Leptin Neutralization Attenuates Inflammaging in Endothelial and Immune Cell Models

Leptin, a proinflammatory adipokine, contributes to the chronic low-grade inflammation seen in obesity, but its role in age-related inflammation, that is inflammaging, has been poorly studied. We thus tested the effect of blocking leptin receptor (LEP-R) binding in five models of inflammaging, that is replicative senescent endothelial cells, hyperglycemia-treated macrophages or endothelial cells, lipopolysaccharide (LPS)-exposed macrophages, and TCR-stimulated CD4+ T cells. In endothelial cells, leptin enhanced senescence, while leptin neutralization suppressed the senescence-associated secretory phenotype, two effects mediated in part by the mTOR pathway. In both macrophages and endothelial cells, leptin blockade blunted hyperglycemia-induced inflammation, while in macrophages, it also suppressed the LPS-induced senescent and proinflammatory phenotype. In T cells, leptin neutralization produced divergent effects, attenuating the expression of inflammatory and senescence markers in conventional T cells but not in regulatory T cells. To assess translational relevance, we measured leptin and inflammaging markers in plasma samples from two independent cohorts, one of healthy individuals (n = 121) and another of people with Type 2 diabetes (n = 93). In healthy subjects, leptin levels were higher in people with hs-CRP ≥ 3 mg/dL compared with those below such threshold, also after adjustment for BMI. Leptin levels showed BMI-adjusted positive correlations with IL-6 and hs-CRP in healthy individuals and with hs-CRP and IL-8 in people with diabetes. These findings suggest that leptin might fuel inflammaging and that its neutralization exerts anti-inflammatory effects across multiple, related models.