Rejuvenating the aging heart by enhancing the expression of the cisd2 prolongevity gene

Chi Hsiao Yeh, Yi Ju Chou, Ting Kuan Chu, Ting Fen Tsai*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

4 Scopus citations


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 per-formance. 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.

Original languageEnglish
Article number11487
JournalInternational Journal of Molecular Sciences
Issue number21
StatePublished - 01 11 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Cardiac rejuvenation
  • Cisd2
  • Inducible cardiac‐specific overexpression
  • cardiac aging


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