I am a huge fan of NAD+ supplementation. My family and I take an NAD supplement on a daily basis. In addition to that, we will occasionally take an Intravenous dose of NAD+. It is indisputable that as we age we absolutely need more NAD+ or we basically face an increasing assault by the ravages of aging. Can NAD+ be like a Trojan Horse and on the outside look promising but at the same time cause danger from the inside? Well if you go to an ill prepared clinic the answer is yes! Like most things in life there is no free lunch. Indeed, we are well aware that NAD+ and its precursors will have significant effects on a number of pathways in the body. The following diagram shows what happens with low NAD levels:
One of the Anti-Aging Pathways that NAD affects is the Sirtuin gene pathway. There are seven different components to the Sirtuin genes. The Sirtuins are a family of proteins that play a huge role in aging by regulating cellular health, especially the health of the mitochondria. They’re responsible for critical biological functions like DNA expression and other aspects of aging. However, sirtuins can only function in the presence of NAD+, nicotinamide adenine dinucleotide, a coenzyme found in all living cells. NAD is an essential building block during energy production. The energy in this case is ATP. We lose up to 50% of our NAD levels between the ages of 40 and 60 as can be seen in the following illustration:
We must also remember that NAD+ is not just used for energy production but also is utilized by enzymes (PARP) that repair DNA damage. These enzymes are also huge consumers of NAD. The Sirtuin genes seems to have significance over the health of our mitochondria. Ultimately, the decline in mitochondrial function causes us to age. A prominent theory of aging holds that decaying of mitochondria is a key driver of aging. To slow down aging one needs to increase NAD+ and its precursors. This is absolutely the case and is practiced by many well-informed people and clinics. Unfortunately, most people and clinics for that matter seem to stop here. The premise is that NAD+ will slow aging and everyone goes on their merry way. What we need to realize that NAD+ alone may in some ways act as a Trojan horse. On the outside it seems to be a gift to our health which in many ways it is. But there are also some aspects of NAD+ therapy that might not be conducive to our health UNLESS WE ADDRESS THESE PROBLEMS AT THE TIME OF THE NAD TREATMENT.
I have previously mentioned one detrimental aspect of NAD+ treatment is its effect on Senescent cells. Remember a Senescent cell is a cell that should have died but continues to survive causing a variety of problems. I wrote an extensive blog on this subject some time ago. Please go to my website and check the blog I wrote entitled “NAD and Senescent Cells on a Collision Course”.
Unfortunately, most clinics are not aware of the potential problems NAD+ may cause with Senescent cells. It can actually make these cells thrive. So low and behold you actually may not make a patient healthier if he is given NAD+ without addressing Senescent cells. You may be going in the opposite direction and possibly cause a decline in their overall health. We have addressed the Senescent cell problem with Senolytic agents for some time now. The Senolytic agents that will directly attack the Senescent cells and aid in their elimination. We have done this for years and will continue to do so.
METHYLATION OR LACK OF IT: A MAJOR HIDDEN DANGER OF NAD THERAPY
Senescent cells can cause havoc by their inflammatory secretions but they are only one problem that can be increased by NAD+ therapy. The other major concern unleashed by NAD+ therapy concerns a process called methylation.
Methylation is the transfer of a methyl group (one carbon and three hydrogens) from one molecule to another in the body and is a fundamental element of our biochemistry. Methylation is accomplished by enzymes. Methylation can modify heavy metals, regulate gene expression, RNA processing and protein function. It is recognized as a key process underlying Epigenetics. Epigenetics involves essentially turning on and off switches of different genes.
