Study reports NAD+ replenishment with NR and NRH reduces cardiomyocyte senescence and improves diastolic function in aged male mice

Researchers found that NAD+ replenishment via NR or NRH reverses cardiomyocyte senescence and diastolic dysfunction in aged male mice, revealing distinct sex-specific mechanisms of cardiac aging.

A preclinical study published in Cardiovascular Research investigated the role of NAD+ metabolism in cardiomyocyte senescence and age-related cardiac dysfunction.

The researchers found that aged male mice exhibited decreased cardiac NAD+ levels, leading to suppressed SIRT1 and SIRT6 activity, cell cycle arrest, and accumulation of senescent cardiomyocytes, accompanied by diastolic dysfunction, hypertrophy, and fibrosis.

A two-month treatment with either nicotinamide riboside (NR) or dihydronicotinamide riboside (NRH) in aged male mice suppressed senescence markers, reduced hypertrophy and fibrosis, and improved diastolic function.

Mechanistically, both compounds activated SIRT1, but NRH demonstrated more robust SIRT1 activation, which deacetylated SIRT6 to promote DNA damage repair.

Aged female mice exhibited diastolic dysfunction without a corresponding decline in cardiac NAD+ levels and did not respond to either NR or NRH treatment.

The findings establish that cardiomyocyte senescence is a key driver of cardiac aging and that its development is highly sex-dependent, with NAD+ depletion acting as a male-specific pathway.

NRH is highlighted as a potentially superior NAD+ precursor to NR due to its stronger activation of the SIRT1-SIRT6 axis and enhanced histone-binding DNA repair activity in cardiac tissue.

The failure of aged female mice to respond to NAD+ precursors emphasizes that cardiac aging pathways differ between sexes, indicating that global, non-stratified NAD+ therapies may not be universally effective.

This study supports the development of NAD+ precursors for specific age-related cardiac indications, such as diastolic dysfunction, but introduces a major clinical translation challenge regarding patient selection.

The therapeutic potential of NRH over NR could shift development interest toward NRH and next-generation NAD+ precursors with higher potency for cardiovascular targets.

Drug developers working on metabolic or longevity-focused cardiac pipelines may need to implement mandatory sex-based stratification in preclinical and clinical trials to ensure endpoint efficacy is not diluted by sex-specific physiological differences.

Preclinical pipeline developments focusing on NRH formulations for age-related diastolic dysfunction and heart failure.

Clinical trial designs of existing NAD+ programs to see if sponsors incorporate sex-specific stratification or target male-dominated cohorts for cardiac endpoints.