Lifespan Project Launched
by Richard Weindruch and Stephen R. Spindler
Page 3 of 4
Coenzyme Q10 (CoQ10) is a small, vitamin like molecule which is an essential component of the electron transport chain in mitochondria, the power plants in our cells. ATP (adenosine-tri-phosphate) is the energy molecule used inside cells to do work. ATP is fabricated in mitochondria. The electron transport chain is the biochemical pathway by which electrons extracted from food are used to fabricate ATP. In the process, the electrons convert the oxygen in air to water. CoQ10 is an electron acceptor and donor. It shuttles electrons back and forth between several of the enzymes which carry out ATP fabrication.
In addition to its function as an electron shuttle, CoQ10 is an antioxidant (Beyer, 1992; Kanter, 1994), which may be especially important inside mitochondria. The electron transport chain generates about 1 trillion oxygen radicals per cell every day. About 2 percent of them get free of the enzymes that try to hold on to them until they can be used to generate energy. These free oxygen radicals are very dangerous to the mitochondria, but also to the rest of the cell. In fact, the reason electron transport takes place in membrane-bound sacks such as mitochondria is, in part, to keep these free radicals trapped inside the mitochondria. This is why having a strong antioxidant like CoQ10 in mitochondrial membranes is important.
Supplementation with CoQ10 raises the levels of this antioxidant in our cells and tissues. Furthermore, CoQ10 increases the activity of the electron transport chain, improving energy generation by mitochondria. We gradually lose some of our ability to produce energy from the food we eat as we age. Supplementation with CoQ10 partially reverses this loss, especially in the heart muscle. In animal experiments, CoQ10 protected the heart against oxidative damage caused by the blockage and restoration of blood flow (Mortensen, 1993). In animal studies, CoQ10 protected the brain from oxidative damage (Beal et al., 1994) and protected the liver from free-radical-generating toxins.
Many tissues use a metabolic strategy termed beta oxidation to "burn" fatty acids to obtain energy. This activity takes place in the mitochondria. Carnitine is a small molecule resembling an amino acid. It serves as a sort of ticket or tag for entry into the mitochondria. Carnitine is chemically attached to the fatty acids in the cell cytoplasm outside the mitochondria. A transport system in the mitochondrial membrane recognizes the attached carnitine ticket, grabs it along with the fatty acid, and moves them both into the mitochondria. Once inside, carnitine is removed from the fatty acid and transported back outside the mitochondria so it can be used again.
In heart mitochondria, this transport process decreases with age, as does mitochondrial function. A decrease with age also has been found in the body's pool of carnitine. This decrease may be responsible for some of the age-related loss in mitochondrial function. There is a growing body of scientific evidence indicating that the accumulation of mitochondrial defects with age can be slowed or reversed by supplementation with acetyl-L-carnitine (ALC) (reviewed in Shigenaga et al., 1994). ALC is the natural precursor to both carnitine and acetylcholine (a "neural transmitter").
Acetyl-L-carnitine improves mitochondrial function in several ways (Shigenaga et al., 1994). For example, ALC fed to old rats increases mitochondrial cardiolipin levels to those of young rats. Cardiolipin is a natural component of mitochondrial membranes, that is important for membrane structure and function. It also is important for the functioning of the enzymes responsible for energy generation within the mitochondria. Aging decreases the cardiolipin content of mitochondria in heart, liver and brain, which generates extra oxygen radicals.
ALC helps to reduce oxidative damage with age, and protects the brains of experimental animals from age- and stroke-related neural degeneration. In humans, one controlled clinical trial showed that the progression of Alzheimer's disease was significantly reduced in patients receiving 2 grams per day of ALC for a year (Bowman, 1992). We will conduct the first test of the effect of ALC supplementation on lifespan.
Cysteine is a non-essential amino acid used for protein synthesis. Although we make some cysteine in our cells, it is also the rate-limiting amino acid for the synthesis of glutathione, a small molecule that plays many essential roles in cells. Cysteine is unstable, somewhat toxic, and weakly mutagenic when taken orally or by injection. But procysteine, a modified form of cysteine, is somewhat less toxic, and much more stable "on the shelf" than cysteine (White et al., 1993). It is rapidly converted into cysteine and carbon dioxide inside cells. This conversion makes it good for raising intracellular concentrations of cysteine, which, in turn, raises intracellular levels of glutathione.
Glutathione is made up of three amino acids, linked together like the amino acids in normal proteins. But, glutathione is a small molecule. It is important in many cellular functions including the folding of proteins into their correct structures. It also is an antioxidant (Kehrer and Lund, 1994) that detoxifies free radicals directly by interacting with them. And, it also is an important contributor to the detoxification of many free radicals and foreign chemicals by enzymes (Hayes and Pulford, 1995; Talalay et al., 1995). For example, it aids in the enzymatic detoxification of lipid peroxides and hydrogen peroxide.
The synthesis of glutathione is often limited by the supply of free cysteine. The concentration of free cysteine is very low in plasma. Low levels of glutathione lead to a decrease in intracellular antioxidant activities, and a decrease in the activities of the enzymes which depend on correct intracellular oxidation-reduction potential for their structure and activity.
