College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
Int J Mol Sci. 2021 Oct 25;22(21):11487. doi: 10.3390/ijms222111487.
Aging is the major risk factor for cardiovascular disease, which is the leading cause of mortality worldwide among aging populations. is a prolongevity gene that mediates lifespan in mammals. Previously, our investigations revealed that a persistently high level of expression in mice is able to prevent age-associated cardiac dysfunction. This study was designed to apply a genetic approach that induces cardiac-specific overexpression ( icOE) at a late-life stage, namely a time point immediately preceding the onset of old age, and evaluate the translational potential of this approach. Several discoveries are pinpointed. Firstly, is downregulated in the aging heart. This decrease in leads to cardiac dysfunction and impairs electromechanical performance. Intriguingly, icOE prevents an exacerbation of age-associated electromechanical dysfunction. Secondly, icOE ameliorates cardiac fibrosis and improves the integrity of the intercalated discs, thereby reversing various structural abnormalities. Finally, icOE reverses the transcriptomic profile of the aging heart, changing it from an older-age pattern to a younger pattern. Intriguingly, icOE modulates a number of aging-related pathways, namely the sirtuin signaling, autophagy, and senescence pathways, to bring about rejuvenation of the heart as it enters old age. Our findings highlight as a novel molecular target for developing therapies targeting cardiac aging.
衰老是心血管疾病的主要危险因素，在老龄化人口中，它是全球范围内导致死亡的主要原因。Klotho 是一种长寿基因，它在哺乳动物中调节寿命。以前，我们的研究表明，在小鼠中持续高水平表达 Klotho 能够预防与年龄相关的心脏功能障碍。本研究旨在应用一种遗传方法，即在老年期的后期，即老年前期，诱导心脏特异性过表达（icOE），并评估这种方法的转化潜力。有几个发现值得关注。首先，Klotho 在衰老的心脏中表达下调。这种 Klotho 的减少导致心脏功能障碍，并损害机电性能。有趣的是，icOE 可防止与年龄相关的机电功能障碍恶化。其次，icOE 可改善心脏纤维化并提高闰盘的完整性，从而逆转各种结构异常。最后，icOE 逆转了衰老心脏的转录组特征，使其从老年模式转变为年轻模式。有趣的是，icOE 调节了许多与衰老相关的途径，即沉默信息调节因子信号通路、自噬和衰老途径，从而使心脏在进入老年期时恢复活力。我们的研究结果强调了 Klotho 作为开发针对心脏衰老的治疗方法的新的分子靶标。
Zotero 插件
