Longevity Articles

Combining NMN and Melatonin to Support Heart Health With Age

A new study finds nicotinamide mononucleotide (NMN) and melatonin in combination are cardioprotective.

While the compounds nicotinamide mononucleotide — also known as NMN — and melatonin have been studied separately for their ability to support health and longevity, the supplements have not often been researched together to assess their cumulative impact. 

A recent study aimed to determine if combining supplemental NMN and melatonin supported cardiovascular health in aging rats with heart injuries. Keep reading this article for a refresher course on NMN and melatonin and the details and results of this important study. 

NMN and Melatonin: The Basics

What is NMN? 

Nicotinamide mononucleotide is a compound that functions as a precursor to NAD+ (nicotinamide adenine dinucleotide). NAD+ is an enzyme required for healthy cells, energy production, and regulation of the aging and disease process. 

Some of the leading areas of recent research involving NMN include its link to supporting brain health and cognitionblood flow and vascular healthmuscle strength and physical performance, and skineyereproductive, and heart health. While most of these studies have been with animals or cell-based cultures, they are still a valuable stepping stone for supporting the use of NMN in humans.

What is Melatonin? 

Melatonin is most well-known for its link to sleep support; however, the hormone has even more wide-reaching benefits to consider. In addition to regulating our body's 24-hour internal clock known as the circadian rhythm, melatonin may support a healthier immune system and inflammatory response. 

Melatonin contains high levels of antioxidants, which reduce oxidative damage to cells and DNA by scavenging for harmful compounds known as free radicals and reactive oxygen species (ROS).  

The mitochondria — our cells' energy powerhouses — are particularly vulnerable to oxidative damage, and their functioning is reduced with aging and disease. Therefore, the combination of NMN and melatonin may be a promising candidate for fighting back on this age-related decline in mitochondrial and cardiovascular health. 

NMN, Melatonin, and Heart Health: Recent Research

Published in the Journal of Cardiovascular Pharmacology and Therapeutics in May 2020, this study looked at the effects of combination therapy of supplemental NMN and melatonin to protect aging rats’ hearts after ischemia/reperfusion (I/R) injury.  

An I/R injury occurs after a blockage of blood flow to the heart. After the ischemic event (the blood flow blockage), reperfusion occurs, which is when blood supply returns to the heart.

Although reperfusion sounds like it would be beneficial, this restoration of blood flow can actually cause tissue damage to the heart due to a surge of harmful ROS and inflammatory immune cells that exacerbate the heart’s injuries.

Therefore, this study hoped to find a novel strategy to support the heart after these I/R injuries that are frequent causes of disability and mortality. 

NMN and melatonin support the heart

Harnessing Better Heart Health With NMN and Melatonin

In this study, aging male rats were randomized to receive NMN, melatonin, NMN plus melatonin, or a placebo. The groups receiving NMN had the compound injected every other day for 28 days before the I/R injury, while melatonin was added to the mix just before the reperfusion occurred. 

The research team looked at how these supplements affected various markers of heart health, as well as oxidative stress and mitochondrial function. They also measured infarct size, which is a measure of damage to the heart, and left ventricular end-diastolic pressure (LVEDP) —  a predictor of mortality in cardiac patients when elevated. 

As expected, the groups who underwent I/R experienced decreased coronary blood flow during the ischemic event and restoration of blood flow after the reperfusion. 

The injured groups also developed damage to heart muscle cells and dyregulated cardiac markers. However, the reperfusion’s harmful aftereffects were mitigated in the NMN, melatonin, and NMN plus melatonin groups, with the most significant effects being seen within the combination group. Let's take a closer look. 

NMN + Melatonin Reduced LVEDP

Melatonin with NMN prevented the increase in LVEDP that is commonly seen in reperfusion injuries. The combination of the two compounds significantly reduced LVEDP more than each compound alone. This indicates improved left ventricle functioning, which is responsible for pumping oxygenated blood from the lungs out into the body. 

