Is there a role for senotherapeutics in the treatment of giant cell arteritis?

Giant cell arteritis (GCA) is a large-vessel vasculitis predominantly affecting individuals over 50 years, with a peak incidence between 70 and 80 years. Its pathogenesis involves complex immunological cascades triggered by vascular dendritic cell activation, recruitment of CD4⁺ T cells and monocytes, T helper lymphocyte polarization, and vascular remodeling driven by myofibroblasts and fibroblasts. Growing evidence implicates cellular senescence(definition) (particularly in vascular smooth muscle cells, fibroblasts, endothelial cells, and immune cells) in the pathophysiology of GCA. Senescent cells (SC) accumulate in affected arteries and display a senescence-associated secretory phenotype (SASP), producing pro-inflammatory cytokines, chemokines, and matrix metalloproteinases, thereby perpetuating inflammation and tissue injury. Senotherapeutics (agents targeting SC) are broadly classified into senolytics(definition), which induce SC apoptosis, and senomorphics, which suppress SASP without eliminating SC. Candidate senolytics include fisetin, quercetin, curcumin, and dasatinib, which also show anti-inflammatory, antioxidant, and vascular-protective effects, although some may cause adverse vascular consequences. Senomorphics such as resveratrol, kaempferol, apigenin, epigallocatechin gallate, mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition), metformin, and ruxolitinib modulate NF‑κB, mTOR, JAK/STAT, and sirtuin pathways, potentially reducing vascular inflammation, restoring immune balance, and preventing remodeling, besides acting on aging-associated modifications. As current treatments primarily suppress inflammation and may not fully target age-related mechanisms contributing to persistent vascular injury, investigating cellular senescence as a potentially actionable component of GCA biology is timely. Key challenges include selecting optimal agents, timing, dosing, and duration, while avoiding adverse vascular effects. The aim of this review was to identify potential clinical and translational applications of senotherapeutic compounds for GCA to guide future research in this field.