A document that will evolve as science eliminates past dogma
This document is a compilation of three decades of “thought secretions” on medicine as a science and an art form. Healing is not axiomatic, yet you would never know that if you opened a new textbook or current journal. Medicine today is all about evidence-based findings. Evidence-based medicine is a great idea if the underlying dogma is based upon undeniably true facts . I think you will find that I do not accept many of the foundations that evidence-based medicine now currently rests upon. For me, biochemistry or physiology are absolute certainties about how humans work. Practice standards are based upon prevailing opinion. For example, evidence-based medicine believes that everyone with total cholesterol over 200 should be treated with a statin medication. After many years of studying this, I realize that we may need to question that kind of advice. The science that is published and in the media today is not based upon truths like biochemistry or physiology are. Sadly, evidence-based medicine founded on data paid for by a corporation or branch of government is subject to the influence of many biases. Several years ago I read an article in The Atlantic titled “Lies, Damned Lies, and Medical Science” that changed my thoughts on this. Shortly after, I read “Good Calories and Bad Calories” by Gary Taubes which confirmed much of what my intuition was telling me. What I saw, and was doing as a surgeon, often felt incongruent to what the reality was for the patient. Many good doctors practice medicine today. I honestly believe that they think they are doing good work. I know this because I was one of them. I thought everything I was taught was based upon solid scientific facts. I allowed my medical and dental educators the intellectual leeway of trusting the facts they told me. Good intentions, however, are not congruent with longevity nor with health. Good doctors were a dime a dozen, I found out; however, great doctors were few and far between. I no longer wanted to be good; I wanted to be great. To be great you have to reject being just good. That was my initial thought after reading the Atlantic article. Yet the current system rewards only good doctors. This document will help you, the reader, differentiate between the great healers and the good ones. Your life actually depends upon it, so I strongly suggest you begin to think as you read.
Today, medicine is dominated by doctrine and dogma that caused us some serious missteps in thinking. These missteps have made us advocate for treatments, behaviors, and thoughts that have become ingrained within our society. With science, the truth always updates itself. Moreover, one must realize that every mile that puts us in the wrong direction will require us to walk two miles back just to return us to square one and a new beginning.
This document is not about our species becoming successful in creating a new generation; it is about making current humans all they can become with respect to the aging cell and where they are now. It is about increasing our life span while we simultaneously expand our health span. I suspect we are going to explore subjects in the future that none of us are thinking about now, because that is the nature of science. Living long without intervention of conventional medicine is the goal. Pointing out the good and bad in medical care will also be helpful to the lay person and healer alike. We should begin to rely on our physicians to guide us to pathways that attain that goal. I believe that my profession will evolve into taking care of healthy humans, and leave behind the old paradigm of trying to repair people after they have already been damaged by disease.
I believe this expertise will become the currency of the new paradigm, and I believe the change will be an obstacle course for many. Patients already know that we do not know everything — just ask them. But I believe we lose our credibility when we do not act congruently with the knowns of biochemistry and physiology. We cannot use treatment algorithms that promote data sets that are not factual or are incredibly flawed. We have all read what has been said by the medical and nutritional gurus about the current beliefs on diet… yet we have the world’s worst weight problem and a massive public health dilemma. Maybe we need to stop making excuses for what we believe to be true, and understand what really is true regardless of the implications it draws.
Accepting the proposition that randomized control trial (RCT) is the golden goose of research has given my profession a slow steady decline in reputation. It is not because a RCT is a bad thing. It is the best thing we have if it’s based upon real facts. Therein lies our real problem. When the underlying science is faulty, the randomized trials become worthless. Do we need a RCT to tell us that a potassium level of 4.0 is good? No we do not. Do we need a RCT to tell us that a potassium level of 3.1 is bad and requires treatment? No we do not. The current thinking in medicine is that we need a RCT for everything we do. This is not true if we practice using the biochemistry and physiology found in humans. We can no longer allow a drug company to tell us that a cholesterol level of 200 is bad when it is not. That is a great opinion when you are selling a statin, for sure. But if it was good for humans then why is heart disease still the number one killer in the US after 50 years of actively lowering LDL cholesterol? At some point you must ask this question if you are a patient or a doctor.
We will not need to have the support of big pharma or medical implant companies to run trials because our focus will be on promoting health longevity and not treating disease. The transition of the healthcare economy is already occurring. Industry has a vested interest in treating sick people and not the healthy. Patients want to be healthy, but struggle to find physicians or insurance coverage who offer those services. Our government makes it easy for the current paradigm to exist, because they advocate for agriculture policy that makes us ill with diets laden with omega 6 fats, fructose, and grains. It’s because processed food stuffs can be stored and shipped to economically feed the world population. They are not doctors or researchers so they can’t know unless we tell them. But they also are now beginning to feel the pain of that decision which is continued currently by their incongruity in intellect. The current healthcare crisis is ground zero for this epic battle to be fought.
Instead of focusing on what I cannot do, (i.e. change Washington, DC thinking), I will instead focus my attention on what I can achieve and teach the public on remaining healthy so they can cure themselves. So we need to start that trend together. This is what my blog is about.
My primary weapon in this battle is thinking. The greatest of humans are deep thinkers. Show me a success and I will show you a thinker. A human is the only animal that can actually change its DNA just by thinking. Moreover, thinking is just a biologic secretion. No different than any hormone released by the pituitary gland. Thinking is a meme that hijacks our brains’ chemistry. Any thought can alter our genetic and biologic purpose in life. Yes, thinking well or badly becomes a vector that changes us all in some fashion. This thought experiment occurs daily in our country on myriad mediums of media. In fact, I believe it is the one thing that is speeding up the evolutionary pressures that we currently face. I think it is a real problem behind many health issues we will explore in the document.
