Rejuvenating the Aging Heart by Enhancing the Expression of the <i>Cisd2</i> Prolongevity Gene
Aging is the major risk factor for cardiovascular disease, which is the leading cause of mortality worldwide among aging populations. <i>Cisd2</i> is a prolongevity gene that mediates lifespan in mammals. Previously, our investigations revealed that a persistently high level of <i>...
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| Autores principales: | , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/28dc4c6dbbcc42778ff77035853f6043 |
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| Sumario: | Aging is the major risk factor for cardiovascular disease, which is the leading cause of mortality worldwide among aging populations. <i>Cisd2</i> is a prolongevity gene that mediates lifespan in mammals. Previously, our investigations revealed that a persistently high level of <i>Cisd2</i> expression in mice is able to prevent age-associated cardiac dysfunction. This study was designed to apply a genetic approach that induces cardiac-specific <i>Cisd2</i> overexpression (<i>Cisd2</i> 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, <i>Cisd2</i> is downregulated in the aging heart. This decrease in <i>Cisd2</i> leads to cardiac dysfunction and impairs electromechanical performance. Intriguingly, <i>Cisd2</i> icOE prevents an exacerbation of age-associated electromechanical dysfunction. Secondly, <i>Cisd2</i> icOE ameliorates cardiac fibrosis and improves the integrity of the intercalated discs, thereby reversing various structural abnormalities. Finally, <i>Cisd2</i> icOE reverses the transcriptomic profile of the aging heart, changing it from an older-age pattern to a younger pattern. Intriguingly, <i>Cisd2</i> 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 <i>Cisd2</i> as a novel molecular target for developing therapies targeting cardiac aging. |
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