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Grab your NADs…and take a deep breath…
NAD+, the oxidized form of nicotinamide adenine dinucleotide mentioned in the previous post as lacking in Covid patients, is a key molecule in cell respiration, known as ‘redox’ reactions in the electron transport chain. It works by grabbing electrons (becoming ‘reduced’) and transferring them to other molecules (becoming ‘oxidized’ again) in a cycle that activates and nourishes the all-important cell signal pathways.
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The NAD ‘group’ of molecules are classed as B vitamins – the ‘energy’ vitamins (B3, nicotinic acid, niacin, etc.)—but the more specific NAD+ could very well be in a class by itself. Regenerative medicine is homing in on NAD+ as an exciting field of study in anti-aging, immune health and cell defense.
NAD+ might make you smarter and may also put the ‘smart’ in nanodevices like biosensors and DNA computers which I don’t yet know as to whether these devices can parasitically rob you of your NAD+. Whatever the case, NAD+ deficiency has serious detrimental downstream effects that I’ve learned are associated with the ‘typical’ (and long) list of radiation exposure diseases.
For the moment, I’ll quote some bioresearch documents on NAD+ and say that this post is going to be accumulative.
Research:
“Numerous studies have indicated that four interacting factors, including oxidative stress, mitochondrial alterations, calcium dyshomeostasis and inflammation, play crucial pathological roles in multiple major neurological diseases, including stroke, Alzheimer’s disease (AD) and Parkinson’s disease (PD). Increasing evidence has also indicated that NAD(+) plays important roles in not only mitochondrial functions and energy metabolism, but also calcium homeostasis and inflammation.”
https://pubmed.ncbi.nlm.nih.gov/22204321/
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“Increasing evidence has indicated critical roles of nicotinamide adenine dinucleotide, oxidized form (NAD+) in various biological functions. NAD+ deficiency has been found in models of a number of diseases such as cerebral ischemia, myocardial ischemia, and diabetes, and in models of aging. Applications of NAD+ or other approaches that can restore NAD+ levels are highly protective in these models of diseases and aging. NAD+ produces its beneficial effects by targeting at multiple pathological pathways, including attenuating mitochondrial alterations, DNA damage, and oxidative stress, by modulating such enzymes as sirtuins, glyceraldehyde-3-phosphate dehydrogenase, and AP endonuclease. These findings have suggested great therapeutic and nutritional potential of NAD+ for diseases and senescence.” https://pubmed.ncbi.nlm.nih.gov/29295624/
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Are nanodevices parasitizng your ‘redox’ energy? Read this– “Confessions of an Engineered Nanoparticle”
Confessions of an Engineered Nanoparticle
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Video of nanodevice in Pfizer vaccine from TimTruth.com https://odysee.com/@TimTruth:b/Pfizer-vaccine-zoomed:e
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According to David A. Sinclair, PhD, in his 2019 book “Lifespan”, humans and other lifeforms have two modes of generating the necessary information that sustains life; one being the DNA/RNA ‘digital’ encoding of genomes (genetic) and the other being the heritable ‘analog’ activity of metabolism (epigenetic). He writes that “Unlike digital, analog information degrades over time—falling victim to the conspiring forces of magnetic fields, gravity, cosmic rays, and oxygen. Worse still, information is lost as it’s copied… [But]…As cloning beautifully proves, our cells retain their youthful digital information even when we are old.” As Sinclair describes it, “The Information Theory of Aging starts with the primordial survival circuit we inherited from our distant ancestors. Over time, as you might expect, the circuit has evolved… Scientists have found more than two dozen [survival circuits] within our genome. Most of my colleagues call these ‘longevity genes’… But these genes don’t just make life longer, they make it healthier, which is why they can also be thought of as ‘vitality genes.’ Together, these genes form a surveillance network within our bodies, communicating with one another between cells and between organs by releasing proteins and chemicals into the bloodstream, monitoring and responding to what we eat, how much we exercise, and what time of day it is… And now that we know [about] these genes…, scientific discovery has given us an opportunity to explore and exploit them… [u]sing molecules both natural and novel, using technology both simple and complex… we can read them, turn them up and down, and even change them altogether.
