I covered this in Levee 25 of the Quilt long ago and now this series will visit this in depth:
Hypoxia/pseudohypoxia. Hypoxia is a cellular state that disrupts normal oxygen supply to the tissue (mitochondria), causing cellular dysfunction. Examples of t 25.his are altitude sickness at high elevations and clots in a blocked artery in an organ causing an organ to fail and die. Apoptosis and autophagy allow cells to adapt over their lifespan to many situations. Hypoxia is directly toxic to mitochondrial energy production. In humans, when oxygen is in short supply we can shift to anaerobic energy production, but it is not as efficient as mitochondrial energy production. Athletes with proper training can perform well in anaerobic conditions but it does appear that they pay a steep price for this adaptation by depleting their stem cell supply. The gateway in mitochondria for hypoxia is pseudohypoxia by blockade of pyruvate which sits atop the TCA cycle inside the matrix. The gatekeeper of the creation of Acetyl-CoA from pyruvate is thiamine. It is the major controller of substate movements in the matrix. As it drops we lose control of UCP-2 and this alters the matrix concentration of hydrogen isotopes.
Thiamine deficiency causes a relative pseudohypoxia and is closely linked to heteroplasmy rate elevation in aging. Coffee and polyphenols destroy thiamine levels. As this occurs there is massive signaling to the SIRT system to affect mitochondrial biology.
As a consequence of pseudohypoxia, NAD+ levels drop and this funnels all the way back to how the aromatic amino acid tryptophan is catabolized in cells. It has multiple pathways it can travel and the pathway chosen will lead to the cell’s fate.
Hypoxia plays a role in aging because as one age the amount of blood to organs declines as the heart fails to deliver the same amount of blood through a stiffened arterial tree throughout the body. THIS IS A PROTECTIVE STATE FOR POOR MITOCHONDRIAL FUNCTION = higher heteroplasmy rate.
This causes cellular oxygen levels to fall and usually is a signal to mitochondrial biogenesis to offset the deficits. As one age, this signaling system is not as accurate in sensing changes to the oxygen level. This can be measured in the pyruvate/lactate levels. Low oxygen tension is a signal to autophagic pathways that normally help repair cells. If this gets impaired, signaling autophagy becomes less effective as we age and results in more organ failure and diseases of aging. Hypoxia is critical signaling in the cell for repair processes. This is disordered in heart disease and in sleep abnormalities such as sleep apnea. Hypoxia decreases cell mass and improves leptin resistance by forcing a calorie restriction via a relative thiamine deficiency state. This only operates well if the person remains in a strong solar environment.
Free radicals and reactive oxygen species (ROS) in particular play an important part in aging because they direct repair and regeneration and taking antioxidants ruins this endogenous signal. Free radicals are (usually small) molecules lacking an electron needed for stability; they will steal an electron from the first thing they bump into. Like pulling a cog out from clockwork, stealing an electron from a protein or enzyme is usually not good for the finely-tuned biochemical machinery of our cells. The free radical might be rendered safe in the process, but it has left some form of chaos and damage in its wake.
Free radicals are sufficiently dangerous to biochemical machinery that some of our body’s defenders use bursts of free radicals as a kill mechanism. That is why Denham’s belief has died too slowly. Science changes though as data comes in.
Scientists now generally concur that accumulated damage throughout the body due to free radicals is one important root cause of age-related degeneration – but the devil is in the details. The vast, overwhelming majority of those free radicals are generated by your own metabolism as an unavoidable byproduct. The rate of free radical generation increases greatly with age as the basic mechanisms of your metabolism are themselves damaged by the free radicals they created. This is not a one-step process, however. I’ve tried to walk through it at a high level at my blog, cribbing from the mitochondrial free radical theory of aging that was proposed by Wallace and working its way into general acceptance because of new data
Within each of your cells are many mitochondria, tiny biochemical power plants that convert chemicals from food to ATP, the basic fuel molecule used by your cells to provide energy for life.
