Health.

HOW TO DELAY THE AGING PROCESS AND HOW TO DELAY OR DAMPEN THE INFLAMMATORY DISEASES CORRELATED TO AGING

Preface

Old age is the largest risk factor for a plethora of medical conditions – from heart failure, stroke, cancer and dementia, to inflammatory and infectious diseases including COVID-19. Aging of the world population is the major challenge of the twenty-first century – it drains the healthcare budget, produces untold misseries that plague the elderly, and decreases overall productivity in the economy which places an economic burden on the shoulders of younger generations. To quote the Deputy Director of the USA Food and Drug Administration (FDA): “If you really are doing something to alter aging, the population of interest is everybody. It surely would be revolutionary if one could bring it off.”

Evidence

The concepts and statements in this article are based on information and data from thousands of peer-reviewed medical research publications; several medical trials and World Health Organization (WHO) registered clinical trials; and hundreds of published medical, biochemical and scientific textbooks. The insights, work and publications over 30 years of Professor Caleb E. Finch and his associates at the University of Southern California on Alzheimer’s disease, inflammation and longevity is acknowledged particularly. For latest publications on the anti-inflammatory effects of extracellular and intracellular magnesium see the many hundreds of peer-reviewed medical articles, at the US National Institutes of Health (NIH) National Library of Medicine website PubMed.gov that cite the anti-inflammatory and anti-cytokine effects of magnesium. For example, see J Immunol (2012).

 

Introduction

Philanthropists and entrepreneurs around the world, including successful Americans Larry Page (Google), Jeff Bezos (Amazon), Peter Thiel (PayPal) and Larry Ellison (Oracle) have invested substantial amounts of money (billions of US dollars) in companies exploring the possibilities of maintaining human health and extending human lifespan. The majority of these companies are biotechnology companies searching for specific genes or therapeutic products (for example, see Calico). The aim is certainly laudable.

 

However, professional human longevity research, including that published in the journal Genetics (November 2018) involving 54 million family trees and over 400 million individuals derived from six billion relatives and ancestors, apportions the majority of human health and longevity to external environmental factors and lifestyle factors and choices such as partners, diet and exercise. The role of genes (heritability) is diminished to less than 10 per cent. In the USA, it has been known for decades that health and longevity can be correlated to environmental factors, including constituents in drinking water supplies and the availability of clean air.

 

In multiple animal studies it has been shown that some bats and marine birds demonstrate little, if any, senescence and have long healthy lifespans that seem to defy explanation. In addition, a range of mammalian species have been identified that are highly fertile with increased lifespans of up to 30 per cent dependent on the specific environment in which they have been born and raised. As published in the relevant scientific and medical literature, there is extensive plasticity in the emergence and progression of senescence and associated diseases.

 

Using the above-mentioned human longevity research as a foundation, can we extrapolate from animals and their environments clear scientific evidence how senescence and associated degenerative and inflammatory diseases may be delayed or dampened, fertility may be maintained and lifespan may be increased in humans? The answer is: Yes. Due to the scientific rigor and professionalism demonstrated by geneticists, scientists and medical researchers, we havfound finally the paradigm and approach we have been seeking. There is little evidence that lifespan is set by cell processes that are intrinsically time-dependent. In terms of health and longevity, the concept that humans exist as individuals independent of their physical, nutritional and social environments is manifestly incorrect. It is an illusion, or more correctly, a misconception or self-deception. The information contained in this article allows the well-funded biotechnology companies to have a firm foundation now from which to move forward with the aim to prevent or treat a range of serious degenerative, inflammatory and debilitating diseases.

Purpose

The purpose of this article is to explore the possibility of delaying the aging process as much as possible so that degenerative, inflammatory and other diseases that are correlated to senescence can be minimized, dampened or prevented. Many medical researchers, particularly gerontologists, have the view that humans undergo senescence because of a lack of empirical knowledge in relation to the prevention of senescence. In other words, there are no absolute causal necessities for living organisms, including humans, to age physically and to suffer from age-related diseases.

Some animals do not die and others have long lifespans

Now, when it comes to populist medical health and longevity claims, one must keep an open mind – though, as the saying goes, the mind should not be so open that the brain falls out. Claims based on evidence are mandatory. However, like the allegory of Plato’s cave, there are realities beyond our perceptions and experiences. Certainly it appears incredulous, and comes as a surprise to many people, to learn that some species of animals do not die from old age. That is, there are some species of animals in which senescence has never been demonstrated. If they die, these animals appear to die from misadventure – not disease or old age.

 

On the empirical evidence available to us, it appears that some sponges do not die from old age, nor do sea anemones. One interesting ‘immortality’ is demonstrated by the jelly fish Turritopsis dorhrnii. Other invertebrates are quoted often as examples of animals that do not die from old age. These include species of flat worms, insects and lobsters. Apparently some lobsters are ‘immortal’ potentially – at least until they are so large that replacement of hard shell tissue at molting either becomes aberrant or takes such a long time that predation becomes inevitable.

 

Are there species of vertebrates that do not show signs of senescence? The evidence is controversial, though certainly the universality of aging in vertebrates remains unproven. In cold-blooded vertebrates such as fish and reptiles body growth appears sometimes to continue slowly and indefinitely. It is considered that only those species of vertebrates that reach a fixed size after maturation may be subject to senescence. Vertebrates that keep growing may keep living. Certainly, those female vertebrates that keep maintaining an egg supply appear to keep living.

 

A fish celebrated for continued growth and egg supply without evidence of senescence is the female plaice. Some ray-finned fish such as the sturgeon and rock fish appear also to have long lifespans with little evidence of senescent change. According to the number of rings on their scales, several rock fish and sturgeon have been identified that are at least 150 years old. Another fish, the Orange Roughy, roams the ocean at around 1,000 meters deep and lives for 200 years or more. Some species of sharks and tortoises, including the Greenland shark and the giant Galapagos tortoise, are quoted often as examples of vertebrates that do not die of old age – they die from misadventure or an unsustainable body size or body mass. It is estimated that the Greenland shark can live 400 years. And, one must not forget Jonathan, a Seychelles giant tortoise, apparently born in 1832 and now 188 years old and living as a celebrity in the grounds of the Governor’s mansion on the volcanic island of Saint Helena.

 

Some species of marine birds have demonstrated no evidence of senescence over periods of scientific study lasting more than 40 years. That is, on objective evidence and examination, their tissues and organs are still ‘young’. In a current celebrated case, the US Fish and Wildlife Service tagged a young (five year old) adult albatross in 1956 named Wisdom which is still laying eggs and hatching chicks on Midway Atoll at about 70 years of age. Wisdom is a Laysan albatross and spends 90 per cent of her life out at sea flying around the volcanic Hawaiian Islands. Does this constant aerobic exercise demonstrate that Wisdom is as wise as her name suggests?

 

What is special about the albatross, and other marine birds, that they appear to have long lifespans? How do these animals maintain high levels of energy for physical activity – both immediate bursts of physical activity and more prolonged physical activity? How do these animals maintain energy for cell and tissue growth and maintenance? How do these animals maintain excellent health? The majority of energy utilized in animal cells, including in particular brain, heart and muscle cells, is specific chemical energy produced in cell organelles called mitochondria. Brain (neurons), heart and muscle cells are packed with mitochondria. Long-lived animals, of necessity, must maintain mitochondrial function in their cells at an optimal level.  Would the maintenance of optimal mitochondrial function in human cells maintain health and increase human lifespan? The short answer is yes. However, to answer this question appropriately requires the use of some specialized scientific terminology for which it is incumbent on the author to apologize to many readers. Unfortunately, descriptions of life processes are complex and range from the unknown through the whole gamut of human knowledge – including knowledge of complex chemical and quantum processes.

The central role of mitochondria

The cell organelles called mitochondria are considered to have originated from symbiotic bacteria that invaded cells of ancient organisms over one billion years ago. Indeed, mitochondria are able often to reproduce themselves independent of cell replication. In animals, including humans, specific mitochondrial genes are inherited maternally via the cytoplasm of the ovum (not from chromosomes in the nucleus) and hence may be described as clones derived from female ancestors. See Mitochondrial DNA. What is so crucial about mitochondria that has allowed some mitochondrial genes, in a sense, to become immortal? One answer is: Mitochondria are able to convert the energy inherent in food molecules into a form of chemical energy that is vital for the life of body cells – hence, vital for their own mitochondrial survival. Technically (and apologies to non-scientists), mitochondria are able to transduce crucial electron quantum processes (including electron quantum tunneling) into vital chemical cellular energy storage. In mitochondria, electrons derived from food molecules pass along the inner mitochondrial membrane to an oxygen sink to produce water. The presence of optimal oxygen concentrations in mitochondria is absolutely vital for optimal mitochondrial function. Electrons transferred from food molecules to oxygen is the most important and fundamental process needed for mammalian and avian life. It must be emphasized that the maintenance of this process maintains cell and body life and that aberrations in this process may be the foundation of senescence and many major diseases. As an aside, about 10 to 20 per cent of total body water is derived from cell mitochondria in this way.