“The longevity genes I work on are called ‘sirtuins,’ named after the yeast SIR2 gene, the first one to be discovered. There are seven sirtuins in mammals, SIRT1 to SIRT7, and they are made by almost every cell in the body… [S]irtuins are enzymes that remove acetyl tags from histones and other proteins and, by doing so, change the packaging of the DNA, turning genes off and on when needed. These critical epigenetic regulators sit at the very top of cellular control systems, controlling our reproduction and our DNA repair. After a few billion years of advancement since the days of yeast, they have evolved to control our health, our fitness, and our very survival. They have also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD… [The] loss of NAD as we age, and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.
“Trading reproduction for repair, the sirtuins order our bodies to ‘buckle down’ in times of stress and protect us against the major diseases of aging: diabetes and heart disease, Alzheimer’s disease and osteoporosis, even cancer. They mute the chronic, overactive inflammation that drives diseases such as atherosclerosis, metabolic disorders, ulcerative colitis, arthritis and asthma. They prevent cell death and boost mitochondria, the power packs of the cell. They go to battle with muscle wasting, osteoporosis, and macular degeneration. In studies on mice, activating the sirtuins can improve DNA repair, boost memory, increase exercise endurance, and help the mice stay thin, regardless of what they eat. These are not wild guesses as to their power; scientists have established all this… And in no small measure, because [NAD+dependent] sirtuins do all of this based on a rather simple program—the wondrous gene B in the survival circuit—they’re turning out to be more amenable to manipulation than many other longevity genes. They are, it would appear…the key to understanding how our genetic material protects itself during times of adversity, allowing life to persist and thrive for billions of years.” —pp22-25, Lifespan, by David A. Sinclair, 2019
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Quantitative Proteomic Analysis Reveals the Deregulation of Nicotinamide Adenine Dinucleotide Metabolism and CD38 in Inflammatory Bowel Disease
[April 2019]…”In the current study… proteomic differences between intestinal tissue from health controls, patients with Crohn’s disease (CD), and patients with ulcerative colitis (UC) were compared… When proteins with fold change >1.2 or <0.84 and P value < 0.05 between groups were considered differentially expressed, the expression of 10 proteins, including CD38, involved in the nicotinamide adenine dinucleotide (NAD) metabolism and signaling pathway showed significant changes in IBD. Using the NCBI GEO database, we confirmed increased CD38 mRNA expression in patients with UC and in mouse colitis models. Protein CD38 expression was higher in CD and UC than in normal controls. CD38 expression was higher in inflamed tissues than in noninflamed tissues, and CD38 was located in F4/80-positive cells. Our study may provide novel insights into the molecular pathogenesis of IBD. Further studies are required on the role of NAD metabolism and CD38 in intestinal inflammation.” https://pubmed.ncbi.nlm.nih.gov/31179321/
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NAD Metabolites Analysis Service – Creative Proteomics
http://www.creative-proteomics.com › services › nad
“…The pyridine dinucleotide, NAD+, is a substrate of sirtuins and coenzyme for hydride transfer enzymes and other NAD+-dependent ADP ribose transfer enzymes. It is a unique cellular molecule produced from the pyridine mononucleotides nicotinic acid mononucleotide (NaMN) or nicotinamide mononucleotide (NMN)”
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Assays for NAD +-Dependent Reactions and NAD + Metabolites
pubmed.ncbi.nlm.nih.gov › 30097862
“Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) is an essential redox cofactor and signaling molecule that controls the activity of enzymes involved in metabolism, DNA repair, and cellular survival, such as the PARPs, CD38, and the sirtuins. Here, we describe three methods for measuring the activity of these enzymes: the etheno-NAD+ assay measures NAD+ hydrolase activity using an NAD+ analog to produce a fluorescent product that is measured in real time; the PNC1 assay converts a native product of NAD+ hydrolysis, nicotinamide, into a quantitative fluorescent readout; and liquid chromatography tandem mass spectrometry (LC-MS/MS) is used to characterize the entire NAD+ metabolome in a sample. These methods will enable new insights into the roles that NAD+ and the enzymes that utilize it play in health and disease.”