NMN + Melatonin Reduced LDH

LDH, or lactate dehydrogenase, is an enzyme found in the heart, brain, kidneys, and lungs. LDH becomes elevated in the blood during times of tissue damage or injury. In cases of I/R, increased LDH release is linked to increased heart damage.

The groups receiving NMN, melatonin, and the combined NMN with melatonin all had significantly reduced LDH release, indicating a reduction in myocardial damage.

NMN + Melatonin Reduced Infarct Size

Larger infarct size is associated with increased mortality after ischemic injuries. Although melatonin and NMN separately reduced infarct size, the most significant effect was seen with the combination therapy. 

In the NMN + melatonin group, the average infarct size was 17.1%, compared to 44.5% in the hearts of the control group, 28.5% in the melatonin group, and 22% in the NMN group.

NMN and melatonin support heart health

NMN + Melatonin Restored NAD+ Levels.

While the melatonin group did increase NAD+ levels in the heart compared to the control group, the NMN group and NMN plus melatonin group experienced the most significant restorations, which were comparable to each other.  

This restoration of NAD+ is likely the leading reason behind how this therapy improved the animals’ cardiac health. We know that NAD+ levels decline with age; it’s also been found that NAD+ levels are reduced in ischemic injuries, leading to a subsequent decline in mitochondrial function and ATP (energy) production. 

The researchers state that the month-long pre-conditioning of the rats with NMN was beneficial to restoring NAD+ levels before the ischemia, which allowed for the effects of melatonin to be more pronounced. When NAD+ levels are elevated, melatonin can better activate its protective mechanisms. Similarly, all three treatment groups experienced boosts to mitochondrial function, with the NMN exhibiting a more significant role in supporting the mitochondria than melatonin. 

Melatonin + NMN Reduced Oxidative Stress Markers 

The combination therapy was most effective, as NMN plus melatonin significantly reduced ROS levels in the heart more than NMN and melatonin singularly. This indicates that the addition of NMN boosts the already-strong antioxidant and free radical scavenging capacities of melatonin. 

Also, MDA (malondialdehyde), SOD (superoxide dismutase), and GPX (glutathione peroxidase) were measured as biomarkers of oxidation. Higher MDA, lower SOD, and lower GPX are indicative of greater oxidative damage. 

In this study, the NMN + melatonin group experienced significant decreases in MDA and increases in SOD and GPX activity compared to each group alone. 

Again, this demonstrates that combining these two compounds significantly boosts their ability to fight oxidative damage, a driving force behind aging.

In summary, combination therapy of NMN and melatonin supported aging rats’ hearts against ischemia-reperfusion injuries and improved many health and longevity biomarkers. The researchers speculate that using NMN prophylactically, before ischemia occurs, could prevent damage from I/R injury and better support heart health.

Key Takeaway:

  • Ischemia-reperfusion injuries commonly occur after blood flow to the heart is reduced, and the subsequent restoration of blood flow can result in cardiac tissue damage and mortality. 
  • In a study with aging rats, combination therapy of NMN and melatonin best supported the heart against these injuries, including restoring NAD+ levels, supporting mitochondrial functioning, and reducing cardiac oxidative damage. 
  • This study was only done with rats; therefore, we cannot extrapolate these results into humans with I/R injuries at this time. 


Hosseini L, Vafaee MS, Badalzadeh R. Melatonin, and Nicotinamide Mononucleotide Attenuate Myocardial Ischemia/Reperfusion Injury via Modulation of Mitochondrial Function and Hemodynamic Parameters in Aged Rats. J Cardiovasc Pharmacol Ther. 2020;25(3):240-250. doi:10.1177/1074248419882002

Jiki Z, Lecour S, Nduhirabandi F. Cardiovascular Benefits of Dietary Melatonin: A Myth or a Reality?. Front Physiol. 2018;9:528. Published 2018 May 17. doi:10.3389/fphys.2018.00528

Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol. 2012;298:229-317. doi:10.1016/B978-0-12-394309-5.00006-7

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