Recent 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 much human longevity to environmental factors and lifestyle 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 longevity can be correlated to environmental factors, particularly to constituents in drinking water supplies. In animal studies it has been shown that some bats and marine birds demonstrate little, if any, senescence and have long lifespans that seem to defy explanation. 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. Can we extrapolate from these animals and their environments clear scientific evidence of how senescence and associated degenerative diseases may be delayed, fertility may be maintained and lifespan may be increased in humans? The answer is: Yes.
The purpose of this article is to explore the possibility of delaying the aging process as much as possible so that degenerative diseases that are correlated to senescence can be minimized 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, to suffer from age-related degenerative diseases and to die.
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 old age.
On the empirical evidence available to us, it appears that sponges do not die from old age, nor do sea anemones.1 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 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.1 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.1,2 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.1 Some species of sharks and tortoises, including 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. And, one must not forget Jonathan, a Seychelles giant tortoise, apparently born in 1832 and now 187 years old and living in the grounds of the Governor’s mansion on the 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 an albatross in 1956 named Wisdom which is still laying eggs 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 cruising the Hawaiian Islands. Is Wisdom 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? The majority of energy utilized in animal cells is specific chemical energy produced in cell organelles called 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 increase human lifespan? To answer this question appropriately below 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.
As an aside, it is to be noted that mitochondria are considered to have originated from symbiotic bacteria that invaded cells of organisms over one billion years ago. Indeed, mitochondria are able often to reproduce themselves independent of cell replication. Specific mitochondrial genes are inherited maternally via the cytoplasm of the ovum and hence may be described as clones derived from female ancestors. 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 the electrons of food molecules into a form of chemical energy that is vital for body cells. Mitochondria are able to transduce crucial electron quantum processes (including electron quantum tunneling) into vital chemical energy storage. In mitochondria, electrons derived from food molecules pass along the inner mitochondrial membrane to an oxygen sink to produce water. This is the most important and fundamental process needed for mammalian and avian life.
Mammalian and avian body cells utilize energy in the form of concentrations of chemical energy that exists mainly as a molecule called ATP (adenosine triphosphate). ATP is in a complex with magnesium ions to shield ATP’s negative charge. ATP exists actually in body cells as magnesium-ATP. Indeed, mitochondria are one of 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 pass through the enzyme which creates the conditions for magnesium-ATP production by the enzyme.3,4,5,6 See Figure 1. An excess of hydrogen ions in mitochondria affects the enzyme, by affecting the hydrogen ion concentration gradient, and consequently decreases magnesium-ATP production. A decrease in magnesium-ATP production in mitochondria is considered to stimulate glycolysis in the cytoplasm and possibly contribute to the development of cancer (see Warburg effect below).
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 cytoplasm of the cell independent of mitochondria. These enzyme reactions are known as glycolysis. 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.
Are aberrations in mitochondrial function correlated to the degenerative diseases associated with aging? Depending on the disease, the answer is probably yes – particularly for heart disease, dementia and cancer. For example, many invasive cancers have a large impairment in magnesium-ATP production in mitochondria. There is an increased rate of magnesium-ATP production by glycolysis in the cytoplasm with a concomitant increase in lactic acid production. This phenomenon is known as the Warburg effect and has been studied by cancer researchers extensively. 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 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? Are bats similar to marine birds in relation to longevity?
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 higher than mammals, have higher heart rates and higher metabolic rates than mammals and produce as many, if not more, 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 argument doesn’t help explain interesting data or help advance knowledge.
Much of the food that is consumed by mammals and birds is broken down in cell metabolism to carbon dioxide and the carbon dioxide is breathed out 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 each day! More carbon dioxide needs to be removed from the body if more food is consumed and metabolized. The majority of carbon dioxide derives from the central matrix of mitochondria. Carbon dioxide in high concentrations reacts with intracellular water to produce hydrogen ion concentrations (‘carbonic acid’), in both mitochondria and cell cytoplasm. The higher the carbon dioxide concentration the higher the concentration of hydrogen ions. 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. Excess hydrogen ion concentrations in cells and tissues (increased acidity) increase the severity of a range of damaging oxidation reactions – including free radical reactions. Hydrogen ion concentrations need to be optimally moderated or buffered if 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. 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 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 small birds (despite ‘less efficient’ lung anatomies). But bats possess a further method of eliminating 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.7,8 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.