https://pubmed.ncbi.nlm.nih.gov/30097862/
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NAD deficiency and Cytokine Storms
Researchers have learned that NAD deficiency corresponds to increased ‘CD38’:
“CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein 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… CD38 is most frequently found on plasma B cells, followed by natural killer cells, followed by B cells and T cells, and then followed by a variety of cell types… [It was] discovered to be not simply a marker of cell types, but an activator of B cells and T cells…[and] can function either as a receptor or as an enzyme. As a receptor, CD38 can attach to CD31 on the surface of T cells, thereby activating those cells to produce a variety of cytokines… The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas,[28] solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions. CD38 increases airway contractility hyperresponsiveness, is increased in the lungs of asthmatic patients, and amplifies the inflammatory response of airway smooth muscle of those patients. ” https://en.wikipedia.org/wiki/CD38
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“Without any NAD we’d be dead in thirty seconds”
David Sinclair explains:
“In 2002, antioxidants were all the rage. They might not have been the antiaging and health panaceas some believed them to be, but that wasn’t yet known. One of [those] antioxidants…was resveratrol, a natural molecule that is found in red wine and that many pants produce in times of stress… [Konrad] Howitz and I were fascinated by the fact that resveratrol is produced in greater quantities by grapes…experiencing stress. We aso knew that many other health-promoting molecules, and chemical derivatives of them, are produced in abundance by stressed plants; we get resveratrol from grapes, aspirin from willow bark, metformin form [‘French’] lilacs, epigallocatechin gallate from green tea, quercetin from fruits, and allicin from garlic. This, we believe, is evidence of xenohormesis –the idea that stressed plants produce chemicals for themselves that tell their cells to hunker down and survive… What this means, if it’s true, is that when we search for new drugs from the natural world we should be searching the stressed-out ones; in stressed plants, in stressed fungi, and even in the stressed microbiome populations in our guts. The theory is also relevant to the foods we eat; plants that are stressed have higher concentrations of xenohormetic molecules that may help us… Look for the most highly colored ones because xenohormetic molecules are often yellow, red, orange, or blue. One added benefit: they tend to taste better… –pp130-131, Lifespan
“As it turned out, resveratrol wasn’t very potent and wasn’t very soluble in the human gut… [But] By studying resveratrol, we also learned that it is possible to activate sirtuins with a chemical. This prompted a flood of research into other sirtuin-activating compounds called STACs that are many times more potent than resveratrol… There are today hundreds of chemicals that have been demonstrated to have an effect on sirtuins… NAD, sometimes written as NAD+…has an advantage over other STACs because it boosts the activity of all seven [human] sirtuins… And because NAD is used by over five hundred different enzymes, without any NAD, we’d be dead in thirty seconds.” –pp133-134, Lifespan
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The Deep COVID Agenda Emerging….
At this point, the NAD subject is going to diverge. I’ll make a sequel about Boosting Your NADs, but for now, I’m going to pursue the questions already arisen from the ‘nanodevice’ proposition above and the extension of work from prior posts; Making and Faking Viruses and the series-in-progress Planting Viruses From Plants! – all linked here https://jenniferlake.wordpress.com/2021/02/03/making-and-faking-viruses/
Zombie Apocalypse
Dr. Sinclair advances his explanation of NAD-dependent sirtuins and anti-aging as a measure of how well our bodies eliminate “senescent cells”—old cells that live on past their ‘Hayflick Limit’ or are simply turned off and do not reproduce by division. He writes,
“Small numbers of senescent cells can cause widespread havoc. Even though they stop dividing, they continue to release tiny proteins called cytokines that cause inflammation and attract immune cells called macrophages that then attack the tissue. Being chronically inflamed is unhealthy: just ask someone with multiple sclerosis, inflammatory bowel disease, or psoriasis. All these diseases are associated with excess cytokine proteins. Inflammation is also a driving force in heart disease, diabetes and dememtia. It is so central to the development of age-related diseases that scientists often refer to the process as ‘inflammaging.’ And cytokines don’t just cause inflammation: they cause other cells to become zombies, like a biological apocalypse. When this happens, they can even stimulate surrounding cells to become a tumor and spread. We already know that destroying senescent cells in mice can give them substantially healthier and significantly longer lives. (–p150) Cellular senescence is a consequence of our inherited primordial survival circuits which evolved to stop cell division and reproduction when DNA breaks were detected… [and] if DNA breaks happen too frequently or they overwhelm the circuit, human cells will stop dividing, then sit there in a panic trying to repair the damage, messing up their epigenome and secreting cytokines… Senescent cells, after all, don’t divide which means that cells with mutations aren’t able to spread and form tumors…
“This is where ‘antagonistic pleiotropy’ comes into play: the idea that a survival mechanism that is good for us when we are young is kept…[in spite of] any problems it might cause when we get older… So we live longer [now] –and evolution hasn’t had a chance to catch up. We’re plagued by senescent cells, which might as well be radioactive waste. If you put a tiny dab of these cells under a young mouse’s skin, it won’t be long before inflammation spreads and the entire mouse is filled with zombie cells that can cause premature signs [and diseases] of aging.” –pp152-153.
