The molecular chaperone GroEL is designed to promote protein folding and prevent aggregation. However, the interaction between GroEL and the prion protein, PrP^C, could lead to pathogenic transformation of the latter to the aggregation-prone PrP^Sc form. Here, the molecular basis of the interactions in the GroEL–PrP complex is studied with cryo-EM and molecular dynamics approaches. The obtained cryo-EM structure shows PrP to be bound to several subunits of GroEL at the level of their apical domains. According to MD simulations, the disordered N-domain of PrP forms much more intermolecular contacts with GroEL. Upon binding to the GroEL, the N-domain of PrP begins to form short helices, while the C-domain of PrP exhibits a tendency to unfold its α2-helix. In the absence of the nucleotides in the system, these processes are manifested at the hundred nanoseconds to microsecond timescale.

Background. The trend towards aging of the population is global, which makes the study of etiology, prevention and treatment of age-related disorders relevant. Increasing number of studies highlights the influence of 25-hydroxyvitamin D deficiency on health state in older people, as well as its correlation with geriatric syndromes prevalence. However, at the moment it is not known whether these patterns persist in patients older than 90 due to the limited number of studies on this population.Aim. To assess the prevalence of vitamin D deficiency in a cohort of centenarians in the central region of Russian Federation and to study its relationship with the presence of geriatric syndromes.Materials and methods. The study was carried out by Russian Gerontology Research and Clinical Centre of Pirogov Russian National Research Medical University and Center for Strategic Planning and Management of Medical and Biological Health Risks. It was a cross-sectional study on the cohort of centenarians (90 years and older). Complex geriatric assessment was performed. Complex geriatric assessment included past medical history, geriatric scales and questionnaires (MMSE, SARC-F, MNA scores). Blood samples were taken to assess the 25-OH vitamin D levels using chemiluminescence method. The study is reviewed by the ethics committee (№ 30 24.12.2019). The statistical analysis was performed using Python version 3.9 and R version 4.1.3.Results. The study included 3,235 people aged 90 to 107 years. Median level of 25-hydroxyvitamin D was 9 ng/ml, 86.7% of participants were found to be 25(OH)D deficient, and in 8.3% insufficiency 25(OH)D was detected. Using the intergroup analysis, the association between 25-OH vitamin D levels and some geriatric syndromes, such as malnutrition, sarcopenia and cognitive impairment was observed. However, after adjusting to physical activity and nutrition statistically significant association was demonstrated only for cognitive impairment.Conclusion. The results obtained on the association between low levels of 25-OH vitamin D and cognitive impairment among centenarians confirm the importance of vitamin D deficiency prevention and might be starting point for future studies.

Neurodegenerative disorders, particularly Alzheimer’s disease, have become a major global healthcare issue. Despite extensive research, the molecular

Objective: Elevated cholesterol levels are associated with the risk of the most socially significant cardiovascular diseases, such as atherosclerosis, ischemic heart disease, and myocardial infarction. Methods: In this study, we sought to study the genetic architecture of lipid metabolism by conducting genome-wide association studies of total cholesterol, LDL-C, and HDL-C levels in a sample of the Russian population ( n = 8,732) who were not carriers of variants linked to familial hypercholesterolemia and did not take lipid-regulating agents. Based on the detected associations and machine learning methods, several polygenic score models were constructed for each lipid type, and the link between polygenic scores and atherosclerosis, ischemic heart disease, and myocardial infarction was examined in an additional sample of patients diagnosed with either of these diseases ( n = 3,954). Results: A meta-analysis of the results of the conducted genome-wide association studies showed that total cholesterol and LDL-C were largely associated with the same variants located in the HMGCR, CERT1, POLK, ANKDD1B, APOC3, BCL3, CBLC, BCAM, NECTIN2, TOMM40, APOE, APOC1, APOC4, and SMARCA4 genes, while HDL-C was associated with variants located in the LPL, ALDH1A2, LIPC, and CETP genes. Men and women differed in genetic predictors of lipid levels, with variants in the SMARCA4 and LDLR genes associated with cholesterol levels only in women. Conclusion: The models developed in this study consider age and a modifiable factor, BMI. Therefore, the personalized polygenic profiling approach presented in this study enables life-long CVD risk assessment.

Aging is a natural process with varying effects. As we grow older, our bodies become more susceptible to aging-associated diseases. These diseases, individually or collectively, lead to the formation of distinct aging phenotypes. Identifying these aging phenotypes and understanding the complex interplay between coexistent diseases would facilitate more personalized patient management, a better prognosis, and a prolonged lifespan. Many studies distinguish between successful aging and frailty. However, this simple distinction fails to reflect the diversity of underlying causes. In this study, we sought to establish the underlying causes of frailty and determine the patterns in which these causes converge to form aging phenotypes. We conducted a comprehensive geriatric examination, cognitive assessment, and survival analysis of 2,688 long-living adults (median age = 92 years). The obtained data were clustered and used as input data for the Aging Phenotype Calculator, a multiclass classification model validated on an independent dataset of 96 older adults. The accuracy of the model was assessed using the receiver operating characteristic curve and the area under the curve. Additionally, we analyzed socioeconomic factors that could contribute to specific aging patterns. We identified five aging phenotypes: non-frailty, multimorbid frailty, metabolic frailty, cognitive frailty, and functional frailty. For each phenotype, we determined the underlying diseases and conditions and assessed the survival rate. Additionally, we provided management recommendations for each of the five phenotypes based on their distinct features and associated challenges. The identified aging phenotypes may facilitate better-informed decision-making. The Aging Phenotype Calculator (ROC AUC = 92%) may greatly assist geriatricians in patient management.

Previous studies examining the molecular and genetic basis of cognitive impairment, particularly in cohorts of long-living adults, have mainly focused on associations at the genome or transcriptome level. Dozens of significant dementia-associated genes have been identified, including APOE, APOC1, and TOMM40. However, most of these studies did not consider the intergenic interactions and functional gene modules involved in cognitive function, nor did they assess the metabolic changes in individual brain regions. By combining functional analysis with a transcriptome-wide association study, we aimed to address this gap and examine metabolic pathways in different areas of the brain of older adults. The findings from our previous genome-wide association study in 1155 older adults, 179 of whom had cognitive impairment, were used as input for the PrediXcan gene prediction algorithm. Based on the predicted changes in gene expression levels, we conducted a transcriptome-wide association study and functional analysis using the KEGG and HALLMARK databases. For a subsample of long-living adults, we used logistic regression to examine the associations between blood biochemical markers and cognitive impairment. The functional analysis revealed a significant association between cognitive impairment and the expression of NADH oxidoreductase in the cerebral cortex. Significant associations were also detected between cognitive impairment and signaling pathways involved in peroxisome function, apoptosis, and the degradation of lysine and glycan in other brain regions. Our approach combined the strengths of a transcriptome-wide association study with the advantages of functional analysis. It demonstrated that apoptosis and oxidative stress play important roles in cognitive impairment.