8 replies to this topic

[Phoebus]

NAD+ is a cellular compound  found in every cell in the body and is essential to life. NAD+ enables the transfer of energy from the foods we eat to vital cell functions. It is also required to turn off genes that accelerate degenerative aging processes.

 

As NAD+ levels decline, mitochondrial function is impaired, resulting in fewer mitochondria surviving. This vicious cycle of mitochondrial depletion results in many of the physical symptoms of aging.

 

The reason for NAD declining is simple - its destroyed by CD38. As we age CD38 levels rise, and CD38 directly destroys NAD+, crippling many biological functions in the process.  

 

 

https://www.ncbi.nlm...les/PMC4911708/

 

Here we demonstrate that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity. We also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.

 

 

The question here is WHY does CD38 rise as we age and how can we address it? 

 

First of lets try to understand the function of CD38. What does it do in the body? As it turns out CD38 seems to be an integral part of the body's immune response to pathogens and cancer. 

 

 

https://en.wikipedia.org/wiki/CD38

 

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein[5] found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.[6]

 

 

 

CD38 is expressed by macrophages, one of the body's most important immune cells. Macrophages are a type of white blood cell, of the immune system, that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the type of proteins specific to healthy body cells on its surface in a process called phagocytosis. 

 

High CD38 levels are markers for inflammation, disease and cancer. 

 

The reason CD38 is a marker for these phenomena is that anytime there is pathogens, disease or cancer the body sends immune cells such as macrophages to address the situation and those immune cells express high levels of CD38. 

 

 

https://www.frontier...2018.01593/full

 

CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions

 

Finally, monocyte analyses in systemic lupus erythematosus patients revealed that, while all monocytes express CD38, high CD38 expression in the non-classical monocyte subpopulation is associated with disease. These data are consistent with an inflammatory marker role for CD38 in human macrophages and monocytes.

 

 

So we know that CD38 is part of the immune system and is expressed by disease fighting  immune  cells. So, severely inhibiting CD38 may have negative consequences for immunity and may not be the smartest approach to rising CD38 levels as we age. 

 

CD38 levels rise as immune response rises and thus CD38 levels correlate with pathogen levels. So then WHY do CD38 level rise as we age? 

 

Another to consider: As we age the thymus slowly degrades, beginning at age 20 and by age 50 nearly 80% of the thymus is lost. That means fewer T cells and an immune system that is crippled relative to the immune system of a 20 year old. 

 

[cont in next post]

[Phoebus]

Here is my theory. The dying thymus slowly cripples the immune system and this allows already present pathogens to start multiplying and gives rise to a series of subclinical pathogenic infections. A subclinical infection is an infection with few pronounced symptoms that most doctors would just ignore. 

 

But! The body doesn't ignore these pathogens and marshals its immune cells to combat it. And what enzyme do immune cells express? CD38. 

 

Now, what pathogens am I referring to? I am talking about chronic pathogens that are nearly impossible to eradicate that live deep in the tissues without creating any overt symptoms. 

 

Globally, an estimated two-thirds of the population under 50 are infected with herpes simplex virus type 1

 

https://www.who.int/...ex-virus-type-1

 

It is estimated that 30 percent of the population carries staph (Staphylococcus aureus) on the skin or in the nose, most with no symptoms

 

http://www.idph.stat...c/hb/hbmrsa.htm

 

A study titled Prevalence of Periodontitis in Adults in the United States: 2009 and 2010 estimates that 47.2 percent, or 64.7 million American adults, have mild, moderate or severe periodontitis

 

The list of pathogens that commonly inhabit hundreds of millions of people is long. 

 

So basically the immune system becomes less effective due to the thymus degrading. This allow pathogens already present in the body to start multiplying. the body sends out more macrophages and other immune cells to deal with the increased pathogen load. 

 

Those immune cells express large amounts of CD38 which then unfortunately destroy NAD+. The loss of NAD then cripples the body's innate immunity even more and this creates a positive feedback loop of more pathogens, more macrophages, more CD38, less NAD+ etc etc etc. This then becomes a death spiral which only ends with actual physical death. 

