Aging-related alterations in mechanistic target of rapamycin signaling promote platelet hyperreactivity and thrombosis
Year: 2024
Type: article
Abstract: Background Aging is an independent risk factor for the development of cardiovascular, thrombotic, and other chronic diseases. However, mechanisms of platelet hyperactivation in aging remain poorly understood. Objectives Here, we examine whether and how aging alters intracellular signaling in platelets to support platelet hyperactivity and thrombosis. Methods Quantitative mass spectrometry with tandem mass tag labeling systematically measured protein phosphorylation in platelets from healthy aged (>65 years) and young human (<45 years) subjects. The role of platelet mechanistic target of rapamycin (mTOR) in aging-induced platelet hyperreactivity was assessed using pharmacologic mTOR inhibition and a platelet-specific mTOR-deficient mouse model (mTOR plt−/− ). Results Quantitative phosphoproteomics uncovered differential site-specific protein phosphorylation within mTOR, Rho GTPase, and MAPK pathways in platelets from aged donors. Western blot confirmed constitutive activation of the mTOR pathway in platelets from both aged humans and mice, which was associated with increased aggregation compared with that in young controls. Inhibition of mTOR with either Torin 1 in aged humans or genetic deletion in aged mice reversed platelet hyperreactivity. In a collagen–epinephrine pulmonary thrombosis model, aged wild-type (mTOR plt+/+ ) mice succumbed significantly faster than young controls, while time to death of aged mTOR plt−/− mice was similar to that of young mTOR plt+/+ mice. Mechanistically, we noted increased Rac1 activation and levels of mitochondrial reactive oxygen species in resting platelets from aged mice, as well as increased p38 phosphorylation upstream of thromboxane generation following agonist stimulation. Conclusion Aging-related changes in mTOR phosphorylation enhance Rac1 and p38 activation to enhance thromboxane generation, platelet hyperactivity, and thrombosis.
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,750
Funders: U.S. Department of Veterans Affairs, American Heart Association, Oregon Health and Science University, International Society on Thrombosis and Haemostasis, National Institutes of Health, Clinical Science Research and Development, National Institute on Aging, National Heart, Lung, and Blood Institute, National Eye Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: Translational Control of Megakaryocyte and Platelet Function in Sepsis, Platelet-Mediated Neutrophil Extracellular Traps Regulate Ischemic Stroke Injury, G2202659028, Platelet Immune Responses in Aging and Influenza, G2535433541, G3695966131, Interferon-Induced Transmembrane Protein 3 (IFITM3) Regulates Thrombosis During Inflammation in Aging, G4374229610, Novel Regulatory Mechanisms of Inflammation-Induced Thrombosis, New Therapies to Restore Vascular Integrity During Sepsis, G4814311130, Pathway maps of platelet phenotype and function, LTQ Orbitrap Velos, G6483166148, G7249880227, Amnis ImageStreamX MarkII Imaging Flow Cytometer, Platelet-Leukocyte Interactions in Sepsis, Translational Control of Megakaryocyte and Platelet Gene Expression in Disease, Patient-specific blood cell reactivity and flow dynamic profiles in transcatheter aortic valve replacement, UT StrokeNet, Ophthalmology Core Facility, OHSU Knight Cancer Institute
OpenAlex ID: W4399388938