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Loss of NRF2 During Aging Contributes to Myocardial Functional Decline
Lenee Shrestha1,2, Yingying Lu3, Wujing Dai1
1Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, 1295 N. Martin Ave, Tucson, AZ 85721, USA.
Antioxidants (Basel, Switzerland)
|June 26, 2026
Summary
Aging hearts show declining Nuclear Factor (Erythroid-derived 2)-Like 2 (NRF2) signaling. Loss of NRF2 accelerates heart aging and dysfunction, contributing to heart failure. This impacts cardiovascular health in aging populations.
Area of Science:
- Cardiovascular Biology
- Aging Research
- Molecular Mechanisms of Disease
Background:
- Aging is a primary risk factor for cardiovascular diseases, with heart failure prevalence increasing significantly with age.
- Nuclear Factor (Erythroid-derived 2)-Like 2 (NRF2) is a key transcription factor regulating antioxidant and detoxification genes, crucial for cellular protection.
- Age-associated decline in NRF2 signaling is implicated in various age-related pathologies.
Purpose of the Study:
- To investigate age-associated changes in NRF2 expression in the myocardium across species.
- To determine the functional impact of NRF2 loss on cardiac aging and function.
- To elucidate the role of NRF2 signaling in mitigating age-related cardiac remodeling and dysfunction.
Main Methods:
- Analysis of RNA-seq data from human myocardial samples (GTEx project) to assess age-related NRF2 transcript levels.
- Evaluation of NRF2 protein expression in the myocardium of aging Rhesus monkeys and Fischer rats.
- Assessment of cardiac function and aging phenotypes in NRF2 knockout mice at different ages.
Main Results:
- A trend of age-associated decline in NRF2 transcripts and downstream antioxidant genes was observed in human hearts.
- NRF2 protein levels decreased with age in the myocardium of Rhesus monkeys and Fischer rats.
- NRF2 knockout mice exhibited diastolic dysfunction, premature aging, and reduced lifespan, indicating accelerated cardiac aging.
Conclusions:
- NRF2 signaling declines with age in the myocardium, suggesting a role in the aging process.
- Loss of NRF2 accelerates maladaptive cardiac remodeling and functional deterioration, contributing to age-related heart failure.
- Maintaining NRF2 activity may be a therapeutic strategy to combat cardiovascular aging.
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