The Energy Homeostat, The Source for Cellular Energy
Ward Dean, MD
The modern neuroendocrine theory of aging was first conceived by the noted Russian gerontologist, Professor Vladimir Dilman in 1954. However, it was not widely known outside Eastern Europe because until recently, it has only been adequately described in Russian. Recently, several books in English have made Dilmans unique theory and innovative therapeutic regimens available to Western readers and scientists (Dilman, 1981; Dilman and Dean, 1992; Dilman, 1994). The 1992 book, which is unfortunately out of print, is the most readable, cohesive and comprehensive exposition of Dilmans unique aging theory that has ever been written.
The essence of Dilmans theory is that aging is due to a progressive loss of sensitivity of the hypothalamus and related structures in the brain to negative feedback inhibition. This loss of sensitivity not only enables organisms to grow and develop, but is the cause of post-maturational diseases, aging and death. The neuroendocrine theory explains the causes of the diseases which lead to over 85% of deaths of middle-aged and elderly individuals. These diseases include:
- Autoimmune Disorders
- Metabolic Immunodepression
Two other diseases — depression and the climacteric — although not fatal, also occur regularly with age. Several of these diseases (hyperadaptosis and metabolic immunodepression) have strange-sounding names, but when one gains an understanding of Dilmans theory, the names no longer seem strange.
Part I of the Neuroendocrine Theory explained Dilman’s revolutionary theory of the causes of aging as well as potential therapeutic approaches. It introduced: 1) the concept of homeostasis and 2) how the progressive loss of hypothalamic sensitivity to inhibition by hormones and other signaling substances by the four homoeostatic systems in the body results in growth, development and aging. Living organisms are characterized by their capacity to 1) reproduce, 2) adapt, 3) regulate the flow of energy, and 4) protect themselves.
These organisms have regulatory control systems (which Dilman called homeostats) that regulate and attempt to maintain homeostasis in each of these four critical areas.
Fig. 1 Mitochondrion, the intracellular powerhouse.
Part II discussed how aging and stress combine to accelerate changes in the adaptive homeostat, resulting in the age-related disease, hyperadaptosis. Part III described the energy homeostat, and how dysfunction of this system results in a decline in physical activity, metabolic rate, subjective feelings of reduced energy, and increased fatigue. In addition, energy homeostat dysfunction results in the age-related diseases of 1) diabetes; 2) obesity; 3) essential hypertension; 4) atherosclerosis; 5) depression; and 6) fatigue.
This article is Part 2 of the discussion of the energy homeostat. In the last issue of Vitamin Research News, Part 1 of the Energy Homeostat, we described the complex interrelationships between the body’s chief fuel sources (glucose and fat), and the hormones that control their utilization (growth hormone and insulin) at the hormonal level. As we age, the hypothalamus becomes less sensitive to insulin, and growth hormone levels dramatically decline. This results in less efficient utilization of glucose for energy, an increase in conversion and storage of glucose as fat, and ultimately, hyperinsulinemia (elevated levels of insulin).
Hyperinsulinemia, in turn, leads to other adverse metabolic changes, ultimately increasing the risk of developing age-related diseases like hypertension, atherosclerosis and coronary artery disease, diabetes, and depression. A second aspect of the energy homeostat – the hypothalamo-pituitary-thyroid axis–was discussed in Vitamin Research News Vol 12, No. 6, Aug. 1998.
In this issue, the 2nd component of the energy homeostat, we explore the nexus between the neuroendocrine, cross-linking and free radical theories. Areas to be discussed cover: 1) the biochemical production of energy at the intracellular (mitochondrial) level; 2) age-related changes that adversely affect cellular energy production; and 3) approaches that can restore cellular bioenergetics to more exhuberant, youthful levels.
