Aging and chronic inflammation have been identified as independent risk factors for the development of atherothrombosis and cardiovascular disease.
We recently identified TNF-α as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α 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 (figure 2). Platelets from old mice (where TNF-α was endogenously increased), and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation (figure 1). These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α 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, we present previously-unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.