The pathways I have identified over my thirty years in healthcare I call “Longevity Levees.” Remember that a levee is a protective barrier from flooding and devastation. These levees are biologic protectors of our cellular machinery. My goal is to share it with the public and my colleagues. As new data emerges, blogs will be added to the quilt by me and I’ll bet by you. This document should be a collaborative effort.
The longevity levees are as follows and in order of importance.
Each one of these will be expanded upon in blog form. I will attempt to go through each one until I begin assembling the quilt in other dimensions. The quilt will link together in hypertext format to allow ease of navigation. I am open to comments and suggestion to make this platform to your liking but I will remove and edit comments I think our counterproductive to the goal of the levee. I hope you enjoy and that we can stimulate some thinking.
DETAILED LEVEE DISCUSSIONS
Current cellular homeostasis determines cellular fates all of the time. This is the cornerstone of my theory of longevity. We must stop focusing in on disease states and instead think about what happens to the cell’s environment that dictates its fate. The cellular terroir are what cause the disease states. This is my cellular theory of relativity. My theory of aging is that the environment the cell finds itself in is directly proportional to outcomes the cell may face.
In my mind, these levees will uncover a new paradigm that requires the “patient” and physician to forget about the disease states and think first about the normal cell. This theory will require you, the reader, to embrace paradox and ambiguity at every turn.
Leptin sensitivity and resistance determines all energy balance. This levee is all about energy. No life can sustain itself without controlling energy metabolism. A body without energy is called a cadaver! Leptin is a hormone secreted by fat that signals the hypothalamus as to what the 20 trillion cells in our body need. Leptin is obtained through breast milk at birth. This immediately loads the hypothalamus with data, much like a disk drive with a PowerPoint presentation on it would do for your laptop. Leptin receptors are very specific in how they work, and they are found concentrated in the lateral hypothalamus. This hormone regulates all aspects of energy metabolism, hormonal status, fecundity, and eventual cellular generation. Simply put, the leptin axis is akin to the relationship the sun and plants have in energy generation. Plants use sunlight to convert carbon dioxide and water into sugar which supports their life via energy generation. Photosynthesis is effective for plant life but it may not have been an efficient mechanism to support animal ascent in the evolutionary development to humans. To continue to allow complexity of life, evolution had to come up with a new mechanism of energy metabolism and a way to control it. It incorporated the plant-like mitochondria into a cell and modified it to generate energy. It appears that quantum biology is critical to this step based upon recent scientific developments. The amount of energy generation was quite impressive and this gave life the power to eventually evolve into complex organisms like humans.
Leptin controls all of this machinery of energy generation for humans. It is our photosynthesis. The sun still plays a huge role in oxidative phosphorylation. Sleep plays an enormous role in here as well. Sunlight and leptin signals remain tied together by the hypocretin neurons in the lateral hypothalamus of the brain. Both hypocretin neurons and leptin neurons are small in number and found in few areas of the mammalian brain. Humans have only 50,000 hypocretin neurons in their brains. Mice have but 3,000. Moreover, these neuronal tracts appears very new in evolutionary times. And, because of that “newness,” they are subject to signaling errors, receptor single nucleotide polymorphisms (SNP’s) and errors, neuropeptide modification, and out of sequence firing due to signaling issues at many steps. So, in humans, it appears obesity has many causes and features that confuse researchers. This levee will have many blogs pointing out the various forms obesity can take due to problems in this system of control. To fully understand the gravity of this hormone, consider this analogy: What would happen to life on earth if, all at once, we eliminated all coal, oil, nuclear fuel, and all sunlight from our planet? I believe life would surely be changed dramatically and quickly. When leptin is not working correctly this is precisely the fate the cell has to deal with and it can dramatically alter how the cell or organ system responds when fuel demands cannot pace needs.
Cellular inflammation is critical. It is akin to the fire in a burning house. The more of it your cell possesses, the more chance bad outcomes will come to the cell. Cellular inflammation comes in many different forms. It tends to flow down in certain biochemical pathways and cause havoc. (link) It also now appears that inflammation is the base cause of obesity, diseases of aging, and the cause of cellular death. There are many pathways it uses to achieve this signaling and this part of The Quilt will delve into matters more deeply and show how they tie concepts together that lead to problems we humans face as we live our lives.
Dietary principles of longevity. We have already seen that energy metabolism is critical to life and why Leptin holds position two in The Quilt. This levee concerns itself with the substrates that give us that energy. We will explore the diet we eat, the energy that comes from it, and nutrition optimization. Humans have adapted to many environments on Earth but this levee is not concerned about what we can do in adaptation; rather it is about how long we can live in our own current dietary edicts. The key principles here will be eating to satisfy the true facts and not the opinions of the day. Our biochemistry and physiology have been carved by millions of years of natural selection and have not failed us yet. It is now becoming clear that biologic systems have for many millions of years used quantum mechanics to do some of the amazing things animals can do. It appears energy generation is one of them. We will explore quantum biology in this levee many times over the next few years to open the discussion of this brand new frontier.
The foundational cornerstones of this levee will be limitation of inflammation, low levels of omega 6 foodstuffs, limited fructose, limited carbohydrate intake, concentration of omega 3 laden protein sources, limited uses of foods known to cause nutrient depletion or nutrient loss in the gut. The balance of this levee will have many blogs tied to the nuances of Epi-paleolithic eating and whether micro or macro nutrient issues should dominate or not. The key points here will be how foods affect telomere lengths and what the research is pointing to, and how food may affect quantum biology.
