The above is the title to a new article published by Dr. Sinclair and his group from Harvard. I had the good fortune of being sent this paper by an associate of mine. The paper is still not officially published but it drives home some significant points. David A. Sinclair, Ph.D., A.O. is a Professor in the Department of Genetics and co-Director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School. I hold Dr. Sinclair in great esteem for his work on understanding why we age and how to slow its effects.  Dr. Sinclair has taught us about Resveratrol and more recently NAD and its supplements.

The paper contains an excellent synopsis of the relationship between Covid-19 and the aging immune system, namely immunosenescence. It gives a comprehensive breakdown on the failures of the innate and acquired immune systems. These are the two major components of our immune system.

The paper itself is a rather technical one and I will try to discuss it in layman terms. First off, let’s take a quick look at some of the benefits of the NAD to our bodies. We can see the effects are wide ranging.

Research | The Sinclair Lab | Harvard Medical School, Department ...

Among other things we see in the above diagram that NAD affects both immunity and inflammation. Many of the other effects indirectly affect immunity and inflammation. We now know that as we age there is steady increase in the abundance and activity of NLRP3 protein. NLRP3 which is a major protein component of an inflammasome. Inflammasomes are a group of protein complexes found in the cytoplasm of the cell. They are formed to mediate host immune responses to microbial infection and cellular damage.  NLRP3 is responsible for a host of problems including auto immune diseases, metabolic disorders, and severe damages from infections such as a cytokines storm. You will definitely be hearing more about NLRP3 as time goes on. It is on the cusp of major scientific research. Now just how does NAD come into the picture when dealing with the NLRP3 inflammasome? The real crux of the matter is that the NLRP3 activation is under the control of SIRT2 gene. Sirtuins are a family of proteins that regulate cellular health. SIRT2 is a member of the NAD+ dependent sirturn family of deacetylases enzymes. If NLRP3 is activated and at the same time one is exposed to Covid-19 virus the combination may cause quite a few problems to the patient. However, it one maintains NAD levels and there is a good chance of alleviating Covid 19 symptoms by the Sirtuin suppression of the NLRP3 inflammasome.

In 2013, Sinclair further reported scientific studies that demonstrated NAD fuels the activity of a group of proteins called the sirtuin proteins, including SIRT2. Sirtuins are a fascinating family of enzyme-genes. It is now clear that sirtuins are involved in the regulation of many fundamental biological processes throughout the body. The following is a diagram of the various Sirtuin genes and where they are found in the cell.

Image result for sirtuin proteins and stem cell aging

If we look in the above diagram we see the SIRT2 gene which is located in the cell cytoplasm. The cell cytoplasm also contains the NLRP3 inflammasome. The bottom line is if the SIRT2 gene is activated it will squash the actions of the NLRP3 and the Covid-19 virus will have a harder time getting established.

What has been a common thread in many patients infected with the Covid-19 virus is that co-morbidities seem to dramatically affect the symptoms of the patient. One of the biggest co-morbidities seems to be obesity. It is well known that obesity will increase the complications of the Covid-19. Obesity will dramatically increase the activity of the NLRP3 inflammasome. Thus, anyone who is obese should absolutely be taking NAD supplements and possibly even take it intravenously. NLRP3 inflammasome is found in the cytoplasm of the cell while many times when we are dealing with infections it is the cell receptors on the cell surface membrane that detects the infection and elicit a response. Multiple studies show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of NLRP3 as well as with decreased inflammation and improved insulin sensitivity. Remember the control of NLRP3 activity is under the direct control of SIRT2, which is dependent upon NAD and its derivatives. Studies have shown old mice, especially those deficient in SIRT2, have accelerated inflammaging, along with decreased glucose tolerance and increased insulin resistance. So, the bottom line is take your NAD!!


The second part of the article talks about BIOLOGICAL CLOCKS. We have developed a number of biological clocks that have been shown to predict human health and longevity more accurately that chronological age. These biological clocks are based on various aspects of aging. There are at present any number of approaches to measuring biological age, the burden of cell and tissue damage that leads to dysfunction.

Circadian Rhythms and Your Immune System?


The first clock to discuss is the EPIGENETIC CLOCK. Epigenetic age seems like a concept pulled from a futuristic science-fiction movie where a drop of blood is fed into a machine, in which an algorithm churns through an accumulation of chemical groups coating a strand of DNA and spits out an individual’s true age reflecting a lifetime of experiences and exposures. 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 decades, 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. The following diagrams illustrate some of these concepts:

The epigenetic clock as a biological age predictor. Disease risk ...

We are able to see from the above diagram that healthy lifestyles cause age deceleration. While the opposite is true with unhealthy lifestyles. Another way of looking at things is found in the diagram below. The blue arrows represent anti-aging while the red arrows represent pro-aging effects on blood chemistry.