Cellular energy is magnesium-ATP

Mammalian and avian body cells utilize energy that is in the form of concentrations of chemical energy existing mainly as a molecule called ATP (adenosine triphosphate). The majority of ATP is produced in mitochondria. ATP is in a complex with magnesium ions to shield ATP’s negative charges. ATP exists actually in body cells as magnesium-ATP. Indeed, mitochondria are the main storage sites of magnesium in body cells. In mitochondria, magnesium-ATP is produced by an enzyme located in the inner mitochondrial membrane. Concentrations of hydrogen ions develop a concentration gradient and hydrogen ions pass through the enzyme which creates the conditions for magnesium-ATP production by the enzyme. See Figure 1. An excess of hydrogen ions in mitochondria (acidification) affects the enzyme detrimentally, by affecting the hydrogen ion concentration gradient. An excess of hydrogen ions also decreases electron transport along the inner mitochondrial membrane. As a consequence there is a decrease in magnesium-ATP production. A large decrease in magnesium-ATP production in mitochondria is considered to stimulate excess activity of the metabolic pathway in cytoplasm called glycolysis which may contribute to the development of cancer (see Warburg effect below).

 

Of particular health interest is the observation that the excess consumption of alcohol leads to cell acidification, a loss of magnesium from mitochondria and an increase in glycolysis which appears to result eventually in the predisposition to, or development of, cancer. The International Agency for Research on Cancer (IARC) has stated that alcohol in alcoholic beverages is regarded as a Group 1 listed carcinogenic compound.

 

Although the majority of magnesium-ATP is produced by the above-mentioned enzyme located in mitochondria, some magnesium-ATP is produced by different enzyme reactions in the glycolysis metabolic pathway of cytoplasm independent of mitochondria. At least three of the enzymes in glycolysis are dependent on magnesium as a cofactor for their activity. Magnesium-ATP production from glycolysis is prominent in the ‘fast’ (or white) muscle fibers of animals, including bats and birds, where short bursts of speed are required. The fast muscle fibers of animals contain less mitochondria than the ‘slow’ (or red) muscle fibers. Indeed, fast muscle fibers have less than half the mitochondria of slow muscle fibers. As a result, fast muscle fibers tire quickly. Human muscle consists of both fast and slow fibers. An athlete who uses bursts of speed uses mainly fast muscle fibers; an athlete in an endurance run uses mainly slow muscle fibers.

Abberations in mitochondrial function

Are aberrations in mitochondrial function correlated to aging and the degenerative, inflammatory and other diseases associated with aging? Depending on the disease, the answer is yes – particularly for heart disease, dementia and cancer. For example, many invasive cancers have a large impairment in magnesium-ATP production in mitochondria of cancer cells. There is an increased rate of magnesium-ATP production by glycolysis in the cytoplasm of these cells with a concomitant increase in lactic acid production. This phenomenon is known as the Warburg effect and has been studied by cancer researchers extensively. [See also the Warburg effect and cancer. And see the Warburg effect and mitochondrial stability.] Indeed, it is the Warburg effect that is the basis for positron emission tomography (PET scanning) that is used for cancer diagnosis and measuring therapeutic responses. More on mitochondrial dysfunction and cancer later.

 

There has been a large increase in recent years in the number of medical and scientific research publications that relate mitochondrial dysfuncti0n to pathology and disease (particularly heart disease, dementia, cancer and diabetes). Peer-reviewed publications at the US National Institutes of Health (NIH) National Library of Medicine website PubMed.gov that involve mitochondria and diseases number over 10,000. Mitochondrial function is extremely complex and the concentration of the mitochondrial matrix is 500 milligrams per milliliter. This concentration makes the mitochondrial matrix a gel or glue rather than an ideal biochemical medium (as used in laboratories). It is thought that this intense concentration favors quantum effects (proton delocation; proton tunneling) which are essential for all life processes.

Maximum lifespan equation and graph

There is a well-known equation (The Mammalian Lifespan Equation) and well-known graph (The Mammalian Lifespan Graph) that describe the correlation between the lifespan of a mammalian species and the species’ body mass. See Figure 2. The heavier the species of mammal, the longer the lifespan – though lifespan increases disproportionally slower than body mass. A mouse lives three years, a pig lives eight years, a horse lives 30 years and an elephant lives 60 years. But bats are mammals and yet bats do not fit the mammalian equation or fit the mammalian graph. Not even close. The little brown bat (Myotis lucifugis) weighs half the weight of a mouse and lives five to 10 times as long. Many bats weigh 10 grams and live to 15 years – outliving other mammals that weigh 1,000 times more. How can this be? It appears small size is not a strict constraint on life span. Are bats similar to marine birds in relation to longevity? If so, how?

 

Birds that have evolved physiological processes to sustain periods of flight such as albatrosses, condors, macaws, ravens, parrots, gulls and fulmars live up to about 60 years. Birds may live to about 10 times as long as mammals of equivalent body weight. A storm petrel weighing 40 grams lives 40 years, a mouse weighing 30 grams lives three years. Birds are warm blooded, have body temperatures at least three degrees centigrade higher than mammals, have much higher heart rates and higher metabolic rates than mammals and produce as many, if not more, oxygen radicals and other free radicals in metabolism. On these criteria birds should not live as long as mammals. Birds function at the temperature of a severely fevered mammal and yet may live 10 times as long. Birds, like bats, have longevity that does not fit the mammalian lifespan equation or the mammalian lifespan graph. One could argue that birds aren’t mammals and therefore birds can’t be compared to mammals. But this logic doesn’t help explain interesting data or help advance knowledge.

Carbon dioxide and oxygen

Much of the food that is consumed by mammals and birds, particularly carbohydrates, is broken down in cell metabolism to carbon dioxide and the carbon dioxide is breathed out (expiration) from the lungs. In humans, this results in at least 300 liters or up to half a kilogram of carbon dioxide being removed by the lungs and breathed into the atmosphere each day! More carbon dioxide needs to be removed from the body if more food is consumed and metabolized. [Note that the term ‘carbohydrate’ is based on the chemical formation of carbohydrate (by photosynthesis in plants); that is, ‘carbon dioxide hydrated’.]

 

In the body, the majority of carbon dioxide derived from metabolism of food originates from the central matrix of cell mitochondria. Carbon dioxide in high concentrations reacts with intracellular water to produce hydrogen ion concentrations (‘carbonic acid’), in both cell mitochondria and cell cytoplasm. The higher the carbon dioxide concentration the higher the concentration of carbonic acid hydrogen ions. Cell acidification decreases magnesium-ATP production significantly. Excess hydrogen ion concentrations need to be moderated or buffered in order not to affect the production of magnesium-ATP in both the mitochondria and the cytoplasm. Chemically, excess hydrogen ion concentrations in cells and tissues (increased acidity) increase the severity of a range of damaging oxidation reactions – including free radical reactions. [Theoretically, this follows from the famous Nernst equation – named after the Nobel laureate Herman Nernst]. Hydrogen ion concentrations need to be optimally moderated or buffered if cell energy and consequent longevity is to be obtained. Do birds and bats moderate excess carbon dioxide concentrations or moderate or buffer excess hydrogen ion concentrations produced by carbon dioxide so that they obtain longevity? Let’s look at the anatomy of the lungs of mammals, including bats, and the lungs of birds. The lungs are the organs that remove most carbon dioxide from the body of mammals and birds.

 

The lungs of mammals contain millions of blind-ending alveoli where gas exchange (carbon dioxide and oxygen) occurs. These alveoli are small blind sacks without a through-flow of air. The alveoli are never emptied completely, so inspired air is mixed always with ‘stale’ air of relatively high carbon dioxide concentration and concentrations of air pollutants. In contrast, the lungs of birds consist of long narrow open-ended tubes called parabronchi. Fresh air is moving always through the parabronchi due to a system of air sacs that function somewhat like bellows. The air sacs allow birds to keep fresh air (oxygen) flowing in flight during both inspiration and expiration. There is no ‘stale’ air of high carbon dioxide concentration, and depleted oxygen concentration, in the lungs of birds. In addition, air flowing through the avian lung moves in the opposite direction to the blood supply. This allows for an efficient counter-current exchange of gases.

