Researchers publishing in Aging Cell report that senescent macrophages in old skeletal muscle release the antiangiogenic VEGF-A165B isoform, impairing endothelial function and slowing revascularization in peripheral arterial disease models.
Key points
Senescent macrophages accumulate in ischemic skeletal muscle of aged mice.
Transplantation experiments show these macrophages inhibit revascularization.
Senescent cells upregulate antiangiogenic VEGF-A165B isoform secretion.
Elevated plasma VEGF-A165B correlates with disease severity in elderly PAD patients.
Senolytics like dasatinib plus quercetin offer a strategy to clear senescent macrophages.
Why it matters:
Uncovering senescent macrophages as drivers of poor vascular regeneration identifies a novel therapeutic target. This insight paves the way for senolytic interventions to improve blood flow recovery in age-related vascular diseases, potentially enhancing healthspan.
Q&A
What are senescent macrophages?
How does VEGF-A165B differ from VEGF-A165A?
What is revascularization?
Why focus on peripheral arterial disease?
What are senolytics?
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Academy
Cellular Senescence: Mechanisms and Impact
What is Cellular Senescence? Cellular senescence refers to the permanent cell cycle arrest that normal somatic cells undergo in response to stress or damage. This state prevents the proliferation of damaged cells but yields distinct changes in cell function and communication. Senescent cells accumulate over time, contributing to tissue dysfunction and driving aging processes.
Senescence Associated Secretory Phenotype (SASP)
Key Features of SASP Senescent cells develop a complex secretory profile called the SASP. They release proinflammatory cytokines, chemokines and proteases that alter the local tissue environment. While SASP factors can recruit immune cells to clear senescent cells, chronic SASP contributes to inflammation, extracellular matrix degradation and impaired tissue repair.
Role of Macrophages in Aging
Macrophage Function Macrophages are innate immune cells that patrol tissues to remove pathogens and debris. They play essential roles in inflammation resolution, tissue remodeling and blood vessel growth. In young tissues, macrophages support angiogenesis by secreting proangiogenic factors such as VEGF A165A and by clearing apoptotic cells.
Senescent Macrophages With age, tissue environments become more prone to inducing macrophage senescence. Senescent macrophages show reduced phagocytic ability and diminished support for new blood vessel formation. They often exhibit increased secretion of antiangiogenic isoforms such as VEGF A165B, which hinders endothelial cell proliferation and migration.
Implications for Vascular Health and Longevity
Impaired angiogenesis and revascularization contribute to age related vascular diseases, including peripheral arterial disease and chronic wounds. Accumulation of senescent macrophages in ischemic tissues leads to poorer outcomes after vascular injury. Understanding macrophage senescence opens pathways to rejuvenate blood vessel growth and improve healthspan.
Strategies to Target Senescent Cells
- Senolytics are compounds that selectively induce apoptosis in senescent cells. Common examples include dasatinib and quercetin, which together clear senescent cells and alleviate age related tissue dysfunction.
- Senomorphics modulate SASP production without killing cells, reducing harmful inflammation and promoting tissue repair.
- Immunotherapy Approaches aim to boost the immune system’s natural ability to clear senescent cells, such as CAR T cells targeting senescence markers.
Conclusion
Targeting senescent macrophages represents a promising avenue to restore vascular function in aged individuals. Advances in senolytic therapies and a deeper understanding of macrophage biology may enhance treatment of age related vascular diseases and extend healthy lifespan.