You have to beware of people who take advantage of the antioxidant theory of aging and have no earthly idea of how mitochondrial creation of free radicals really works. This is why supplement makers and coffee makers are pushing the false narrative that antioxidant use is wise. Marketing is legalized lying.
Mitochondria were once a separate organism that came to live in symbiosis with ancestral cells. As such, they brought their own DNA to the party; some of it still remains within our mitochondria, separate from the DNA we carry in chromosomes in the cell nucleus.
Mitochondria have a couple of ways of generating ATP. The more efficient of these methods – oxidative phosphorylation (OXPHOS) – generates some amount of free radicals as a natural byproduct, and requires the proteins coded in the mitochondrial DNA to function. It is the predominant way by which healthy cells generate their power.
Free radicals created through OXPHOS within a mitochondrion are most likely to damage that mitochondrion; they’re very reactive, so they won’t get far before sabotaging something. The components that really matter are (a) a membrane that helps organize the movement of various chemicals in the process of generating ATP, and (b) the mitochondrial DNA.
Sufficient free radical damage to mitochondrial DNA shuts down OXPHOS within that mitochondrion, as the necessary proteins can no longer be produced. The mitochondrion switches over to using a less efficient method of producing power, one that doesn’t produce free radicals but has to run at a much higher rate to produce the same level of ATP.
Mitochondria, like most cellular components, are recycled on a regular basis. Components called lysosomes are directed around the cell in response to various signals, engulfing and breaking down damaged or worn components. After the herd has been culled, surviving mitochondria within a cell divide and replicate, much like bacteria, to make up the numbers.
The signal to break down a mitochondrion is triggered by sufficient damage to its membrane: a sign that it’s old, leaky, inefficient and needs to be replaced with a shiny new power plant.
BUT: if a mitochondrion has had its DNA damaged to the point of stopping OXPHOS/beta-oxidation/alpha-oxidation, it will no longer be producing NORMAL free radicals that can damage its membrane. So it will never get broken down by a lysosome. When the time comes to divide and replicate, it will replicate its damaged DNA into new mitochondria and disease is spread like a bacterial infection in your tissues. None of those new mitochondria will be producing free radicals via OXPHOS, and so will not be recycled either (autophagy).
One DNA-damaged, non-OXPHOS mitochondrion will eventually take over the entire mitochondrial population of a cell in this way. At that point, the trouble really gets started.
By the time you hit late life, perhaps 1% of your cells are in this state of being taken over by non-OXPHOS mitochondria. As for any neighborhood or city, it only takes a small proportion of dangerous criminals to make life really unpleasant for the rest of us. Same true here at the tissue level.
Non-OXPHOS mitochondria have the unfortunate effect of depleting a needed molecule used in many cellular processes, NAD+. This is a carrier molecule in the OXPHOS process, given an electron (and turned into NADH in the process) to port between point A and point B within the mitochondria. Once the electron is delivered, the NADH becomes NAD+ again. But without a working OXPHOS process to return NAD+ into circulation, the cell would quickly build up a deadly excess of NADH, run out of NAD+ and hypoxia occurs and cells die. (Sinclair, 2013)
Fortunately for the cell, and unfortunately for us, there is another way to recycle NADH into NAD+. Since NADH is just NAD+ with [amongst other things] an electron stuck to it, all the cell has to do is export those unwanted electrons to other proteins via the Jablonski diagram I have posted over and over.
In the points above, I omitted details of the reaction that transforms NAD+ to NADH in order to focus on the electron that is ported around. Wikipedia gives an introduction to the full picture, which also involves an extra hydrogen atom (non-deuterium) – NADH is NAD+ with the addition of a hydrogen atom (one proton, one electron), and an additional electron. Nonetheless, it is the shuttling and exchange of electrons that is important here.