 

Do bats have efficient gas exchange in their lungs that permits efficient removal of excess carbon dioxide concentrations from the body? The answer is: Maybe. Small bats in particular have lungs that appear nearly as efficient physiologically as birds (despite ‘less efficient’ lung anatomies). But bats possess a further method of eliminating excess carbon dioxide concentrations from their bodies. On a weight basis, bats have a relatively larger skin surface area than other mammals. This contributes to carbon dioxide loss. For example, the large thin hairless wing membranes contribute up to about 10 per cent of the total carbon dioxide loss in bats. In addition, those bats that hibernate, including the little brown bat, drop their body temperature considerably which slows metabolism and decreases carbon dioxide production to negligible levels.

 

Both birds and bats are good flyers and can even migrate over long distances. Normal flight requires an eight to ten fold increase in oxygen consumption and during flight bats have a similar oxygen consumption to birds of similar body weight. This high oxygen consumption contributes to their longevity. But bats have mammalian denucleated red blood cells whereas birds have nucleated red blood cells. How can red blood cells that are so very different have very similar gas exchange (oxygen/carbon dioxide) capabilities? Normally, carbon dioxide from metabolism in the tissues mainly promotes dissociation of oxygen from hemoglobin in red blood cells to supply oxygen to the tissues. In birds and bats, it appears that the acidification of blood from lactic acid, derived from high metabolic rates required for flight, dissociates oxygen from hemoglobin to supply oxygen to the tissues. In addition, the high body temperature of birds contributes to the dissociation of oxygen from hemoglobin. The dissociation of oxygen from hemoglobin under acidic conditions is known as the Bohr effect. [The Bohr effect is named after the Danish physiologist Christian Bohr – father of the famous physicist Neils Bohr, one of the founders of quantum physics.]

Increased longevity in domestic animals, including  cattle, sheep and horses

There are places in the world where domestic animals, including cattle, sheep and horses have been identified to live about 30 per cent longer than neighboring animals, maintain high fertility for longer than neighboring animals and have delayed senescent changes. See Figure 3. On many pathological and technical tests, it has been found that biological and molecular order are maintained for prolonged periods. For example, in sheep in parts of Australia, wool fiber quality is maintained for longer than wool fiber quality in sheep in other areas. That is, the complex physiology of skin and fiber production is maintained. [This gives a commercial benefit to local farmers who sell their mid-age sheep as young sheep in neighboring areas!]. In North America, some dogs and cats in particular have delayed senescent changes. These long-lived domestic animals, without exception, consume drinking water from a young age that contains high concentrations of calcium, magnesium and bicarbonate. The water generally derives from magnesium-rich volcanic basalt springs. Note that mitochondria contain high concentrations of magnesium, enzymes in glycolysis require magnesium, the universal chemical energy supply to body cells is magnesium-ATP, and bicarbonate can buffer excess hydrogen ion concentrations formed from carbon dioxide. Indeed, healthy human plasma contains large concentrations of bicarbonate for this, and other, buffering purposes. It is known also that magnesium regulates volume, ion composition and magnesium-ATP production within mitochondria which modulates the metabolic interaction between mitochondria and the host cell. For example, see Arch Biochem Biophys (2011). [It is to be noted that the tumor suppressor p 53 gene appears also to regulate the balance between glycolysis and mitochondrial function. See later below.]

Increased longevity in humans

We come now to a scientific investigation conducted under the auspices of the National Research Council of the National Academy of Sciences in the USA. The results of the investigation were published in a US Government report titled Aging and the Geochemical Environment. Increased longevity (low death rate) areas and decreased longevity (high death rate) areas were identified in the USA and correlated to factors in the geochemical environment. In the population group studied, aged 35 to 74 years, the increased longevity areas had death rates from natural causes of about 10 per 1,000 population. The decreased longevity areas had death rates from natural causes of about 20 per 1,000 population.

 

In the investigation, the increased longevity areas had drinking water with high concentrations of calcium, magnesium, sodium and bicarbonate. In particular, magnesium concentrations exceeded 30 milligrams per liter and bicarbonate concentrations exceeded 200 milligrams per liter in most waters. Some drinking waters had considerably higher magnesium and bicarbonate concentrations. The decreased longevity areas had drinking waters with low concentrations of calcium, magnesium, sodium and bicarbonate. Magnesium concentrations were below five milligrams per liter and bicarbonate concentrations were below 100 milligrams per liter in most waters. Despite a vast range of geological variables, the large difference in magnesium concentrations in drinking water was the most significant difference between the increased longevity areas and the decreased longevity areas in the USA. What is remarkable is that the beneficial influence of magnesium in drinking water could be demonstrated despite a range of different lifestyles and the consumption of a range of different foods and liquids (fats, alcohol, etc.) in a range of different geological and sociological areas.

 

There have been other investigations involving drinking water supplies that correlate longevity with water containing magnesium. These investigations have been completed in Europe, Japan, Britain, USA and Canada. Many of these investigations involved examining epidemiological evidence of the role of drinking water supplies in prevention of atherosclerosis, heart disease and stroke. It was found often that magnesium concentrations that exceeded 30 milligrams per liter in drinking water were correlated significantly to decreased prevalence of heart disease. Heart muscle cells require a large amount of chemical energy (magnesium-ATP); consequently they contain large numbers of mitochondria that all require magnesium for optimal function. In addition, heart disease often results from inflammation of heart muscle and/or atherosclerosis of coronary arteries. The role of magnesium in dampening inflammation and the role of magnesium in possibly preventing atherosclerosis by decreasing parathyroid hormone release from the parathyroid glands is discussed below. Parathyroid hormone has been often labelled the ‘slow death’ hormone.

 

According to the USA National Institutes of Health (NIH) Magnesium Fact Sheet for Health Professionals, magnesium is required for the synthesis of DNA, RNA and the major antioxidant glutathione. The NIH states also that magnesium is a cofactor for more than 300 cell enzyme systems in the body that regulate protein synthesis, muscle and nerve function, blood glucose control and blood pressure regulation.  Magnesium is vital to nerve conduction, muscle contraction and normal heart rhythm. According to the published medical literature, many diseases have been associated with low magnesium status or low serum magnesium concentrations.  These diseases are among the main causes of morbidity and mortality in Western societies and include Type 2 diabetes, hypertension, atherosclerosis, coronary heart disease, heart attack, stroke, the metabolic syndrome, osteoporosis and osteoarthritis. What is not known with certainty is whether low magnesium status is the cause of these diseases or the result of these diseases.

Clinical trial results

In a major World Health Organization (WHO) registered clinical trial conducted in a prestigious medical teaching hospital, water that was consumed with added magnesium (120 milligrams per liter) and bicarbonate (600 milligrams per liter) was found to be a source of systemically available magnesium that significantly increased serum magnesium concentrations and significantly stabilized serum parathyroid hormone concentrations. Cell chemical energy stores (creatine phosphate) were increased significantly. In conjunction with further experiments, this increase in creatine phosphate was interpreted to have derived from increased serum magnesium that had entered body cells (that is, had become intracellular). This finding has health significance for controlling inflammation and disease because intracellular magnesium can modulate pro-inflammatory pathways stimulated by calcium. Indeed, it has been found recently that intracellular magnesium concentration is correlated strongly to extracellular magnesium concentration in a dose-dependent manner and that intracellular magnesium homeostasis is essential for anti-viral and anti-tumor immunity. Magnesium supplementation in certain patients restores intracellular magnesium concentration and promotes natural killer cell activity while concurrently reducing Epstein-Barr virus infected cells. See medical research article in Science (2013).

 

The concentrations of magnesium and bicarbonate consumed in water in the clinical trial were identical to that consumed by long-lived dogs, cats, sheep, cattle and horses described above. The significant increase in serum magnesium in the clinical trial was sufficient to provide magnesium as an agonist for the calcium-sensing receptors of the parathyroid glands which resulted in significant clinical stabilization of parathyroid hormone (‘slow death’ hormone) release. See Figure 4.

 

As identified in the clinical trial, extensive medical literature confirms also that magnesium acts as a ‘brake’ on parathyroid hormone release. That is, magnesium is an agonist of calcium for calcium-sensing receptors of the parathyroid glands (in other words, a calcium antagonist). Importantly, magnesium is considered to dampen inflammation and inflammatory responses by acting as an intracellular antagonist to calcium and modulating the opening of intracellular calcium channels involved with inflammatory responses. See review articles in Arch Biochem Biophys (2007) and Arch Biochem Biophys (2011). Low magnesium levels are implicated in inflammation and endothelial dysfunction resulting in cytokine exaggerated responses. See review articles in Ann Nutritional Metab (2012) and Magnes Res (2017). [See description later of cytokine responses in Coronavirus diseases.] Chronic inflammation is correlated so strongly to aging that the term ‘inflammaging’ has become synonymous with senescence. For more results from the magnesium clinical trial visit magnesiumremedy.com.