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‘Virus drugs’ and ‘stress chemicals’
Sinclair’s ‘Lifespan’ moves on from zombie cells to ‘telomeres,’ the DNA repeats on the ends of chromosomes that shorten and become exposed and ‘frayed’ over damaging time.
He writes,”The selfish genes…called LINE-1 retrotransposons, and their fossil remnants, make up about half of the human genome, what is often referred to as ‘junk DNA.’ It’s a lot of genetic baggage… In young cells, these ancient ‘mobile DNA elements’ also known as retrotransposons are prevented by chromatin from jumping out of the genome, then breaking DNA to reinsert themselves elsewhere. We and others have shown that LINE-1 genes are bundled up and rendered silent by sirtuins. But as mice age, and possibly as we do as well, these sirtuins become scattered all over the genome, having been recruited away to repair DNA breaks elsewhere, and many of them never find their way home. This loss is exacerbated by a drop in NAD levels… Without sirtuin to spool the chromatin and silence the transposon DNA, cells start to transcribe these endogenous viruses. This is bad. And it only gets worse.”—pp154-155
Endogenous viruses? From your own traveling DNA? Indeed. Finally, a flat and straightforward statement from the ‘lab’. The ‘viruses’ inside you come from your own disintegrating DNA, the “retrotransposons” we call retroviruses, and were called “jumping genes” by their discoverer Barbara McClintock in the 1920s after examining X-irradiated corn plants. In a continuous flow from the paragraph above, David Sinclair writes:
“Over time, as the mice age, the once silent LINE-1 prisoners [held by telomeres] are turned into RNA and the RNA is turned [transcribed] into DNA which is reinserted into the genome at a different place. Besides creating genome instability and epigenomic noise that causes inflammation, LINE-1 DNA leaks from the nucleus into the cytoplasm where it is recognized as a foreign invader. In response, the cells reease even more immunostimulatory cytokines that cause inflammation throughout the body… Convincing evidence has come from experiments showing that antiretrovirals, the same kinds used to fight HIV, extend the lifespan of SIRT6 [knockout] mice about twofold. It may turn out that, as NAD levels decline… sirtuins are rendered unable to silence retrotransposon DNA. Perhaps one day, safe antiretroviral drugs or NAD boosters will be used to keep these jumping genes silent… [before] total anarchy ensues… In 2018, scientists at Stanford University reported that they had developed an inoculation… with stem cells…” –p155
“What if we could reset the aging clock and prevent cells from ever losing their identity and becoming senescent in the first place?… Yes, the solution to aging could be cellular reprogramming, a resetting of the landscape… The DNA blueprint to be young, after all, is always there even when we are old… (–p158). The implications of these experiments are profound. What they show is that aging can be reset.” (–p161) …I predict, and my students are now showing in the lab, that we can use [genetic]…switches not just to reset our cells in petri dishes but to reset an entire body’s epigenetic landscape…sending sirtuins back to where they came from, for instance. Cells that have lost their identity during aging can be led back to their true selves… We are making progress every week…by delivering reprogramming factors. The pace of discovery is mind spinning.” –164
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Payload- carrying virus –like your ‘virus’—has long been the treatment of choice and also constitutes the ‘future treatment’ of David Sinclair’s anti-aging cure. During the 1990s, the poliovirus was rigorously experimented with as a delivery vehicle, but often resulted in cancer, cells with lost identity – Oops. It turned out that poliovirus existed on the margin of “error catastrophe,” able and likely to mutate out of existence because of its very small genome: That is, unless the poliovirus is continuously injected. One fork-in-the-road for poliovirus research has been to recreate it from lab chemicals and override its potential genomic instability, accomplished by Eckard Wimmer and published in 2003—at just the time of the appearance of a much larger genome virus, SARS, now taking its own forks. And here’s some ‘news’: The poliovirus is identical to several small plant viruses that might typically pass through your gut and was originally obtained for vaccines from human feces. More news: “plant viruses don’t exist as such” –so, are they better termed as “stress chemicals”?
