NAD+

NAD+ 

NAD+ stands for Nicotinamide Adenine Dinucleotide. It’s a crucial molecule found in all living cells and plays a fundamental role in cellular energy production and many other cellular processes. NAD+ is considered a coenzyme because it helps enzymes carry out their functions. It is especially important in the process of converting food into energy, a vital reaction that happens in the mitochondria of cells.

In addition to its role in energy metabolism, NAD+ is also involved in repairing damaged DNA and regulating cellular signaling. As we age, the levels of NAD+ in our body naturally decrease, which has been linked to age-related diseases and metabolic disorders.

NAD+ is essential for energy production, maintaining DNA integrity, and overall cell health. Its decline with age is thought to contribute to various age-related health issues.

Potential Benefits Under Research

• Aging and Longevity: Enhancing NAD+ levels may slow certain aging processes and increase lifespan by improving cell health and function. 
• Neuroprotection: Increased NAD+ levels might protect against neurodegenerative diseases like Alzheimer’s and Parkinson’s by supporting brain health and neuronal function. 
• Metabolic Health: NAD+ is pivotal in metabolism, and boosting its levels could improve conditions such as diabetes and obesity by enhancing energy utilization. 
• Cardiovascular Health: NAD+ could help maintain heart function and prevent cardiovascular diseases by supporting the energy demands of cardiac cells. 
• DNA Repair: It promotes the repair of damaged DNA, crucial in preventing cancer and other genetic disorders. 
• Immune Function: Emerging evidence suggests NAD+ might enhance immune system performance, potentially helping combat infectious diseases and inflammation. 
• Addiction Treatment: NAD+ has been studied for its potential to reduce cravings and withdrawal symptoms associated with substance abuse. The theory is that NAD+ can help reset the brain’s neurotransmitter levels, which are often disrupted by addiction. 

Overview

NAO+, short for nicotinamide adenine dinucleotide, is the oxidized form of NAOH. It’s main biological function is to carry electrons from one biochemical reaction to another, acting to shuttle energy within a cell and, in certain conditions, to extracellular locations as well. NAO+ also plays roles in enzyme activation/deactivation, posttranslational modification of proteins, and cell-to-cell communication. As an extracellular signaling molecule, NAO+ has been found to be released from neurons in blood vessels, the bladder, the large intestine, and from certain neurons in the brain.

Structure

Sequence: N/A
Molecular Formula: C21H21N1014P2 Molecular Weight: 663.43 g/mol
PubChem CID: 925
CAS Number: 53-84-9
Synonyms: nicotinamide adenine dinucleotide, beta-NAO, NAO, Endopride

NAD+ Effects

• NAO+ activates sirtuins and other enzymes, like Poly-ADP-ribose polymerases, involved in DNA repair and inflammatory processes. Sirtuins are the same enzymes linked to the life-extending benefits of calorie restriction.
• NAO+ controls the production of the protein PGC-1- alpha, which protects neurons and other cells in the central nervous system from oxidative stress. Research in mice shows that this particular effect may be linked to improved memory, particularly with aging.
• In mouse models, NAO+ helps to protect blood vessels against age-related hardening and the deposition of atherosclerotic plaques. In some studies, the cofactor even helps to reverse age­related dysfunction of the aorta.
• Mice given NAO+ show increased rates of metabolism and improved lean body mass.
• Increased NAO+ levels can increase muscle strength and endurance in older mice.
• NAO+ has been linked to extracellular signaling, particularly for smooth muscle. It may be of benefit to GI function. This effect is likely responsible for NAO+ benefits on blood pressure obtain synergistic effects with few to no side effects. This is particularly true when NAD+ is combined with other natural supplements. Research in mice bears this out in several specific cases. 

NAD+ Additions and Synergies

• Combining NAD+ and high-dose biotin may help to combat pain and reduce levels of pain.
• CoQl0, another cofactor in energy metabolism, may work synergistically with NAD+ to improve neurological function and protect the central nervous system against oxidative stress.
• Reservatrol and NAD+ work together to reduce oxidative damage, lower inflammation, and help to lower levels of LDL (a.k.a. bad) cholesterol. They may also work together to protect against diabetes and neurodegenerative disease.
• Vitamins Bl, B2, and B6 help to boost NAD+ salvage. When combined with NAD+ supplementation, they may help to improve overall NAD+ levels.
• Combining NAD+ with mitochondrial and energy supplements, such as creatine and alpha-lipoic acid, may boost antioxidant and anti-aging effects.

