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Notes from "Oxygen: The Molecule that Made the World"

These are my notes from "Oxygen: The Molecule that Made the World", by Nick Lane. The book goes into great detail about the origins of life and oxygen on Earth. It explains oxygen cycles and the effect the combustible molecule has on life. Of particular interest to me is the explanation of whether oxygen is good for us or not, especially how it relates to free radical production, disease, and aging in animals. The book is very thorough and a bit long but has great information.

Chapter 1

Breathing oxygen at high concentrations is obviously toxic. Breathing pure oxygen at two times atmospheric pressure causes convulsions and sometimes death. Breathing pure oxygen at atmospheric pressure can cause life-threatening lung damage.

The oxygen levels in the tissues of the body remain the same with slightly varying levels of oxygen concentrations in the air. The body adapts by producing more or less red blood cells based on the oxygen available. This means we cannot gain any long term benefit from either low or high oxygen levels.

All forms of oxygen toxicity are caused by the formation of free radicals from oxygen.

Free radicals are not just toxic. Fire is impossible without free radicals. So too is photosynthesis or respiration. When we use oxygen to extract energy from food, we have to produce free radical intermediates. The secret to all the chemistry of oxygen, whether we think of it as good or bad, is the formation of free radicals.

The idea that free radicals cause aging is disarmingly simple. We produce free radicals continuously inside every cell of our body as the cells respire. Most of these are mopped up by antioxidant defenses, which neutralize their effects. The trouble is that our defenses are not perfect. A proportion of these free radicals slip through the net, and they can damage vital components of cells and tissues such as DNA and proteins. Over a lifetime, the damage gradually accumulates until it finally overwhelms the ability of the body to maintain its integrity. This gradual deterioration is known as aging.

Chapter 2

Chemically speaking, oxidation refers to the removal of electrons from an atom or molecule. The reverse process is called reduction. Oxidation is named after oxygen, which is good at stripping electrons from molecules.

According to one theory, in early Earth, the cyanobacteria learned to harness the energy of the sun, and silently polluted their environment with toxic oxygen waste. Some of this oxygen would have reacted with minerals dissolved in the oceans or eroded from the rocks, oxidizing them and locking up the oxygen in mineral compounds. These enormous natural resources acted as a buffer against free oxygen for hundreds of millions of years. In the end, however, the buffer became completely oxidized. With nothing left to take up the slack, the oceans and atmosphere became contaminated with excess oxygen.

The overall reaction of respiration in which oxygen and sugars are consumed and the overall waste products carbon dioxide and water are produced, is almost exactly the opposite of photosynthesis and consumes essentially the same amount of oxygen that is being produced by photosynthesis.

The oxygen released by the photosynthesizers is almost completely, 99.99%, used up by the animals, fungi, and bacterial which feed on the remains of the producers or on each other. The apparently trivial 0.01% discrepancy however, is in fact responsible for all life as we know it. It represents the organic matter that is not burned, but is instead buried under sediments over several billion years. If organic material is buried instead of eaten, then the complete reuptake of oxygen by consumers is prevented. For every molecule of CH2O or its equivalent in other organic matter that is buried and not burned up by respiration, 1 molecule of O2 is left in the air. The leftover oxygen accumulates in the atmosphere. Almost all our precious oxygen in the air is derived from a 3 billion year mismatch between the amount of oxygen generated by the primary producers, and the amount used up by the consumers.

The original source of oxygen in the atmosphere was not photosynthesis however, but a chemical equivalent. Solar energy, especially the ultraviolet rays, can split water to form hydrogen and oxygen without the air of a biological catalyst. Hydrogen is light enough to escape the Earth's gravity. Oxygen, a much heavier gas, is retained in the atmosphere.

Chapter 3

The Principle of Mass Balance says that what's buried below the ground cannot be found above the ground. This basically allows us to do carbon-dating by examining the ratios of carbon 12 to carbon 13.

Chapter 4

Rock can be eroded by dissolved carbon dioxide, which is weakly acidic. As a result of this reaction, carbon dioxide is lost from the air and becomes petrified in carbonates.

The length of any food chain is determined by the amount of energy lost from one level of the chain to the next. This depends on the efficiency of energy metabolism. Energy metabolism is generally less than 10% efficient in the absence of oxygen. As a result, food chains tend to be very short in the absence of oxygen. Metabolism with oxygen is around 40% efficient.

Chapter 5

Oxygen can accumulate in the air if there is an imbalance between the amount produced by photosynthesis and the amount consumed by respiration, rocks, and volcanic gasses. Permanent burial of organic matter is the most important way of disrupting this balance because it prevents the consumption of oxygen by respiration. Organic remains that are buried are not oxidized to carbon dioxide so the oxygen is left over in the air.

Sprinters cannot breathe in enough oxygen to power their efforts, and their muscle cells must instead resort to the less efficient process of energy production by anaerobic glucose breakdown, or glycolysis, which produces a mild poison, lactic acid, as a byproduct. The more we persist in violent exercise, the more lactic acid builds up, until finally we are left half paralyzed even if we are running for our lives.