Parathyroid hormone

It has been found that if parathyroid hormone is continuously elevated, even for a few hours, it initiates processes leading to the resorption of bone with a consequent increase in plasma phosphate concentration. Increased plasma phosphate is associated with a range of cell pathologies. Clinically, continuous elevation of parathyroid hormone, with consequent bone resorption, results in osteoporosis. It is known that the parathyroid hormone receptor is expressed extensively in various tissues including blood vessels, cartilage and skin.  The receptor on cartilage cells (chondrocytes) is considered to play a role in the development of osteophytes in arthritis. The receptor on stem cells and smooth muscle cells in the walls of blood vessels may play a role in atherosclerosis and vascular calcification; indeed low grade inflammation and pathology of capillaries and small arteries is considered a factor in many, if not most, degenerative diseases. It is known that the phosphate removed from bone substance (hydroxyapatite) under the influence of parathyroid hormone instigates crystal formation in the walls of small arterties. Pathology of small arteries and pathology of capillaries by parathyroid hormone/phosphate/inflammation combination is considered to be a factor in the acute pathology of COVID-19 (see below). Alterations in plasma parathyroid hormone levels per se are associated with cardiac dysfunction and detrimental cardiac remodeling. There is medical epidemiological data on parathyroid hormone levels correlated to clinical diseases. For example, see Circulation (2009). There is medical data associating elevated parathyroid hormone and low magnesium with osteoarthritis. Indeed, osteoarthritis can be severe in people with low magnesium status. For photos of the treatment of clinical osteoarthritis with magnesium and bicarbonate see Figure 5.

Bats hang upside down

It appears on empirical evidence that optimal levels of magnesium and oxygen are necessary for optimal mitochondrial, cell and body function. It appears also that excess carbon dioxide concentrations and consequent high hydrogen ion concentrations (acidity) need to be moderated or buffered. This can be achieved certainly to some extent with bicarbonate or water consumption. But does hibernation and an extra 10 per cent carbon dioxide loss through the thin wing membranes of bats explain their absolutely extraordinary longevity relative to other mammals? Bats just hang around upside down much of the day and squabble. But wait. Carbon dioxide is 50 per cent heavier than air. When bats hang upside down, and squabble and move, much of the excess carbon dioxide (and small particles from dust, pollen and polluted air) in their lungs falls out due to gravity and leaves the lungs. [In upright, and often sedentary, humans carbon dioxide (and small particles from polluted air and cigarette smoke) concentrates in the lower lobes of the lungs due to gravity.] Like birds, there are no excess carbon dioxide concentrations or excess hydrogen ion concentrations (acidity) in the body cells of bats. Instead of being dangerous and vile animals as portrayed in novels and movies, bats have developed a method of excess carbon dioxide removal in order to survive and therefore have given us an insight into the role carbon dioxide plays in senescence. Indeed, a fungal disease of bats in Canada and the USA called white-nose syndrome affects the nose and the skin of wing membranes resulting in a large increase of carbon dioxide in the blood (up to 50 per cent) with a consequent increase in hydrogen ions (acidosis) in the blood. The diffusion of carbon dioxide from the body is hindered by the swollen tissues of the nose and wing membranes. White-nose syndrome in bats is invariably fatal.

 

In both animals and humans, exhaustive scientific studies have demonstrated clearly that the environment is the strongest determinant of lifespan. Not only do outcomes of aging depend on lifestyle choices, diet and exercise, but also on exposure to air borne toxins which are now known to have major roles in aging. Air borne toxins induce oxidative stress and inflammatory responses shared with many diseases and aging processes. Toxic particles and vapours penetrate deep into the lungs which causes oxidative stress and the inducing of genes for detoxification and inflammatory pathways throughout the body. Oxidative stress is enhanced under acidic conditions. As stated above, when bats hang upside down, much carbon dioxide and small particles from air fall out due to gravity and leave the lungs.

 

Bats are hosts to an impressive number of coronaviruses. Many of these viruses appear to exist in bats without causing any major disease. These coronaviruses include the viruses, or direct ancestors of the viruses, that cause epidemics in humans SARS-CoV-1 (SARS), SARS-CoV-2 (COVID-19) and MERS-CoV (MERS). The World Health Organization (WHO) states that the virus causing COVID-19 has arisen naturally from bats. See Coronavirus disease 2019 (COVID-19) WHO Situation Report – 94.

 

Accepting that bats may possess an immune system that restricts virus numbers and infectivity, are there other factors such as physiological factors and biochemical factors that prevent coronavirus disease outbreaks in bats? Bats aren’t all that compliant with physical social distancing and physical isolation, yet bats do not appear to suffer from coronavirus epidemics. Accordingly, during the time it takes for humans to develop an effective vaccine against COVID-19, or an effective anti-viral treatment, shouldn’t we be asking the questions: What are the physiological and biochemical differences between humans and bats that protect bats from coronavirus disease outbreaks or, at least, dampen the severity of coronavirus disease? Can humans use knowledge of these differences to possibly prevent or lessen COVID-19 and dampen its detrimental effects? It must be realised that there has never been a successful vaccine against any coronaviruses in humans. Indeed, many coronavirus vaccines trialed in animals have caused acute pathologies. Accordingly, prevention strategies may be the best option until a successful vaccine arises. And, according to the WHO, the coronavirus causing COVID-19 may never go away which supports the concept of prevention by either vaccine (when available) or other strategies (now). And, any antibodies developed to COVID-19 seem to decline completely within months.

 

It is known with coronavirus infections, particular in COVID-19, that the real danger is not from the virus per se but from an uncontrolled overreaction of the body’s immune system. This overreaction of the immune system is manifested by what is known as a ‘cytokine storm’ where a flood of inflammatory chemicals (cytokines) produce inflammation of the heart, blood vessels and lungs. Damage to the heart, blood vessels and lungs results in a lack of oxygen to body organs with subsequent death in some individuals. See Coronavirus affects the blood vessels as well as the lungs. Aged individuals, with their senescent cells and tissues and metabolic pathologies, are particularly vulnerable – particularly those with poor kidney function and aberrations of the hormones of the bone-kidney axis (dehydration, low calcitriol/vitamin D status, increased parathyroid hormone levels and increased phosphate levels for example). Some young people appear to be susceptible also. Multisystem Inflammatory Syndrome (MIS-C) of young people appears to be a disease linked to COVID-19 where there is an excessive inflammatory response. [Inflammatory response partially as a result of a low magnesium and high phosphate, high calorie diet?]

 

It is to be noted that the virus causing COVID-19 attaches to the cell receptor known as angiotensin-converting enzyme 2 (ACE 2). This cell surface protein enzyme (ACE 2) protects blood vessels, lung and heart from the pro-inflammatory effects and vasoconstrictor effects of the blood pressure hormone called angiotensin II. Protection from angiotensin II is lost when the COVID-19 virus (SARS-CoV-2) binds to the ACE 2 receptor. Angiotensin II produces its pro-inflammatory and vasoconstrictor effects through a process involving a rise in intracellular calcium levels. Would an increase in intracellular magnesium levels dampen inflammatory and vasoconstrictor processes? It has been found recently that intracellular magnesium concentration is correlated strongly to extracellular magnesium concentration in a dose-dependent manner (see Appendix 1). Extracellular magnesium rises with the consumption of certain well-defined magnesium salts. See clinical trial results at magnesiumremedy.com; and see Nutrients (2019); and see BMC Nutrition (2017).

 

ACE 2 appears to increase in concentration in endothelial cells of capillaries associated with additive pathology from previous diseases. It is considered that the more ACE 2 cell receptors that occur, the more COVID-19 virus that can attach and enter cells. Hence, old age and obesity and ongoing disease pathology become factors in the seriousness of COVID-19 pathologies.

 

Bats possess low body acidity (low carbon dioxide concentrations), low body phosphate concentrations (bats, like marine birds, excrete phosphate as guano), and optimal dietary magnesium levels. In addition, bats consume food with low calorie density. These parameters are known to prevent, modify or dampen inflammatory responses in a range of diseases in all animals studied – including inflammatory responses to lung injury. Bats have evolved a way to prevent or lessen coronavirus diseases and their detrimental effects. It is relatively easy for humans to adopt the above parameters to prevent the severity of COVID-19. Humans also have several advantages that bats don’t have – humans can adopt physical social distancing and have continuous access to drinking water (which results in optimal hydration, optimal kidney function, optimal phosphate excretion and optimal electrolyte balance with associated acid excretion).