The Brain Gut axis is critical to organizational health. The major route into and out of the human body is via the gut. The brain senses this axis before food even touches the palate via the five senses. When food touches any part of the tongue, signals are immediately made on leptin receptors on the tongue to begin digestion and assess the dietary values of what we are eating to see how it will affect our energy balance. Almost the entire gut is innervated by one cranial nerve, called the vagus nerve, that provides this feedback. The vagus nerve is extremely specialized and carries many special fibers to and from the brain and its targets. It originates in the floor of the fourth ventricle of the brainstem and covers every cell down to the transverse mesocolon of the large intestine to give the brain constant feedback on the energy coming into the animal. The incretin system is monitored directly by this nerve. If this axis is disturbed in the time it takes for food to pass through, or in the integrity of its lining, it can have drastic effects upon energy utilization. In some cases it can open the blood-brain barrier to direct assault and cause fatal brain damage quite quickly. The immune system plays a monster role in regulation of this levee and the autonomic nervous system has over a billion cells in the wall of the gut to monitor progress of how this axis continues to function as the human ages. If this axis fails in some fashion, disease usually follows quickly thereafter. Major diseases like MS, ALS and autism are affected by this axis, as are the neurodegenerative disorders. Depression and Alzheimer’s also are greatly affected by a defect in this axis. IBS and Crohn’s disease are common diseases that cause massive leaky gut scenarios. A disease I treat as a neurosurgeon also plays a role in this levee: cerebral aneursymal rupture and the development of vasospasm. To date, no theory in neurosurgery has been able to find the cause of this deadly phenomena. My theories point to the leaky gut as the conduit to it rise.
Immunity affects regulation. This levee is critical because it is the major protective arm of the body. It contains two major parts, cell mediated immunity and humoral immunity. We will delve into both of these systems to show you how they are imperative for protection of organ systems, integrating development of the organism as it grows from a fetus to an adult, and how the system adapts to pathogens it faces as it grows and ages. Moreover, this system has so much complexity that is can also be turned back upon itself and cause huge issues for the organism with autoimmune diseases. These can wreak havoc and cause early death and disease if not kept in check. This system works in tight balance and is built with many redundancies to protect from malfunction but it does happen if the cell faces the wrong environments with a mismatch. Examples would be the effect of HIV on cell mediated immunity, the lack of a functioning brain-gut axis, graft versus host disease, molecular mimicry, low vitamin D levels, or failures of the complement system in humoral immune response.
ROS generation. ROS stands for Reactive Oxygen Species generation. We all know life is based upon energy production from the use of oxygen. This process is called oxidative phosphorylation. Examples of ROS include oxygen ions and peroxides. Oxygen species are highly reactive due to the presence of unpaired outer shell electrons. ROS forms as a natural byproduct of the normal metabolism of oxygen and has important roles in cell signaling and homeostasis. This process occurs in the mitochondria. When we generate energy packages, adenosine triphosphate (ATP), from nutrients, we also generate free radicals of oxygen that leak from the cytochromes of our mitochondria. Cytochromes are the furnaces in mitochondria where ATP is made. This “leakiness” is critical to life and to the death programs inside our cell. The more “leaky” our mitochondria the more ROS we generate. Generally ROS is a bad omen for the cell but it can also signal the cell to lengthen its telomeres at times or to recruit the formation of new mitochondria to make energy. ROS generation is a measure of cellular stress, and that stress can be so great that is can damage cellular structures so that they no longer work properly. Examples are UV exposure or radiation exposure.
In general, lower ROS is better for longevity of the cell and for it to function optimally. A simple example of this fact is coenzyme Q10. Most people have heard of this cofactor, and this protein is used up to a great degree when you are making energy or the cell is stressed. Statin drugs cause depletion of this protein because of their mode of action on enzymes in blocking the building blocks of cholesterol, so they cause the cell to be more inefficient making energy as the CoEnQ10 is depleted. It is also used up when we are under stress due to long term insulin or cortisol secretion. Depletion of CoEq10 is why people can get cognitive change and muscle cramping when they are on statins too long or the dose becomes too high. The cause is because the cells in that part of the body can’t make the energy they require because of the side effect of the drug. Therefore many patients are told to add CoEnQ10 to their supplement list daily if they are on a statin.
ALE’s. ALEs are short for advanced lipoxidation end-products. These are proteins that are modified in our body after we assimilate the nutrient and they become harmful to us. Most of us know about AGEs — advanced glycation products from excessive sugar intake. Estimates have put the oxidative stress of ALE’s at four to six times as great as AGEs. Clearly, both are bad and our levee will deal with how to limit the collateral damage of ALEs. These proteins are made from PUFAs (polyunsaturated fats) and become malondialdehyde (MDA for short). MDA is a biomarker for ALE stress in the cell. Malonaldehyde reacts with deoxyadenosine and deoxyguanosine in DNA, forming DNA adducts, the primary one being M1G, which is mutagenic. The guanidine group of arginine residues condense with MDA to give 2-aminopyrimidines. MDA plays a big role in the development of keratoconus in the eyes or osteoarthritis of the joints of the body. One clinical measure we use of ALE toxicity in the body is presence of skin tags in folds of the skin. This finding seems to correlate with the omega 6/3 ratio in plasma. Generally we want a diet that approaches a 1 to 1 balance of omega 6 (PUFA) to omega 3 fats but in the standard American diet (SAD) that ratio can be up to 40 to 1 with heavy intake of processed foods. This is the reason we have seen tremendous increases in orthopedic joint replacement and degenerative spinal conditions in the American population. I believe it is a great contributing factor to the tremendous increases we have seen in osteoporosis and metabolic bone disease caused by hormonal disruption of bone metabolism. It leads to damage and early aging of all tissues. ALEs also generate carboxymethyllysine (CML). These can be seen in foods with added ascorbate and PUFA enrichments, such as salad dressings and Similac. Many baked wheat products are particularly prone to CML formation. Since I am a clinician who treats neurodegenerative diseases and complex spine conditions, this levee will contain many entries over the years. Moreover, it will be the levee that stimulates me to write a book about my thoughts on spine disease in the modern world
AGEs. AGEs stands for Advanced Glycation Products. This is the levee that concerns itself with how high levels of sugars we intake cause disease. The disease process is mediated through a receptor system. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand N(epsilon)-carboxymethyllysine (CML) results in the activation of NF-kappaB (the 911 system for the cell) and the production of proinflammatory cytokines. This is the mechanism of how degenerative disease begins and progresses. Moreover, it is now clear that this process feeds forward if the stressor is present chronically, as it is in diabetes. For the lay person, a good way to understand what glycation by glucose, sucrose, or fructose does to our organs and proteins over time is to think of this analogy: Imagine pouring maple syrup on your granite counter top and leaving it there for three months then trying to remove it on month four. It becomes rock hard and does not allow you to use the counter top like it was designed to. That is what an AGE does. Limiting AGE generation is a clear levee of protection and we will examine many areas here for study and prevention. Damage by AGEs is common in diabetic neuropathy, Alzheimer’s, high blood pressure, stroke, atherosclerosis, osteopenia, and generation of epithelial cancers.
