The ISG15 axis: a central mediator and therapeutic target in vascular inflammaging

Area of Science:

• Vascular Biology
• Immunology
• Aging Research

Background:

• Vascular aging drives cardiovascular disease, involving chronic inflammation (inflammaging) and cellular senescence.
• The molecular links between inflammaging and senescence in vascular aging remain unclear.
• Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier with roles in antiviral defense.

Purpose of the Study:

• To propose ISG15 as a critical nexus integrating inflammaging and cellular senescence in vascular aging.
• To elucidate the dual role of ISG15 (extracellular and intracellular ISGylation) in vascular pathology.
• To identify the ISG15 axis as a potential therapeutic target for age-related vascular dysfunction.

Main Methods:

• Review of existing literature on ISG15, inflammaging, cellular senescence, and vascular aging.
• Discussion of evidence linking the cGAS-STING pathway to ISG15 activation in sterile inflammatory conditions.
• Analysis of ISG15's proposed mechanisms in endothelial dysfunction and smooth muscle cell switching.

Main Results:

• ISG15 acts as a molecular node connecting chronic inflammation and cellular senescence in aging blood vessels.
• Extracellular ISG15 promotes pro-inflammatory signaling, while intracellular ISGylation disrupts cellular homeostasis.
• ISG15 activation, via sterile triggers and cGAS-STING, exacerbates oxidative stress, senescence, and proteostasis disruption.

Conclusions:

• The ISG15 system is a key driver of endothelial dysfunction and vascular smooth muscle cell alterations in aging.
• Targeting ISG15 (e.g., inhibiting ISGylation, neutralizing extracellular ISG15) presents a promising therapeutic avenue.
• Further research into the ISG15 axis is crucial for developing diagnostics and interventions for vascular health preservation.