How can humans moderate carbon dioxide concentrations or moderate or buffer hydrogen ion concentrations? Let’s start with cattle, sheep and horses. There are places in the world where 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.9 See Figure 3. On many objective technical tests, it has been found that biological and molecular order are maintained for prolonged periods. For example, in sheep, wool fiber quality is maintained for longer than wool fiber quality in sheep in other areas.10 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!]. These long-lived 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, human plasma contains 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.11 [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.]
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 (white males 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.12
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 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.13,14,15 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) and so they contain large numbers of mitochondria that all contain magnesium. In addition, heart disease often results from atherosclerosis of coronary arteries. The role of magnesium in possibly preventing atherosclerosis by decreasing parathyroid hormone release from the parathyroid glands is discussed below.
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.
In a World Health Organization (WHO) registered clinical trial conducted in a prestigious medical teaching hospital involving post-menopausal women, 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. The concentrations of magnesium and bicarbonate consumed in water in the clinical trial were identical to that consumed by long-lived sheep, cattle and horses described above. The 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 stabilization of parathyroid hormone release. See Figure 4. Why is this important?
Well, it is known that if parathyroid hormone is continuously elevated, even for a few hours, it initiates processes leading to the resorption of bone. 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 pathology of capillaries and small arteries is considered a factor in many, if not most, degenerative diseases. Alterations in plasma parathyroid hormone levels are associated with cardiac dysfunction and detrimental cardiac remodeling.16 There is medical epidemiological data on parathyroid hormone levels correlated to diseases.17,18,19,20 There is medical data associating low magnesium with osteoarthritis.21,22,23 For photos of the treatment of osteoarthritis with magnesium and bicarbonate see Figure 5.
It appears on empirical evidence that optimal levels of magnesium are necessary for mitochondrial, cell and body function. It appears also that high carbon dioxide concentrations and consequent high hydrogen ion concentrations need to be moderated or buffered. This can be achieved certainly to some extent with bicarbonate 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 carbon dioxide in their lungs is displaced by rising nitrogen gas from inspired air, falls out due to gravity and leaves the lungs. [In upright, and often sedentary, humans carbon dioxide 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 in the body cells of bats. Instead of being the dangerous and vile animals of novels and movies, bats have developed a method of excess carbon dioxide removal 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.
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, don’t consume excess food that will produce 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 the only successful active assault that has been made on the problem of senescence and associated degenerative diseases in mammals.1 Rodents on calorie restricted diets live about 30 per cent longer than control groups on unrestricted diets.24,25,26,27,28,29 Note that an increase in lifespan of about 30 per cent is identical to the increase in lifespan of cattle, sheep 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 that occur naturally with aging and degenerative diseases in laboratory rodents are negated completely on calorie restricted diets.1,30 Do the long-lived cattle, sheep 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 – that is, the rodents were adequately hydrated. As stated above, drinking water that contains magnesium and bicarbonate stabilizes parathyroid hormone concentrations in humans. 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.31
So, how do we slow the aging process in humans as much as possible so that degenerative diseases are minimized? Let’s make a start. Don’t consume excess amounts of foods that are high in calories, such as starch-rich and sugar-rich foods, which produce large concentrations of carbon dioxide 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 concentrations in the body. Avoid smoking (smoking decreases carbon dioxide removal from the lungs) and avoid excess alcohol consumption (alcohol acidifies body cells, causes a loss of magnesium from mitochondria, and is a diuretic leading to dehydration of the body).11 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 and low-calorie foods into your diet. [What does Jonathan the 187 year old tortoise eat? Fresh green grass growing in volcanic basalt soil that is high in magnesium of course!] Drink plenty of water, about two liters per day. If possible, drink water containing relevant magnesium and bicarbonate concentrations (more than 30 milligrams magnesium per liter). Magnesium and bicarbonate in drinking water are bioavailable in mammals; that is, they are absorbed into the body and not passed in feces.
Most importantly, you may have noticed 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 cattle, sheep, horses and elephants). 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. 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 cattle, sheep, horses and elephants. 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.32,33,34,35 Calcium, phosphate and magnesium comprise the major mineral components of bone.
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 parathyroid hormone then parathyroid hormone is anabolic for bone and bone synthesis occurs.36,37 Parathyroid hormone has a half-life of four minutes.38 Long term continuous secretion of parathyroid hormone is catabolic; strong pulses of parathyroid hormone are anabolic. During normal human aging, progressive deficit 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.39,40 An excessive increase in circulating levels of phosphate in the blood is associated with a range of major pathologies.41, 42
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. 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 which promotes anabolic cell responses in all body cells.
Do birds and bats have a diet high in magnesium so that parathyroid hormone 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 not particularly high in magnesium concentrations. However, the little brown bat can consume its own body weight of insects each day, particularly if pregnant or lactating. Hence, the total amount of magnesium consumed is relatively large.