The above diagram illustrates the intersection between methylation and control of our genes. As noted above, methylation generally acts as a suppressor for many of the gene regulatory elements such as insulators, promoters, enhancers and repressors. These regulatory elements play a significant role in maintaining the integrity of chromosomes and homeostasis of organisms. Epigenetics ensures that only a single allele (different forms of the same gene) should be expressed for that specific gene. This process is known as imprinting. In the case of failed imprinting, it can result in a spectrum of diseases. In simplistic terms, epigenetics involves putting a methyl group on a DNA strand. Methyl groups are organic molecules. What we are really dealing with is called DNA methylation. DNA methylation occurs when a methyl group is added to a DNA strand. DNA methylation is a tool to typically lock genes into their off position. Aberrant DNA methylation, which is a nearly universal finding in cancer results in disturbed gene expression. DNA methylation is modified by environmental factors such as diet that may modify cancer risk and tumor behavior. Abnormal DNA methylation has been observed in several cancers. These alterations in DNA methylation may play a critical role in cancer development and progression. Dietary nutrient intake and bioactive food components are essential environmental factors that may influence DNA methylation. In recent years, researchers have learned a great deal about DNA methylation, including how it occurs and where it occurs, and they have also discovered that methylation is an important component in numerous cellular processes. So, we can see that DNA methylation is crucial to our well-being and healthspan.
HOW DO DNA METHYLATION AND NAD THERAPY INTERSECT WITH EACH OTHER?
We are able to see the importance methyl groups play in our health and well-being. Below we see a diagram of the metabolism of NAD+. The problem develops when we start to
metabolize the byproducts of NAD+. Although NAD+ is used by the body to create ATP, NAD+ is also metabolized to a methylated nicotinamide molecule called MeNAM. The process of metabolizing NAD+ stresses the body’s “methyl pool,” the molecules that donate methyl groups. The methyl pool is crucial to maintain one’s health. A methyl group needs to be added to NAD+ to create MeNAM, which uses up methyl groups that are needed for other biochemical reactions. If adequate amounts of methyl groups are not available than methylation is diminished allowing genes to either be kept on or off sometimes resulting in significant problems. Also, when NAD+ treatments are given, as the NAD+ is metabolized it is converted into a compound called Methionine which is ultimately converted into a compound called Homocysteine. Homocysteine is a byproduct of methionine metabolism. It is a powerful pro-oxidant and free-radical generator known to be a leading cause of heart disease and other problems as the following illustration shows.
A clinical study of niacinamide supplementation showed not only an increase in MeNAM, but also an increase in homocysteine levels, which is an independent risk factor for heart disease. There appears to be a relationship between high levels of homocysteine and artery damage. That can lead to atherosclerosis (hardening of the arteries) and blood clots. We must also realize many individuals in the United States – some estimates are as high as 60% have a genetic defect in a critical enzyme involved in methylation – MTHFR. This makes methylation even more difficult. Here is a good illustration of the damage homocysteine causes to the vessels:
The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving the vitamin folate (also called vitamin B9). Specifically, this enzyme converts a form of folate called 5,10-methylenetetrahydrofolate to a different form of folate called 5-methyltetrahydrofolate. This is the primary form of folate found in blood, and is necessary for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.
When dealing with homocysteine, if one gets adequate amounts of vitamin B6, either from foods or supplements, a portion of the body’s homocysteine is converted into cystathionine, an antioxidant and free-radical deactivator. About half of our homocysteine is detoxified by this process. The other half is detoxified by the addition of a methyl group. With the addition of methyl groups, homocysteine is converted to methionine by the transfer of the methyl group from a methyl donating compound such as Trimethylglycine (TMG). We have been using TMG for some time now in our clinics. In brief, TMG detoxifies homocysteine, recycles methionine and supplies B15. Thus, we are able to see that NAD+ treatment will worsen the ongoing shortage of methyl groups in the body. Unless methyl donating compounds are utilized with NAD+ treatment we will exacerbate the methyl group shortage which could adversely affect the patients’ health and well-being on a few different levels.
When we are giving a patient intravenous NAD+ we have found that Trimethylglycine (TMG) dramatically enables to patient to receive intravenous doses of NAD at a much faster rate. Typically, if the rate is too fast, patients will develop a variety of symptoms including flushing, chest tightness etc. Although these symptoms sound serious they are benign and cause the patient no problems other than some anxiety. One of the big reasons for eliminating these symptoms is the fact that Trimethylglycine is a potent and rich methyl donor. The propriety trick is to know when and how much TMG to use. By utilizing TMG as methyl donor, we are eliminating unpleasant symptoms and at the same time improving the patient’s health on many levels. So again, make sure the if you receive any type of NAD treatment that Senescent cells and the methyl group problem be addressed. Your health and well-being depend upon it.
Thanks,
Dr. P
