A dvanced age, even in healthy individuals, is accompanied by progressive decline of cognitive, metabolic and physiological abilities, and can enhance susceptibility to neurodegenerative, cardiovascular and chronic inflammatory diseases 1,2. Operationally, it is often difficult to determine whether age-associated signatures reflect changes of individual cells or changes in cell-type abundances, especially when performing whole-tissue transcriptional or epigenetic characterization. And even despite a large amount of clinical and epidemiological data 3-7 , we understand very little about the nature of age-associated changes in specific primary cell populations of healthy individuals, particularly with respect to age-associated alterations of the epigenetic landscape. To address this question directly, we focused on classical CD14 + CD16 − monocytes, as they are homogeneous, easily accessible and relatively abundant in blood, which permits multiomics profiling of these cells obtained from a single blood draw. Epigenetic aging can manifest in two key aspects: via age-associated changes in chromatin modifications and in DNA methylation. Robustness of the connection between aging and DNA methylation has been well acknowledged 8-12 ; yet, despite the large number of studies, cell-specific regions of age-associated DNA methylation/demethylation have not been reported so far. Previous studies have predominantly used DNA methylation arrays that detect changes of a predefined set of distant solitary cytosines across the genome 4. This design prevents identification of differentially methylated regions (DMRs), which are expected to be more biologically relevant compared with changes in single isolated CpG sites. In this Article, we used parallel multiomics approaches to characterize intracellular states and extracellular environments of monocytes along healthy aging. To allow for simultaneous identification of continuous age-associated DNA methylation regions and corresponding chromatin context, we utilized enhanced reduced representation bisulfite sequencing (eRRBS) coupled with the ultra-low-input chromatin immunoprecipitation followed by sequencing (ULI-ChIP-seq) 13 approach to profile chromatin modifications from limited input material. Our approach led to the identification of more than 1,000 DMRs, which could not be achieved via methylation array technology. We found no evidence of large-scale remodelling of the chromatin modification landscape along healthy aging, yet revealed distinct chromatin features that were characteristic of age-associated DNA hyper-and hypomethylated regions. Integration of the obtained DMR signatures with

Mutations of the GBA gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for Parkinson’s disease (PD) with frequency between 5% and 20% across the world. N370S and L444P are the two most common mutations in the GBA gene. PD carriers of severe mutation L444P in the GBA gene is characterized by the earlier age at onset compared to N370S. Not every carrier of GBA mutations develop PD during one’s lifetime. In the current study we aimed to find common gene expression signatures in PD associated with mutation in the GBA gene (GBA-PD) using RNA-seq. We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.

To assess the biology of the lethal endpoint in patients with SARS-CoV-2 infection, we compared the transcriptional response to the virus in patients who survived or died during severe COVID-19. We applied gene expression profiling to generate transcriptional signatures for peripheral blood mononuclear cells (PBMCs) from patients with SARS-CoV-2 infection at the time when they were placed in the Intensive Care Unit of the Pavlov First State Medical University of St. Petersburg (Russia). Three different bioinformatics approaches to RNA-seq analysis identified a downregulation of three common pathways in survivors compared with nonsurvivors among patients with severe COVID-19, namely, low-density lipoprotein (LDL) particle receptor activity (GO:0005041), important for maintaining cholesterol homeostasis, leukocyte differentiation (GO:0002521), and cargo receptor activity (GO:0038024). Specifically, PBMCs from surviving patients were characterized by reduced expression of PPARG, CD36, STAB1, ITGAV, and ANXA2. Taken together, our findings suggest that LDL particle receptor pathway activity in patients with COVID-19 infection is associated with poor disease prognosis.