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).8 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. And, 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 Hawaiian Islands. The magnesium content of sea water is correlated also to the long lifespan of the bowhead whale. 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.
Both Wisdom the albatross and bowhead 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.3
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.40 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 with or without bicarbonate increases sodium content in the blood with subsequent decrease in hydrogen ions and therefore is beneficial. See Figure 6. The consumption of water per se also increases the filtration rate in the kidneys which assists in the excretion of excess phosphate. 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 by 50 per cent in concentration than the high death rate (decreased longevity) areas in people in the USA (which are less than 100 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.43,44,45
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.46 Prolonged physical 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.46
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. 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 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.47,48
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.3 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 removal of carbon dioxide (via appropriate exercise, etc). Electron flux is optimized also by the utilization of chemical energy (magnesium-ATP) in muscle cells and other body cells (again by appropriate exercise, etc.).
It is interesting that the electron transfer proteins involved in mitochondrial function have iron atoms at their core. However, some of the longest lived animals are marine birds and whales which consume and digest organisms from the ocean. The ocean has negligible concentrations of iron – about one to three parts per billion. Is iron (and copper) in mitochondria essential for electron flux or can other transition metals suffice? Where does the iron for the hemoglobin in red blood cells of marine birds and whales derive from? Do iron concentrations increase in the tissues of marine organisms up through the food chain? It has been reported that in photosynthesis, some phytoplankton species, which arguably are the base of the ocean’s food chain, have the ability to switch from iron-rich to non-iron containing electron transfer proteins.49
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 and 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 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). 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.50, 51, 52,53 In addition, there is a rapidly growing body of evidence linking oncogenes and tumor suppressor genes to cellular energy metabolism.54 For example, the tumor suppressor p 53 gene appears to regulate the balance between glycolysis and mitochondrial function.55 There is active debate currently whether mitochondrial dysfunction is the cause or the result of malignant cancer. Perhaps an aberrant intracellular environment (acidosis from carbon dioxide?) affects both mitochondria and genes. Certainly, it is established that environmental factors and lifestyle choices 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.56 Carbon dioxide and excess calories – 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. 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 cells, cannot. As people become obese, less exercise is undertaken. Another perfect storm.
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:
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 intracellular and mitochondrial function. The potential is huge.
From the information available: It appears that active physical pursuits, stabilisation of parathyroid hormone levels due to 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 of degenerative diseases. In addition, the consumption of magnesium and bicarbonate in appropriate volumes of water appears to be highly beneficial, if not essential, to buffer carbon dioxide and hydrogen ion concentrations in the mitochondria and cytoplasm of body cells for health and longevity.
LONGEVITY, SENESCENCE, AND THE GENOME
The University of Chicago Press, Chicago
The mortality of plaice
Nature, 115, 495-496
BIOENERGETICS AT A GLANCE
Blackwell Science Ltd., Oxford
Academic Press, London
Cambridge University Press, Cambridge
Cutaneous gas exchange in bats
Am. J. Physiol., 215, 506-508
Fifth Edition, Cambridge University Press, Cambridge.
As quoted by Bowers P. (2002)
Peter Bowers on the clues that led to the water
The Sydney Morning Herald, April 9, 2002
Unpublished CSIRO research results
Cellular magnesium homeostasis
Arch. Biochem. Biophys., 512(1), 1-23
AGING AND THE GEOCHEMICAL ENVIRONMENT
National Academy Press, Washington, D.C.
Review of epidemiological studies on drinking water hardness and cardiovascular diseases.
Eur. J. Cardiovasc. Prev. Rehabil. 13(4), 495-506.
A systematic review of analytical observational studies investigating the association between cardiovascular disease and drinking water hardness.
Water Health. 6(4), 433-442.
Calcium and magnesium in drinking water and risk of death from cerebrovascular disease.
Stroke 9(2), 411-414.
PTH, vitamin D, and the FGF-23-klotho axis and heart: Going beyond the confines of nephrology.
Eur. J. Clin. Invest., 48(4).
Parathyroid hormone, cardiovascular and all-cause mortality: A meta-analysis.
Clin. Chim. Acta. 455, 154-160.
Plasma parathyroid hormone and the risk of cardiovascular mortality in the community.
Circulation. 119(21), 2765-2771.
Serum parathyroid hormone is associated with carotid intima-media thickness in postmenopausal women.
Int. J. Clin. Pract. 62(9), 1352-1357.
Serum parathyroid hormone levels predict coronary heart disease: the Tromsø Study.
