The Science

NEW UNDERSTANDING IN THE SCIENCE OF AGING

Cellular Respiration and Mitochondrial Health are key factors in promoting good health and maintaining proper metabolic function, especially as we age. Cellular respiration which includes Glycolysis, the Citric Acid Cycle, and the ETC (Electron Transport Chain), is a metabolic process that converts food or nutrients such as glucose into ATP, the energy currency of every living cell. As we age, the mechanics of cellular respiration begin to breakdown, mitochondrial function becomes impaired, physical endurance and athletic performance decline because we no longer produce enough ATP cellular-energy. DNA-Repair and SIRTUIN gene silencing are also reduced, leading to mutations and changes in gene expression. 

For decades, the clues have been showing up within the research data, but only recently did Harvard scientists successfully showed, that some aspects of the aging process could be reversed. They supplemented old mice with Nicotinamide Mononucleotide (NMN) to replenish NAD+ (the oxidized form of Nicotinamide Adenine Dinucleotide), a critical co-enzyme that is central to Cellular Respiration. The intracellular communication between the nucleus and the mitochondria was restored, impaired mitochondrial function and ATP energy production was recovered, and biometric markers subsequently measured in the old mice, resembled those of much younger mice. It was the human equivalent of a 60-year old with some biomarkers resembling those of a 20-year old. This was accomplished via the activation of SIRTUINS, an NAD+ dependent class III histone deacetylase family of genes, commonly referred to as the longevity-genes. 

"A New—and Reversible—Cause of Aging" - Harvard Medicine School

"Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging"

New insights from the Harvard researchers also show that NAD+ binds to another protein called DBC1, thereby reducing its interference with the normal DNA-Repair process. NAD+ acts both as a substrate for, and as a promoter of the DNA-Repair process. DNA-Repair is critical for protecting the integrity genome and to keep cells working normally as the DNA code intended. 

HARVARD SCIENTISTS PINPOINT CRITICAL STEP IN DNA REPAIR, CELLULAR AGING ...

A conserved NAD+ binding pocket that regulates protein-protein interactions during aging.

As we age, NAD+ levels fall. In simple terms, this is the core concept that is behind the science, a clear link between falling NAD levels and aging. This rate of decline is greater than the body’s own natural ability to maintain an adequate supply of NAD. NMN Nicotinamide Mononucleotide is a direct NAD+ precursor supplement that helps to replenish the NAD supply. It has been established in principle, by treating old mice with NMN, that at least some biometric markers used to measure the aging process can be reversed.

Why is NAD+ so critical?

There are three fundamental functions that require NAD+ which are critical for the normal operation of all living cells. First, NAD+ is responsible for the production of ATP, the chemical energy necessary to sustain life. For example, turning food into energy requires the NAD+/NADH redox cycle which drives mitochondrial oxidative phosphorylation. Mitochondria are the energy-producing power plants of the body. Secondly, SIRTUINS, the so-called "longevity-genes" that regulate or silence other genes, do not work without an adequate supply of NAD+. Thirdly, NAD+ is a facilitator and a substrate that is used for the repair of broken DNA strands. Together SIRTUINS and NAD help to maintain the integrity of the genetic code by protecting against various epigenetic mutations.

NAD levels decline over time because NAD+ is used and CONSUMED as a substrate by SIRTUINS, DNA-Repair enzymes and aggressively by another enzyme called CD38 for calcium balancing and immune function response. Inflammatory cytokines released by the immune system causes the production of CD38. The problem is further exacerbated, at least in theory by senescent cells, cells that can no longer divide but increasingly causes the release of even more inflammatory cytokines and more CD38 expression. Eventually, more NAD gets consumed than the ability to replenish the supply, contributing to the over-all decline that is experienced with aging.

It is now evident that supporting the NAD pool is vital for promoting good health & wellness, especially as we age. So far early trial data showed that NMN 100mg, 250mg and 500mg doses are safe for human consumption with no adverse effects.

Why NAD+ Declines during Aging: It’s Destroyed

The Role of Macrophages in NAD+ Homeostasis During Aging

Sirtuins are part of a complex regulatory system that control gene expression. Their job is to keep the house in order by maintaining normal cell function and good health. It can be said that all cells are genetically identical and what makes one cell different from another are the genes that are expressed. As we age, gene regulation becomes impaired and more genes are left turned on, or up-regulated than normal. This is due partly to low and declining NAD+ substrate availability.

Under normalized conditions where NAD+ substrate is ample, or during caloric restriction as observed by researchers, Sirtuins activate, directly binding to targeted genes, while simultaneously binding the NAD+ molecule.  This process then involves removing a small group of molecules called an acetyl group from the gene, and transferring it (Acetyltransferase) to the NAD+ molecule, after first removing the NAD’s nicotinamide ring. This process renders the gene silent or down-regulated, as it’s electrical charge is modified, controlling its transcriptional capability. Sirtuins are NAD+ dependent and DO NOT work without available NAD+.

