Inflammaging as a Mediator of Age-Dependent Cardiovascular Disease – an Investigation of Underlying Mechanisms and Potential Therapeutic and Preventive Targets

Abstract

Despite diagnostic and therapeutic advances of recent years, cardiovascular disease (CVD) still is the leading cause of mortality and morbidity worldwide. Although CVD can present in middle-aged or rarely even in young adults, its incidence rises notably beyond 60 years of age and its prevalence increases linearly with age. Thus, it classifies as an age-related disease (ARD). As life expectancy continues to grow, ARD and CVD in particular will pose an ever-greater strain on global health. Thus, delineating mechanisms underlying the age-dependent increase in cardiovascular morbidity is paramount to prevent and treat disease and promote healthy aging. This thesis aims to explore the effects of age per se on ischemic stroke – a major and often debilitating age-related cerebrovascular disease. Based on the concept of inflammaging – a chronic, sterile, low-grade inflammatory condition in elderly individuals, we first investigated the effects of persistent inflammation on stroke in young age, using a mouse model of rheumatoid arthritis. After confirming the pathogenic role of lingering inflammation and the feasibility of targeted anti-inflammatory treatment in the context of stroke, we explored the effects of old age per se on stroke outcomes. Finally, we examined safe and long-term preventive options using a dietary intervention with a plant-derived Omega-3 (n3) fatty acid alpha linolenic acid (ALA). The studies included in this thesis revealed the following results: 1) a state of chronic inflammation mediated by an overexpression of tumor necrosis factor alpha (TNF-α), does indeed result in larger and functionally more deleterious ischemic strokes by a mechanism of increased blood brain barrier (BBB) disruption. Targeted anti-inflammatory treatment with a TNF-α antibody is not only feasible in the context of acute ischemic stroke, but also ameliorates stroke outcomes. 2) Old age per se, in absence of potentially confounding comorbidities, predisposes to larger strokes and worse neurological outcomes due to a mechanism of increased inflammation, which can be counteracted by TNF-α inhibition. 3) A long-term dietary intervention with the n3 fatty acid ALA attenuates the adverse effects of old age on stroke outcomes via anti-inflammatory mechanisms. In summary, we demonstrate the role of chronic inflammation for unfavorable stroke outcomes in general and in the context of advanced age. We show potential merits of acute anti-inflammatory treatment in the setting of stroke at an advanced age and a possible non-invasive and safe preventive strategy using dietary means.