 

Do the long-lived humans in the USA who consume high levels of magnesium in drinking water possess a diminished prevalence of coronavirus diseases? Evidence from medical trials suggests that those people consuming at least 100 milligrams per liter magnesium in water may not suffer symptoms of the common cold (the common cold virus is a coronavirus). Does magnesium in drinking water dampen an overreactive immune response? Magnesium appears certainly to be anti-inflammatory. [See the many hundreds of peer-reviewed medical articles, at the US National Institutes of Health (NIH), National Library of Medicine website PubMed.gov that cite the anti-inflammatory and anti-cytokine effects of magnesium.] Published epidemiological articles suggest that magnesium deficiency may be a factor in the acute pathology of COVID-19. See J Am Coll Nutr (2020). And see Magnes Res (2020). It is known that magnesium in bioavailable formulations can restore intracellular free magnesium which is essential for reducing virus infections and improving tumor immunosurveillance. See Science (2013). Indeed, recent clinical evidence appears to support the treatment of acute cases of COVID-19 with 100 milligrams per day of magnesium (plus an essential element of the bone-kidney axis – vitamin D).

 

It appears that appropriate magnesium concentrations in the body have far-reaching implications relevant to a wide range of inflammatory-mediated diseases, including the development of interventions inhibiting pathological inflammation while leaving the immune system capable of responding appropriately. See J Immunol (2012).

Calorie restriction

How can mammals that aren’t bats, including humans, either prevent or remove excess carbon dioxide concentrations and excess hydrogen ion concentrations from the body? One answer is: In the first instance, limit the consumption of excess food that invariably produces excess carbon dioxide – particularly in the evening when food consumption is followed by a lack of physical activity during hours of sleep. Have scientific studies been published that show decreased food consumption, and subsequent decreased carbon dioxide production, improves longevity in any laboratory mammals? Yes, these studies have been repeated many times over the past 60 or more years. Experiments involving food (calorie) restriction in rodents still represent one of the only repeatable and successful active assaults that have been made on the problem of senescence and associated degenerative diseases in mammals. Rodents on calorie restricted diets live about 30 per cent longer than control groups on unrestricted diets. Note that an increase in lifespan of about 30 per cent is identical to the increase in lifespan of some dogs, cats, sheep, cattle and horses that consume from a young age calcium and magnesium and bicarbonate in drinking water that is derived from volcanic basalt springs. It has been observed in many experiments that rodents fed calorie restricted diets suffer less from degenerative diseases, chronic inflammatory diseases and cancer than control animals. The large increases in parathyroid hormone (the ‘slow death’ hormone) that occur naturally with aging and degenerative diseases in laboratory rodents are blunted significantly on calorie restricted diets. Do the long-lived dogs, cats, sheep, cattle and horses consuming magnesium and bicarbonate in drinking water, that is derived from volcanic basalt springs, have low parathyroid hormone levels?

 

It is to be noted that rodents on calorie restricted diets had unlimited access to water and mineral supplements  (calcium and magnesium and trace elements) – the rodents were adequately hydrated. As stated above, drinking water that contains magnesium and bicarbonate stabilizes parathyroid hormone concentrations in humans (by limiting parathyroid hormone release from the parathyroid glands). It is of interest that, as far as the author is aware, the first patents granted in the World for specifically increasing lifespan in humans were granted in the USA for a water solution of magnesium and bicarbonate. [See USA Patent No.s 6,328,997; 6,544,561; 6,048,553.]

 

So, how do we slow the aging process in humans as much as possible so that degenerative diseases are minimized or dampened? Let’s make a start. Avoid consuming large amounts of foods that are high in calories (and phosphorus or phosphates), such as starch-rich and sugar-rich processed foods. These foods produce large concentrations of carbon dioxide and acid when being metabolized. Take advice from qualified nutritionists (not from commercial food and supplement packaging or advertising) and consume foods that produce low carbon dioxide concentrations and low hydrogen ion (acid) concentrations in the body. Avoid smoking (smoking decreases carbon dioxide removal from the lungs and adds small inflammatory particles to the lungs) and avoid excess alcohol consumption (alcohol acidifies body cells, causes a loss of magnesium from mitochondria, affects the structure of water molecules and therefore macromolecules in the body, and is a diuretic leading to dehydration of the body). Avoid excess coffee consumption – coffee is a diuretic. All green plants contain magnesium because magnesium atoms are the central atoms in chlorophyll molecules and chlorophyll molecules are essential for photosynthesis. Incorporate green leafy salads, green spinach, and low-calorie foods into the diet. [What does Jonathan the 188 year old tortoise eat? Fresh green grass growing in volcanic basalt soil that is high in magnesium of course!] Drink plenty of water, up to two liters per day (more under medical advice). If possible, drink water containing relevant magnesium and bicarbonate concentrations (more than 30 milligrams magnesium per liter). As demonstrated in clinical trials, magnesium and bicarbonate in drinking water are bioavailable in mammals; that is, they are absorbed into the body and not passed in feces. See magnesium clinical trial results at magnesiumremedy.com.

Physical activity

Most importantly, it should be noted that the longest lived warm-blooded animals that don’t fit the mammalian lifespan graph or mammalian lifespan equation (bats and marine birds) not only have low carbon dioxide concentrations but have periods of prolonged physical activity relative to the other animals (bats and marine birds travel further each day than dogs, cats, sheep, cattle and horses). This prolonged physical activity promotes anabolic cell responses in all body cells, including those in the brain, and improves blood supply to all tissues and organs which assists in providing oxygen to, and removing carbon dioxide from, body cells. Low oxygen levels in cells results in cell acidification and loss of magnesium-ATP. Physical activity increases oxygen to cells, alleviates acidification and increases magnesium-ATP production.

 

The prolonged physical activity in birds and bats is associated with periods of flight. Animals that fly require low bone mass. The bone mass in birds and bats is low relative to other animals. That is, the bones of birds and bats have reduced mineralization – certainly less mineralization than dogs, cats, sheep, cattle and horses. Are the complex processes involved in the mineralization and reduced mineralization of bone somehow related to longevity? Certainly the interrelation between a range of hormones and vitamins, including parathyroid hormone and calcitriol/vitamin D, and a range of cell types affecting the bone-kidney axis is very complex and has direct effects on calcium, phosphate and magnesium balance. Calcium, phosphate and magnesium comprise the major mineral components of bone.

Excess phosphate

Birds and bats need low bone mass whereas non-flying mammals such as humans need more mineralized bone consisting of calcium and phosphate and magnesium. Birds and bats have slightly opposing needs to humans in relation to bone mineralization. The principle mineral in bone is a form of hydroxyapatite which is a calcium phosphate compound. In humans, continuous elevation of parathyroid hormone results in bone resorption and osteoporosis. That is, continuous elevation of parathyroid hormone is catabolic for bone. However, calcium and phosphate balance and bone mineralization are complex. When the body intermittently pulses increased concentrations of parathyroid hormone then parathyroid hormone is anabolic for bone and bone synthesis occurs. Parathyroid hormone has a half-life of four minutes. Long term continuous secretion of parathyroid hormone (the ‘slow death’ hormone) is catabolic; strong pulses of parathyroid hormone are anabolic. See Curr Opin Pharmacol (2015). Life processes are certainly complex!

 

During normal human aging, progressive deficits in skin, kidney and intestinal function result in progressive inefficiency of vitamin D and calcium metabolism. This causes an increase in the secretion of parathyroid hormone from the parathyroid glands which results in resorption of bone and an increase in blood phosphate levels. Normally, under the influence of parathyroid hormone, the kidneys excrete excess phosphate but with age and dehydration and decreased kidney function the level of phosphate in the blood is increased considerably. When there is serial kidney failure, vitamin D will not be activated, serum calcium levels will decrease, and phosphate levels will increase in the circulation to excessive levels. An excessive increase in circulating levels of phosphate in the blood is associated with a range of major pathologies including microvascular dysfunction, vascular calcification, mitochondrial dysfunction and premature aging. See Clin J Am Soc Nephrol (2019) and J Cell Physiol (2015).  Indeed, there is a negative association of serum phosphate and lifespan in mammals. See Nat Rev Nephrol (2018). Elevated serum phosphate levels promote aging and cellular senescence. See review in Toxins (2020). Bats possess relatively low serum phosphate – this maintains a low bone mass to facilitate flight.

 

Marine birds and bats produce an excrement called guano which is rich in phosphate. Guano contains high levels of phosphate and hydrogen ions (that is, phosphoric acid) and has been utilized as a phosphate fertilizer in agriculture for many years. Food grade phosphoric acid is added to carbonated soft drinks – especially colas, to give a tangy or sour taste. See Phosphoric acid. People who consume large quantities of high calorie carbonated soft drinks are considered to be at risk of cancer. Marine birds and bats excrete phosphoric acid – some humans actively consume it!