NAD+ Research

Anti-Aging Research and NAD+ 

One of the primary results of the standard aging process is a decline in both the quality and activity of mitochondria. Mitochondria are the body’s power plants, producing the energy for everything from neuron firing to digestion and muscle function. A decline in mitochondrial function has been and even changes in stem cell activity that reduce rates of healing and make it harder for the body to recover from injury in old age.

According to Nuo Sun of the Heart, Lung, and Blood Institute of the National Institutes of Health, mitochondria cannot simply be viewed as bioenergetics factories, but “rather as platforms for intracellular signaling, regulators of innate immunity and modulators of stem cell activity.” He goes on to explain that “mitochondria can be linked to a wide range of processes associated with aging including senescence, inflammation, as well as the more generalized age-dependent decline in tissue and organ function.” In other words, mitochondria are the lynchpin of cellular aging and understanding how to protect their function is a necessary first step in understanding how to slow, stop, or even reverse the aging process. 

New research suggests that at least some of the age-related decline seen in mitochondria can be reversed through dietary supplementation with NAO+. This function of NAO+ was uncovered, or at least made popular in research circles, by David Sinclair of Harvard University. Sinclair is the same researcher who uncovered the anti-aging effects of reservatrol (a component of red wine). In 2013, Sinclair revealed that mitochondria in the muscle of mice could be restored to a more youthful state via injection of a precursor to NAD+.

Research completed in 2013 showed that declining levels of NAD+ lead to a pseudohypoxic state within cells. This, in turn, interrupts the normal signaling that takes place between the nucleus, where DNA resides, and the mitochondria. By supplementing old mice with NAD+. 

At least part of the reason that NAD+ helps to offset the effects of aging is that it activates SIRT 1 function in the nucleus and prevents the normal age-related decline in expression of this particular gene. SIRT 1 is a gene encoding a protein known as sirtuin 1 (short for NAO-dependent deacetylase sirtuin-1). Sirtuin 1 is an enzyme that plays an important roles in regulating proteins involved in cellular metabolism and processes linked to stress, longevity, and inflammation. 

The Role of NAD+ In Muscle Function 

Another link between aging and NAD+ can be seen in skeletal muscle tissue. In mouse models, age­related muscle decline occurs in two steps. In the first step, oxidative phosphorylation (the process mitochondria use to produce energy) declines because of reduced expression of mitochondrial genes (mitochondria contain their own DNA). In the second step, genes regulating oxidative phosphorylation begin to malfunction in both the mitochondria and nucleus. Phase 1 is reversible. If NAD+ is administered, mice in these studies show improved mitochondrial function and do not progress to step 2. If, however, the mice are allowed to progress to stage 2 without intervention, then NAD+ cannot rescue them. This evidence suggests that intervention in mitochondrial aging is possible using NAD+, but that waiting too long results in refractory dysfunction. It is the best argument yet that early supplementation with NAD+ is critical to fighting off aging in the long term. 

Research shows that exercise training actually has co-activator 1-alpha (PGC-1-alpha) signaling that lead to mitochondrial dysfunction.

Research in mouse models of skeletal muscle aging suggests that exercise training helps to maintain muscle oxidative capacity over a lifetime. At least part of the reason that this works is that exercise increases PGC-1-alpha levels, which in turn helps to protect mitchondrial DNA, oxidative proteins, and angiogenic (blood vessel stimulating) proteins.

NAD+ in Neurodegenerative Disease 

Much of what has been learned about NAD+ and the aging process is actually applicable to a number of disease conditions. In particular, changes in NAD+ appear to have far-reaching effects in the central nervous system and have been linked to a number of neurodegenerative diseases such as Alzheimer’s and Huntington’s diseases. A review article published in 2019 explained the current state of the knowledge as it relates to NAD+ and the central nervous system. In short, NAD+ is neuroprotective in a number of mouse models of human diseases such as Huntington’s disease. It appears that the cofactor is important in improving mitochondrial function, which in turn decreases the production of reactive oxygen species (ROS). ROS are known to cause damage in a number of inflammatory and disease conditions. They also accelerate the aging process. There is interest in a possible synergistic effect that could be gained through NAD+ supplementation in combination with a class of medications known as PARP inhibitors. PARP proteins are involved in DNA repair and programmed cell death. Though activated PARP is important to DNA repair, too much PARP activity can actually deplete cellular energy stores and induce motor deficits and the death of dopaminergic neurons in the substantia nigra. This suggests that NAO+ may not only help ameliorate the symptoms of Parkinson’s disease, but may actually slow or even prevent the development of the disease in the first place.