Eur. J. Cardiovasc. Prev. Rehabil. 11(1), 69-74.
Evidence of altered bone turnover, vitamin D and calcium regulation with knee osteoarthritis in female twins.
Rheumatology. 42(11), 1311-1316.
Association between Dietary Magnesium Intake and Radiographic Knee Osteoarthritis.
PLoS One. 10(5), e0127666.
Relationship between Serum Magnesium Concentration and Radiographic Knee Osteoarthritis.
J Rheumatol. 42(7), 1231-1236.
Action of food restriction in delaying the aging process
Proc. Natl. Acad. Sci. USA, 79, 4239-4241
Does food restriction retard aging by reducing the metabolic rate?
Am. J. Physiol., 248, E488-E490
Slowing aging by caloric restriction
Nature Medicine, 1, 414-415
THE ANTI-AGING PLAN Strategies and Recipes for Extending Your Healthy Years
Four Walls Eight Windows, New York
The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans
Proc. Natl. Acad. Sci. USA, 89, 11533-11537
Biology of aging: facts, thoughts, and experimental approaches
Lab. Invest., 65, 500-510
Modulation of age-related hyperparathyroidism and senile bone loss in Fischer rats by soy protein and food restriction.
Endocrinology. 122(5), 1847-1854.
US Patent No. 6,328,997
US Patent No. 6,544,561
US Patent No. 6,048,553
Parathyroid hormone: anabolic and catabolic actions on the skeleton.
Curr. Opin. Pharmacol. 22, 41-50.
Catabolic and anabolic actions of parathyroid hormone on the skeleton.
Endocrinol. Invest. 34(10), 801-10.
PLoS One. 13(12), e0208514.
Different duration of parathyroid hormone exposure distinctively regulates primary response genes Nurr1 and RANKL in osteoblasts.
T cells, osteoblasts, and osteocytes: interacting lineages key for the bone anabolic and catabolic activities of parathyroid hormone.
Ann. N.Y. Acad. Sci. 1364, 11-24.
Catabolic and anabolic actions of parathyroid hormone on the skeleton.
Endocrinol. Invest. 34(10), 801-810.
Parathyroid hormone: anabolic and catabolic actions on the skeleton.
Curr. Opin. Pharmacol.
Kinetic analyses of parathyroid hormone clearance as measured by three rapid immunoassays during parathyroidectomy
Clinical Chemistry. 48 (10) 1731-1738
Pathophysiology – The biologic basis for disease in adults and children, 3rd Edition
Mosby Harcourt, St Louis.
Basic & Clinical Endocrinology, 7th Edition.
McGraw Hill, New York.
Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community.
Kidney. 83, 160-166.
Fibroblast growth factor 23 as a predictor of cardiovascular and all-cause mortality in prospective studies.
Atherosclerosis. 261, 1-11.
The effect of parathyroid hormones on hair follicle physiology: implications for treatment of chemotherapy-induced alopecia.
Skin Pharmacol. Physiol.28(4), 213-25.
Vitamin D and endometrium: A systematic review of a neglected area of research.
Int. J. Mol. Sci 19(8).
Vitamin D is positively associated with sperm motility and increases intracellular calcium in human spermatozoa.
Hum. Reprod. 26(6), 1307-1317.
Evolved to Exercise.
Scientific American. 320, 20-27
Mitochondrial genome anatomy and species-specific lifespan.
Rejuvenation Res. 9(2), 223-236.
NUMT (“new mighty”) hypothesis of longevity.
Rejuvenation Res. 13(2-3), 152-155.
Iron chemistry in seawater and its relationship to phytoplankton: a workshop report.
Marine Chemistry. 48, 157-182.
The Warburg effect and the hallmarks of cancer.
Anticancer Agents Med. Chem. 17(2), 164-170.
The Warburg effect and mitochondrial stability in cancer cells.
Mol. Aspects Med. 31(1), 60-74.
Mitochondria in cancer cells: what is so special about them?
Trends Cell Biol. 18(4), 165-73.
Mitochondria as targets for cancer chemotherapy.
Semin. Cancer Biol. 19(1), 57-66.
Multiparameter metabolic analysis reveals a close link between attentuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells.
Am. J. Physiol. Cell Physiol. 292, C125-C136.
P53 regulates mitochondrial respiration.
Science. 312, 1650-1653.
Consumption of sugar-sweetened and artificially sweetened soft drinks and risk of obesity-related cancers.
Public Health Nutrition. 21(9), 1618-1626.