Mitochondrial Signaling is Pleotrophic and adaptable. Pleotrophic means the process can move in multiple directions—both good and bad in this context depending on the amount of cellular stress. We have already seen examples in cellular stressors in the above levees. Mitochondria are the cells’ power plant to make energy. Cells use ATP (adenosine triphosphate) generated from multiple pathways of biochemistry as their fuel. Mitochondrial signaling is a pathway of communication from mitochondria to the nucleus and cytoplasm of a cell that influences many cellular and organismal activities under both normal and pathophysiological conditions. In animal cells, retrograde signaling is linked to mTOR signaling, which directly affects the cells next biologic step in its life. In mammalian cells, mitochondrial dysfunction sets off signaling cascades through altered Calcium concentration reactions, which activate factors such as NFκB, NFAT, and ATF. Retrograde signaling also induces invasive behavior in otherwise non-tumorigenic cells, implying a role in tumor progression. Anterograde signaling appears to be significant in mitochondrial biogenesis and in activation of telomerase to lengthen the cell’s telomeres to allow it to divide and the tissue to live longer. This levee has many unknowns but is vitally important to understanding how we avoid disease and live longer. It should be clear to any reader that life, healthy or not, is all about energy generation and utilization. The mitochondria are the engine within our Ferrari and we need to keep that engine working efficiently if we are to remain fit.
mTOR pathway is life or death. We just mentioned mTOR in levee 10. I did not describe it because it is a levee by itself. mTOR stands for mammalian target of rapamycin pathway. This pathway is a giant factor for the cell. Signaling through mTOR is activated by amino acids, insulin, and growth factors, and impaired by nutrient or energy deficiency. mTOR plays key roles in cell physiology and disease states. mTOR regulates numerous components involved in protein synthesis, including initiation and elongation factors, and the biogenesis of ribosomes themselves. Oncogenesis uses mTOR pathways to make parts for the immortal cell when mTOR is biochemically linked to phosphatidylinositide 3-kinase (PI3K)-AKT. Insulin and leptin play huge roles in PI3K as well. Strategies are being developed and used now involving horizontal and vertical blockade of the pathway, as well as the use of biomarkers to select appropriate patients for certain treatments. Moreover, this pathway is being used to provide proof of target modulation. Curcumin, cacao chocolate, and ECCG have been found to give some of their clinical effects by interrupting this pathway.
The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism. The pathway has two major components call Rictor and Raptor. Rictor is involved in protein–protein interactions and is not as well conserved in all animals as is Raptor. Ironically, Rictor is also not blocked by Rapamycin either. The rapamycin-insensitive rictor–mTOR pathway regulates Akt/PKB, PKCa, Rho/Rac to control cell survival, proliferation, metabolism and the cytoskeleton. Raptor complex of mTOR is highly conserved in animals and is blocked by Rapamyin. Raptor is a cellular kinase protein that has wide ranging effects. Long term research has shown that raptor mTOR positively regulates cell growth and that its inhibition causes a large decrease in cell size. The mitochondria signal through mTOR raptor directly. This pathway is worked out fully and can be seen in most biochemistry textbooks today. Most research has focused on Rictor and Raptor inhibitors but it’s a pathway that has vexed scientists. Most recently, research in this pathway has focused on the dual nature of mTOR that is integrated by the mTOR complex 1 and complex 2. These two complexes are formed and regulated by different proteins and are also driven by multiple different compensatory feedback loops making understanding them very complex.
PPAR gamma is the confluent gate. PPAR (peroxisome proliferator-activated receptor) gamma is regarded as the master regulator of the adipocyte and of lipid metabolism in the cell. It is under the direct control of leptin and its receptors. There are three total PPAR, alpha, delta and gamma. PPAR gamma are nuclear proteins that function as transcription factors regulating gene expression from all aspects of dietary metabolism. PPAR gamma’s role is essential in cellular proliferation, energy generation, cellular differentiation, and tumorogenesis.
γ (gamma) – although transcribed by the same gene, this PPAR through alternative splicing is expressed in three forms:
γ1 – expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
γ2 – expressed mainly in adipose tissue (30 amino acids longer)
γ3 – expressed in macrophages, large intestine, and white adipose tissue.
