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Posted by star on 2019-08-07 14:35:47 Hits:313
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Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. 
Scientists from University of Colorado hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified TNF- as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. 
They further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF- receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status and thrombocytosis. 
Single-cell RNA-sequencing (scRNA-seq) analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF- was endogenously increased), and from young mice exposed to exogenous TNF- exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF- blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF- levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. 
Altogether, they present previously-unrecognized evidence that TNF- critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis. Their study has been published in Blood recently.
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