Ames B.N., Shigenaga M.K., Hagen T.M. (1993)
Oxidants, antioxidants, and the degenerative diseases of aging
Proc. Natl. Acad. Sci. USA, 90, 7915-7922
Anderson T.W., Neri L.C., Schreiber G.B., Talbot, F.D.F., Zdrojewski A. (1975)
Ischemic heart disease, water hardness and myocardial magnesium
Can. Med. Assoc. J., 113, 199-203
Arnheim N. and Cortopassi G. (1992)
Deleterious mitochondrial DNA mutations accumulate in aging human tissues
Mut. Res., 275, 157-167
Babcock G.T. and Wikstrom M. (1992)
Oxygen activation and the conservation of energy in cell respiration
Nature, 356, 301-309
Brand M.D. (1990)
The proton leak across the mitochondrial inner membrane
Biochim. Biophys. Acta, 1018, 128-133
Brand M.D. (1990)
The contribution of the leak of protons across the mitochondrial inner membrane to standard metabolic rate
Theor. Biol., 145, 267-286
Brand M.D., Couture P., Else, P.L., Withers K.W., Hulbert, A.J. (1991)
Evolution of energy metabolism
Biochem. J., 275, 81-86
Brown G.C. and Brand M.D. (1991)
On the nature of the mitochondrial proton leak
Biochim. Biophys. Acta, 1059, 55-62
Busa W.B. and Nuccitelli R. (1984)
Metabolic regulation via intracellular pH
Am. J. Physiol., 246, R409-R438
Comfort A. (1979)
THE BIOLOGY OF SENESCENCE
Churchill Livingstone, Edinburgh and London
Darrach B. (1992)
Life, 15, 32-43
Duffy P.H., Feuers R., Nakamura, K.D., Leakey J. and Hart R.W. (1990)
Effect of chronic caloric restriction on the synchronisation of various physiological measures in old females Fischer 344 rats
Chronobiol. Internat., 7, 113-124
Else P.L. and Hulbert A.J. (1985)
Mammals: an allometric study of metabolism at tissue and mitochondrial level
Am. J. Physiol., 248, R415-R421
Gevers W. (1977)
Generation of protons by metabolic processes in heart cells
Mol. Cell. Cardiol., 9, 867-874
Godfrey J. (1996)
Nature, 380, 15
Hafner R.P., Brown G.C., Brand M.D. (1990)
Analysis of the control of respiration rate, phosphorylation rate, proton leak rate and protonmotive force in isolated mitochondria using the ‘top-down’ approach of metabolic control theory
Eur. J. Biochem., 188, 313-319
Linnane A.W., Marzuki S., Ozawa T., Tanaka M. (1989)
Mitochondrial DNA mutations as an important contributor to aging and degenerative diseases
Lancet, March 25, 642-645
Linnane A.W., Zhang C., Baumer, A., Nagley P. (1992)
Mitochondrial DNA mutation and the aging process: bioenergy and pharmacological intervention
Mut. Res., 275, 195-208
Mitchell P. and Moyle J. (1967)
Respiration-driven proton translocation in rat liver mitochondria
Biochem. J., 105, 1147-1162
Murphy M.P. and Brand M.D. (1987)
The control of electron flux through cytochrome oxidase
Biochem. J., 243, 499-505
Papa S. (1976)
Proton translocation reactions in the respiratory chains
Biochim. Biophys. Acta, 456, 39-84
Pettigrew G.W., Meyer T.E., Bartsch R.G., Kamen M.D. (1975)
pH dependence of the oxidation-reduction potential of cytochrome c2
Biochim. Biophys. Acta, 430, 197-208
Porter R.K. and Brand M.D. (1993)
Body mass dependence of H+ leak in mitochondria and its relevance to metabolic rate
Nature, 362, 628-630
Ricklefs R.E. and Finch C.E. (1995)
A Natural History
Scientific American Library, New York
Rusting R.L. (1992)
Why do we age?
Scientific American, December, 86-95
Shigenaga M.K., Hagen T.M. and Ames B.N. (1994)
Oxidative damage and mitochondrial decay in aging
Proc. Natl. Acad. Sci. USA, 91, 10771-10778
Trounce I., Byrne E., Marzuki S. (1989)
Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in aging
Lancet, March 25, 637-639
Walford R.L. (1983)
MAXIMUM LIFE SPAN
W.W.Norton and Company, New York
Walford R.L. (1986)
THE 120-YEAR DIET
How to Double Your Vital Years
Simon and Schuster, New York
Wallace D.C. (1992)
Mitochondrial genetics: a paradigm for aging and degenerative diseases?
Science, 256, 628-632