A Weill Cornell team reports that aged male mouse hearts lose about 38 percent of their NAD+, a molecule that powers hundreds of metabolic reactions and fuels the sirtuin enzyme family. That loss silences two sirtuins, SIRT1 and SIRT6, allowing heart muscle cells to slip into a senescent, inflammatory state that stiffens the ventricle and impairs relaxation. Eight weeks of injected NAD+ precursors, either nicotinamide riboside or the more potent dihydronicotinamide riboside, reduced senescence markers, shrank enlarged heart cells, cut fibrosis, and improved a standard measure of diastolic function. The more potent compound worked better, and the authors argue this is because only a large NAD+ increase engages SIRT6 in addition to SIRT1. Aged female mice showed the same diastolic dysfunction but no NAD+ deficit and no response to either drug.
The heart does not fail in old age only because it pumps weakly. In most people over 65 who develop heart failure, the pumping stroke looks normal on an ultrasound. What has gone wrong is the refill. The ventricle has become stiff and cannot relax and fill properly between beats. This condition, heart failure with preserved ejection fraction, has almost no effective drug therapy, and the reason is that nobody has pinned down a single reversible mechanism driving it.
A group at Weill Cornell Medicine now proposes one. Their argument starts with NAD+, a molecule every cell uses as a metabolic go-between and which a family of enzymes called sirtuins consume as fuel. Measuring the hearts of 24-month-old male mice, roughly equivalent to humans in their seventies, the team found NAD+ had fallen by about 38 percent. The shortfall came from three directions at once. The machinery that builds NAD+ had been downregulated. The transporters that move it in and out of mitochondrial storage had declined. And the enzymes that destroy it, including CD38 and PARP1, had become more active.
The consequence was that sirtuins, which have a weak grip on NAD+ compared with those destructive enzymes, effectively ran out of fuel. Heart muscle cells then accumulated the classic hallmarks of cellular senescence: elevated p16 and p21, persistent DNA damage signals, and the secretion of inflammatory factors that make neighbouring cells swell and surrounding tissue scar. Those hearts were heavier, more fibrotic, and measurably worse at relaxing.
The team then tested whether this could be run in reverse. They gave aged male mice one of two NAD+ precursors by injection, three times a week for two months. Nicotinamide riboside, already sold as a supplement, produced a moderate NAD+ rise. Dihydronicotinamide riboside, a more potent compound discovered in the same laboratory, produced a larger one. Both reduced senescence markers, cell size and fibrosis. Both improved relaxation, though only the stronger compound reached statistical significance on the primary functional measure.
The most interesting claim is about why. The authors argue the two compounds are not simply different doses of the same thing. A moderate NAD+ rise wakes up SIRT1, which strips an activating chemical tag off the protein p53 and dials down the cell cycle brakes. A large rise additionally wakes up SIRT6, which works on chromatin and DNA repair. Crucially, SIRT6 needs SIRT1 to remove a tag from SIRT6 itself before it can engage. That makes sirtuin activation a threshold phenomenon rather than a smooth dial, which would explain a great deal of inconsistency in the NAD+ literature.
Then comes the complication. Aged female mice had the same stiff hearts, but their cardiac NAD+ was barely reduced, and neither compound helped them at all.
Actionable Insights
The magnitude first. In the treated old males, the relaxation measure improved by roughly ten units against a spread of about seven units between individual animals. In plain terms, the average treated mouse ended up better off than about nine in ten untreated mice. That sounds impressive, and on its face it is. But with only six to ten animals per group, the honest range around that estimate stretches from “barely detectable” to “enormous.” One or two animals moving would change the picture substantially.
Three practical points. The compound that actually worked, dihydronicotinamide riboside, is not sold, is not food-grade, has never been given to a human, and has shown cell-killing effects in at least one human liver cell line. Nicotinamide riboside, which is sold, missed significance on the main functional endpoint here, and the NIA Interventions Testing Program, cited in this paper’s own reference list, found it does not extend mouse lifespan in either sex.
Second, the drugs were injected, not swallowed, and the authors themselves say oral absorption is far lower.
Third, half the animals, the females, got no benefit whatsoever.
Context and Source
- Open Access Paper: NAD+ Replenishment Reduces Cardiomyocyte Senescence and Improves Diastolic Function in the Aged Male Heart
- Lead institution: Department of Pharmacology, Weill Cornell Medicine, New York, USA. Collaborating institutions: Changchun University of Chinese Medicine, China; North Carolina A&T State University, USA; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
- Country: United States, with Chinese collaborating sites.
- Journal and Impact Evaluation: bioRxiv is a preprint server, not a journal,
