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NAD⁺ Replenishment Mitigates Cardiomyocyte Senescence and Corrects Heart Failure with Preserved Ejection Fraction in
Insights
NAD⁺ metabolism impacts heart aging. Supplementing with NAD⁺ precursors like NRH reversed cardiomyocyte senescence and improved heart function in aged mice, offering a potential therapy for age-related heart failure.
Area of Science:
- Cardiovascular Biology
- Aging Research
- Metabolic Pathways
Background:
- Cardiomyocyte senescence contributes to heart failure with preserved ejection fraction (HFpEF) in older adults.
- Aging is associated with reduced cardiac NAD⁺ levels and impaired heart function.
- NAD⁺ metabolism is a potential target for mitigating age-related cardiac dysfunction.
Purpose of the Study:
- To investigate the role of NAD⁺ metabolism in cardiomyocyte senescence and cardiac function.
- To evaluate the therapeutic potential of NAD⁺ precursors, nicotinamide riboside (NR) and dihydronicotinamide riboside (NRH), in aging hearts.
Main Methods:
- Assessment of cardiac NAD⁺ levels, biosynthesis, and consumption in aged mice.
- In vitro studies using senescent AC16 cardiomyocytes treated with NAD⁺ precursors.
- In vivo administration of NR or NRH to aged mice for two months.
- Analysis of cardiomyocyte senescence markers, DNA damage repair, and cardiac function (diastolic function).
Main Results:
- Aged mice showed decreased cardiac NAD⁺, increased cardiomyocyte senescence, and diastolic dysfunction.
- NAD⁺ depletion in cardiomyocytes promoted senescence, which was reversed by NR and NRH.
- NR and NRH treatments improved diastolic function and reduced senescence in aged mice.
- NRH demonstrated superior activation of SIRT1 and SIRT6, enhancing DNA repair and deacetylating acetylated H2AX.
Conclusions:
- NAD⁺ availability is crucial for regulating cardiac senescence.
- NAD⁺ precursors, especially NRH, are promising therapeutic agents for combating aging-associated HFpEF.
- NRH effectively reduces cardiomyocyte senescence and improves cardiac function by modulating SIRT1/SIRT6 activity.
Abstract:
Cardiomyocyte senescence, characterized by elevated cell cycle inhibitor expression, persistent DNA damage response, and mitochondrial dysfunction, contributes to myocardial stiffness and the progression of heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure affecting individuals over 65. In this study, we investigated the role of NAD⁺ metabolism in cardiomyocyte senescence and cardiac function. Aged mice exhibited reduced cardiac NAD⁺ levels, impaired NAD⁺ biosynthesis and mobilization, and increased consumption, leading to suppressed SIRT1/6 activity and accumulation of senescent cardiomyocytes. This was accompanied by diastolic dysfunction consistent with HFpEF. In senescent AC16 cardiomyocytes, NAD⁺ depletion promoted senescence, which was reversed by the NAD⁺ precursors nicotinamide riboside (NR) and dihydronicotinamide riboside (NRH). In aged mice, two months of NR or NRH treatment improved diastolic function and reduced cardiomyocyte senescence. While NR primarily activated SIRT1 to suppress cell cycle arrest markers, NRH more robustly activated both SIRT1 and SIRT6, enhancing DNA damage repair. Acetylated H2AX, a SIRT6 substrate elevated in aged hearts and senescent cells, was selectively deacetylated by NRH. These findings identify NAD⁺ availability as a critical regulator of cardiac senescence and support NAD⁺ precursors, particularly NRH, as promising senescence-reducing therapies for treating aging-associated HFpEF.
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