Trans-Resveratrol is thought to be one the most potent of the known natural Sirtuin-activation compounds (STACs), which are small molecules that can have an effect on Sirtuin activity. It has been demonstrated that Trans-Resveratrol can directly activate Sirtuins such as SIRT1, but this largely depends on the hydrophobic configuration of the targeted protein. Trans-Resveratrol not only activate Sirtuins but some evidence also show that Resveratrol up-regulates the bottlenecking NMNAT enzyme, which catalyzes the conversion of NaMN to NAAD and NMN to NAD+. This has the potential effect of speeding up the NAD+ precursor recycling process as well as the NAD+ de novo synthesis pathway.

Resveratrol has several key benefits that promotes longevity and supports NAD+ metabolism that makes it a perfect synergistic match for NMN and other NAD boosting supplements.

*Resveratrol speeds up the biosynthesis and recycling of NAD+ in our bodies. It does this by up-regulating the NMNAT gene, which is a bottleneck-enzyme responsible for the production of NAD+.

* Resveratrol can also directly, though selectively, turn on our "longevity genes" called Sirtuins, such as SIRT1, mimicking some benefits of caloric restriction and promoting mitochondrial biogenesis. 

*Resveratrol aids in the protection of NAD+ by suppressing inflammatory cytokines that cause the expression of ectoenzyme CD38. CD38 is the greatest destroyer of NAD+ in our bodies.

* Resveratrol is also an AMPK activator which is a fatty acid oxidation pathway normally induced by exercise and is known to be one of the most beneficial longevity pathways.

* Resveratrol is an mTOR inhibitor, which is considered another major longevity pathway.  Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition

* A 2016 study showed, one way in which Resveratrol promotes a healthy cardiovascular system. Is by remodeling the gut bacteria to reduce the production of TMA and subsequent TMAO. TMAO interferes with the normal removal of cholesterol from the bloodstream by blocking its conversion to bile acids in the liver.  

* A recent study show resveratrol may have the ability to rejuvenate senescent cells and elongate telomeres. ” making senescent cells not only look physically younger, but start to behave more like young cells and start dividing.”

* Resveratrol promotes general health and wellness in a multifaceted way that makes it indispensable as a nutritional supplement. “Antioxidant effect of resveratrol in the cardiovascular system”

More Reference links

Resveratrol Increases Intracellular NAD+ Levels Through Up regulation of The NAD+ Synthetic Enzyme Nicotinamide Mononucleotide Adenylyltransferase

Resveratrol-Induced AMP-Activated Protein Kinase Activation Is Cell-Type Dependent: Lessons from Basic Research for Clinical Application.

Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced A---* by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota

Old human cells rejuvenated in breakthrough discovery on aging

Antioxidant effects of resveratrol in the cardiovascular system 

Resveratrol Increases Intracellular NAD+ Levels Through Up regulation of The NAD+ Synthetic Enzyme Nicotinamide Mononucleotide Adenylyltransferase

NADH is the reduced form of Nicotinamide Adenine Dinucleotide (NAD), and NAD+ is the oxidized form of the very SAME molecule. 

NADH has been on the market as a supplement for many years but its benefits have been vastly overlooked. Most individuals have heard of the energy boosting benefits of supplemental NADH, however, somehow missed its value as an anti-aging supplement. In principle, an NADH molecule successfully transported into the cytoplasm of a cell, is generally oxidized directly into NAD+ by dehydrogenase enzymes such as Lactate Dehydrogenase, Glyceraldehyde 3-Phosphate Dehydrogenase and the Malate-aspartate Shuttle. NADH may also be broken down or catabolized into NAD precursors and recycled back into NAD+/NADH.

NADH + CoQ10 Creates ATP Energy and NAD+

In the past, it was generally accepted that NADH could not make it passed the acidic conditions of the stomach and be absorbed. However, a study using mice that was published in the “Frontiers in Bioscience” in 2008 by Rex and Fink showed, that should oral NADH be protected against the acidic conditions of the stomach, it is absorbed, principally in the small intestine. Here is the link to the article below; the absorption rate was low but fast and the NADH molecules that were absorbed, remained intact. (the NADH we use is Panmol, which is acid protected and comes in a chewable tablet for superior absorption.)

"Pharmacokinetic aspects of reduced nicotinamide adenine dinucleotide (NADH) in rats"

NADH IS CONVERTED TO NAD+ AFTER ABSORPTION INTO LIVING CELLS

It was also debated whether the NADH molecule was too large to travel across cell membranes, however, multiple research studies have shown that NADH can be transported across the plasma membrane through a special receptor called P2X7R as well as some other unknown pathways, with great affinity. 

NADH was shown to be transported across the plasma membrane of astrocytes (brain and spinal cord cells) by the P2X7 receptor and led to increases in both intracellular NADH and NAD+. Interestingly enough, the study also showed that a small treatment with extracellular NADH was ONLY able to increase intracellular NAD+ levels because in small concentrations NADH is quickly oxidized NAD+. 

"P2X7 Receptors mediate NADH transport across the plasma membranes of astrocytes"

A comprehensive study, using newer and more advanced techniques, with the remarkable capability to measure and track the movement of NADH, into and inside, the sub-cellular compartments of living cells, confirmed definitively, that NADH moves readily across the plasma membrane and improves the NAD+ ratio.