Energy is produced in the body within mitochondria, tiny sausage-shaped intracellular organelles (Fig 1) found in virtually every human cell. Mitochondria are also called intracellular powerhouses, because it is within them that the citric acid or Krebs cycle (named for Hans Krebs who first described the cycle) occurs. The citric acid cycle (Fig. 2) is a series of biochemical reactions that convert carbohydrates, fats and proteins into adenosine triphosphate (ATP), the universal energy molecule which provides energy for all living functions. The system in mitochondria that generates ATP is termed oxidative phosphorylation. The synthesis of ATP in mitochondria by oxidative phosphorylation involves four enzyme complexes. These include complex I (NADH-ubiquinone oxidoreductase), complex III (reduced ubiquinone oxidoreductase c-oxidoreductase) and complex IV (cytochrome c oxidase [COX]).1
Fig. 2 The citric acid or Krebs cycle, the final oxidative pathway of glucose,
fats and amino acids, by which ATP is produced, and the important role
of many dietary supplements in its optimum functioning.
When mitochondria function efficiently, energy and health are maintained at high levels. However, if the mitochondria become damaged or function at sub-optimal levels, energy production decreases, resulting in fatigue, obesity, depression and other chronic degenerative diseases.
With age, a number of changes take place in the mitochondria, causing a loss in their ability to efficiently produce energy. These changes can include: 1) increased fragility1; 2) increased production of free radicals; 3) alterations in the amount of mitochondrial enzymes; 4) decrease in complex I and complex IV in the respiratory chain; 5) reduction in the number of mitochondria; and 6) increase in mitochondrial size. All of these changes contribute to an overall reduction in mitochondrial function and a marked decline in production of cellular energy.3
A defining characteristic of mitochondria is the ability to reproduce using their own unique DNA (deoxyribonucleic acid), the stuff of which genes and chromosomes are made. Mitochondria consume about 90% of the oxygen used by the body. Unfortunately, mitochondrial electron transport is not perfect, and even under ideal conditions some electrons leak from the electron transport chain. These stray electrons interact with oxygen to produce superoxide radicals. The close proximity of mitochondrial DNA (mtDNA) to this flux of superoxide radicals (or hydroxyl radicals), and its lack of protection and repair mechanisms, leads to free radical-www.ed mutations and deletions of mtDNA.
Consequently, mtDNA is especially susceptible to severe oxidative damage—in fact, mtDNA is ten times more susceptible to free radical-induced damage than nuclear DNA.4-6 This leads to mitochondrial dysfunction, disruption of cellular energy production, and accelerated cellular aging.7
Denham Harman, who originated the free radical theory of aging in 1956, extended the theory in 1972 to focus attention on the mitochondria. Harman stated that decreasing the level of deleterious free radical reactions in an organism might be expected to result in a decreased rate of biological degradation with an accompanying increase in the years of useful life. While addition of antioxidants to the diet of experimental animals extended the mean lifespan, these substances had little effect on the maximum lifespan. Harman attributed this apparent lack of effect on the maximum lifespan to the failure of antioxidants to exert their effects within the mitochondria.
Evidence is accumulating that mitochondrial dysfunction is an underlying contributor to many common pathologies. Mitochondrial defects have been identified in Parkinson’s disease, Alzheimer’s disease [Hutchin and Cortopassi, 1995], heart disease, fatigue syndromes, and numerous genetic conditions. Also, many common nutritional deficiencies can impair mitochondrial efficiency.
Aging Intervention by Optimizing Mitochondrial Function
Reductions in mitochondrial efficiency and the resultant output of ATP may underlie many age-associated phenomena. The successful use of mitochondrial support nutrients to ameliorate serious mitochondrial diseases may prove to be generalizable to the subclinical complaints of normal, healthy, aging humans. Although antioxidant therapy is an obvious approach to deal with increased oxidative stress and decreased antioxidant levels, scientists and doctors have been slow to apply this technology.
Researchers have started investigating the effect of vitamin E towards this end, but antioxidants are much more effective in combinations than they are singly. More importantly, vitamin E is lipid soluble and provides minimal antioxidant protection to the aqueous (watery) metabolic compartments of the brain that are stressed in Parkinson’s disease. It makes much better sense to employ a broad-spectrum antioxidant intervention which emphasizes water-soluble antioxidants like vitamin C, glutathione, N-acetyl cysteine, polyphenols, proanthocyanidins, lipoate, NADH, DMSO, etc.
