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An Adiponectin Receptor Agonist Dispersed via Nonencapsulative Exosomes Alleviates Aging-Associated Cardiac
Yin Zhou1,2, Xue Li3, Lilei Wang1
1State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong510120, China.
Insights
A new drug, CardiAdip (CAD), shows promise in treating aging-related cardiac dysfunction by improving heart function and reducing aging markers in mice. Exosome-assisted formulation enhances its delivery, offering a potential therapy for senescent hearts.
Area of Science:
- Cardiovascular Research
- Aging Biology
- Pharmacology
Background:
- Aging-related cardiac dysfunction is a growing health issue with few treatments.
- Adiponectin receptor activation shows cardioprotective effects but lacks clinical translation for aging hearts.
Purpose of the Study:
- To develop and evaluate CardiAdip (CAD), a novel adiponectin receptor agonist, for treating cardiac aging.
- To assess the efficacy of an exosome-assisted formulation (CAD-cluster) for systemic administration.
Main Methods:
- Developed CardiAdip (CAD), an adiponectin receptor agonist.
- Tested CAD in d-galactose-induced senescent cells and naturally aged mice.
- Formulated CAD into an exosome-assisted aqueous dispersion (CAD-cluster) for intravenous delivery.
- Analyzed cardiac function, histology, and molecular markers of aging.
Main Results:
- CAD attenuated senescence in cardiomyocytes and improved cardiac function in aged mice.
- CAD reduced cardiac hypertrophy, fibrosis, and molecular aging hallmarks.
- CAD-cluster enhanced systemic exposure and achieved therapeutic effects at lower doses via intravenous injection.
- Therapeutic benefits were linked to restored mitochondrial-endoplasmic reticulum homeostasis and reduced oxidative stress.
Conclusions:
- CardiAdip (CAD) is a promising therapeutic candidate for aging-related cardiac dysfunction.
- Exosome-assisted nonencapsulative dispersion is a viable strategy for delivering poorly soluble drugs like CAD.
- This approach enhances translational feasibility for treating senescent hearts.
Abstract:
Aging-related cardiac dysfunction constitutes a major and growing global health challenge with limited effective treatment options. While adiponectin receptor activation has demonstrated cardioprotective potential, its translation into a viable therapy for the senescent heart remains unrealized. In this study, we developed CardiAdip (CAD), an agonist with improved predicted binding affinity for adiponectin receptors. In d-galactose (d-gal)-induced senescent H9c2 cardiomyocytes, CAD attenuated senescence-associated phenotypes and reduced stress-responsive signaling. In naturally aged mice (24 months), oral administration of CAD significantly improved cardiac function, alleviated myocardial hypertrophy and fibrosis, and suppressed molecular hallmarks of cardiac aging. Transcriptomic and molecular analyses indicated that these benefits were mediated through the restoration of mitochondrial-endoplasmic reticulum homeostasis and the alleviation of oxidative stress in aged myocardium. To enable effective systemic administration, we reformulated CAD into a stable aqueous dispersion (CAD-cluster) via exosome-assisted nonencapsulative dispersion. This approach expanded the administration route to intravenous injection and significantly enhanced systemic exposure. Remarkably, intravenous administration of CAD-cluster achieved therapeutic efficacy comparable to high-dose oral CAD while requiring a markedly reduced cumulative dose. Together, these findings identify CAD as an effective therapeutic candidate for aging-related cardiac dysfunction and support nonencapsulative exosome-assisted dispersion as a practical strategy to improve the translational feasibility of poorly soluble membrane-targeted small molecules.