Abstract
Aging is the major risk factor for cardiovascular disease, which is the leading cause of mortality worldwide among aging populations. Cisd2 is a prolongevity gene that mediates lifespan in mammals. Previously, our investigations revealed that a persistently high level of Cisd2 expression in mice is able to prevent age-associated cardiac dysfunction. This study was designed to apply a genetic approach that induces cardiac-specific Cisd2 overexpression (Cisd2 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, Cisd2 is downregulated in the aging heart. This decrease in Cisd2 leads to cardiac dysfunction and impairs electromechanical performance. Intriguingly, Cisd2 icOE prevents an exacerbation of age-associated electromechanical dysfunction. Secondly, Cisd2 icOE ameliorates cardiac fibrosis and improves the integrity of the intercalated discs, thereby reversing various structural abnormalities. Finally, Cisd2 icOE reverses the transcriptomic profile of the aging heart, changing it from an older-age pattern to a younger pattern. Intriguingly, Cisd2 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 Cisd2 as a novel molecular target for developing therapies targeting cardiac aging.
Highlights
Aging is the major risk factor for the development of multi-morbidity-related ageassociated disorders such as cardiovascular diseases, various cancers, diabetes, and a range of neurodegenerative diseases [1]
Our previous study demonstrated that the level of Cisd2 expression in the heart is decreased in mice after the age of 13 months [14], and the Cisd2 protein level in the myocardium of 26-mo wild type (WT) mice is significantly reduced by about 50% compared to 3-mo WT mice [17]
The perception is that an anti-aging drug will be able to increase the healthy lifespan; it will not be a fountain of youth nor will it lead to eternal life [60]
Summary
Aging is the major risk factor for the development of multi-morbidity-related ageassociated disorders such as cardiovascular diseases, various cancers, diabetes, and a range of neurodegenerative diseases [1]. Cardiovascular disease is the leading cause of mortality among persons aged over 65 years [2]. One third of all deaths in older persons are due to heart disease [3]. Research has shown that among Americans younger than 80 years, 15–43% of the deaths caused by cardiac diseases are preventable via appropriate interventions and/or a modification of lifestyle [4]. Non-proliferative fully differentiated cardiomyocytes are affected by a variety of problems that gradually bring about structural damage and functional decline [5]. Previous studies have revealed that cumulative oxidative stress results in an accumulation of damaged proteins, of dysfunctional organelles, and of DNA damage
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