PDF] Epigenetic clock analysis of diet, exercise, education, and ...


Pictorial summary of our main findings. The blue and red arrows depict anti‐ aging and pro‐aging effects in blood respectively. The two clocks symbolize the extrinsic epigenetic clock (enhanced version of the Hannum estimate) and the intrinsic epigenetic clock (Horvath 2013) which are dependent and independent of blood cell counts, respectively.

What does this boil down to? Age-associated changes to the epigenome, essentially our DNA, have profound effects on the immune system, including T cell function, cytokine production and macrophage (white blood cell) pattern recognition. DNA methylation is believed to set the pace of the aging clock in several of our tissues, including hematopoietic (Red and White Blood) cells of the immune system. Recently there was a study that restoration of the thymus gland using a drug cocktail of metformin, growth hormone and DHEA (dehydroepiandrosterone) led to the reversal of features of immunosenescence which is the decline in the immune system that comes with aging. This is actually a monumental study that may have profound implications on our health. Most of the existing research suggests that DNA methylation relies at least in part on folate, vitamin B-12, vitamin B-6, and choline, in addition to other vitamins and minerals. Increasing your intake of these nutrients may help to support DNA methylation, preventing certain genes from being expressed. One parting thought is that the pattern of methylation in DNA has been shown to be an even better predictor of not just biological age, but also lifespan and healthspan.


What is A1C test? Answered, 101 HbA1C Question You Want to Ask!

The above diagram is a very real biological clock. One method of measuring the glycosylation clock can be measured be a simple blood test which is called the A1C hemoglobin blood test. This is a common blood test performed in diabetic patients. It gives a snapshot of blood glucose levels over a period of time. It gives a picture of the amount of glucose that is binding to the hemoglobin protein molecule. The higher the number of the A1C the greater the number of glucose molecules attached to the hemoglobin protein and thus the worst the control of the diabetes.

The glycosylation clock is clearer than most biological clocks. It is a very direct assessment of the chronic inflammation associated with aging. In more technical terms, Glycosylation is the enzymatic process by which carbohydrates called glycans are attached to proteins or lipids, typically on the cell surface or in the bloodstream. An individual’s repertoire of glycans, a notable example being the type of N-glycans attached to immunoglobulins, changes with age and environmental factors such as such as smoking and poor diet. The type of glycans attached to IgGs affects their pro- and anti-inflammatory properties. IgGs are a type of antibody representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. It is instrumental in fighting most infections. The real problem with glycosylation is the production of what are called “advanced glycation end products” (AGEs). This occurs when the sugars bind to proteins causing a host of problems as can be seen in the following diagram. Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney disease, and Alzheimer’s disease. Animal-derived foods that are high in fat and protein are generally AGE-rich and prone to new AGE formation during cooking. In particular, grilling, broiling, roasting, searing, and frying propagate and accelerate new AGE formation.  The following diagram shows the variety of the clinical manifestations of glycosylation.



Recent advances in detection of AGEs: Immunochemical ...

As we can see these are very damaging to various systems in the body. Remember, glucose is one of the main driving forces in the production of AGE products! Another great diagram of the effects of AGEs is found in the following diagram. Realize that AGEs and glycosylation can lead to significant musculoskeletal symptoms.


Advanced Glycation End Products are Bad for Bone, Cartilage and ...



The biological clock influences immune response efficacy - http ...

The last clock to mention is the IMMUNE CLOCK. There is an old saying that we are as old as our immune system. There is some good scientific literature that the immune system may be made “younger” by among other things a type of cell found in the body called a V cell. Here is the study from a research journal which explains this concept.

What the V cells do is extend the Telomere length of the cells of the immune system. Telomeres are the ends of the DNA of the cells. When cells reproduce they lose a snippet of DNA which is called the telomere. The smaller the DNA length typically the less effective the cell becomes. Well the V cells restore the length of the DNA telomere and thus increase the effectiveness of the cell. They are literally making the cell take on younger characteristics. V cells are found in each and every one of us. The trick is to activate them (which we have mastered) to than let them perform their good deeds.

When all is said and done what effect will this article have upon myself? The answer quite a bit. I am already a big believer in NAD and I am becoming more to cognizant of Nature’s Biological Clocks and how we can manipulate them. I practice what I preach. V cells have been on my horizon and will continue to remain there. Hopefully this article has opened your eyes on the “Biological” clocks in the body and how we can influence them with certain life style changes, procedures, and medications such as NAD which I consider one of nature’s elixirs. Remember time always moves forward but there is no reason why we cannot slow down its progression.




-Dr. P


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