Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg⁻¹ · d⁻¹, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg⁻¹ · d⁻¹) or THBru (25, 50 mg · kg⁻¹ · d⁻¹) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 μM) and THBru (20, 40 μM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated mitophagy and suggests its clinical application prospects.

心脏衰老的特点是左心室肥厚和舒张功能障碍，进而诱发多种心血管疾病。目前还没有治疗药物可以改善心脏衰老引起的心脏异常。在这项研究中，我们研究了小檗碱（BBR）及其衍生物四氢小檗红素（THBru）对心脏衰老过程的保护作用。通过皮下注射D-半乳糖（D-gal，120mg·kg ^-1 ·d ^-1 ，皮下注射）12周来诱导小鼠心脏老化。同时给小鼠口服小檗碱(50 mg·kg ^-1 ·d ^-1 )或THBru(25, 50 mg·kg ^-1 ·d ^-1 )12周。我们发现，BBR 和 THBru 治疗可显着减轻 D-gal 诱导的衰老小鼠的舒张功能障碍和心脏重塑。此外，在体外，用 BBR (40 μM) 和 THBru (20, 40 μM) 处理可抑制 D-gal 诱导的原代新生小鼠心肌细胞的衰老。总体而言，在相同剂量下，THBru 表现出比 BBR 更高的功效。我们发现在体内和体外衰老过程中线粒体自噬水平显着降低，THBru和BBR以不同的效力促进线粒体自噬。我们证明 THBru 的线粒体自噬诱导作用是由于抑制素 2 (PHB2) 的 mRNA 稳定性增加所致，抑制素 2 (PHB2) 是线粒体自噬过程中的关键因素，从而上调 PHB2 蛋白表达。 PHB2 的敲低有效逆转了 D-gal 处理的心肌细胞中 THBru 的抗衰老作用。相反，PHB2 的过度表达会促进线粒体自噬并延缓心肌细胞衰老，就像 THBru 一样。 总之，本研究确定 THBru 是一种有效的抗衰老药物，可诱导 PHB2 介导的线粒体自噬，并提出其临床应用前景。