Sleep mediates age-associated vascular inflammation and cardiovascular risk

• Applicant: Dr. Teresa Gerhardt
• Subject Area: Cardiology, Angiology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508840157

Longstanding clinical evidence has established that sleep protects against cardiovascular (CV) disease. In humans, chronic sleep fragmentation (SF) strongly increases atherosclerotic lesion size and the incidence of myocardial infarctions. Sleep quality and duration deteriorate with advancing age. Concomitant with reduced sleep, CV risk is elevated in the elderly and ageing is the strongest known determinant of atherosclerosis. Despite these associations, the biological mechanisms that link sleep with atherosclerosis and ageing remain poorly understood. Myeloid-biased hematopoiesis and a persistent low-grade inflammation called inflamm’ageing accompany the ageing process. Inflamm’ageing is mediated in part by epigenetic modifications and is a key driver of age-related CV risk. It is characterized by vascular cell senescence and activation of a proinflammatory senescence-associated secretory phenotype that includes secretion of interleukin (IL)-6. The systemic and vascular processes that have recently been identified to mediate increased atherosclerosis during SF in mice, strikingly resemble these key hallmarks of ageing. Specifically, data from the host laboratory show that, like ageing, SF increases atherosclerotic lesion size by enhancing myeloid-biased hematopoiesis in mice. More recent preliminary data suggest that akin to inflamm’ageing, SF upregulates IL-6 and might induce vascular cell senescence through epigenetic alterations. These conspicuous parallels between SF and ageing sparked the idea that the two could be mechanistically linked through inflamm’ageing. Building on this and supported by published and unpublished data, we hypothesize that SF accelerates the vascular ageing process by inducing transcriptional and epigenetic alterations that enhance IL-6-controlled cell senescence and inflammation. To test this, we will use state-of the art mouse models and technologies to study sleep-mediated dynamics of the key vascular cell types across the lifespan. We have defined four objectives, including quantification and qualitative analysis of the plaque (objective I), and analysis of activation and senescence (objective II), as well as transcriptomic and epigenetic profiling (objective III) of vascular cells, each during SF and ageing. The role of IL-6 during this process (objective IV) will be studied using general- and cell-specific IL-6 knock-out models. We will use human blood and tissue samples available through collaborations with sleep physicians for translational validation of our findings. A detailed understanding of the fundamental mechanisms by which sleep modification shapes inflammation and vascular pathology during the ageing process can provide insights into new disease mechanisms and could reveal novel targets for personalized prevention and therapy to curb the substantial CV risk that remains beyond conventional risk factors.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Cameron McAlpine