The serum soluble Klotho alleviates cardiac aging and regulates M2a/M2c macrophage polarization via inhibiting TLR4/Myd88/NF-κB pathway

Aging is a continuous and irreversible process that leads to a progressive deterioration in cardiac geometry and function. Klotho is an anti-aging protein with cardioprotective effect. However, the relationship between Klotho and cardiac aging and its possible mechanism are not completely clear. We applied D-galactosamine (D-Gal) to replicate cardiac senescence by increasing oxidative stress in the heart. M2 anti-inflammatory markers in the aging hearts were observed significantly lower than those in adult mice. Therefore, in this study, we demonstrated that serum soluble Klotho (sKL) could exert its cardioprotective and anti-inflammatory effects by regulating the phenotype of macrophages by inhibiting TLR4/MyD88/NF-κB. In terms of mechanism, supplementation of serum soluble Klotho can prevent excessive oxidative stress, inflammation, apoptosis and cardiac dysfunction in the aging heart. In RAW264.7 cells, sKL induced macrophages to differentiate into M2a/M2c macrophages, and the culture supernatant of M2a/M2c macrophages significantly reversed the senescence of cardiomyocytes and improved myocardial viability compared with the control group. Therefore, supplementation of sKL can improve aging cardiac function, reduce cardiac oxidative stress, inflammation and apoptosis by promoting M2a/M2c polarized macrophages via inhibiting the TLR4/Myd88/NF-κB pathway.