But really it’s all in the packaging and labels:
“Chromatin is a complex of DNA, protein and RNA found in eukaryotic cells.[1] Its primary function is packaging long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes” https://en.wikipedia.org/wiki/Chromatin
And, yup, it’s NAD+ dependent.
I was taught in nursing school that a ‘pathogen’ was simply a microbe out of place. What’s a ‘microbe’?– just a bunch of molecules that stick together. Don’t be fooled by jargon.
Chromatin is a precious structural element that provides a ‘slinky’-like coil shape to DNA, allowing it to become a spooled ‘coiled coil’. Wikipedia shows two images of chromatin; the twisted “30 nanometer fiber” of a chromatin segment and the stacked tube formation of chromatin fibers that link together.
Stacked chromatin ‘linkers’ looks like this top row. The bottom row shows cross-section ‘discs’
Shape-wise, and shape matters, a chromatin tube is a match for a familiar plant ‘virus’ called Tobacco Mosaic Virus (TMV) and its extended family of rod-shaped viruses. TMV is the first discovered virus in viral history (which was then only a fluid extract) and among the most investigated—considered the model ‘type species’ of rod-shape crystals infecting many hundreds of common food plants. It is also the principal ‘stress chemical’ subject in the Planting Viruses series.
In a novel 1957 experiment by Heinz Fraenkel-Conrat at UCBerkeley, TMV was dissolved and reconstituted under a microscope, producing ‘shorter’ rods –very similar, I think, to shorter telomeres which are markers of aging and associated in this work to a deficiency of NAD. Most interesting perhaps is that commercial niacin, our vitamin B3 ‘supplement,’ was historically and may still be derived from tobacco. Tobacco makes NAD and then NAD’s derivative, niacin, is turned back into NAD when we eat it. See? Is the extract niacin as nutritionally good as the original tobacco NAD+ ? Is it better to just eat tobacco? It’s a good question worth pursuit, and so is asking if chromatin and TMV are the same. If so, the ‘structural’ TMV could be the carrier of life-giving NAD and might supply an answer to the hydrogel fiber phenomenon known in this blog as “TMV-PVP.” The experimental combination of the chromatin-like Tobacco Mosaic Virus and the substance called polyvinylpyrrolidone (PVP) coagulates into a “branched hollow fiber” resembling blood vessels that grow. Back in 2012, I found this substance while looking for possible sources of Morgellon’s extrusions. TMV-doped PVP looks identical to some of the Morgellon’s specimens I’ve seen– written up here (see the blog index) as ‘Morgification.’ To my horror, PVP is used extensively as a filler and food additive. The TMV-PVP combo seems to have a life of its own. An NAD-dependent life.
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TMV graphic above as both discs and stacked tube, showing the ‘skirt’ of proteins that decorate the helical core.