In a form of chemical waste dumping, this is just what the cell does. Structures on the cell membrane known as the plasma membrane redox system (PMRS) export electrons from NADH, recycling it into NAD+. This process is only very active in cells that have been taken over by DNA-damaged, non-OXPHOS mitochondria, but their outer surfaces are little hotspots of electron dumping.
What do these electrons do? Well, for one, they combine with oxygen molecules – which are abundant in any of our living tissue – to create reactive oxygen species (ROS): more free radicals. Sick cells have pseudohypoxia to limit the damage and try to survive as autophagy is defective. This causes organ failure. So you have the Rube Goldberg system outlined above whereby a few free radicals have caused a cell to become an ongoing, major exporter of free radicals into the surrounding environment. These will make life unpleasant for surrounding cells, but that is most likely not the real problem. ROS just can’t travel far enough to explain how a corrupt 1% of our cells can cause a large fraction of the difference between being young and being old.
A more likely target for all the newly created ROS is cholesterol. Cholesterols, such as low-density lipoproteins (LDL) are used everywhere in the body and travel widely. If ROS reacts with nearby LDL – and there will always be nearby LDL – to form damaged, oxidized cholesterol, that damaged cholesterol can then be incorporated into and further damage biochemical processes throughout the body. For example, its effects on our arteries is well known: What is not well known is how the light that excites that electron damages cholesterol rings by how it is programmed. If the right frequency of light is on the electron cholesterol works well……if not you get a disease.
In conditions with elevated concentrations of oxidized LDL particles, especially small LDL particles, cholesterol promotes atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease.
There are many other ways in which accumulations of oxidized cholesterol can send biochemical processes awry. This, then, seems to be a good candidate for the plausible, systematic method by which a small number of cells can work such varied damage upon your entire body. Mitochondrial damage acts just like an infection does at the tissue level. Aging does the same. This is why health is the slowest form of death we chose by using the right light that excites electrons. Mitochondria deal the right electrons to the right tissues to build health.
Do you know the purpose of the unusual construction of the mitochondrial membranes? Did you know that the inner mitochondrial membrane is the ONLY membrane in humans that is DEVOID of DHA? Do you know why the membranes in the mitochondria are built by Nature to be extremely hydrophobic? Do you know that these membranes can carry voltages close to 30 million volts because of this build-out? Do you know that one of these membranes actually makes water from food? Did you know that the atomic construction of this water also has to be specifically depleted of a certain isotope? Do you know why all these things exist in your mitochondria?
The answer might shock you. Uncle Jack is going to tell you that all these things occurred 650 million years ago to suspend the laws of physics to allow nature to do things not even gods could fathom. Nature figured out how to use nanoscale spaces to suspend physics to build the possibility of life.
Did you know when a thin layer of water is squeezed between two hydrophobic surfaces, the laws of classical physics break down? Well, I have been teaching my members this since my epic April 2016 webinar on what life really is up too. Now you have more data I am on the right track and the paradigm and all my critics remain myopic.
The take-home is this: PHYSICS IS THE SCIENCE OF PROBABILITIES. BIOLOGY IS THE STORY OF THE IMPROBABLE AND BIOLOGY CAN ONLY MAKE SENSE FROM THE PERSPECTIVE THAT THE LIVING STATE IS ONLY PROBABLE USING REACTIONS WHICH ARE STATISTICALLY IMPROBABLE.
So Nature built cells to have the ability to suspend what we should expect to give us the most improbable answer why life really exists and happens. She figured out how to suspend her own laws using things she built. How is that for counterintuitive?
That is why I teach Black Swans how to think. I call these people Black Swan mitochondriacs. They are called this because they are rare in nature. Humans that actually take the time, to read, research and read about science that on the surface seems superfluous, but is foundational to our health on the submolecular quantum level.
Nature does not employ any “balanced protocol” in her usage. She is all about unbalancing the scales to favor the tasks that cells need to accomplish. NEVER FORGET IT.
And anyone who says otherwise will have to explain this new finding.
People who have open minds to accept new data that blows your paradigm of beliefs apart.