Fig. 3 Schematic of sites and mechanisms of action of orotate salts,
aspartate salts, and aminoethanolamine salts.
In addition to the use of broad-spectrum antioxidants mentioned above, and liberal use of nutritional components outlined as integral components of the Krebs cycle (Fig. 2), other nutrients can be considered as bioenergetic enhancers which maintain and restore optimal functioning of the energy producing mitochondria. Some of these bioenergetic enhancing substances are outlined below.
Fig. 4 Mechanism of the transfer of fatty acids across the mitochondrial membranes.
Salts of orotic acid (calcium, magnesium, sodium, potassium and lithium) have been extensively tested in Europe for a wide range of clinical conditions. The therapeutic effects of the orotates are believed to be due to enhanced membrane transport of minerals to the mitochondria (Fig. 3) where they enhance various aspects of mitochondrial bioenergetics, and enhance DNA and RNA synthesis, thus promoting repair of free radical induced damage. Supplements of orotate salts have been highly effective in normalizing lipids, reducing oxygen requirements of the heart and skeletal muscles, treating angina pectoris and improving heart function after heart attacks.8
Sharing similar but subtly different properties of the orotates are the aspartates. They are highly efficient mineral transporters, which preferentially penetrate and deliver minerals to the inner layer of the outer cell membrane (Fig. 3).9 Salts of potassium and magnesium aspartate have been used to enhance energy and alleviate fatigue in both animals and humans in a number of studies.10-13 Beneficial effects were usually noted after 4-5 days, but in some cases 10-14 days were required. Daily doses of 1 gram of each salt appeared to produce optimum results.
L-Carnitine is the amino acid substrate for a number of enzymes known as carnitine acyltransferases. The crucial role of these enzymes is to carry fatty acids across the mitochondrial membranes to a site where they are oxidized to produce energy (Fig. 4). Carnitine is necessary to transport long-chain fatty acids into the mitochondrion for use as fuel and for the manufacture of cardiolipin (diphosphatidylglycerol), a special phospholipid that is unique to the inner mitochondrial membrane and which provides important structural support to several of the enzymes in the electron transport chain [Hoch, 1992]. Although cardiolipin levels drop dramatically in mitochondria in aged organisms, acetyl-L-carnitine (and perhaps L-Carnitine) is able to restore the content of cardiolipin to youthful levels (Okayasu, 1985). By restoring cardiolipin levels, cytochrome oxidase activity and ADP carrier transport, ALC also restores overall respiratory activity (oxygen energy conversion) of aged rat mitochondria to normal levels.13 I believe it may help normalize human mitochondrial function as well.
L-Carnitine also enhances thermogenesis in brown adipose tissue (thereby explaining its frequently reported ability to accelerate fat loss), normalizes the lipid profile (lowers triglycerides and LDL cholesterol, and raises HDL cholesterol), improves liver function, enhances immunity, alleviates cardiovascular disorders like hypertension and angina pectoris.14 Athletes and sufferers from chronic fatigue have also reported dramatic improvement.
Strikingly, I just discovered a 20 year-old article that indicated the synergystic effect of carnitine and the anti-diabetic drug, Metformin (see VRN, Vol 12, No. 9, Nov, 1998). Metformin, by itself, is one of the most effective anti-aging/life extension substances known. The combination of carnitine and Metformin appears to enhance the effects of both, and reduces the rare but potential side effect of lactic acidosis from Metformin (Sandor, et al, 1979). The herb Goat’s Rue (Galega oficinalis) would probably have a similar complementary effect as Metformin and GluControl, since the two are structurally very similar. Effective dosages of L-Carnitine range from 1,000 to 2,000 mg per day.
Coenzyme Q10 (ubiquinone) is an essential component of the mitochondrial membrane. It is a critical electron transfer molecule that transports electrons from Complexes I and II to Complex III. CoQ10 has been found to decrease progressively with age in both animals15 and humans16. Deficiencies of coenzyme Q10 are associated with numerous pathologies, the most common of which is probably cardiomyopathy (heart muscle disease) and congestive heart failure. The heart muscle is especially rich in mitochondria due to its extremely high energy requirements.
