Study Reports Sex Dimorphism in Cardiovascular Aging and HO-1 Modulation in Mice

A preclinical study published in GeroScience demonstrates that d-galactose-induced accelerated aging causes sex-specific cardiovascular pathologies in mice, where heme oxygenase-1 induction selectively rescues male systolic dysfunction while endogenous HO-1 activity remains critical for female cardiac preservation.

Researchers evaluated the cardiovascular effects of chronic d-galactose (d-gal) injection—a model of accelerated aging—and the impact of modulating heme oxygenase-1 (HO-1) in male and female C57BL/6 mice.

The study reported that chronic d-gal treatment caused systolic dysfunction (evidenced by reduced ejection fraction and fractional shortening), elevated cardiac oxidative stress, and decreased cardiac catalase levels selectively in male mice.

HO-1 induction via cobalt protoporphyrin (CoPP) reversed d-gal-induced systolic impairment and reduced oxidative stress in male mice.

Female mice were protected from systolic decline but developed diastolic dysfunction, associated with reduced cardiac levels of the autophagy protein Beclin-1 and elevated levels of the senescence marker beta-galactosidase.

In female mice, HO-1 induction with CoPP reversed diastolic prolongation (isovolumetric relaxation time) but did not affect autophagy or senescence markers, while HO-1 inhibition via zinc deuteroporphyrin bisglycol (ZnBG) led to systolic dysfunction and cardiac hypertrophy.

The findings show that cardiovascular aging in this preclinical model is driven by distinct sex-specific pathways: oxidative stress and antioxidant depletion in males, and impaired autophagy and cellular senescence in females.

The study demonstrates that therapeutic modulation can have asymmetrical effects based on sex, indicating that HO-1 induction holds therapeutic potential primarily for male-type systolic pathologies, while endogenous HO-1 activity is vital for maintaining female cardiac function.

These differences underscore the risk of using single-sex cohorts in preclinical drug discovery, as candidate therapies targeting oxidative stress or autophagy may yield vastly different efficacy and safety profiles in male versus female subjects.

Longevity biotechnology companies developing cardiovascular or metabolic disease pipelines may need to implement sex-stratified patient selection in clinical trials to optimize therapeutic efficacy and mitigate safety risks.

The distinct mechanisms of female diastolic decline suggest that antioxidant-focused pipelines may have limited efficacy in treating female cardiovascular aging, pointing instead to a need for targeted autophagy enhancers or senolytics.

Preclinical regulatory packages for anti-aging candidates will likely face higher scrutiny regarding the inclusion of robust, sex-balanced animal cohorts to validate translational relevance.

Further preclinical studies investigating the role of circulating ovarian hormones and the estrous cycle in protecting females from d-gal-induced systolic impairment.

Development of tissue-selective HO-1 modulators that can target male-specific cardiovascular remodeling without disrupting systemic homeostasis.

Preclinical programs evaluating whether combination therapies targeting both autophagy and oxidative stress can comprehensively rescue both male and female cardiac aging phenotypes.