TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging

Area of Science:

• Cardiovascular Biology
• Immunology
• Hematology

Background:

• Aging and chronic inflammation are independent risk factors for atherothrombosis and cardiovascular disease.
• Platelet hyperreactivity and increased thrombotic risk are observed during aging.

Purpose of the Study:

• To investigate the role of aging-associated inflammation in promoting platelet hyperreactivity and thrombotic risk.
• To identify the specific inflammatory mediators involved and their mechanisms of action.

Main Methods:

• Functional platelet studies in aged-frail adults and old mice.
• In vivo studies using a mouse model of aging with TNF-α receptor blockade.
• Analysis of bone marrow compartments and megakaryocyte progenitor cells.
• Single-cell RNA-sequencing and metabolomics of mouse platelets.
• Comparison with platelets from patients with myeloproliferative neoplasms.

Main Results:

• Aged platelets exhibit hyperreactivity and form larger thrombi.
• Tumor necrosis factor alpha (TNF-α) is identified as the key pro-inflammatory cytokine driving platelet hyperreactivity.
• Abrogating TNF-α receptor signaling in vivo neutralized platelet hyperreactivity.
• Aging leads to platelet-biased hematopoiesis and megakaryocyte reprogramming.
• TNF-α induces mitochondrial changes (increased mass, oxygen consumption) in platelets, which are reversible upon blockade.
• Age-dependent metabolic profiles in platelets may influence activation.

Conclusions:

• TNF-α critically regulates megakaryocytes in the bone marrow niche.
• TNF-α is a key driver of aging-associated platelet hyperreactivity and thrombosis.
• Targeting TNF-α signaling may offer a therapeutic strategy to mitigate age-related thrombotic risk.