There are no large clinical trials that demonstrate health benefits from glutathione or NADH supplementation. But a decrease in glutathione levels has been found in aging animals and humans, and in various disease states (Meydani et al., 1995). Glutathione levels decrease in the lens of the eye as we age. Lower glutathione levels have been found in the lens, spleen, liver, kidney and heart of old mice compared to young mice. In one study, half of elderly subjects had lower blood glutathione concentrations than younger subjects. There is a positive correlation between tissue glutathione levels and lifespan in mice. Glutathione inhibits liver cancer growth in humans and oral cancer in hamsters. Thus, the decline in glutathione levels with age may be related to the increase in cancer.
The decrease in glutathione levels with age also may partly explain the age-related decrease in immunity. And, decreased glutathione may partly be responsible for the liver's loss of detoxification ability. This loss is found in most mammals, including humans. Low glutathione levels are associated with arthritis, diabetes, heart disease and cataracts.
In clinical studies in the elderly, higher glutathione levels are associated with fewer illnesses and the perception of improved health. Finally, dietary supplementation with glutathione, or with supplements that raise glutathione levels, appears to improve the immune response in humans and experimental animals.
NADH (a form of nicotinamide adenine dinucleotide) is a coenzyme that assists enzymes involved in energy production within mitochondria. NADH plays an important role in the generation of ATP, the body's energy currency, and has been found to be deficient in several age-related degenerative diseases. Uncontrolled studies in Europe have found NADH beneficial for patients suffering from Parkinson's disease, Alzheimer's disease, and depression (Birkmayer, et al, 1990).
NADH also is needed for the regeneration of glutathione after it becomes oxidized (Sies and Stahl, 1995; Kehrer and Lund, 1994). If NADH levels are depleted, glutathione levels also may fall. Thus, supplementation with NADH also may help restore glutathione to its active form.
Melatonin is a mammalian hormone, secreted at night during sleep by the pineal gland. Although melatonin's role as a hormone is subtle, it is clearly a potent antioxidant (Reiter et al., 1996). It is both water- and membrane-soluble, and acts as an antioxidant in both lipid and aqueous environments. Dosages that raise blood levels of melatonin to higher-than-normal levels protect against agents that damage cells by generating oxygen radicals.
These include ionizing radiation, the chemical carcinogen safrole, the diabetes-inducing toxin alloxan, the herbicide paraquat, bacterial lipopolysaccharide, and the liver toxin carbon tetrachloride. Melatonin also protects against cataracts caused by buthionine sulfoxamine, a drug that blocks the production of glutathione.
Melatonin is absorbed readily when taken orally, and has very low toxicity. In fact, few if any negative side effects have ever been reported for melatonin. In addition to its antioxidant effects, melatonin has been proposed as a regulating agent for the biologic aging clock. A previous study suggested that melatonin may be able to extend lifespan in rodents. Our study will seek to determine if this is possible.
The Mystery of Aging
Two additional theories of aging also will be examined during The Lifespan Project.
The questions? How does glycation and hormone depletion influence longevity?
Why do we age? In addition to the free radical and energy-depletion theories of aging, there also are the glycation and hormonal theories. Each theory proposes different biochemical mechanisms for aging. It's possible that all four are right, that their concerted action produces the symptoms of aging.
Anthony Cerami and colleagues proposed the glycation theory of aging. This theory postulates that cellular damage from glucose (blood sugar) is a factor in aging. Diabetes, which is characterized by abnormally high levels of blood glucose, is probably a form of accelerated aging.
High blood glucose levels are associated with long-term neurologic problems, kidney damage, atherosclerosis, loss of vision, cataracts and impaired cellular immunity (Ziyadeh. & Cohen, 1993; Anonymous, 1993; Rossetti et al., 1990).
High insulin levels often are found in people with heart disease, atherosclerosis and high blood pressure (Ferrari & Weidmann, 1990; Stout, 1990; Ducimetiere et al., 1980). These are many of the diseases and complications that occur in old age.
In fact, one of the characteristics of human aging is a progressive rise in blood glucose levels. Blood glucose rises because insulin becomes less effective in causing glucose uptake by muscle and fat cells.
Glucose reacts slowly with proteins, fats, lipids and even with the genetic material of our cells (Lee & Cerami, 1992). With the passage of time, it forms toxic chemicals that have been given the name "advanced glycation end products," or AGEs (Baynes, 1991). This same process takes place much faster through the heat of frying or broiling, which is what gives cooked meat its brown color. During this process, reactive glucose forms free radicals which continue and amplify the reaction, enlarging the damaged area. Over a lifetime, this kind of damage accumulates, even in people without diabetes. The damage may even be involved in the loss of neurologic functions during aging.
Recent research has shown that the effects of many small strokes in older people accumulate over the years to finally rob us of short-term memory. The neurofibrillary tangles and senile plaques in the brains of patients with Alzheimer's disease contain AGE, while little if any of these products are detected in healthy brain regions, even within the same brains as the afflicted persons (Smith et al., 1994).
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