 

So, marine birds and bats have low carbon dioxide concentrations, low hydrogen ion concentrations and have evolved a method to excrete high levels of phosphate from the body. In addition, both marine birds and bats have periods of prolonged physical activity associated with high oxygen consumption which optimizes mitochondrial function and promotes anabolic cell responses in all body cells.

 

Do marine birds and bats have a diet high in magnesium so that chronic parathyroid hormone release can be stabilized? What is the diet of the little brown bat? The little brown bat consumes a diet of arthropods including insects and spiders. Studies have shown that this diet is only moderately high in magnesium concentrations. However, the little brown bat weighs about 10 grams and can consume its own body weight of insects each day, particularly if pregnant or lactating. Little forest bats weigh about 5 grams and consume around 1,000 mosquitos or more each night. Hence, the total amount of magnesium consumed by small bats is relatively large. Fruit bats, which are bigger, consume many fruits and nectars – all relatively high in magnesium concentration.

Diets high in magnesium

What is the diet of Wisdom the albatross which is still laying eggs on Midway Atoll at about 70 years of age? Wisdom is a Laysan albatross and Laysan albatrosses have a diet consisting mainly of squid and fish eggs. The magnesium content of squid is very high and is identical to the magnesium content of sea water (squid tissue 55 millimoles magnesium per kilogram; sea water 54 millimoles magnesium per kilogram). Fifty millimoles magnesium per kilogram is equivalent to 1,300 milligrams magnesium per liter! So, Wisdom certainly has found a high source of magnesium. Wisdom appears to be as wise as her name suggests – not only a high magnesium diet but constant aerobic exercise. According to the United States Geological Survey, Wisdom has flown over 3 million miles (120 times the circumference of the Earth) since she was first tagged in 1956 and has survived earthquakes and tsunamis. She uses fast muscle fibers for bursts of speed to avoid danger and slow muscle fibres to cruise around the volcanic Hawaiian Islands.

 

The magnesium content of sea water is correlated also to the long lifespan of bowhead whales. Bowhead whales have a diet of marine zooplankton and marine crustaceans rich in magnesium. Adults consume over 1,500 kg per day. Bowhead whales have an average lifespan of 210 years according to the Scripps Institute of Oceanography in California, USA. See also the Scientific American article: How to Age Gracefully? Ask a Bowhead Whale. And another whale, the blue whale, is the largest animal known of all-time and can reach up to thirty metres long and weigh 200 tonnes. The blue whale actively ranges across vast swathes of the open ocean. The diet of the blue whale consists mainly of marine krill and zooplankton which are very rich in magnesium.

 

It is known that intracellular magnesium concentrations are maintained in body cells if magnesium is consumed constantly in a bioavailable form. Sea water contains high levels of magnesium as soluble salts (chlorides, sulfates, bicarbonates) which are in solution and bioavailable. Long lived animals associated with the sea, such as fish, whales and sea birds, would have a constant flux of magnesium entering their body cells.

 

Both Wisdom the albatross and bowhead and blue whales also have a diet high in calcium – about 400 milligrams per liter (squid tissue 10 millimoles calcium per kilogram; sea water 10 millimoles calcium per kilogram). A diet high in calcium is essential to maintaining bone, heart and skeletal muscle physiology and function and to assist notably in stabilizing parathyroid hormone levels via the calcium-sensing receptors of the parathyroid glands. Calcium is essential also for a specific control of optimal mitochondrial function, especially in heart muscle. Increased cytoplasmic free calcium is the main signal tuning the cardiac mitochondria to an increased workload. And, what element is present in relatively low concentrations in sea water? Phosphorus of course – with subsequent low concentrations of phosphate.

Hormone activities are complex

In addition to its effect on bone, elevated parathyroid hormone levels also affect bicarbonate reabsorption from the kidneys into the circulation and affect sodium-hydrogen ion exchange in the kidneys. That is, in the presence of parathyroid hormone sodium is not exchanged for hydrogen ions in the kidneys and bicarbonate is not reabsorbed into the blood. An acidosis results. This can be overcome to some extent by consuming more water, particularly water containing bicarbonate. During aging, consuming water per se either with or without bicarbonate increases sodium content in the blood with subsequent decrease in hydrogen ions and therefore is beneficial. See Figure 6.

 

Consuming water also increases plasma (serum) albumin. Albumin is an essential blood protein which the body uses as a transport carrier for entities such as thyroid hormone, steroid hormones, fatty acids, bilirubin and calcium. Albumin also functions to maintain colloid osmotic pressure within the blood plasma and is a major anti-oxidant. The clinical trial described earlier demonstrated that after several months of water consumption, serum albumin increased by up to 4 grams per liter. [For those readers with a science background, the correlation between water consumption and increase in serum albumin was P = 0.02.] Increased serum albumin levels have been correlated positively to a decrease in death from all medical causes. Read peer-reviewed medical articles on increased serum albumin decreasing all-cause mortality. Increases in serum albumin are correlated positively and significantly to increases in serum magnesium concentrations. It is known also that cell hydration is anabolic per se. See  The cellular hydration state: a critical determinant for cell death and survival.

 

The consumption of water per se also increases the filtration rate in the kidneys which assists in the excretion of excess phosphate and a range of toxins. The bicarbonate concentration in sea water is 150 milligrams per liter which makes sea water slightly alkaline at a pH value of 8.1. When Wisdom consumes squid she is consuming bicarbonate ions that are greater (at least) by 50 per cent or more in concentration than the high death rate (decreased longevity) areas in people in the USA (which are less than 100 milligrams bicarbonate per liter – often 5 to 10 milligrams bicarbonate per liter).

 

As stated previously, the interrelations of a range of hormones affecting the bone-kidney axis, including parathyroid hormone and calcitriol/vitamin D, is very complex. It is known that these same hormones affect also skin and hair follicle physiology and male and female fertility.

Humans

Apart from birds and bats, are there other mammals or warm-blooded animals that do not fit the mammalian lifespan equation or the mammalian lifespan graph? Yes. There are humans. According to the mammalian lifespan equation and mammalian lifespan graph, humans should not live past 25 years or thereabouts. But, humans live three to four times as long. What is the reason? Recent work by anthropologists and anatomists has shown that modern humans (Homo species) evolved about one to two million years ago as hunters along with an anatomy designed for the extensive walking and running needed for hunting. Prolonged physical aerobic activity is in our bones and has increased our longevity relative to our human ancestors and our ape cousins (who do fit the equation and graph). Indeed, empirical evidence has now identified that prolonged exercise in humans, using both fast and slow muscle fibers, is essential for optimal human health and longevity. We must exercise to be healthy.

 

How does exercise keep us healthy? How does the physical activity of bats and marine birds contribute to the maintenance of longevity? The answer is: Health and longevity rely on the maintenance of optimal mitochondrial function which relies on an optimal source of oxygen. As humans and other animals undergo physical activity the blood supply, and therefore oxygen supply, increases to all organs and tissues in the body as cell chemical energy (magnesium-ATP) is utilized and needs to be replaced by further production. More electrons derived from food molecules pass along the inner mitochondrial membrane to oxygen to produce water as an end product. Oxygen acts as the ultimate electron sink. Electron flux is optimized. [For those biochemists among the readers: an optimal NAD+/NADH ratio and an optimal ADP/ATP ratio are maintained.] It is mitochondrial electron flux that is the fundamental basis of all life processes in mammals and birds (and other animals). It is not the mitochondria per se – it is the flux through the mitochondria that is most important.

 

And, the good news is that the maximal aerobic capacity (that is, oxygen supply to cells and tissues) can be substantially increased even at advanced ages by exercise. Hematologic values such as red blood cell numbers and hemaglobin concentrations can be maintained. The bad news is that in sedentary people with advancing age, aerobic capacity (oxygen supply to be body cells and tissues) fades. This predisposes sedentary people to a range of pathological conditions.

 

It is of interest that the most vital process in the human body in the vast majority of body cells (electrons transferred to an oxygen sink) is the result of electron flux through protein subunits in the inner mitochondrial membrane that arise from transcription of maternal mitochondrial genes. Mothers rule. It is of interest also that the specific composition of mitochondrial genes (DNA base composition) is correlated significantly to maximum lifespan in all species studied.

 

It is to be noted that the DNA in mitochondria of two mammalian orders, that both contain long-lived species, appears to be very similar despite very large differences in physical appearances between the orders. The mitochondrial DNA of bats and whales appears to share similar sequences. Do these sequences code for mitochondrial amino acids/proteins that optimize mitochondrial function under appropriate environmental conditions? The longest lived whales consume marine invertebrates. The longest lived bats consume terrestrial invertebrates. Similar mitochondria and similar diets and similar relatively long lifespans. And physically, bats fly through the air and whales fly through the water.