Chapter 6

The lethal effects of both ionizing radiation and oxygen poisoning are both mediated by exactly the same intermediates called free radicals. These intermediates can be produced from either oxygen or water. In radiation poisoning, they are produced from water. In oxygen poisoning, from oxygen. However, normal respiration also produces the same reactive intermediates from oxygen. Respiration can therefore be seen as a very slow form of oxygen poisoning. We shall hear that both aging and the diseases of old age are caused essentially by slow oxygen poisoning.

Ionizing radiation knocks electrons free of atoms and also produces many other effects including heat generation, electron excitation, breaking of chemical bonds, and nuclear reactions, such as nuclear fission.

The free radical is loosely defined as any molecule capable of independent existence that has an unpaired electron. This tends to be an unstable configuration that is quick to react with other molecules.

Free radicals cause the molecules they react with to become reactive, leading to a chain reaction.

Just one chlorine atom might set in motion a chain reaction that destroys 100,000 ozone molecules.

There are only two ways for a free radical chain reaction to end. When two radicals react with each other then their unpaired electrons can join in a blissful chemical union. Or when the free radical product is so feebly reactive that the chain reactions fissile out.

Taking electrons from water requires a large input of energy which can be provided by ionizing radiation, UV, or sunlight in the case of photosynthesis. Oxygen on the other hand releases energy when it reacts, a sure sign of favorable energetics. Burning is the reaction of oxygen with carbon compounds. The rate that the fuel is burned doesn't effect the amount of energy released. Whether it's burned quickly as in fire or slowly as in respiration, the same amount of energy is released.

Magnetism results from the spin of unpaired electrons.

Chapter 9

Only about 10mg per day of vitamin C are required to get rid of the symptoms of scurvy. When the dose is increased beyond 60mg per day, the excess vitamin C is excreted in urine, so there is no benefit beyond that amount.

In their normal bodily environment, collagen fibers are the most important structural and shock absorbing component of connective tissues including bone, teeth, cartilage, ligaments, skin, and blood vessels. In the absence of vitamin C, collagen fibers do not form properly.

In the process of collagen synthesis, vitamin C donates an electron to iron, which is embedded at the core of the enzymes that carry out the hydroxylation reaction. The iron thrusts this electron onto oxygen, which can now be attached to amino acids in collagen. In the process, iron is oxidized to the biologically inactive form Fe3+ until it receives an electron back from vitamin C.

The precise behavior of an antioxidant depends on its surroundings. Whether vitamin C acts as an antioxidant or a pro-oxidant, or somewhere in between, depends primarily with its reactions with other molecules.

Chapter 10

An antioxidant is an electron donor that prevents a substance from being oxidized, or stripped of electrons.

Two of the most important antioxidant enzymes are superoxide dismutase and catalase.

Antioxidant supplements have the potential to exacerbate some diseases.

Perhaps it is the balance of antioxidants and mild toxins that confers the benefits of fruits and vegetables.

Chapter 11

Even in the absence of predation or other life-shortening factors, there is a tradeoff between longevity and fecundity, in which the price of longevity is the suppression of fecundity earlier in life.

The "disposable soma theory" of aging argues that the rate of aging is dictated by the level of resources that are committed to bodily maintenance.

Chapter 12

There is some evidence that stature influences longevity in people. Populations studies show that small wiry men live on average 5-10 years longer than taller heavier men.

Chapter 13

Most mammals have the same number of heartbeats over their lifetimes. They also have roughly the same total volume of blood pumped, the quantity of glucose burned, or the weight of protein synthesized over a lifetime. Each of these parameters relates to the metabolic rates, which is quantified as the oxygen consumption per hour. Smaller animals generally have faster metabolic rates to maintain their body temperature. The constant is known as the lifetime energy potential. This is due to the fact that metabolism produces superoxide radicals. The faster the oxygen consumption, the faster these free radicals will be produced. Smaller mammals that life fast and die young have higher rates of free radical production. Across all mammals, there is an inverse correlation between free radical production and lifespan.

One exception to this rule is birds, which live much longer than the lifetime energy potential predicts. Studies have shown that the percentage of oxygen converted into free radicals in pigeons is about 10% of that in rats, corresponding to the roughly ten times longer lifespan of pigeons.

We are only just beginning to unravel the mechanism by which calorie restriction extends lifespan. The mechanism certainly involves the number of calories, rather than a reduction in any particular macronutrient. Calories restricted diets involve cutting calories by 30-40%.