So why do I call this the confluent gate? Because all metabolism goes through this path to directly affect DNA activity. This is precisely how epigenetics occurs. Diet directly affects our DNA function.
All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. Lipids transformed into free fatty acids (FFA’s) play a huge role in the physiologic function of PPAR gamma. Endogenous ligands for the PPARs include free fatty acids and eicosanoids. PPARγ is activated by PGJ2 (a prostaglandin).
Defective signaling responses can wreck havoc. All cellular homeostasis is based upon this principle. If you have no control over the systems that govern how a cell works, then you have chaos. Cancer in my way of thinking is a complete loss of signaling. The most vital signal in a cell is that of energy homeostasis. This is dominated by leptin sensitivity. If one is leptin resistant there is no way to control cellular biology and disease processes begin. This levee is acts much like a conductor does over an orchestra. If we look at the New York Symphony ensemble individually we all know they are expert musicians and can play extraordinarily well independently. But it is the conductor who brings these 300 musicians together and coordinates their activities so well that the music sounds magical. Now think about what the music would sound like if there were no direction. The trombones and flutes would no longer be synched to the drums or violins. In essence we would have noise, not music. This is what a lack of signaling can do to the cell. Bad signaling can cause cell death, cell senescence, diabetes, neuro degenerations, autoimmunity, or cancer. Understanding how to maximize this levee is a study in maintenance of your cellular machinery to make sure it functions long term.
Epigenetic modifications is quick and dynamic. We saw in the PPAR gamma levee that dietary forces can force immediate gene transcription on the cell in question. Not only does diet induce immediate changes in DNA activation but so does the organism’s hormonal status. Moreover, humans are the only animals that can induce DNA changes just by the way we think. We know that DNA activation occurs with thoughts from functional MRI data and PET scans on brain function. Many call this area the mind/body connection but I find this to be a misnomer. The mind is the sum total function of the central nervous system (CNS) and its endocrine secretion is called a thought. That secretion can directly up regulate DNA and RNA activity with gene expression and protein formation. This happens within nanoseconds according to functional MRI data, and EEG strips. It’s nothing short of amazing to think evolution can move that fast on a micro level but still not affect the phenotype of the organism in any great macro way. Another paradox of life revealed I guess. (link)
We also know that epigenetic modifications usually involve activation of NF kappa beta at some point in the pathway. Therefore we must, in this levee, consider inhibitors to NFkappa beta in future additions to “The Quilt”
Autophagy. In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell’s own components through the lysosomal machinery. Why, you ask, is this so important? Well, the leading cause of death in humans is heart disease. Autophagy is the mechanism that cardiomyocytes die from. Therefore, if we can understand this pathway in detail and how to protect ourselves from it we may finally do something to stop cardiac death. All of the cardiologists in the world believe in the lipid hypothesis of heart disease. I think, however, that the data overwhelmingly shows that it is not the case; understanding how autophagy occurs will help you understand why this levee may be extremely useful to us as humans. Autophagy was first described in the 1960s, but it took a back seat for the last twenty years to apoptosis, the new darling find in cell biology.
Autophagy is best described to the non-scientist as a mechanism the cell uses to auto digest cellular components. This is called microautophagy because it involves parts of the cell. Chaperone mediated autophagy (CMA) is a process of selective autophagy. Entire cells can be engulfed and taken out. The tissue then has more stroma/scars and less cells. This is precisely what occurs in heart disease. A dying heart loses heart muscle cells and replaces them with scar stroma. The remaining cells have to hypertrophy to compensate but they never can get back to the baseline and so the heart’s function slowly wanes with time. Autophagy is heavily influenced by mTOR signaling; therefore, what activates mTOR affects cardiac death. One of the major players in mTOR is the polyphenols of cacao. If you Google search the MARS Corporation and see what they are up to in the Amazon basin you might become very interested in slowing your own cardiac autophagy down. This topic will surely interest many people because it affects all of us with a heart.
Oncogenesis. I bet most of you thought this one would have been higher on the list? Most people really fear cancer. I think once we develop this part of the The Quilt it may move down in importance. Cancer incidence and prevalence has risen dramatically in the last 125 years in our country. I do not believe that something magically has changed in the world to cause this. Instead, I think our focus on curing cancer is completely backwards. I think we need to prevent it and not worry about curing it. Once cancer occurs we have a cellular mutant that is made immortal by altering normal cellular pathways to make it resistant to normal cellular death pathways. I doubt we ever get a chance to reverse it. I do however think once we know how cancer begins we can avoid it. If we control the cellular environment and limit damage to it, the cell will never have to make the choice to become immortal due to the chaos we are causing it. The factors causing cancer are all multifactorial and include: metabolic, dietary, environmental, genetic, senescent.
The key is to focus on the cell and not the cancer.
