Repurposing niclosamide to mitigate inflammaging: a review of multi-target mechanisms in cellular senescence and age-related decline.

<h4>Background</h4>Chronic low-grade inflammation, or inflammaging(definition), drives age-related multimorbidity and cellular decline, yet pharmacological interventions targeting its root causes are lacking. Niclosamide, a WHO-listed anthelmintic with a long safety record, has recently emerged as a multi-target geroprotector with potent anti-inflammatory properties, though historical poor absorption limited its systemic use.<h4>Objectives</h4>This review consolidates molecular and preclinical evidence supporting niclosamide's repurposing for inflammaging, focusing on its ability to simultaneously engage core pathways of cellular aging and inflammation. It also evaluates recent data from reformulated oral formulations that achieve sustained plasma concentrations (0.5-3 µmol/L) sufficient for systemic effects.<h4>Key findings</h4>Niclosamide acts through six interconnected mechanisms: (1) mild reversible mitochondrial uncoupling, limiting ROS and cGAS-STING activation; (2) mTORC1 inhibition via lysosomal deacidification, with indirect IGF-1/IGF-1R modulation through AMPK activation; (3) restoration of autophagic flux and lysosomal biogenesis via TFEB nuclear translocation; (4) selective senolytic and senomorphic effects, suppressing NF-κB and STAT3 to neutralize the senescence(definition)-associated secretory phenotype (SASP) and reduce IL-6, IL-1β, and TNF-α; (5) blockade of canonical Wnt/β-catenin signaling to prevent tissue fibrosis; and (6) rebalancing of aged immune function by downregulating PD-1/PD-L1 and upregulating Vasorin to inhibit TGFβ‑mediated fibrosis. Unlike single-pathway agents, niclosamide offers a unique polypharmacological profile that mitigates sterile inflammation at its source.<h4>Conclusions</h4>Reformulated niclosamide combines multi-target anti-inflammaging activity with a decades-long safety record. Randomized, placebo‑controlled trials targeting inflammaging, frailty, and biological age biomarkers are now an immediate translational priority.