NAD+ replenishment reduces cardiomyocyte senescence and improves diastolic function in the aged male heart

Why it matters

As the heart ages, many of its muscle cells (cardiomyocytes) become senescent: they stay alive but switch into a damaged, non-dividing state that is tied to a stiff heart that fills poorly between beats, known as diastolic dysfunction, and to heart failure in older adults. There are few proven ways to slow or reverse this. NAD+ is a molecule every cell needs for energy metabolism, and it is also the fuel for sirtuins, enzymes that include SIRT6, which helps repair DNA. NAD+ levels are known to fall with age in several tissues. This study asks whether restoring NAD+ can undo heart cell senescence, and links the effect to DNA repair, which ties it to genomic instability as a hallmark of aging.

What they did

According to the abstract, the team measured heart NAD+ metabolism, senescence markers and heart function in young and old mice of both sexes. In heart muscle cells grown in the lab, they lowered NAD+ to see whether that alone caused senescence, then added two NAD+ precursors, nicotinamide riboside (NR) and dihydronicotinamide riboside (NRH). They then treated aged male mice with NR or NRH for two months and examined senescence markers, diastolic function, heart enlargement (hypertrophy) and scarring (fibrosis). Finally they looked at how the sirtuins SIRT1 and SIRT6 were involved. The abstract does not give animal numbers or doses.

What they found

Old male mice had lower heart NAD+, which the authors traced to reduced production, limited mobilisation from mitochondria and higher consumption. Their SIRT1 and SIRT6 activity was suppressed and senescent heart muscle cells had built up, along with diastolic dysfunction, hypertrophy and fibrosis. In lab-grown heart cells, depleting NAD+ caused senescence, and NR or NRH reversed it. In old male mice, two months of either precursor reduced senescence markers, improved diastolic function and lessened hypertrophy and fibrosis. Both activated SIRT1 and lowered cell cycle arrest markers. NRH gave stronger SIRT1 activation; SIRT1 then removed acetyl tags from SIRT6, helping SIRT6 bind histones and improving DNA damage repair. Old female mice also had diastolic dysfunction, but without a clear fall in heart NAD+, and they did not respond to either treatment.

Limits

This synopsis is based on the abstract only; the paper does not appear to be open access. All results are in mice and cultured cells, so it is not known whether NR or NRH would have the same effect in older people. The benefit was seen only in males, and females, who did not lose heart NAD+, did not respond, so the approach may not apply to everyone. The abstract does not report how much DNA repair improved or which repair markers were measured, and the role of SIRT6 is part of a proposed mechanism rather than a direct test in the animals.

Key terms

NAD+

Nicotinamide adenine dinucleotide, a molecule cells use in energy metabolism and as fuel for sirtuin enzymes.

NR and NRH

Nicotinamide riboside and dihydronicotinamide riboside, precursors the body converts into NAD+.

Sirtuins (SIRT1, SIRT6)

NAD+-dependent enzymes that remove acetyl tags from proteins; SIRT6 helps maintain DNA repair and chromatin.

Cellular senescence

A state in which a cell permanently stops dividing but stays active, often releasing inflammatory signals.

Diastolic dysfunction

When the heart muscle is too stiff to relax and fill properly between beats.

Histones

Spool-like proteins that DNA wraps around inside the nucleus.