 

So I see 3 options on how to address CD38 destroying NAD. 

 

1. Suppress CD38 levels, which could have a negative impact on the immune system. 

 

2. Regenerate the Thymus 

 

3. Find ways of addressing the increased pathogen load as we age. 

 

 

 

 

[Phoebus]

 

 In a study published today (January 12) in Science Immunology, researchers identified a growth factor protein, BMP4, which is produced by endothelial cells in the inner wall of the thymus and is critical for its repair in mice. They also found that injecting these cells either into the blood stream or into the thymus itself sped up thymus recovery.

 

The study’s authors identified a new axis in thymus regeneration, says Avinash Bhandoola, head of the T-Cell Biology and Development Unit at the National Cancer Institute’s Center for Cancer Research, who was not involved in the study. “They showed that endothelial cells make this molecule BMP4, and this is actually really important for accelerating regeneration of the thymus after damage.”

 

Therapies based on the research would be more likely to use isolated BMP4 than an endothelial cell line, says Serwold. “Another future interesting direction would be whether this same pathway could be used in the aging thymus,” he says. In this scenario, or in damage associated with chronic conditions, perhaps boosting BMP4 activity would also drive thymic regeneration, Serwold speculates.

“Trying to reverse some of these age-related effects [on the thymus] as well will also be quite important, and this is something we hope we will be able to take these approaches to,” says Dudakov.

https://www.the-scie...se-thymus-30421

[Phoebus]

 

Dr. Greg Fahy, has been working on the rejuvenation of the thymus for a number of years, and, in 2015, he conducted a small-scale human trial to see if the earlier results in animals would translate to people. His approach focuses on the use of human growth hormone (HGH) and dehydroepiandrosterone (DHEA) to regenerate the thymus.

The initial study results showed that there was a substantial increase in the density of the thymus, suggesting that the fatty tissue found in the aged thymus was being replaced with denser, water-rich, immune cell-producing tissue. In previous studies on human immunodeficiency patients, this tissue replacement was correlated with improved thymic function.

https://www.leafscie...s-regeneration/

[sinkpoint]

It's an interesting theory. I have noticed reduced resistance to colds when taking large dose quercetine to inhibit CD38, and have also came across papers on CD38's role in the immune system. Especially a possible role where it denies NAD+ to pathogens. 

I've since then stopped taking NR/NMN and quercetine when I feel a cold is coming. Haven't gotten sick since. 

[sinkpoint]

There's a programmed aging theory by Imai et al (NAD world 2.0) that postulated NAD+ concentration as part of the internal age clock-keeping mechanism.

Which means age-related development changes such as thymus atrophy might be related to NAD+ in the body. 

Found a paper that seem to support this hypothesis:

 

"NAD+ loss, a new player in AhR biology: prevention of thymus atrophy and hepatosteatosis by NAD+ repletion"

https://www.ncbi.nlm...les/PMC5442136/

 

 

 

[Phoebus]

There's a programmed aging theory by Imai et al (NAD world 2.0) that postulated NAD+ concentration as part of the internal age clock-keeping mechanism.

Which means age-related development changes such as thymus atrophy might be related to NAD+ in the body. 

Found a paper that seem to support this hypothesis:

 

"NAD+ loss, a new player in AhR biology: prevention of thymus atrophy and hepatosteatosis by NAD+ repletion"

https://www.ncbi.nlm...les/PMC5442136/

 

oh very interesting! From that study

 

 

 

Strikingly, treatment in vivo with the NAD+ repleting agent nicotinamide, a form of vitamin B3, prevented thymus atrophy and hepatosteatosis by dioxin and increased sirtuin activity, providing a therapeutic approach for preventing dioxin toxicities in vivo.

[male_1978]

Maybe destroying senescent cells relieves some of the strain on your immune system? Like any other intervention, which improves your global health?

[LawrenceW]

Does anyone know if long term supplementation with NAD+ precursors increases the intracellular load of NAD+?