# NAD+ controls circadian rhythmicity during cardiac aging

## TL;DR

NAD+ levels decline with age, disrupting heart rhythms, and supplementing with an NAD+ precursor can restore some age-related changes in the heart's circadian clock.

## Contribution

The study reveals that NAD+ regulates the circadian clock in the aging heart and that its supplementation can reverse some age-related cardiac changes.

## Key findings

- Aging disrupts diurnal gene expression in the heart, which is partially reversed by NAD+ precursor supplementation.
- Reduced NAD+ levels impair circadian rhythms in cardiomyocytes, which can be rescued by nicotinamide riboside.
- NR's effects on the cardiac transcriptome partially depend on SIRT1 activity.

## Abstract

Disruption of the circadian clock as well as reduced NAD+ levels are both hallmarks of aging. While circadian rhythms and NAD+ metabolism have been linked in heart disease, their relationship during cardiac aging is less clear. Here, we show that aging leads to disruption of diurnal gene expression in the heart. Long-term supplementation with the NAD+ precursor nicotinamide riboside (NR) boosts NAD+ levels, reprograms the diurnal transcriptome, and reverses naturally occurring cardiac enlargement in aged female mice. In addition, drastic reduction of NAD+ levels in cardiomyocytes impairs PER2::luc oscillations, which is rescued by NR supplementation. Finally, we demonstrate that changes to the cardiac transcriptome due to NR treatment partially depend on the activity of SIRT1. These findings reveal an essential role for NAD+ in regulation of the cardiac circadian clock upon aging, which opens up new avenues to counteract age-related cardiac disorders.

Aging experiments in female mice show that cardiac NAD+ decreases with age, leading to changes in rhythmicity of transcription that is partially restored by NAD+ precursor supplementation.