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March 2010 — “Branched hollow fibers are common in nature, but to form artificial fibers with a similar branched hollow structure is still a challenge. We discovered that polyvinylpyrrolidone (PVP) could self-assemble into branched hollow fibers in an aqueous solution after aging the PVP…. Our work suggests that the self-assembly of the PVP molecules in the solution can serve as a general method for directing the formation of branched hollow inorganic fibers. The branched hollow fibers may find potential applications in microfluidics, artificial blood vessel generation, and tissue engineering.” http://europepmc.org/article/PMC/2844465
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*This ‘search clip’ below, offered at face value, is an indicator of nanomaterials from TMV-PVP
Genetically Improved Monolayer-Forming Tobacco Mosaic Viruses …
http://www.academia.edu › 12687712
“Thus, a precursor solution with a ratio of [PVP]/ composite 30%TMV-His6 mutant (30% His6CP/70% wt CP) [Zn2+]/[TEAOH] = 1:1.3:2.8 and final concentrations of [Zn2+] = are known to bind mono- and divalent metal ions.29 These 11.4 mM, [PVP] = 8.6 mM, and [TEAOH] = 24.3 mM were obtained. “
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3 images of the same ‘Morgellons’ extrusion over time on the back of a persons upper arm. Is this an artificial NAD-dependent lifeform? The person who suffers this disorder reports chronic and crushing fatigue. These pictures are presented in the program ‘From Chemtrails to Pseudo-life, Part 2, Living in the Manhattan Project’ by Sofia Smallstorm.
https://byebyebluesky.com/sofia-smallstorm-chemtrails-to-pseudo-life-part-2/
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So, what about ‘viruses’ in general –are they also NAD+dependent ‘lifeforms’ (better termed ‘stress chemicals’) responsible for the crushing fatigue of acute illness like flu and worse?
(Above) ‘rod and sphere’ electron microscope image of H5N1 influenza: We’re unaccustomed to seeing the rod-shape stack tubes of influenza, looking very much like Tobacco Mosaic Virus. Current EM images of viral infections show TMV-like rods all over the place. Most notably, a small but recent study ‘isolated’ TMV in stool from exclusively breast-fed infants under 4 weeks of age whose parents never handled tobacco but were agricultural workers. Sixteen other “plant viruses” similarly shaped (liked Pepper Mild Mottle Virus, PMMoV) were also found passing the gut of these newborns though they had never tasted anything other than mothers’ milk. Is this proof of conferred maternal immunity or actually proof that the so-called viruses are native particles of the human genome, loaded with NAD energy? Is NAD the ‘power’ of ‘viruses’, for good and ill?
(Above) Electron Micrograph of H7N9 influenza
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Which, what and where’s the flu virus? Are we really looking at viruses?
“In the same way that genetic information is stored as DNA, epigenetic information is stored in a structure called chromatin. DNA in the cell isn’t flailing around disorganized, it is wrapped around tiny balls of protein called histones. These beads on a string self-assemble to form loops, as when you tidy your garden hose…by looping it into a pile… If you could somehow plug one end of the DNA into a power socket and make the histones flash on and off, a few cells could do you for holiday lights… Epigenetic information is what orchestrates the assembly of a human newborn made up of 26 billion cells from a single fertilized egg and what allows the genetically identical cells in our bodies to assume thousands of different modalities. If the genome were a computer, the epigenome would be the software.” –p21, Lifespan
“A few recent studies have suggested that the so-called selfish genes we all carry in our genome, called LINE-1 elements, replicate and cause cellular havoc as we get older, accelerating our physical demise… Does it matter whether LINE-1 comes from your parents directly or via a virus? Would you want to eradicate LINE-1 from humanity or let it grow in your kids and inflict horrible diseases on them? Would you say that LINE-1 causes a disease or not?… Whether it’s a virus, a selfish DNA element, or simply the makeup of our cells that causes these health problems, what’s the difference? The end result is the same.” –p82, ibid.
