Metabolic drift in the aging nervous system is reflected in human cerebrospinal fluid

Chronic diseases affecting the central nervous system (CNS) like Alzheimer’s or Parkinson’s disease typically develop with advanced chronological age. Yet, aging at the metabolic level has been explored only sporadically in humans using biofluids in close proximity to the CNS such as the cerebrospinal fluid (CSF). We have used an untargeted liquid chromatography high-resolution mass spectrometry (LC-HRMS) based metabolomics approach to measure the levels of metabolites in the CSF of non-neurological control subjects in the age of 20 up to 74. Using a random forest-based feature selection strategy, we extracted 69 features that were strongly related to age (page < 0.001, rage = 0.762, R2Boruta age = 0.764). Combining an in-house library of known substances with in silico chemical classification and functional semantic annotation we successfully assigned putative annotations to 59 out of the 69 CSF metabolites. We found alterations in metabolites related to the Cytochrome P450 system, perturbations in the tryptophan and kynurenine pathways, metabolites associated with cellular energy (NAD+, ADP), mitochondrial and ribosomal metabolisms, neurological dysfunction, and an increase of adverse microbial metabolites. Taken together our results point at a key role for metabolites found in CSF related to the Cytochrome P450 system as most often associated with metabolic aging.

Clinical manifestation features of chronic heart failure with comorbid obesity in consideration of cytochrome P450 system CYP2D6*4 gene polymorphism

In order to assess the characteristics of the clinical manifestation of CHF with obesity, taking into account the polymorphism of the CYP2D6*4 gene of the cytochrome P450 system in terms of patient’s quality of life a prospective randomized controlled trial was conducted, 127 people (93 men and 34 women) aged 32-87 (61) years with CHF of II—III stages, 1^1 functional class according to the classification of the New York Heart Association (NYHA) have been examined. The main group consisted of 73 patients with obesity of 1 degree and higher, the comparison group consisted of 54 patients without obesity, the control group consisted of 21 people without cardiovascular disorders. Research methods included estimation of clinical symptom score scale, 6-minute walk test, quality of life (with the Minnesota questionnaire for patients with heart failure), assessment of subjective symptoms and course of the disease, anthropometric data, determination of objective signs of the disease; instrumental methods (Doppler echocardiography, basic laboratory examination, etc.), as well as genetic research (G1846A variants of the CYP2D6 gene real-time polymerase chain reaction), statistical non-parametric methods (with 0.05 p-value thresold). It is shown, that in the clinical aspect, patients of the main group have been characterized by a tendency to more expressive pathological manifestations of CHF, especially in carriers of the heterozygous GA variant of the CYP2D6*4 gene of the cytochrome P450 system. According to the Minnesota questionnaire, the clinical condition of patients and the quality of life in case of GG polymorphism variant was better than in GA carriers of the CYP2D6*4 genotype variant of the cytochrome P450 system. Keywords: chronic heart failure, quality of life, obesity, genetic polymorphism, treatment, prognosis.