If we do many things correctly over long periods of time we will not face cancer, and I believe the incidence and prevalence will fall. Let me give you this scenario: In 1900 colon cancer was the 37th leading cause of death in the USA. Today, it is the second. So what exactly happened to us in this country in the last 112 years? There will be many theories after some read this. But my theory is simple: To have a huge short-term shift in a disease prevalence and incidence in an entire population ties it to a common source. That source is the introduction of cereal fibers and grains into our diet in massive forms. I think if you go back and read about how grains came to dominate American politics and culture, you will see several trends that begin with Mr. Kellogg, a growing population that needed cheap food, a large plot of land that was underutilized for years (the bread basket), and the political decisions that monetized the agriculture complex to cheaply feed the masses during a great economic downturn. Add that to the false hypothesis (See Ancel Keyes) made about animal products and proteins and fats as well as the promulgation of industrial seed oils loaded in omega 6 PUFAs (see Eisenhower’s cardiac issues) which was further expanded in the 1960s by the increase of soybean oil. In the 1970s we took Japan’s worst idea ever, high fructose corn syrup (HFCS), and tried to use it to replace all fats in everything that was food. From the 1980s on, we have gotten fatter and sicker and suffered from increased cases of colon cancer. Simultaneously, our government pushed USDA foods because they realized we could make lots of it cheaply and export it all over the world to make tons of money. The only part Senator McGovern did not foresee was the current healthcare nightmare that the US now faces. Our diet depletes the distal colon of omega 3s from butyric acid (butter) and limited use of fermented carbs that convert to protective omega 3s. This leads to ROS chronically in the face of constant glycation and lipoxidation. Are you starting to see how colon cancer went from 37th to 2nd in 112 years? Moreover, the explosion in the use of grains caused massive changes in our gut biology, breaking down our immunity to allow the guts toxins to see the gut-associated lymphatic tissue (GALT) and directly affect oncogenesis production through loss of p53 gene control. P53 gene is the guardian gene of our entire genome. Once it goes south, chaos ensues at the cellular level and oncogenesis occurs with amazing regularity.
If we change what we do to our cells, we avoid what we fear. It’s that simple.
Stem Cell depots. This one, I bet, will move up as I age. I think what we are learning now is nothing short of amazing. As autophagy and apoptosis take out cells as they age, get infected with vectors, eliminated by ROS, ALEs, AGEs, and many other things, they get replaced with new cells that are not differentiated as yet that are hiding in our stroma as soldiers in waiting. The real issue is we do not appear to have an unlimited supply of them. Scientists are now challenging that assertion, and I hope they are right, because if they are, we all might start living a long time.
The key to this levee is time and context. My theory holds that if you deplete your depot too early in life, your lifespan is shortened tremendously. In fact, I will be less tactful: If you abuse your body from ages 0-40, I think it has greater effects than if you abuse your body from 40-80. The reason is simple: The less we need to replace early in life allows us to have many more as we age when the effects of time and cellular damage accumulate. This is why the major diseases in humans all get more common as we age. We no longer have the reserves we once had. If science proves that we can go back and create pluripotential cells and reengineer our stem cell depot then this risk certainly lessens. Right now this option does not exist. Damaging your depot includes poor dietary choices, trauma, cellular and emotional stress, and endurance exercise. We need to protect our stem cells at every age but we tend to lose most of them when we are young because we do not employ a levee strategy until we get to the back half of life.
Sirtuins as a black box. Sirtuins have been described as guardians of the cell. They hit the scene in the early 2000s with the discovery of resveratrol and its effect on lifespan. In people, for example, they seem to halt the normal cellular cycle that ends with old cells committing suicide, and instead help rejuvenate them by beefing up their DNA repair processes and stimulating production of protective antioxidants. It appears that if a cell is at a point of deciding whether to live or to die, these sirtuins push toward the survival mode and allow the cell the option to survive longer to rejuvenate itself.
Sirtuin, or Sir2 proteins, are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity and are found in organisms ranging from bacteria to humans. Sirtuins work in calorie restricted states to improve cellular stress response and regulate transcription. However, their main effect is on energy generation by improving the NAD/NADH ratio to decrease mitochondrial leakiness at the first cytochrome. This generates less ROS than we would normally see. Resveratrol works with quercetin and is generally found in certain wines, grapes, and cacao chocolates. Quercetin is found in grapes and apples.
Sirtuins bring about the effects of calorie restriction in the brain’s IGF axis, known as the somatotropic signaling axis, which controls growth and influences lifespan and lengthens telomeres.
Apoptosis. Apoptosis is the preprogrammed cell death in animal cells. Apoptosis has certain biochemical features that characterize it. These changes include blebbing, loss of cell membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. Excessive tissue apoptosis is seen in atrophy and insufficient amounts occur in cancer generation.
Apoptosis is controlled by both intracellular and extracellular signals to affect the cell. Some of those extracellular processes are toxins, growth factors, nitric oxide, cytokines, and hormones. These signals can both positively or negatively regulate cell suicide. Intracellular signals come from glucocorticoids, heat, radiation, nutrient depletion, viral infection, and hypoxia.
Before the actual process of cell death is precipitated by enzymes, apoptotic signals must cause regulatory proteins to initiate the apoptosis pathway. This step allows apoptotic signals to cause cell death, or the process to be stopped, should the cell no longer need to die. Several proteins are involved, but two main methods of regulation have been identified: targeting mitochondria functionality, or directly transducing the signal via adaptor proteins to the apoptotic mechanisms. Another extrinsic pathway for initiation identified in several toxin studies is an increase in calcium concentration within a cell caused by drug activity, which also can cause apoptosis via a calcium binding protease, calpain. The process involves increasing mitochondrial permeability and induces swelling and eventual cell death.
Supply side stability. Clearly, if an organism doesn’t survive its early stages, then genes that promote survival in later life are meaningless. Supply side stability is important in the later stages of life to increase lifespan. It is becoming clear that the guardian of the genome gene P53 executes this function. P53’s main function seems to be inducing cell cycle arrest in somatic cells, the cells that currently make up our organs. They do not include stem cells or the cells of reproduction. If the cell cycle is arrested, that cell cannot go on to form a cancer because it cannot divide. Loss of P53 control, however, can and does lead to chaos many times. Ironically, it also appears that P53 controls the stem cell supply of many organs as well. This appears to be true in the mammalian brain based upon current research. It also appears that the cellular machinery used to go from stem cell to a somatic cell is present in human aging but the supply of stem cell is now the rate-limiting factor for longevity. This points to two areas of thinking: One, we must look to youth to keep the supply vibrant as we age, or two, we must figure out a way to reverse-engineer the somatic cells in our organs today back to the pluripotential cells that we had as children to redivide and replenish our diminished stock of stem cells. Sounds idealistic, no? It appears it is possible based upon what we now know. This levee will explore this area.