Interesting research into a metabolic process known as the kynurenine pathway (KP) has shown that NAO+ supplementation may help to ward off disease by preventing the breakdown of neurotransmitters and by reducing the need to shunt protein precursors to the production of NAO+. Tryptophan is an essential amino acid and is a building block of a number of neurotransmitters and proteins. This amino acid is broken down, however, via the KP to produce NAO+. Thus, the production of NAO+ directly cannibalizes essential neurotransmitters. Research has linked imbalances in KP activity to Parkinson’s, Alzheimer’s, and Huntington’s diseases as well as psychiatric disorders like schizophrenia and bipolar disorder. There is ongoing research to determine if NAO+ supplementation can prevent imbalances in KP and thus ameliorate or prevent the neurodegenerative conditions mentioned. 

The Role of NAD+ in Reducing Inflammation 

NAO+ levels are regulated by a number of factors, one of which is NAM PT. This particular enzyme is known to be associated with inflammation and is often overexpressed by certain types of cancer. Researchers are, in fact, targeting NAMPT as a potential anti-cancer treatment. The regulator has also been linked to the development of obesity, type 2 diabetes, and nonalcoholic fatty liver disease. It is reduces NAMPT activation and thus modulate inflammation.

There is good evidence to suggest that the NAD+/NAMPT dichotomy is a primary driver of the insulin resistance that has been linked to obesity and so often leads to type 2 diabetes as well as heart disease. It appears that obesity leads to inflammation and that leads to an overall reduction in NAD+ levels, which in turn increases free fatty acid levels in the blood as a result of adiponectin down-regulation. This then causes the liver to produce more glucose even as it interferes with the insulin-mediated uptake of glucose by skeletal muscle. The result is insulin resistance, which the pancreas attempts to overcome by producing more insulin. The net result, over time, is high glucose levels and diabetes.

NAD+ in Addiction Treatment 

It has long been known that drugs and alcohol can have a deleterious effect on NAD+ levels. This leads to nutritional deficits, but has also been linked to changes in mood and awareness. Supplementation with NAD+ to help overcome these deficits started in the 1960s, but has recently gained popularity as a result of studies showing that NAD+ in combination with specific amino acid complexes can actually boost recovery and lead to more profound and lasting results during addiction rehabilitation. Research indicates that the combination of NAD+ and certain amino acids can reduce cravings and improve stress and anxiety levels.

NAD+ Supplementation and the Future of Aging Research 

There has been a strong push to test NAD+ in clinical trials of neurodegenerative disease and chronic type 2 diabetes. In both cases, the simple cofactor holds a great deal of promise for, at the very least, slowing the progression of these devastating diseases. There is even hope that NAD+ can, by itself or in combination with other therapies, reverse certain disease processes or even regulate the aging process itself. 

NAD+ exhibits minimal side effects, low oral and excellent subcutaneous bioavailability in mice. Per kg dosage in mice does not scale to humans. 

Article Author

The above literature was researched, edited and organized by Dr. E. Logan, M.D. Dr. E. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.

Scientific Journal Author 

Shin-ichiro lmai’s, MD, PhD major interest is to understand the systemic regulation of aging and longevity in mammals and translate that knowledge into an effective anti-aging intervention that makes our later lives as healthy and productive as possible … Three key tissues have been identified as basic elements in mammalian aging and longevity control: the hypothalamus as the control (Imai, npj Systems Biology and Applications, 2016). Through these projects, they aim to understand the importance of these critical inter-tissue communications among the hypothalamus, skeletal muscle and adipose tissue in mammalian aging and longevity control. The anticipated outcome of these studies will allow us to develop effective anti-aging interventions. 

Shin-ichiro lmai’s, MD, PhD is being referenced as one of the leading scientists involved in the research and development of NAO+. In no way is this doctor/scientist endorsing or advocating the purchase, sale, or use of this product for any reason. There is no affiliation or relationship, implied or otherwise, between Guide to Peptide and this doctor. The purpose of citing the doctor is to acknowledge, recognize, and credit the exhaustive research and development efforts conducted by the scientists studying this peptide. Shin-ichiro lmai’s, MD, PhD is listed in [8] under the referenced citations. 

Referenced Citations 

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