 

Now, as would be expected, the maintenance of optimal mitochondrial function is very complicated. There are different fatty acids constituting the mitochondrial membranes of different species; there are different levels of hydrogen ion (proton) leakage across the inner mitochondrial membranes of different species – affected by different hormones such as adrenaline (epinephrine) and thyroid hormone; and there are different membrane charge potentials and field strengths across the inner mitochondrial membranes of different species. However, overriding all the above, it has been observed experimentally multiple times that a large enhancement in electron flux occurs with a modest decrease in the hydrogen ion concentrations in mitochondria. This is known as Mitochondrial Respiratory Control. Mitochondrial function (electron flux) is optimal in an optimal low hydrogen ion environment. Hydrogen ion concentrations are decreased by food (calorie) restriction or by consumption of bicarbonate in a suitable form or by a decrease of carbon dioxide in the body or by an increase in oxygen supply to body cells. Electron flux is optimized also by the utilization of chemical energy (magnesium-ATP) in muscle cells and other body cells during physical activity.

Cancer

As stated above, mitochondrial function is optimal in a low hydrogen ion (low acid) environment. In cancer, the Warburg effect is defined by an increased rate of glycolysis with increased lactic acid production and a concomitant decline in mitochondrial energy (magnesium-ATP) production. This is consistent with a metabolic strategy that allows cancer cells to proliferate under adverse conditions such as low oxygen levels (hypoxia). Mitochondrial function requires oxygen; glycolysis does not. As an aside, optimal mitochondrial function requires optimal oxygen concentrations which depend on clean oxygenated air and an optimal oxygen delivery system (lungs, heart, blood vessels, red blood cells). Certainly, air pollution contributes significantly to aging and disease.

 

Malignant cancer cells depend on glucose as the primary substrate and depend on the glycolysis pathway to utilize glucose for energy and other purposes. Many studies are emerging now that show mitochondrial dysfunction is involved in malignant transformation. In addition, there is a rapidly growing body of evidence linking oncogenes and tumor suppressor genes to cellular energy metabolism. For example, the tumor suppressor p 53 gene appears to regulate the balance between glycolysis and mitochondrial function. There is active debate currently whether mitochondrial dysfunction is the cause or the result of malignant cancer. Perhaps an aberrant intracellular environment (acidosis from excess carbon dioxide; acidosis from low oxygen; acidosis from excess alcohol consumption?) affects both mitochondria and genes. Certainly, it is established that environmental factors and lifestyle factors are correlated to longevity (see Genetics). Recent epidemiological studies have shown that people who regularly consume sugar in carbonated soft drinks are at risk of several types of cancer. Excess carbon dioxide and excess calories (and possibly excess phosphate/phosphoric acid) – a perfect storm.

 

Why are obese people subject to an increase in the occurrence of many cancers? Fatty acids from fat stores cannot be utilized by human cells to produce glucose (hence, because fats cannot produce glucose it is hard to lose weight without becoming hungry). Accordingly, carbon dioxide and lactic acid from glucose metabolism are not present when fatty acids are metabolized. Yet obese people develop cancer. The reason this occurs is that fatty acids are metabolized inside mitochondria (the central matrix). The metabolism of fatty acids gives rise to carbon dioxide and, independently, enormous numbers of hydrogen ions resulting in acidity of mitochondria. As stated above, mitochondrial dysfunction is involved in malignant transformation. How does one utilize fatty acids appropriately? The answer is – exercise. Muscle cells can utilize fatty acids for energy whereas many other cells, such as red blood cells and brain neurons, cannot. As people become obese, less exercise is undertaken. Another perfect storm.

 

Are there any nutritional guidelines that may prevent cancer by decreasing the rate of glucose metabolism in the glycolysis pathway? The answer is: Possibly.

  1. Limit glucose consumption (particularly sugar in drinks).
  2. Limit cell acidification (particularly limit alcohol consumption).
  3. Consume water for optimal cell hydration and kidney function.
  4. Consume green vegetables (rich magnesium source).
  5. Consume fruits high in citrate.

 

Citrate is known to regulate the rate of glucose through the glycolysis pathway by inhibiting the function of an initial enzyme in the pathway known as phosphofructokinase-1. The inhibition of phosphofructokinase-1 redirects sugar into the pentose phosphate pathway. An active pentose phosphate pathway produces a necessary ingredient (NADPH) needed for the synthesis of the anti-oxidant reduced glutathione which is the major cellular anti-oxidant protecting cells from hydrogen peroxide. Note that the USA National Institutes of Health (NIH) states that magnesium (as a vital cofactor for enzymes of the pentose phosphate pathway) is vital for glutathione production. The pentose phospate pathway produces also ribose 5-phosphate which is an essential precursor for the synthesis of RNA (ribose nucleic acid) and DNA (deoxy-ribose nucleic acid). Nutritionally, the highest concentration of citrate is found in citrus fruits. Grapefruit juice contains around 65 mmol/L citrate followed by lemon juice (50 mmol/L) and orange juice (45 mmol/L). Do people who regularly consume citrus fruits have a decreased cancer risk? Though controversial, there is some evidence that very high concentrations of citrate may deter cancer growth.

 

The cells that transport oxygen to the tissues, red blood cells, possess an active pentose phosphate pathway. Major enzymes in the pathway require magnesium and thiamine (vitamin B1) as cofactors. Red blood cells contain oxygen in high concentrations and consequently are vulnerable to oxidative damage by hydrogen peroxide. Oxidative damage is prevented by reduced glutathione which is generated by NADPH formed in the pentose phosphate pathway of red blood cells. Nutritionally, the highest concentration of thiamine is found in whole grains and nuts. Would maintaining optimal red blood cell biochemistry and function help to maximise oxygen delivery to tissues to maintain optimal mitochondrial function in body cells? Experiments demonstrate the answer is a definite yes.

 

It is to be noted that both magnesium and thiamine are required for the major enzyme regulating the passage of sugars into mitochondria of body cells. The function of this enzyme (pyruvate dehydrogenase) is vital to move glucose (more correctly its partial breakdown products) rapidly through the glycolysis pathway into mitochondria. Optimal mitochondrial function and decreased overload of the glycolysis pathway decreases cancer risk considerably.

 

There appears to be a correlation between low water consumption and the prevalence of cancer. For example, see Cancer Epidemiol., Biomarkers & Prev (1997). It is known that increased water consumption results in an increase of serum albumin. Among other functions, albumin is the blood calcium transporter. Low serum albumin results in low blood calcium levels which result in increased parathyroid hormone release and correlation to an increase in death from all causes.

Alzheimer’s disease and dementia

There is no successful treatment for Alzheimer’s disease despite decades of research, billions of dollars in investment and over 300 Alzheimer’s disease clinical trials involving treatments. Medical specialists and scientific researchers are divided on what to do next and what direction to take. See Alzheimer’s drug failure raises questions about research.

 

It is established that lifestyle choices such as diet, social contact and exercise are correlated to longevity. Are these factors correlated also to the prevention of Alzheimer’s disease and dementia? There is a growing consensus that when it comes to preserving brain health, the more healthy habits you adopt the better (see The Lancet Commission on Dementia Prevention, Intervention and Care). There is consensus also that brain neurons critically depend on mitochondrial function to establish membrane excitability and to execute the complex processes of neuro-transmission and plasticity. Mitochondria are of central importance for the complex behaviour of neurons and there is a fine-tuned coupling between neuronal activity and function. What do mitochondria need for optimal function in addition to magnesium? The answer is: Oxygen. Can the Earth maintain clean air for optimal oxygen concentrations? It is known that most diseases of aging are accelerated by airborne pollutants. This is particularly true of the brain where there is a remarkable convergence of inflammatory processes shared by atherosclerotic plaques and the senile plaques of aging brains.

 

How does one exercise brain neurons? The answer is education, education, and more education coupled with physical exercise, physical exercise, and more physical exercise coupled with social contact, social contact and more social contact. And, there is increasing evidence that a diet high in green leafy vegetables (such as spinach), other vegetables, berries, nuts and whole seeds and grains may significantly lower the incidence of dementia and Alzheimer’s disease. This well-known diet is known as the MIND diet. (See also A Mediterranean diet and exercise to reverse dementia?) What do green leafy vegetables, nuts, seeds, grains and berries contain? Why, high levels of magnesium of course (see USA the National Institutes of Health (NIH) Magnesium Fact Sheet for Health Professionals).