CoQ10 supplementation has been found to be of benefit in a wide range of clinical conditions, including congestive heart failure17, breast cancer18, hypertension, coronary artery disease, and periodontal disease.19 For therapeutic purposes for these conditions, supplementation with doses in the range of 300 mg/day appears to be highly effective. Although CoQ10 does not seem to affect maximum life span (Lonnrot, et al, 1998), it has been shown to reduce mortality when given to experimental animals for prolonged periods (Fig. 5).
It is well known that DHEA (dehydroepiandrosterone) declines dramatically with age. One of the numerous benefits of replacement to youthful levels is that it helps increase transport of carnitine into the mitochondria.
Calcium aminoethyl phosphate (Ca-AEP) is the colamine phosphate salt of calcium that is essential for cellular membrane functions. Colamine phosphate salts are vitamin-like factors like carnitine and coenzyme Q10. Conditions which respond to the enhanced cellular bioenergetics and membrane integrity enhancing qualities of Ca-AEP include:
- Multiple sclerosis
- Pulmonary (lung) diseases like asthma, emphysema, and chronic bronchitis
- Autoimmune disorders
- Inflammatory disorders
- Kidney diseases
- And presumably, the aging process9.
EDTA’s ability to stabilize and enhance mitochondrial function has been known for over 40 years. Although the benefits of EDTA in a variety of health conditions are most often attributed to its ability to chelate calcium and other heavy metals, 20 suggested that EDTA enhanced mitochondrial function by complexing with the mitochondrial membrane. I agree with his premise, since one of the first effects noted by many of my chelation patients is a dramatic increase in energy. This increase in energy occurs sooner than any significant enhancement in blood flow could occur due to the chelation treatments.
NADH (Coenzyme 1)
NADH (also called coenzyme 1) is a key electron transfer molecule between the citric acid cycle and Complex I. NAD (short for nicotinamide adenine dinucleotide) exists in both oxidized (NAD+) and reduced (NADH) forms. Both forms participate in countless reactions throughout the body, where NAD+ serves as an electron acceptor and NADH as an electron donor. The electron transport chain starts with NADH on Complex I and ends with oxygen on Complex IV. Under average circumstances, about one-third of NAD is produced from vitamin B3 (niacin or niacinamide) and about two-thirds from the catabolism of tryptophan21.
Mechanisms of action of NADH include its ability to 1) enhance cellular energy production, 2) promote DNA repair, 3) stimulate the immune system, 4) act as an extremely potent antioxidant, and 5) increase the biosynthesis of dopamine and adrenaline. Based on its multi-faceted actions, NADH supplementation has demonstrated value in a variety of conditions, including chronic fatigue,22depression,23 Alzheimer’s disease24 and Parkinson’s disease.25 Implications for the aging process are also evident.
Lipoic acid not only plays a critical role in the respiratory chain, assisting in the generation of ATP, but also normalizes impaired glucose tolerance and prevents hyperinsulinemia. In addition, lipoic acid is a powerful antioxidant that is effective at scavenging both water- and lipid-soluble free radicals,26 picking up some of the free radicals that vitamins C and E miss.26
Mitochondrial dysfunction clearly appears to be a critical feature of the breakdown of the energy homeostat with aging. A principle cause of adverse mitochondrial changes with aging also appears to be due to damage of the mitochondrial DNA (mtDNA) and mitochondrial membranes by free radicals produced by the mitochondria themselves. Although many attempts to intervene in free-radical-induced aging by the use of antioxidants resulted in amelioration of many age-related diseases, and an increase in mean lifespan, no increase in maximal lifespan has been achieved.
Dilman believed that the reason maximum lifespan was not extended by the use of antioxidants was because the neuroendocrine causes of aging were not also simultaneously addressed.
Utilization of a combination of antioxidants and bioenergetic substances appears to be a unique and potentially beneficial approach to prevent free radical-induced damage to the mitochondria and their vital energy-producing role, as well as to restore mitochondrial energy production to more youthful levels. It is thus not surprising that substances with multiple mechanisms of action at a fundamental level have such widespread beneficial effects on so many apparently unrelated conditions.
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