When I see many different advertisements from different “anti-aging” clinics, I sort of chuckle a bit.  There is no doubt that these clinics are helping many patients, but quite honestly, they are usually not doing anything that is a game changer. They will often concentrate on correcting hormonal imbalances, and at the same time, attempt to correct some problems with a variety of supplements.  I am guilty of this on myself, and so are many of my stem cell patients.  I take a handful of supplements every day to try an fend off aging, or at least slow it down.  The problem with many supplements is that they have poor absorption.  On paper they should work, but in real life they have some effect. Many times the effect is not as much as we like.  It is well documented that many of these compounds could at least slow down the clock of aging, but the real question is — even if we increase the absorption, will it be a game changer?  The simple answer is — probably not, but there may be two big exceptions.  These exceptions might be NAD/NADH and another compound called P-53.  I would like to discuss NAD in this blog.   If we look at the above diagram we can see that most of the major perimeters of anti- aging are found here.  We want to increase longevity.  What can help increase longevity?   We increase longevity by giving the cells more energy, increasing their telomere length, boosting the immune system, repairing DNA, and stimulating certain genes which foster longevity.

One compound which is attracting much attention is NAD/NADH.  NAD stands for Nicotinamide adenine dinucleotide (NAD). It is 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.  It would seem simple enough to just replace the levels to keep things working at an appropriate level.  Just exactly what does NAD seem to effect in the body?  The simple answer is that it effects the mitochondria.  The mitochondria are the power houses of the cell.  Mitochondria seem to misbehave as we age.  They ultimately decline in their function and cause us to age. A prominent theory of aging holds that decaying of mitochondria is a key driver of aging.  NAD deficiencies are thought to lead to a multitude of problems stemming from heart disease to various neurological conditions.

 

Image result for nad

 

Much of the work concerning NAD comes from the research of David Sinclair of Harvard.  Dr. Sinclair first shed light on the compound called Resveratrol.  It was thought that Resveratrol stimulated a certain set of genes called the Sirtuin genes.  It was discovered that these genes were turned on by exercise and the one other entity that has scientific background of slowing down aging, namely starvation. It is felt that resveratrol mimics starvation.  It appears now that another compound called pterostilbene which is found in blueberries and grapes may have a better effect than resveratrol because it is more bioavailable.

In 2013, Sinclair further reported scientific studies that demonstrated NAD fuels the activity of a group of proteins called the sirtuin proteins, including SIRT1. Although the field of sirtuin research has gone through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an aging/longevity regulator.  Sirtuins are a fascinating family of enzyme-genes.  It is now clear that sirtuins are involved in theregulation of many fundamental biological processes throughout the body.  I would like to give a diagram of the various Sirtuin genes and where they are found in the cell.

We can see that some are found in the mitochondria while others are found in the nucleus.  While a third group is found in the cytoplasm of the cell.  It is the communication of these various genes with each other that control the health, numbers and function of the mitochondria.  Remember that the mitochondria have a downstream effect of most cellular functions.

Sirtuins have evolved to respond to the availability of NAD+, an essential element of cellular metabolism and DNA damage repair.  The sirtuins are a family of proteins that are intimately associated with NAD.  It has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level.  The hypothalamus acts as the connector between the endocrine and nervous systems.  It plays a part in many essential functions of the body such as:body temperature, thirst, appetite, weight control, emotions, sleep cycles, and a host of other functions.  These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and result in the diseases of aging.

 

 

Image result for sirtuin proteins and stem cell aging

 

In mammals seven sirtuin family members exist, including three members, Sirt3, Sirt4, and Sirt5, that localize exclusively within the mitochondria while Sirt1, Sirt6, and Sirt 7 are found in the nucleolus.  Although originally linked to life-span regulation in simple organisms such as yeast, this family of proteins appears to have various and diverse functions in higher organisms including man.  An emerging consensus from recent studies is that sirtuins may act as metabolic sensors, using intracellular metabolites such as NAD to modulate mitochondrial function to match nutrient supply.  The more NAD there is in cells, the more Sirt genes do beneficial things.  Notice I said “IN THE CELLS”.  We will talk more about that later. 

    There are studies that show the SIRT1 protein induces the formation of new mitochondria.  NAD can also activate another sirtuin, SIRT3, which is thought to keep mitochondria running smoothly.  We are able to see that there is great potential for using NAD. The relationship between mitochondria and our health is extremely important on many different levels from aging to cancer.  The question becomes how much of the NAD do we absorb in an oral form?  The answer is probably not much.

For some time now, it is thought that the best way to deliver NAD to the cells is via an Intravenous (IV) method.  Until now this was considered the gold standard of delivery.  However, the intravenous method has many drawbacks.  First off it is very time-consuming requiring at least 8 hours to be properly delivered.  There are potential serious side effects.  Even with the IV route there is still a question if enough NAD is being delivered to the cells.  We can measure levels in the serum but does that translate to adequate levels in the cells?

