Lecture 2 – Philosophical Underpinnings: Breaking Alzheimer’s – The Definitive Lecture Series

The first step in the Breaking Alzheimer’s journey is to understand the differences between health and disease, life and death, and average lifespan versus maximum lifespan. Loss of function leads to disease and then to death. The average time to death from a diagnosis of Alzheimer’s is about five years. So, let’s start by understanding death.

Death is the final time milestone. Our obsession with the end of our time creates a framework that we indiscriminately apply to everything. Everything must have a beginning and an end. This is the opposite of health. Health is indefinite. Only death is definite. Our obsession with time causes us to obsessively segment time into time windows and time-based milestones. Accordingly, the epidemiology of life expectancy has been studied extensively for hundreds of years. For most of recorded history, average life expectancy has hovered around 30–50 years of age. Since the advent of modern medicine, average life expectancy has dramatically improved to over 80 years of age in wealthy nations. This scientific and medical achievement deserves respect and praise. The remarkability of this success does not change the fact that it has nothing to do with improving human longevity. Our ability to reduce human death forms the basis of our success. Reducing death and increasing longevity are two distinct conceptual constructs, and they have absolutely nothing to do with one another. To use a sports analogy, reducing or preventing death is like playing to not lose. Increasing longevity is playing to win.

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The maximum human lifespan has remained virtually unchanged. A substantial amount of data from diverse geographical and ethnic populations indicates that the maximum human lifespan under our currently practiced diet, lifestyle, and medical technologies is (and has always been) about 115 years. The truth of these observations is that science has once again proven the obvious: diseases cause death. Science has also proven that the absence of disease does not cause longevity. This observation should not surprise anyone, and we cannot apply this logic to anything else in our lives. Fixing a flat tire does not make it last longer; it just enables the tire to live out its natural life within its current working environment and avoid premature death. The better we get at fixing tires, the more likely it will be that they live to their natural limit, improving their average life expectancies. This achievement has no impact on the maximum lifespan of the tire. To make the tire last longer, we need to rebuild and restore the wear and tear, or we need to change the tire’s working environment. Thankfully, the human body is not a tire. Focusing on disease and death prevention will not extend our lives, only prevent us from dying sooner. To live longer, we must preserve and enhance life, not only prevent death.

Cellular chemistry is the physical and classical physics and thermodynamics are the theoretical components necessary to maintain physical life. Our everyday physical realm is primarily governed by the first two laws of thermodynamics. The first law represents the conservation of matter (or energy). Matter (or energy) cannot be created or destroyed – only transformed. This law is absolute. This means that everything that goes into our body will be transformed within our body or it will come out, untransformed. Your biochemical books will always balance, whether you like the outcome or not. Our actions control how they balance. Understanding and applying the first law is paramount to being able to neutralize the second law. The second law is the law of entropy. This is a tricky law. This law is the heart and soul of aging. It is the one that chips away at our immortality. The general reading of this law is that all systems tend to devolve into greater and greater states of disorder or randomness. However, this is not technically true. Technically, the second law of thermodynamics states that energy will always flow from a high state to a low state and that heat will always flow from hot to cold. When you put an ice-cube into a cup of coffee the heat from the coffee will always move into the ice-cube.  The ice-cube will never get colder and the coffee hotter. A pile of lumber will not spontaneously turn into a house, but a house will spontaneously turn into a pile of lumber if left unattended. The point is that the more organized and ordered a system becomes, the more stored up energy is contained in it and the more energy is needed to maintain it. 

Your body started as a single cell, which was nurtured and fed as it divided and grew. An enormous amount of energy was expended to create the complex, ordered system that is your body. Every day, we convert carbon-based foods into carbon dioxide and water and use the energy released by this process to maintain this order. The human body has no thermodynamic purpose. The very existence of the human body defies thermodynamics. Likewise, death has no thermodynamic purpose other than the slow plodding of entropy. Scientists often misinterpret statistical associations as causative. They falsely believe that aging is a predetermined and active process. It is not, and it is illogical to think so. Aging is not a disease and, therefore, cannot be treated like one. Likewise, diseases of aging, like Alzheimer’s, are not diseases in the classical sense. They do not have a beginning or an end; so, they cannot be “cured” like a broken leg or an infection. They are ever-present. These diseases exist on a spectrum; they are balance sheet diseases. Your everyday living expenses are also ever present, and your income is constantly at war with them. If you want to take an unpaid holiday, you need to create an income reserve beyond the expenses that will occur during this time. Classical diseases are one-time expenses, like those incurred by your water heater failing. Diseases of aging are continuous expenses, like rent or electricity. Biochemistry is the currency your body uses to pay its bills — both one-time bills and continuous ones.

The human body is an affront to entropy. To achieve immortality (the honest word to use for maintaining health) you must be able to maintain this affront indefinitely.  From a thermodynamic perspective, immortality is the ability to keep your morning cup of coffee hot forever.

The core of our physical existence is electrochemical (discussed in detail in Lecture 9 – The Biochemistry of Oxidative Stress). This electrochemical energy is powerful, but it is dangerous. This electrochemical energy gives us life, but it kills us when it becomes uncontained. Due to its inherent danger, it is the most regulated and protected of all biological functions. Just because we take it for granted, does not change the fact that the first priority of your body’s regulatory systems is to ensure that this electrochemistry does not escape its biochemical constraints. Our ability to respond to voluntary and involuntary environmental changes and challenges depends entirely on our ability to redistribute electrochemical energy from one need to another. These environmental challenges range from stubbing your toe to getting a viral infection to throwing and catching a football. All of these challenges ultimately filter their way down to each of the 1,000,000,000,000+individual cells in your body. Each cell has a logic of its own that is optimized for its local environment, just like each of us has a logic in our daily lives. Somehow, we choose to be farmers or school-teachers or scientists and the longer we stay within a particular function the more optimized we become to perform that function.

