisms.

Prevalence and features of polymorbidity of servicemen of different age groups according to the results of their medical examination to determine the category of fitness for military service

The prevalence of polymorbidity and its features in military personnel of various age groups was studied. It has been established that polymorbidity during medical examinations of military personnel occurs in all age groups, increasing with age. For each age group of military personnel, its characteristic polymorbidity models are formed. So, in the age group up to 35 years, polymorbidity occurs in one third of the examined and is characterized by both functional disorders of the circulatory system and digestive organs, and the presence of organic pathology of the circulatory system (congenital malformations (developmental defects), mitral and other valve prolapse), digestive organs (chronic gastritis, gastroesophageal reflux disease) and the musculoskeletal system (flat feet, dorsopathies). At the age of 35 to 45 years, polymorbidity occurs in93,5% of those examined and is characterized by the presence of a cardiac and gastroenteric component in all polymorbidity models, in 80% of the models - the musculoskeletal component, in 60% - the metabolic component, in 40% - the endocrine component. Polymorbidity occurs in 97,5% of those examined over the age of 46 years and is characterized by the presence in all models of polymorbidity of the cardiac, cerebrovascular and musculoskeletal component, in 75% of the models - the metabolic component, in 50% - the endocrine component.

ASIC1a does not play a role in evoking the metabolic component of the exercise pressor reflex in a rat model of peripheral artery disease

The role of ASIC1a in evoking the metabolic component of the exercise pressor reflex in peripheral artery disease is unknown. Using a within-rat experimental design, we found that the contribution of ASIC1a decreased in a rat model of peripheral artery disease. These results have key implications to help finding better treatments and improve morbidity, quality of life, and mortality in patients with peripheral artery disease.

ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats

The role of the acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex is unknown, despite the fact that ASIC1a is opened by decreases in pH in the physiological range. This fact prompted us to test the hypothesis that ASIC1a plays an important role in evoking the exercise pressor reflex in decerebrated rats with freely perfused hindlimb muscles. To test this hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles on the reflex pressor responses to four maneuvers, namely 1) static contraction of the triceps surae muscles (i.e., the exercise pressor reflex), 2) calcaneal tendon stretch, 3) intra-arterial injection of lactic acid, and 4) intra-arterial injection of diprotonated phosphate. We found that the 2 ASIC1a blockers, psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 μg/kg), decreased the pressor responses to static contraction as well as the peak pressor responses to injection of lactic acid and diprotonated phosphate. In contrast, neither ASIC1a blocker had any effect on the pressor responses to tendon stretch. Importantly, we found that ASIC1a blockade significantly decreased the pressor response to static contraction after a latency of at least 8 s. Our results support the hypothesis that ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex. NEW & NOTEWORTHY The role played by acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex remains unknown. In decerebrated rats with freely perfused femoral arteries, blocking ASIC1a with psalmotoxin-1 or mambalgin-1 significantly attenuated the pressor response to static contraction, lactic acid, and diprotonated phosphate injection but had no effect on the pressor response to stretch. We conclude that ASIC1a plays a key role in evoking the exercise pressor reflex by responding to contraction-induced metabolites, such as protons.

METABOLIC INTEGRITY – A FACTOR IN AGING AND A PLAYER IN THE MECHANISMS OF CR

An emerging paradigm in aging research identifies metabolic dysfunction as a root cause in age-related disease vulnerability. Several diseases of aging, including diabetes, cancer, and neurodegeneration, have an established metabolic component. Our studies have focused on links between metabolic status and disease vulnerability. Caloric restriction (CR) delays aging and the onset of age-related disease in diverse species, including nonhuman primates. Molecular profiling identifies CR responsive elements in the transcriptome, proteome, and metabolome that are highly enriched for metabolic pathways and in particular mitochondrial processes. These data show that improvements in health and survival are associated with maintenance of system wide metabolic homeostasis and preserved energy metabolism among tissues. Metabolic biomarkers identified in these studies may be clinically relevant for the early identification of elevated disease risk in humans and could even be potential targets for the development of novel strategies to lower disease vulnerability as a function of age.

Type 2 Diabetes and Hashimoto Thyroiditis-Possible Associations and Clinical Correlations - Preliminary Results

Background and aims: The primary objective is to evaluate the possible relationship between Type 2 Diabetes (T2DM) and Hashimoto Thyroiditis (HT), since the only correlation described until now is between Type 1 Diabetes and HT based on the autoimmune mechanism. The secondary end-point is to evaluate if there is a correlation between the characteristics of Type 2 Diabetes and autoimmune thyroiditis and if the metabolic component may be a factor of association. Material and method: We designed a retrospective, observational research, enrolling patients from “Sanamed” Hospital from Bucharest. Between 2016 and 2017 in our clinic a number of 150 patients were enrolled, in the following groups: 50 only with T2DM, 50 only with HT and 50 with both T2DM and HT. Results: The main observations of the study were the following: the prevalence of obesity was higher in patients with T2DM (p<0.001) than in the group with HT (p<0.001); Dyslipidemia was higher in the HT group (p<0.001) than in the group of T2DM (p<0.001); Ischemic cardiac disease was more frequent in the HT group (p<0.001) than in the Diabetes group (p<0.001); in the group that had both T2DM and HT, the HbA1c was correlated with pre-existing Thyroid pathology (p<0.001), also Dyslipidemia was associated with hepatic steatosis (p<0.001). Conclusions: After assessing all the parameters we have reached the conclusion that there is an association between the characteristics of T2DM and HT, as well as an interaction between these two diseases, considering their metabolic component.