Friday, April 26, 2024
4/26/2024
Project Summary/Abstract The research objective is to characterize the role of necroptosis-induced inflammation on aging. Chronic, low-grade inflammation (inflammaging) is a hallmark of aging and is one of the ‘seven pillars of aging’. Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people because a variety of age-related diseases (e.g. type 2 diabetes, cardiovascular diseases, cancer, and neurodegenerative diseases) share a strong inflammatory phenotype. Despite the link between inflammation, aging and age- associated diseases, two major gaps currently exist in our understanding of the role inflammation plays in aging: (1) the molecular mechanism(s)/pathway(s) responsible for the chronic, low-grade inflammation and (2) whether inflammaging is a causative factor in aging or occurs secondary to aging. Damage-associated molecular patterns (DAMPs) play a role in age-associated chronic inflammation and necroptosis is a newly identified pathway of programmed necrosis that plays a major in the generation of DAMPs. Necroptosis is initiated when necroptotic stimuli sequentially activate the receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain like (MLKL) protein through phosphorylation. Phosphorylated MLKL binds to and disrupts the plasma membrane of cells, releasing DAMPs. The DAMPs in turn trigger chronic low-grade inflammation through increased production of inflammatory cytokines such as TNF¿ by innate immune cells, which can activate RIPK1 in other cells in a positive feedback loop. Studies show that inhibiting necroptosis by knocking out Ripk3 reduces necroptosis as well as inflammation in several mouse models. Our preliminary data provides the first evidence showing that necroptosis might play a role in aging, i.e., necroptosis increases with age in wild type (WT) mice and in a model of accelerated aging (Sod1-/- mice), and reducing/blocking necroptosis (both genetically and pharmacologically) reduces inflammation in Sod1-/- mice. Based on our preliminary data, we hypothesize that necroptosis plays a role in chronic, low-grade inflammation, which occurs with age, and preventing necroptosis will attenuate inflammation, leading to increased lifespan and improved healthspan. To test this hypothesis, in Aim1 we will determine the role of necroptosis in age-associated chronic inflammation by identifying progression of necroptosis and inflammation in various tissues of young, middle-aged and old male and female WT mice and determine the effect of reducing necroptosis either genetically (Ripk3+/- and Ripk3-/- mice) or pharmacologically (necrostatin-1s, a RIPK1 inhibitor) on inflammation; in Aim2 we will determine the mechanism by which necroptosis mediates age-associated inflammation by assessing the activation of inflammatory pathways in tissues and cells of young and old WT mice and determine the effect of genetic inhibition of necroptosis on inflammatory pathways; in Aim3, we will determine the role of necroptosis in aging by comparing the lifespan, healthspan and age-associated pathology of Ripk3+/- and Ripk3-/- mice to WT mice.
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