Adaptogens. These are plant derivatives that can affect the neuroendocrine and immune systems to bring back a sense of balance to those systems when they are deregulated by cellular stressors. These plants have been used for thousands of years in Chinese Medicine and Ayurveda medicine. Their longevity and safety is clearly documented by time, but western medicine often does not support their use because they have not been subjected to RCTs. It is ironic that most of the chemotherapeutic drugs western medicine uses are also used without an RCT but we seem to overlook this fact easily. The interesting point about adaptogens is that they have really begun to be looked at by research scientists recently because most of the adaptogens used for thousands of years have been shown to contain heat shock proteins that are very important in the biologic system. Licorice is very common in candies yet most Americans do not know that this is an adaptogen. So are Maca, Rhodiola, Resveratrol, Quercetin, Ginseng, Holy Basil, and astralagus. The interesting factor is that astralagus extracts are now commercially being developed by major biotech companies and being sold as telomere lengthening devices. TA-65 is one such example that was developed from Geron Corp. in the last 15 years. This is a levee that I think will grow in importance as we learn more about how adaptogens effect the biologic system.
Cellular Depletions. It appears that cellular damaging and aging can occur from depletion of certain co-factors. For example, the depletion of ATP in cells causes them to lose their cytoskeleton architecture very quickly. The cell can no longer function and undergoes apoptosis rapidly. This is most commonly seen in lack of oxygen or blockage of blood flow. (link) We have known in medicine for years that dialysis leads to early heart disease. For many years it was not well established why this occurred. We now know that dialysis membranes remove water-soluble proteins, and the B-complex vitamins are water soluble. This is why we see very high homocysteine levels in renal patients on dialysis. And the depletion of the B vitamins leads to early heart disease. Chronic Coumadin use depletes cells of vitamin K analogues. This leads to earlier osteoporosis and calcification in the blood vessels all over the body.
High levels of glucose, and fructose in the diet, causes cells to use massive amounts of B6 and Magnesium in the production of energy, leading to cellular depletion over time. This is clearly seen in diabetics and is being looked at in the development of neuropathy and nephropathy by those patients. B6 and Magnesium are also co-factors in the production of serotonin from 5HTP. This might explain why depression is more common in diabetics than in those who are not diabetic. Beta blockers and diuretics also deplete Magnesium and B6. Recently, the anesthesia literature has begun questioning the higher complications seen in those treated with beta blockers. See how depletion can hurt a cell or animal? Magnesium depletion is very common these days due to the diet being loaded with fructose. Drugs like Digoxin and Nexium are commonly used in older Americans and also deplete magnesium. These all cause restless leg syndrome in older people. This problem is endemic because of a wide variety of ways Magnesium is depleted in our diets.
HIV cocktails contain several antiviral meds that all deplete zinc. Zinc is vital for testosterone production and for wound healing. Certain legumes contain lecthins and phytic acid that block absorption of minerals from the gut, worsening the cellular environment. This levee will cover how cellular depletions can cause disease and rapidly increase aging.
Iatrogenic effects. This levee will concern itself with the negative outcomes we get from trying to heal or help the human live longer. Estimates have reported that close to 100,000 deaths a year are caused by medical errors—a fact that caused quite a stir when the study came out. I believe this number is actually too low because we do not realize how many things that we advocate for today are bad medicine in disguise. For example, an iatrogenic effect may be the use of mammography (X-rays) to detect breast cancers from 1 mm to 1 cm in size. We know X-rays are oncogenic, and since it takes decades to develop cancer there clearly is an iatrogenic risk here. We now have new technology, like thermography, being developed that can detect breast cancer much sooner. When I was in residency, thermography was looked at as quackery, but this technology uses angiogenesis and heat to detect changes in cells that are quite small in breast tissue. This technology was recently used to find and kill Osama Bin Laden in Pakistan and is currently deployed in all our smart weapons in our missile systems. It likely will make a huge impact in medicine, and change the standard of care, once it is realized how much more sensitive this technology is compared to the mammograms of today. It can detect cancers much smaller than 1 mm in size when they can easily be eradicated by today’s conventional treatments.
This levee will cover numerous areas of iatrogenic errors in dentistry, medicine, alternative medicine, denial, drug interactions, and in failing to diagnosis or treat issues. Many specialties will be discussed in this section as well as potential problems that can arise from complications.
DNA/RNA alterations. Over the last decade, the human genome project has allowed us to sequence our entire genome. This has allowed researchers to study genomic alterations and the mRNA they lead to. Those mRNAs tend to lead to genes that alter the DNA to force certain cellular biochemical pathways to become operational or to shut down completely. Genome-wide studies are now routine for examining diseases using arrays based on hybridization techniques. These studies have shown us much about how certain diseases begin and propagate, and how the biochemical pathways influence decision pathways in the cell. It allows us to identify genes that are expressed by certain stimuli in cells to cause disease propagation quite efficiently.
This levee will explore the complexities in DNA and RNA function and how both can affect the human or animal in aging and disease. For example, we now realize that fat lipodystrophy that occurs in HIV-positive patients is caused by the effects of antiretroviral drugs on depletion of mitochondrial DNA and RNA, and it leads to interactions that alter fat biology in these patients. This also explains why Growth Hormone treatment in HIV patients is quite effective in also restoring their normal body composition.
