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Publications

Publications

The following articles have been published based on the results of Longitudinal Multi-Omic Study of Aging Determinants:

Irina Shchukina, Juhi Bagaitkar, Oleg Shpynov, Ekaterina Loginicheva, Sofia Porter, Denis A. Mogilenko, Erica Wolin, Patrick Collins, German Demidov, Mykyta Artomov, Konstantin Zaitsev, Sviatoslav Sidorov, Christina Camell, Monika Bambouskova, Laura Arthur, Amanda Swain, Alexandra Panteleeva, Aleksei Dievskii, Evgeny Kurbatsky, Petr Tsurinov, Roman Chernyatchik, Vishwa Deep Dixit, Marko Jovanovic, Sheila A. Stewart, Mark J. Daly, Sergey Dmitriev, Eugene M. Oltz & Maxim N. Artyomov

The impact of healthy aging on molecular programming of immune cells is poorly understood. Here we report comprehensive characterization of healthy aging in human classical monocytes, with a focus on epigenomic, transcriptomic and proteomic alterations, as well as the corresponding proteomic and metabolomic data for plasma, using healthy cohorts of 20 young and 20 older males (~27 and ~64 years old on average). For each individual, we performed enhanced reduced representation bisulfite sequencing-based DNA methylation profiling, which allowed us to identify a set of age-associated differentially methylated regions (DMRs)—a novel, cell-type-specific signature of aging in the DNA methylome. Hypermethylation events were associated with H3K27me3 in the CpG islands near promoters of lowly expressed genes, while hypomethylated DMRs were enriched in H3K4me1-marked regions and associated with age-related increase of expression of the corresponding genes, providing a link between DNA methylation and age-associated transcriptional changes in primary human cells… READ MORE

Denis A. Mogilenko, Oleg Shpynov, Prabhakar Sairam Andhey, Laura Arthur, Amanda Swain, Ekaterina Esaulova, Simone Brioschi, Irina Shchukina, Martina Kerndl, Monika Bambouskova, Zhangting Yao, Anwesha Laha, Konstantin Zaitsev, Samantha Burdess, Susan Gillfilan, Sheila A. Stewart, Marco Colonna, Maxim N. Artyomov

Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8+ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK+CD8+ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK+ Taa cells as a potential target to address age-associated dysfunctions of the immune system. READ MORE

Laura Arthur, Ekaterina Esaulova, Denis A. Mogilenko, Petr Tsurinov, Samantha Burdess, Anwesha Laha, Rachel Presti, Brian Goetz, Mark A. Watson, Charles W. Goss, Christina A. Gurnett, Philip A. Mudd, Courtney Beers, Jane A. O’Halloran & Maxim N. Artyomov

We examine the cellular and soluble determinants of coronavirus disease 2019 (COVID-19) relative to aging by performing mass cytometry in parallel with clinical blood testing and plasma proteomic profiling of ~4,700 proteins from 71 individuals with pulmonary disease and 148 healthy donors (25–80 years old). Distinct cell populations were associated with age (GZMK+CD8+ T cells and CD25low CD4+ T cells) and with COVID-19 (TBETEOMES CD4+ T cells, HLA-DR+CD38+ CD8+ T cells and CD27+CD38+ B cells). A unique population of TBET+EOMES+ CD4+ T cells was associated with individuals with COVID-19 who experienced moderate, rather than severe or lethal, disease. Disease severity correlated with blood creatinine and urea nitrogen levels. Proteomics revealed a major impact of age on the disease-associated plasma signatures and highlighted the divergent contribution of hepatocyte and muscle secretomes to COVID-19 plasma proteins. Aging plasma was enriched in matrisome proteins and heart/aorta smooth muscle cell-specific proteins. These findings reveal age-specific and disease-specific changes associated with COVID-19, and potential soluble mediators of the physiological impact of COVID-19… READ MORE

Nature Reviews Immunology, 23 November 2021

Immune ageing at single-cell resolution

Denis A. Mogilenko, Irina Shchukina & Maxim N. Artyomov

Ageing leads to profound alterations in the immune system and increases susceptibility to some chronic, infectious and autoimmune diseases. In recent years, widespread application of single-cell techniques has enabled substantial progress in our understanding of the ageing immune system. These comprehensive approaches have expanded and detailed the current views of ageing and immunity. Here we review a body of recent studies that explored how the immune system ages using unbiased profiling techniques at single-cell resolution. Specifically, we discuss an emergent understanding of age-related alterations in innate and adaptive immune cell populations, antigen receptor repertoires and immune cell-supporting microenvironments of the peripheral tissues. Focusing on the results obtained in mice and humans, we describe the multidimensional data that align with established concepts of immune ageing as well as novel insights emerging from these studies. We further discuss outstanding questions in the field and highlight techniques that will advance our understanding of immune ageing in the future… READ MORE

O. Spadaro, Y. Youm, I. Shchukina, S. Ryu, S. Sidorov, A. Ravussin, K. Nguyen, E. Aladyeva, A. N. Predeus, S. R. Smith, E. Ravussin, C. Galban, M. N. Artyomov, and V. D. Dixit

The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene Pla2g7 encoding platelet activating factor acetyl hydrolase (PLA2G7) is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span… READ MORE

Emily Stephenson, Gary Reynolds, Rachel A. Botting, Fernando J. Calero-Nieto, Michael D. Morgan, Zewen Kelvin Tuong, Karsten Bach, Waradon Sungnak, Kaylee B. Worlock, Masahiro Yoshida, Natsuhiko Kumasaka, Katarzyna Kania, Justin Engelbert, Bayanne Olabi, Jarmila Stremenova Spegarova, Nicola K. Wilson, Nicole Mende, Laura Jardine, Louis C. S. Gardner, Issac Goh, Dave Horsfall, Jim McGrath, Simone Webb, Michael W. Mather, Rik G. H. Lindeboom, Emma Dann, Ni Huang, Krzysztof Polanski, Elena Prigmore, Florian Gothe, Jonathan Scott, Rebecca P. Payne, Kenneth F. Baker, Aidan T. Hanrath, Ina C. D. Schim van der Loeff, Andrew S. Barr, Amada Sanchez-Gonzalez, Laura Bergamaschi, Federica Mescia, Josephine L. Barnes, Eliz Kilich, Angus de Wilton, Anita Saigal, Aarash Saleh, Sam M. Janes, Claire M. Smith, Nusayhah Gopee, Caroline Wilson, Paul Coupland, Jonathan M. Coxhead, Vladimir Yu Kiselev, Stijn van Dongen, Jaume Bacardit, Hamish W. King, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID-19 BioResource Collaboration, Anthony J. Rostron, A. John Simpson, Sophie Hambleton, Elisa Laurenti, Paul A. Lyons, Kerstin B. Meyer, Marko Z. Nikolić, Christopher J. A. Duncan, Kenneth G. C. Smith, Sarah A. Teichmann, Menna R. Clatworthy, John C. Marioni, Berthold Göttgens & Muzlifah Haniffa

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy… READ MORE