The first logical construct to understand is that there is no central control of your cells – they are all regulated by their local environment – their local needs and their local demands. Think of a big city. Nobody is controlling the person working at the convenience store and the delivery driver and farmer, yet somehow you can go to a convenience store and get a quart of milk. The amount of milk at the store is also not centrally regulated. It is regulated by the use demands of the environment. All complex systems are self-regulated.

Each of the cells of your body contain the same genome. But they are all unique, all different. Their differences are based upon how each of them has adapted and optimized themselves to their individual and personal environments. To understand this reality, you have to understand how the biochemistry of your cells are organized and regulated.

There are three primary organizational levels that interact with each other to perform and regulate the daily operational needs of every cell in your body. The top level is genetics, also known as the genotype. Our individual uniqueness is written in our genetic code, and this genetic code is stored in the nucleus of every cell in your body. Your genome is a library of all the blueprints for all of the possible proteins that you are capable of making. The genome is not directly involved in any operational or structural functions of the cell. The middle level is the proteins.  Unlike the genome, each cell of your body has its own unique set of proteins. Collectively, all of the proteins in a cell are called the proteome. Proteins are the operational and structural components of your cells. Proteins are how your genes “sense” and adapt to their environment. The genome of each cell is only responsible for that cell. The only actions available to the genome to react to a changing environment is which proteins to make and how much of each protein to make. The nucleus of each cell “learns” how to best respond to changes in the cell based upon the effectiveness of its changes to its proteome. This is where the power of the genome ends. It can go no further. The third and final organizational level is all the small molecules or metabolites. Metabolites are not derived from your genotype; they are derived from the environment – both your internal environment and your external environment. Collectively, all your metabolites are called your metabolome. The primary purpose of your genome and proteome is to regulate and maintain homeostasis within your metabolome.

Metabolic precursors enter your cells and metabolic products and by-products and waste exit your cells. The proteins of your cells are the sensors that your genome uses to sense these changes – both on the inside of the cell as well as on the outside of the cell. It is changes in the metabolome that elicit compensatory reactions from your genome. Remember the first law of thermodynamics – matter and energy cannot be created or destroyed, only transformed. Proteins are how your body controls and manipulates this chemical energy.

We are all born with a genetic code that is comprised of a complex blending of mostly subtle gene sequence variations from generations of our ancestors. In its entirety, our genome comprises the sum total of biological responses that we are capable of executing. Our genome is born when we are born. It does not know where it will be born or under what circumstances it will be born. As we grow, it learns, just as we learn, its optimal responses to changes in the environment. It has no control over the environment that it becomes exposed to.

The second logical construct to understand is that your genes are not your enemy. They are you. Fighting with your own genes is the pinnacle of self-hate. The purpose of your genes is to keep you alive. They react and behave in a completely logical manner. Your genes react and adapt to changes in your metabolome. Human life exists solely based upon our ability to effectively apply the first law of thermodynamics within the second law of thermodynamics and constantly and artificially maintain maximum order. Every time an environmental mishap occurs at the cellular level, the result is always an electrochemical imbalance – which is severe disorder. The cell’s first reaction is to restore order and protect itself (you) by dampening energy usage and production. This dampening also turns down overall cellular operation and function. This creates a temporary new normal for the cell. The genome is doing its job by keeping the cell alive. When the internal and external environment returns to normal, the cell will gradually ramp itself back up to full production. But the cell remembers this bad event and becomes sensitized to similar insults in the future. Each time it experiences a similar event it responds more quickly and recovers more slowly, more cautiously.  This is how function is gradually lost over a lifetime. Eventually, the cell can become senescent.

It is easy to humanize this process. We all start life with a high degree of social trust. When we experience a negative social interaction, we recoil and become slightly less extroverted. We also become sensitized to a similar negative interaction in the future. However, if we continue to socialize and our continued social interactions are positive, we eventually recover our original extroverted behavior. If we experience multiple negative reactions, eventually we will stop interacting all together. At this point, we become the human equivalent of a senescent cell. If our extroverted behavior is positively re-enforced we become more trusting in our social interactions and more extroverted. A vibrant human society is one with a trusting extroverted environment. A diseased human society is one with a paranoid introverted environment. The human cellular environment is no different.

To maintain and restore cellular vitality, we must create a safe and trusting environment for our cells to flourish. They have to learn that it is OK to be young again. They cannot be forced. Current thinking in genetics and molecular biology is completely backwards. This backward thinking exposes our failure to accept responsibility for our actions and our ignorance. Genetic differences result in proteins with differing abilities to perform biological functions. However, only in rare circumstances is this function completely lost. Also, in most circumstances there are alternative protein adjustments that the genome can make to compensate for any one gene defect. Additionally, metabolomic adjustments can be made to sure that a genetic weakness is not stressed to the breaking point.

Genes cannot and do not cause disease. We cause disease. We cause disease by failing to understand how to modify our environment to match and support our genome.  Trying to modify our genomes to match our environment is a fool’s game unless we create a fixed and common environment for everybody’s genome to operate in – There will be a lot of food channels out of business if that was the case!

Your genome does not operate in secret. Its ability and inability to regulate the metabolome is evident every hour of every day. It is always broadcasting what it is doing. The problem is that nobody is listening. And your genome is left to fight its daily battles on its own never knowing if you are going to be working with or against it each day.

In Lecture 2 – Philosophical Underpinnings, Dr. Goodenowe explains the relevant research and literature relating to the basis of health, disease, death and longevity. The lectures integrate Dr. Goodenowe’s own research and over 50 years of research from leading researchers from around the world.