Hypoxia. Hypoxia is a cellular state that disrupts normal oxygen supply to the tissue, causing cellular dysfunction. Examples of this are altitude sickness at high elevations and clots in a blocked artery 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.
Hypoxia plays a role in aging because as one ages 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 causes cellular oxygen levels to fall and usually is a signal to mitochondrial biogenesis to offset the deficits. As one ages, this signaling system is not as accurate in sensing changes to the oxygen level. Low oxygen tension is a signal to autophagic pathways that normally help repair cells. If this gets impaired, signaling autophagy become less effective as we age and results in more organ failure and diseases of aging. Hypoxia is a critical signaling in the cell for repair processes. This is disordered in heart disease and in sleep abnormalities such as sleep apnea.
Organizational failure of structure. This levee will deal with organs and tissues, how they sustain failures as we age, and what we can do to prevent this. All organs have different rates of failure and some organs fail in typical patterns. We will look at ways to stop this from happening and at strategies designed to prevent it from occurring.
A simple tissue failure to understand is that of a bone fracture. This is well understood and rather straight forward to deal with. Osteoporosis is another type of failure of bone that is much more complex to deal with and is a result of the failure of multiple systems acting upon the bone. Heart failure is very common and occurs under autophagic control. The causes vary but we understand how the heart fails. What we do not understand well yet is how to modify the process to facilitate health as one ages.
For the brain, we now believe that most degeneration occurs by autophagic processes but it is clear that the interaction with other systems plays a huge role on its ability to stave off functional decline. We have already seen this in the brain-gut axis but it is clear that the brain is impacted by most other organ systems in some fashion once they begin to decline. The brain must compensate to offset that loss of efficiency.
In this levee we will look at organ systems and see how they fail both acutely and chronically over time, and see how these failures can be impacted by strategies to lessen their effects for increased longevity.
Heat shock proteins (HSP). HSPs are proteins that are only expressed when the cell is faced with higher temperatures or other cellular stress. It appears that heat shock proteins’ origins come from direct transcriptional processes once a stressor is encountered. Most heat shock proteins are named by their weight, but the more important ones have names. One such example is ubiquitin, which is a HSP that marks proteins for degradation. Most HSP can be thought of as cellular pathway chaperones that help the cell do the business of homeostasis more effectively. They are very active in infection, trauma, burns, inflammation, exercise, hypoxia, starvation, nitrogen depletion, alcohol use, UV radiation, and heavy metal poisoning.
The interesting thing about these proteins is that they seem to affect tertiary and quaternary structural folding of proteins in our bodies. This effect seems to be lost as we age so we see a defect in protein folding in aging related diseases. They also are critical in transporting proteins across cell membranes in all tissues. HSP are also vital in maintenance of steroid receptor function. Folding issues are thought to play major roles in Mad Cow disease, Alzheimer’s disease and Parkinson’s disease.
Sleep. Why we sleep is currently unknown. This sounds crazy considering we spend one third of our life sleeping, but it is factual. There are, however, some plausible theories. It appears sleep is vital for auto repair processes to occur in the body and brain. It also appears that sleep, and energy metabolism, are tightly regulated in the hypothalamus. Cognitive decline is obvious with sleep deprivation, and learning is impaired. Sleep apnea is a known killer in humans and generally appears in those with obesity, again linking energy metabolism to sleep. It appears that less than 5.5 hours or more than 9 hours of nightly sleep seem to predict a shorter longevity—clearly, sleep is critical to longevity.
This process is quite complicated but incredibly fascinating; we will explore many facets of how sleep and obesity are likely close relatives, and we will introduce you to concepts that you may not have ever heard of. I think sleep will turn out to be a top ten levee before too long, but there is so much we don’t know about it at this time it is hard to make a claim to put it there now. With energy metabolism at position two and sleep clearly tied to it, I guess you could say this is this documents quantum entanglement!
Hormesis. Hormesis is the biologic process that allows for a favorable biologic response on a cellular level to a small or low-dose exposure of the hormetic agent. A good example of hormesis is exercise. In the right amount, it confers longevity and lengthens our telomeres. In excess, it will hurt us by causing high cortisol levels and generating ROS to deplete our stem cells and cause us to use anaerobic energy production which does not suit our biochemistry long term.
When cells are faced with mild stressors, it seems to confer an increase in function and longevity. This occurs in all organs of the body that have been tested, but we do not know if this effect has a floor or a ceiling in some cases, though in others it is obvious. Too much exercise or alcohol can kill a human. This is true of stress and certain drugs as well. Cardiac hypoxia without cell death has been shown to increase cardiac output and stroke volume and improve heart function.
Curcumin and Ginger are examples of spices with hormetic effects. Resveratrol and Quercetin are plant polyphenols that have similar effects on humans. This levee will discuss this biologic process and its role in aging.
Geopathic stressors and Quantum biology. Geopathic stress is a natural phenomenon affecting certain places and can be damaging to our health. In some cases it may actually help us. Birds use geopathic stressors to map their flights during migrations. It relates to irregularities in the earth’s magnetic field, which can be aggravated by a variety of features. One way humans may be affected by this is from cell phones. The EMF signal appears to be a geopathic stressor. It also appears to be the root cause in the death of honey bees. Electric power grids, earth transitions in agriculture are well known geopathic stressors that can affect cellular function. Signs of geopathic stress are areas in the earth prone to mold or lichen formation. Many animals will avoid these areas because they function sub-optimally. Many in conventional medicine do not believe this is a factor, but quantum biology may help answer why this occurs. Many new exciting research areas are pointing to no-locality factors in the earth that dramatically affect the way biologic systems operate. This levee will examine this fascinating frontier of disease and see how it can affect our longevity.