Calorie restriction does not necessarily reduce metabolic rate at all. When measured in terms of metabolic rate per kilogram of lean weight, oxygen consumption may actually increase. Calorie restriction can therefore increase the lifetime energy potential to get more heartbeats. For male rats, this increase is in the order of 50%. The effects of calorie restriction are mediated by concerted changes in gene expression. In all animals studied so far, calorie restriction delays aging, not just the timing of death. This is true for more than 80% of the 300 indices aging tested in rodents, including physical activity, behavior, learning, immune responsiveness, enzyme activity, gene expression, hormonal action, protein synthesis, and glucose tolerance. The net effect of calorie restriction is to increase stress resistance. Blood glucose levels fall, and this in turn lowers insulin levels. Metabolism is switched away from sex and towards bodily maintenance. Resistance to oxidative stress increases, especially in tissues where damage is normally highest, such as the brain, heart, and skeletal muscle.

Stress can be avoided either through the countering action of stress proteins or by lowering the rate of respiration and the intensity of inflammation. The secret to a long life is low metabolic stress.

We can reasonably conclude that oxygen free radicals are a primary cause of aging, and that aging can be slowed down by altering the expression of genes responsible for bodily maintenance.

The evolved structure of the human body is simply not compatible with eternal life, unless we can find a way of replacing worn out neurons.

All of our mitochondria are inherited from our mothers. This is true for most organisms, including plants.

Even without succumbing to genetic disease, we will eventually die from mitochondrial wear and tear. The maximum human lifespan is around 115-120 years.

Chapter 14

If a gene becomes more or less active, the effects are felt by other genes. The activity of all genes depends on their immediate environment. In other words, the chemical balance inside cells. Oxidative stress shifts the spectrum of active genes regardless of the exact cause of the stress. The rise of oxidative stress over a lifetime means that many genes that are active when we are 20 are less active when we are 70, and vise versa. Other genes keep working throughout our lives, but their effects shift because their environment changes.

Cigarette smoke is dangerous because it is the most dastardly free radical generator known. A single puff of cigarette smoke contains 10^15 free radicals. Cigarette smoke also activates inflammatory cells, which at their own toxins to the brew. The result is oxidative stress, especially in the lungs and the walls of blood vessels.

Too much glucose is another modern killer. Poor control of blood glucose levels is the hallmark of diabetes. Glucose reacts in a complex manner with proteins to form brownish caramels that accumulate with age, known as advanced glycation end products (AGEs). This accounts for the clouding of the lenses of the eye in cataracts. Caramelization of protein is accelerated by oxygen, and most AGEs are really oxidation products. Caramelization blocks the function of proteins. AGEs, like amyloid, are free radical amplifiers. They are mostly formed by free radicals, and then exert their toxic effects by producing even more free radicals, causing oxidative stress and so inflammation. Because glucose is delivered to cells via the bloodstream, the vessel walls are most affected. In diabetes, small blood vessels in the eyes, kidneys, and limbs become damaged and blocked, causing blindness and kidney failure and all too often necessitating amputations. This whole process is speeded up in diabetes, but it happens at a slower speed in everyone as AGEs accumulate with age as a result of mitochondrial leakage in all tissues. For this reason, diabetes is usually referred to as a form of accelerated aging. It is really an accelerated form of oxidative stress. Inflammation of blood vessel walls induces cellular proliferation, oxidation, and deposition of cholesterol and the development of atherosclerosis.

Because oxygen itself produces the same radicals as ionizing radiation, it is in fact a carcinogen, or more technically, a pro-carcinogen. The more air we breathe, the more likely we are to get cancer, hence the strong association between caner and age.

Chapter 16

Plant toxins are likely to have beneficial effects on our immune system. This may help to explain why plants are beneficial to our health while antioxidant supplements are much less so.

High heme oxygenase activity makes people look younger.

There is a dilemma at the heart of immune modulation, however refined it is. The benefits are always part of a tradeoff between susceptibility to infections on the one hand and to age related diseases on the other. Any benefits will depend on a delicate balancing act in which genes, diet, environment, behavior, and luck all have a role.

To reverse the changes that take place as we age, we need to reverse the changes in gene expression, and this is much easier than altering the sequence of the genes themselves.

Bruce Ames and his colleagues reported that carnitine given together with lipoic acid improved the mitochondrial integrity and function in old rats and boosted their energy levels.

Exercise itself benefits mitochondria. The health of a population of mitochondria reflects the rates of replication and breakdown. Damaged mitochondria are broken down more slowly than healthy mitochondria in old tissues. Because the rate of mitochondrial replication is very slow in such tissues, the damaged mitochondria ultimately take over. This vicious circle can be broken by gentle exercise. When we exercise the higher demand for energy stimulates mitochondrial replication. The healthiest mitochondria now replicate fastest and this regenerates the stock of viable mitochondria. As usual, there is a catch. Vigorous exercise often causes more oxidative damage than it cures, and it is hard to know at what point we do harm. Gentle aerobic exercise like walking or swimming is probably about right.

Rational guide to live long: Eat widely, but not too much. Don't be obsessively clean or get overly stressed. Don't smoke. Get regular exercise. Keep an active mind. Start now.

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