Formula for health and longevity

It appears that our evolutionary history and our maternal mitochondrial inheritance allows us to live potentially three times to four times the lifespan predicted by the mammalian lifespan equation and mammalian lifespan graph. As the anonymous poem reminds us, many mammals that are similar in weight to humans live only 10 to 20 years:

But then –

Gluttonous, sinful, rum-soaked men

Live for three score years and ten

 

With the recent knowledge that human longevity can be apportioned to environmental factors and lifestyle choices, imagine how long we could live, and what we could achieve, if we looked after ourselves as carefully as Wisdom the female albatross and utilized the knowledge we have gleaned from her to maintain optimal mitochondrial function for ourselves and our offspring. Optimal mitochondrial function in ova may optimise mitochondrial function in offspring. The potential is huge.

From the information available:

It appears that active physical pursuits to maximise oxygen supply to the tissues; the maintenance of mitochondrial function by appropriate magnesium consumption; the stabilization of parathyroid hormone levels by appropriate magnesium consumption; the decreasing of chronic inflammation by appropriate magnesium consumption; and the absence in the body of excess carbon dioxide concentrations and excess hydrogen ion concentrations are correlated strongly to longevity and the prevention or dampening of degenerative diseases.

 

Well-funded biotechnology companies can focus now on the biochemical processes that enhance and maintain cellular magnesium homeostasis and enhance and maintain optimal mitochondrial function. The rest of us should incorporate the information stated above in relation to magnesium, maximise oxygen supply to our tissues by appropriate physical pursuits in non-polluted air and maintain optimal body hydration and kidney function by appropriate consumption of non-polluted water.

APPENDICES
Appendix 1
Brief medical and scientific summary on magnesium

Magnesium exists in body cells as a divalent cation with a small ionic radius and a high charge density. In water, the cation has a large hydrated radius and coordinates six oxygen atoms in its first coordination shell.

 

Magnesium cations have a high affinity for oxyanions. For example, magnesium links together two phosphate groups in macromolecules which is responsible, together with optimal hydration, for the appropriate folding and structure of biomolecules such as protein enzymes, DNA and RNA. Magnesium charge shielding of the phosphate groups in the ‘energy molecule’ adenosine triphosphate (ATP) allows cell function at all levels. Magnesium protects the ATP molecule from being complexed by calcium and other chemical groups.

 

Magnesium-ATP occurs in high concentrations in the cytoplasm of cells and is hydrolysed (decomposed by adding water) to release energy to assist in body cell functions. Most, if not all, cell energy requirements depend ultimately on magnesium-ATP concentrations and the concentration of available water (that is, optimal cell hydration). The hydrolysis of magnesium-ATP is complex and not completely understood. Indeed, both the production of magnesium-ATP and the hydrolysis of magnesium-ATP form the foundation of medical and biological thermodynamics.

 

Optimal utilization of magnesium-ATP requires large concentrations of magnesium-ATP to be produced in mitochondria and optimal hydrolysis of magnesium-ATP by water in the cytoplasm. Magnesium-ATP concentrations in cytoplasm are several hundred times that of mitochondria. Water availability in cytoplasm is many times that of mitochondria. A magnesium-ATP molecule is utilized for energy within a minute after its formation. In humans, approximately 50kg of magnesium-ATP (continuously formed and recycled) are utilized in 24 hours. The concentrations of intracellular magnesium and water are vital for optimal magnesium-ATP utilization to maintain and maximise life processes.

 

It is considered that the chemistry of magnesium instigated the first chemical processes which led to the origin of life and the promotion of evolution. Certainly, the fundamental requirements for magnesium in biological processes pose constraints on cell function. It is to be noted that human primates evolved in the Rift Valley of Africa – an area rich in magnesium soils and waters. It is probably no coincidence therefore that magnesium plays an important role in the human nervous system. Disorders of magnesium homeostasis are involved in Parkinson’s disease, Alzheimer’s disease, dementia and demyelination.

 

The cytotoxic functions of natural killer cells and CD8 T lymphocyte cells are essential for control of viral infections and tumor immunosurveillance. It has been found recently that intracellular magnesium concentration is correlated strongly to extracellular magnesium concentration in a dose-dependent manner and that intracellular magnesium homeostasis is essential for anti-viral and anti-tumor immunity. Indeed, magnesium supplementation in certain patients restores intracellular magnesium concentration and promotes natural killer cell activity while concurrently reducing Epstein-Barr virus infected cells. See medical research article in Science (2013). People infected with Epstein-Barr virus appear to have a predisposition to lymphoma.

 

Scientific and medical observations support the notion that an optimal magnesium level in cells is essential to guarantee cell cycle progression and retention of proper cell morphology and function, and prevent the undesired progression toward cell death or neoplastic destiny. It is crucial therefore to regulate magnesium concentration with optimal dietary intake levels not only for normal function and development but also for the prevention of a plethora of diseases.

Appendix 2
Brief medical and scientific notes on water and hydration

 

The water molecule consists of one oxygen atom and two hydrogen atoms and has the chemical formula H2O. Water is a polar molecule where the oxygen atom is partially negatively charged and the hydrogen atoms are partially positively charged. The partial charges within water molecules are responsible for water’s physical properties and for all its biological and chemical activities. The partial charges within a water molecule attract other water molecules forming bonds called hydrogen bonds.

 

Research conducted internationally over the past several decades has shown that water’s role in the body is far more important than initially realized. Indeed, all intracellular chemistry and all cellular activities do not just take place in water but are determined actively by water. Water is an active component in the formation of intracellular components. The chemical (polar) nature of water determines the structure, function and hydration of intracellular biomolecules and assemblies. For example, the classic double-helix of DNA is hydration dependent and does not exist per se. Among other factors, appropriate charge shielding by water and counter ions (magnesium, possibly sodium and potassium) is essential to screen the electrostatic repulsion between phosphate groups in DNA so that structure and function are maintained.

 

Quantum effects

It cannot be denied that chemistry has its foundation in quantum mechanics and that quantum mechanics gives an accurate explanation for chemical structure and chemical reactions. Until recently it was considered that quantum effects per se would not be detectable in chemical reactions, including biological chemical reactions, and that quantum mechanics would remain only an excellent explanation.

 

Quantum delocation

Recent experiments show that water demonstrates quantum effects which can be detected and measured.  The hydrogen atoms (protons, hydrogen ions) involved in hydrogen bonding in water and associated biomolecules appear to be delocalised (that is, in a superposition of being in two locations). Hydrogen bonding in water and intracellular biomolecules is involved in enzyme activity, DNA structure and protein folding and function.  It appears that optimal hydration of body cells allows the quantum nature of protons in hydrogen bonds to be optimized for cell function and health.

 

Quantum tunneling

It is becoming increasingly clear that quantum proton tunneling is vital for optimal energy production in the mitochondria of body cells and for the function of other cell components.

 

That proton tunneling occurs in cell protein enzymes is now widely accepted.  For example, see Atomic description of an enzyme reaction dominated by proton tunneling.  The tunneling distance of 0.1 to 1.0 Angstroms is often quoted.  Certainly, decreasing the tunneling distance increases the tunneling probability.  It is considered that the degree of proton tunneling in protein enzymes is equivalent to proton tunneling in water, and the quantum nature of water is highly relevant to enzyme function.

 

Proton tunneling during nucleic acid function is yet to be positively established.  However, quantum proton tunneling occurs between the hydrogen bonds of the bases of DNA.  This may result in mutation (tautomerism).  It is yet to be established if appropriate hydration limits these, and other, mutations.  See published epidemiological articles on water consumption and decrease in cancer prevalence.  For example, see possible decrease in colon cancer and breast cancer risk.

 

Brain

Optimal hydration in the brain is an area of active medical research because neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and the spongiform encephalopathes are characterised by altered protein homeostasis leading to protein misfolding and the aggregation of proteins into insoluble fibrils.  See Ligand binding and hydration in protein misfolding.  Accurate protein folding is hydration dependent.  Slight dehydration leads to protein misfolding and aggregation because, technically, dehydration lowers the free-energy barrier of a protein.  It is the hydrated free-energy barrier that prevents conversion of proteins to misfolded entities with aggregation.

 

Water molecules can easily cross the blood-brain barrier, probably by passing through the phospholipid molecules that compose the plasma membrane of blood capillaries (though other mechanisms certainly exist).  Water crossing the blood-brain barrier is considered to be driven by osmotic forces as the concentrations of sodium ions in the cerebrospinal fluid and the extracellular fluid of the brain is three per cent higher than blood plasma.  See Fluid and ion transfer across the blood brain barrier.

 

That hydration of the body affects brain activity is well known.  Even mild dehydration affects cognitive ability.  For example, see Minor degree of hypohydration adversely influences cognition:  a mediator analysis.