NEW UNDERSTANDING IN ANTI-AGING SCIENCE
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 show that some aspects of the aging process could be reversed. By supplementing 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 known as the longevity-genes.
"A New—and Reversible—Cause of Aging" - Harvard Medicine School
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.
As we age NAD+ levels fall. Within our cells, the NAD+ pool helps to breakdown sugars from the food we eat into energy. It is also an absolute requirement for the function of SIRTUINS, our "longevity-genes" that promotes overall health and wellness by regulating normal cell metabolism and gene silencing.
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 response. The emerging theory places CD38 as the primary culprit, activated by cytokines in response to progressive low-grade inflammation leading to the over-consumption of NAD+ and less Sirtuin activity.
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 the most potent of the known natural Sirtuin-activation compounds (STAC), 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 also up-regulates the bottlenecking NMNAT enzyme, which catalyzes the conversion of NaMN to NAAD and NMN to NAD+. This has the effect of speeding up the NAD+ precursor recycling process as well as the NAD+ de novo synthesis pathway.
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.)
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+.
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 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.
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.
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.