Can Combining NMN and Melatonin Protect the Heart? A Look at Recent Research

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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 promote 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 exhibited cardioprotective benefits 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. 

Supplemental NMN is linked to increased lifespan in animal studies, improved mitochondrial functioning and sirtuin expression, and reduced cellular senescence, as these processes are all dependent on NAD+. A disruption or dysfunction of these processes drives accelerated aging and disease development. 

What is Melatonin? 

Melatonin is most well-known for its link to improved sleep; however, the hormone has even more wide-reaching benefits to consider. In addition to regulating the circadian rhythm, melatonin is associated with anti-inflammatory and anti-aging qualities and immune support. 

Melatonin contains high antioxidant levels, which reduce oxidative damage to cells and DNA by scavenging for free radicals and reactive oxygen species (ROS).  

As mitochondria are particularly vulnerable to oxidative damage and their functioning is reduced with aging and disease, the combination of NMN and melatonin is a good candidate for protecting this age-related decline in mitochondrial quality. 

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 — sometimes called reperfusion injury or reoxygenation injury — occurs after myocardial ischemia, which indicates a blockage of blood flow to the heart and can result in a heart attack. After the ischemic event, reperfusion occurs, which is when coronary 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 therapy that could protect the heart against these I/R injuries that are frequent causes of disability and mortality after ischemic heart events. 

NMN and melatonin protect the heart against ischemia/reperfusion injuries.

What Did The Study Look At? 

The researchers took 60 aging male rats and randomized them into five groups: 

  1. The sham group, without I/R
  2. The control group, with I/R 
  3. I/R with melatonin (“melatonin group”)
  4. I/R with NMN (“NMN group”)
  5. I/R with NMN and melatonin (“NMN + melatonin group”)

The groups receiving NMN had the compound administered intraperitoneally at 100 mg/kg every other day for 28 days before the I/R injury. Melatonin was added at 50 µM just before the reperfusion occurred. 

The outcomes measured were myocardial blood parameters, cardiac mitochondrial function, oxidative stress markers, and infarct size, which is a measure of damage to the heart. 

They also measured left ventricular end-diastolic pressure (LVEDP); elevated LVEDP is a predictor of heart failure and mortality in cardiac patients.  

What Did The Study Find? 

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 myocardial infarctions, damage to cardiomyocytes, and dysfunctional cardiac markers. However, the reperfusion’s harmful aftereffects were mitigated in the NMN, melatonin, and NMN + melatonin groups, with the most significant effects being seen within the combination group. 

The main findings included:

1. 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. 

2. 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, disease, or injury. In cases of I/R, increased LDH release is linked to increased myocardial damage.

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

3. 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 prevented cardiac damage, restored NAD+ levels, and improved mitochondrial function.

4. 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 + 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 these 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 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. 

5. NMN + Melatonin Improved Mitochondrial Function

Mitochondrial function was measured through its membrane potential, reflecting the performance of electron transport, oxidative phosphorylation, and ATP production. A reduction in mitochondrial membrane potential indicates dysfunction in these processes, as measured by increased depolarization. 

All three treatment groups experienced less depolarization and improved membrane potential. However, the NMN and NMN + melatonin groups were comparable and significantly less depolarized than the melatonin group, indicating that NMN played a larger role in protecting mitochondrial membrane potential than melatonin. 

6. Melatonin + NMN Reduced Oxidative Stress Markers 

The combination therapy was most effective, as NMN + 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, the driving force behind aging and disease. 

In summary, combination therapy of NMN and melatonin protected aging rats’ hearts against ischemia-reperfusion injuries and improved many health and longevity biomarkers. The researchers hypothesize that using NMN prophylactically, before ischemia, could prevent damage from I/R injury and improve vascular function. 

The 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, heart attacks, and death. 
  • In a study with aging rats, combination therapy of NMN and melatonin protected the heart against these reperfusion injuries, restored NAD+ levels, improved mitochondrial functioning, and reduced 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. However, NMN and melatonin are both safe supplements to take. 

Show references

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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