Genes behaving badly seems to be Dr. Sinclair’s point in Lifespan. Despite the Human Genome Project announcement in 2003 that mapping was complete, he writes, “it really wasn’t. There were, in fact, huge gaps in the sequence… The parts of the genome that were missing, generally overlapping sections of repetitive nucleotides, were just not considered important. These were areas of the code…once derided as ‘junk DNA’ …[and]disregarded as ‘noncoding.’ From… the best minds in science at the time, those regions were little more than ghosts of genomes past, mostly remnants of dead hitchhiking viruses that had integrated into the genome hundreds of thousands of years ago… Yet by some estimates, that genetic dark matter accounts for as much as 69 percent of the total… [Since 2003, scientists have found thousands more genes, with some tiny ones] as short as 21 base pairs…[but] there’s something we still won’t be able to find. We won’t be able to find an aging gene…because our genes did not evolve to cause aging.” –pp27-28, Lifespan
–Read: “did not evolve to cause aging” or disease because in this mindset aging is disease leading to untimely death.
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He states: “If the information theory is correct –that aging is caused by overworked epigenetic signalers responding to cellular insult and damage—it doesn’t so much matter where the damage occurs. What matters is that it is being damaged and that sirtuins are rushing all over the place to address that damage, leaving their typical responsibilities and sometimes returning [after repairs] to other places along the genome where they are silencing genes that aren’t supposed to be silenced… It’s not hard to intentionally break DNA [to prove it]… You can do it with chemotherapy. You can do it with X-rays. (p48).
…”[In mice] we’d simply broken the mice’s DNA…and forced the cell to paste, or ‘ligate,’ them back together… Those breaks had induced a sirtuin response…[and] their absence from their normal duties and presence on other parts of the genome altered the ways in which lots of genes were being expressed at the wrong time… The digital code…was the same as it has always been. But the analog machine built to read that code was able to pick up only bits and pieces of the data. (p50).
…”Here’s the vital takeaway: we could age mice without affecting any of the most commonly assumed causes of aging. We hadn’t made their cells mutate. We hadn’t touched their telomeres. We hadn’t messed with their mitochondria…[or] exhausted their stem cells…[A]ll the symptoms of aging…were being caused…by the epigenetic changes that come as a result of DNA damage signals. We hadn’t given the mice all of those ailments. We had given them aging. And if you can give something, you can take it away.” –p52, Lifespan, by David A. Sinclair, 2019, Thorsons/HarperCollins publisher.
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Wrap-up and Un-wrap-up
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In this 2021 experiment to create ‘self-sufficient’ engineered cells, mutant E.coli use NAD to generate an ‘alternative’ redox circuit that substitutes the nucleobase cytosine (‘C’, and CTP) for adenine (‘A’, ATP), creating an NCD-dependent circuit, versus an NAD-dependent circuit, which the researchers anticipate as useful in synthetic biology. Their successful conclusion suggests,“This will be amenable to those on-going efforts using non-natural bases and non-natural amino acids to expand our capacity interms of understanding and reprograming life.”
They write: ”To facilitate NCD-linked redox chemistry in vivo, it is essential to realize NCD biosynthesis. In bacteria, nicotinic acid mononucleotide (NaMN) adenylyltransferase (NaMNAT) catalyzes the condensation of ATP and NaMN to form nicotinic acid adenine dinucleotide (NaAD) (Fig. 1a), which is the key step for de novo NAD biosynthesis16. Conceptually, if the binding pockets of ATP and NaMN of NaMNAT [its analog enzyme] are redesigned to favor cytidine triphosphate (CTP) and NMN [the common vitamin product of NAD used by humans], respectively (Fig. 1b), the engineered enzyme is expected to make NCD following a similar condensation mechanism, and can be designated as NCD synthetase (NcdS). As both CTP and NMN are endogenous metabolites, no auxiliary nutrients are required to synthesize NCD by those NcdS-empowered cells… However, it is intimidating to engineer a two-substrate enzyme for active variants specific with two new substrates. On one hand, simultaneous mutating key residues within two-substrate-binding pockets will lead to large [metabolite] libraries beyond our screening capacity. On the other hand, engineered molecular interactions favoring one substrate may have unanticipated effects on those for the other, and vice versa.”
…and what happens to the organism?
“Again, NCD production led to reduced NAD levels…”
Read it here, April 2021—Nature Magazine
https://www.nature.com/articles/s41467-021-22357-z
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Jennifer Lake's Blog 