In this study published in "Cell Press" 2011, multiple mammalian cell lines were treated with extracellular NADH and the total NAD+:NADH pool in the cells, increased by about 25%. Furthermore, blocking of the P2X7 receptor did not stop the observed high-affinity transport of NADH into living cells.

see the 2011 study - Genetically Encoded Fluorescent Sensors for Intracellular NADH Detection

Again, once NADH is successfully transported into the cytoplasm of any cell, NADH is generally oxidized into NAD+. This takes place through multiple dehydrogenase processes, where NADH gives up the H (Hydrogen),by passing its energy rich electrons to further the production of ATP.

The increased NAD+ pool may then serve to activate the Sirtuin family of genes, sometimes referred to as the longevity genes. Sirtuins regulate gene expression, they decide when some genes get turned on and when some genes get turned off, ensuring normal cell function. Sirtuins are NAD+ dependent, meaning, they do not work without available NAD+, which gets used and consumed in the process. Some DNA repair enzymes also use and consume NAD+ as substrate or raw-material for the repair broken DNA strands. The cell membrane surface enzyme CD38 greatly consume NAD+ in large amounts for intracellular calcium homeostasis and as an immune response.

Replenishing the NAD+ supply is indispensable in the battle against the aging process. NADH + CoQ10 is a great addition to any NAD+ boosting regimen because it helps to maintain robust energy levels and reduces lipid peroxidation as an NAD+ boosting antioxidant.

NADH is a Potent Scavenger of the free-radical Peroxynitrite

NADH + CoQ10 is a profoundly powerful antioxidant combination that significantly reduces lipid peroxidation. NADH can react directly with DNA damaging free-radical peroxynitrite yielding NAD+ in the process. This reduces nitrosylation of tryptophan & tyrosine and protects the nitric oxide cofactor BH4 from peroxynitrite oxidation. Reducing peroxynitrite levels ultimately helps to support normal brain function, the cardiovascular system, immune function and blood vessel vasodilation or blood flow. 

NADH reacted 5-100 times faster with peroxynitrite than do the known peroxynitrite scavengers glutathione, cysteine, and tryptophan

NADH IS CONVERTED TO NAD+ BY RED BLOOD CELL MEMBRANE ENZYMES  

NADH + CoQ10 servers as an electron donor for redox transport across red blood cell membranes. This is yet another example where NADH oxidized directly into NAD+. The mechanics revealed in this study demonstrated how NADH + CoQ10 may work to support healthy red blood cells that promotes better oxygen transport, by reducing methaemoglobin. Combined with the improvements seen in ATP energy production, this could also explain some of the endurance and stamina benefits of NADH + CoQ10. 

Redox reactions and electron transfer across the red cell membrane.

full pdf

Investigation of methaemoglobin reduction by extracellular NADH in mammalian erythrocytes.

NADH and CoQ10 are natural coenzymes that serve both as antioxidants and as electron carriers, protecting the mitochondria while promoting ATP energy production. NADH + CoQ10 work synergistically to ensure energy efficiency, boosting athletic performance, physical endurance and mental focus. NADH + CoQ10 is also a potent antioxidant combination that helps neutralize cytotoxic radicals and lipid peroxidation. NADH converts to NAD+ and is used as substrate that stimulates DNA repair and Sirtuin gene regulation for Real Anti-Aging benefits. Essentially, NADH absorbed into the cytoplasm acts as an NAD+ Donor. CoQ10 absorbed into the mitochondria would act as the final electron carrier, donated by NADH, allowing for efficient electron transport and reduced bottle-necking.  

NADH dehydrogenase (ubiquinone, Complex I) is an enzyme that transfers the energy rich electron from NADH to CoQ10, which begins the Electron Transport Chain, and ends with the production ATP energy. The catalyzing enzyme requires both co-enzymes to work more efficiently, which helps to reduce electron leakage and the formation of excessive ROS (reactive oxygen species).

The mitochondrial NADH pool also serves to balance the NADPH pool, via the proton driven inter-membrane enzyme NNT. This allows Glutathione (the body's master antioxidant) to be converted back to its reduced form for detoxification. It also supports the adrenal cortex steroidogenesis for hormonal balance which depends on NADPH as a co-enzyme. It makes more sense that supplementing NADH + CoQ10 together, is the more effective option for promoting ATP energy production, while limiting and reducing the formation of excessive radicals and peroxides.

A 2016 human study on supplementation with NADH plus CoQ10 for eight weeks was found to be safe and well tolerated. The study also found the NADH CoQ10 group to have lower heart rates during an exercise test.

2016 research study on NADH + CoQ10 supplementation

At MAAC10 Formulas we take a comprehensive, whole-system synergistic approach, to addressing the NAD+decline in the body. Our first products NADH + CoQ10, Trans-Resveratrol + BioPerine  and NMN begin to coalesce around the idea, that NAD levels can be supported naturally, that the age related decline in energy metabolism can be improved while suppressing excessive free-radical formation. We believe, that a comprehensive strategy offers a greater opportunity to achieve the best results.