We have found that one of the main precursors or building blocks of NAD is nicotinamide ribose.  We have investigated this further and found that on its own, nicotinamide riboside (NR) does not promote longevity or cell health.  In most organisms it is the kinase precursors (nicotinamide riboside kinase 1 &2 NRK) that signal conversion of supplemental NR to NAD.  In easy words to understand, the kinase acts as an enzyme in the reaction to convert NR to NAD.  This Kinase enzyme is thought to be the missing link.  This is the enzyme that we have in diminished amounts as we age.  Any clinical treatment, especially in regenerative medicine and stem cell treatments, should be done with this pathway in mind.  Unfortunately, this pathway is where we ultimately run into problems as we age.  It essentially starts to shut down requiring us to go in a roundabout way to produce NAD.  Let me give a great analogy about this concept.  Think about the NAD as a supply being stored in a warehouse.  We need a method to deliver the NAD from the warehouse to the consumers, in this case the cells.  One way we can deliver the supplies in the warehouse to the consumers (cells) is by a horse drawn cart.  We will get some supplies to the consumers but not in a very efficient manner. On the flip side we can deliver the warehouse supply of NAD via a fleet of modern trucks.  In this case the kinase enzyme acts as a fleet of trucks. We get plenty of supplies to the cells.

My good friend Dr. Jo Serrentino has done the work on the NRK 1+2 kinase enzymes.  Dr. Serrentino is an expert in the field of growth factors and their delivery to the cells. She has worked with me for years with growth factors and their ramifications.  We have utilized her growth factor patch systems for years with excellent results.  She has enabled us to deliver growth factors to the joint when combined with penetrating molecules.  This mixture is placed on a simple patch left on for about 8 hours.  I asked her to look at the NAD question and come up with some game changing conclusions. She opened my eyes about the kinases and their actions and importance.

We know that NAD levels decrease with age and so we can surmise that the mechanisms of NAD pathways also decrease with age.  Therefore, restoring the pathway is key because supplementing with vitamins, whether orally or intravenously, will only provide limited results; especially in the age-related metabolism.  So, the bottom line is that the supplementation of nicotinamide ribose (NR) can improve the mechanism by allowing more production of NAD, however, the process of getting the net NAD to cells through supplementation with an IV of NR is rather archaic not to mention expensive and invasive.  Remember what I said earlier it is the cells that need the NAD. They are the consumers of NAD.  A better way is to shortcut through the pathway itself and provide the precursors that will work at the cellular level rather than through the serum and excipient nutraceutical level.  The important thing to remember is that in real life (in vivo) you want to get the NAD to the cells. This is quite different than a simple serum level of a vitamin such as NAD.  Many complex biochemical paths are involved and most especially cell membrane traversing, to reach mitochondria.  This is where the penetrating molecules come into play.  They help to deliver the compounds thru the cell membrane

NAD is important to Cellular Function,Cell Cycle and ENERGY METABOLISM.  Using the kinases is a direct route into the cells.  This is the main difference between the patches and the current IV method.  The latter simply infuses a concentration of active NAD into the blood.  Once in the blood the difficulty is getting the NAD into the cell.  The Patchless patch infuses signaling molecules to engage the pathway, programming the cell environment.  The pathway can use Nano (meaning very small amounts) concentrations of nicotinamide from food or from a nutraceutical (supplement), but does not require a micro-concentration (much larger amounts) of vitaminas does the IV.

The protocol/product we propose can be a truly restorative and a preventative protocol for anti-age clinical application. More importantly, it is likely a safer way to induce NAD, because IV can cause rapid increase of NAD+ (by 2-3-fold) in the circulation which can have some serious side effects.  Also, the IV application may cause methyl donor dysfunction in the long run and subsequent kidney dysfunction as well as liver dysfunction.  Methylation is the process of taking a single carbon and three hydrogens, known as a methyl group, and applying it to countless critical functions in your body such as repairing DNA, turning on and off genes, fighting infections and getting rid of environmental toxins to name a few. Methylation defects are tied to a wide variety of conditions including cancer, diabetes etc.  This is an important consideration when dealing with any vitamin drip, but particularly NR or NA. The kinase protocol is in part a regulator and can safeguard these considered flaws in the current IV protocol. The protocol we suggest contributes safer and better effects within the pharmacokinetic (the branch of pharmacology concerned with the movement of drugs within the body) parameters at hand.

Some parting thoughts about NAD and our special pathway.  We feel this will revolutionize applications of NAD and make their applications work much better clinically.  This will be revolutionary for anti-aging but also should help in all our stem cell procedures.  The other aspect of this new type of NAD treatment pertains to addiction problems. We are aware of NAD treatments alone seem to help with many different types of addiction problems.  We think that combining our new NAD treatment with our V cell treatment may open up some new horizons in this challenging field.

We are quite excited about this new division our of clinic.  We have named it the Advanced Cellular Repair Division. Anti-aging and well-being are all about cellular repair.  This new technology will take anti-aging and all of its collateral interests to the next levels   We will continue to add different components to this division.  We will start Co-Q-10, NAD and P-53 (the subject of my next blog). The Co-Q-10 and P-53 will be delivered directly to the body while the NAD will be optimized by the kinase   We will attain high cellular levels of these compounds via the delivery of a patch.  With these new technologies the sky may be the limit.    Thanks Dr. P