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You are here: Biology of Aging >

Mechanisms of Aging: Accumulation of Wastes

How much garbage do you throw into a trash can every day? If you are a citizen of a developed country, it should be, on average, about 10 pounds. Now multiply that by the population of your country and by 365 days a year. The impressive number you will get is not even a half of the picture. The manufacturers of the products for our disposable lifestyle generate waste that often exceeded several-fold the volume of the production itself. On top of that, there is human and farm sewage, car exhaust, tabloids and numerous other sources and forms of waste. To maintain at least a temporary balance, our industrial civilization has developed a variety of techniques for waste reduction, disposal and recycling. We have landfills, incinerators, sewage treatment plants, catalytic converters and biodegradable diapers. The sad truth, however, is that the amount of waste in our environment gradually increases, and its not just the growth of landfills, but also changes in the atmosphere and oceanic water. At present, all these things are relatively easy to ignore because environmental changes, such as global warming, are not yet disruptive enough to upset our way of life. But if present trends are allowed to continue, the amount of global damage, some predict, will increase exponentially, i.e. our problems will be worsening progressively faster.

It is amazing how many similarities can be found between the environmental predicament of mankind and the aging of the human body. Our metabolism produces waste all the time. Most of it gets efficiently eliminated through breathing, urine, feces and sweat. The easiest to eliminate are small soluble molecules like urea, electrolytes and carbon dioxide. Larger molecules, such as proteins or nucleic acids, have to broken down before they can be excreted or burnt as fuel. Cells have special digestive enzymes that break down unwanted or damaged proteins and nucleic acids into removable or usable units. Especially hard to eliminate is the waste resulting from random cross-linking and other unplanned reactions between cellular structures, particularly proteins. The resulting molecular aggregates are usually large, poorly soluble and difficult to break down. Most damaged or cross-linked proteins are chopped up by intracellular proteases (protein-digesting enzymes) before they aggregate into large poorly manageable clumps. Evidence indicates that low activity of cellular proteases favors the formation of large aggregates of molecular junk. Apparently, when a regular cleanup is inefficient, huge piles of garbage become more common. For digesting large chunks of tough waste, cells have special organelles called lysosomes, which essentially are membrane sacks filled with a variety of concentrated aggressive digestive enzymes.

Despite all garbage disposal systems of the body, some types of waste do accumulate with age. If you compare under the microscope neurons from the brains of young and old animals, you will find some remarkable differences. In the cytoplasm of old neurons you will see strange yellowish deposits. These are deposits of lipofuscin, an age pigment invariable found in many tissues of old animals or humans. Age pigments are a group of substances that visibly accumulate with age in various tissues and appear to have no useful function. Most age pigments are poorly degradable, insoluble by-products of various physiological and pathological processes. They are not chemically aggressive, but take progressively more space and eventually begin to interfere with normal cellular functions.

Lipofuscin is the most prevalent and well studied of age pigments. As we age, it invariably accumulates in most tissues, but especially in the heart muscle, the skeletal muscle and the brain. For quite some time it has been considered a relatively innocuous by-product of normal aging and some diseases. There is much evidence now that lipofuscin is a significant contributor to aging and age-related diseases.

The accumulation of lipofuscin is closely related to other mechanisms of aging: free radicals and cross-linking. It was found that lipofuscin is an end result of free radical damage to biological membranes. Lipids (fatlike compounds that are an essential part of cell membranes) are very easily damaged by oxygen free radicals in a process called lipid peroxidation. Lipid peroxides (products of lipid peroxidation) react with other lipids and proteins eventually forming large insoluble clusters. Cells try to break down such clusters using proteases and lysosomes, but this does not always work. The aggregates of cross-linked molecular garbage that could not be digested eventually turn into lipofuscin deposits. It appears that the greatest accumulation of lipofuscin occurs in the cells that burn large amounts of fuel and rarely or never divide. Understandably, the more fuel is burnt (oxidized) the more free radicals are generated and the cross-linked garbage is formed. It is not quite clear why frequently dividing cells do not accumulate much lipofuscin; one possible explanation is a greater activity of proteases and lysosomes in such cells.

Three main categories of cells that do not divide are neurons (brain cells), heart muscle cells and skeletal muscle cells. Accumulation of lipofuscin appears to contribute to age-related impairment in these tissues. All cellular processes are dependent on normal flow of nutrients and other molecules in and out of cells. Lipofuscin may damage tissues by mechanically obstructing normal flows, reducing the delivery of fuel and structural units and slowing down the elimination of wastes. The amount of lipofuscin in cells may exceed half of their volume, which is more than enough to disrupt normal traffic of molecules. There is a good correlation between the severity of dementia or congestive heart failure and the amount of lipofuscin in neurons and heart muscle cells correspondingly.

In one study, lipofuscin-like material was added to the culture of human fibroblasts from a young donor. Under certain conditions, fibroblasts can be made to engulf large amounts of the pigment. Such forced lipofuscin accumulation quickly blocked cellular division and caused fibroblasts to behave as though they came from a very old person. This is a direct evidence that lipofuscin accumulation is not coincidental, but indeed contributes to age-related pathologies.

A number of things can affect the rate of lipofuscin accumulation. Any process that promotes free radical formation or impairs the body's antioxidant defenses would promote the growth of lipofuscin deposits. The most common such factor is stress. It rises metabolic rate in the nervous system, heart muscle and skeletal muscle, causing more free radicals to be generated. When rats were subjected to 24 or 48 hour immobilization stress, the amount of lipofuscin in their neurons increased by 29 and 38 percent correspondingly. Another important factor for the rate of lipofuscin accumulation is the activity of cellular proteases. Young rats who received protease inhibitors (drugs that reduce protease activity) had a dramatic increase in lipofuscin deposits.

While lipofuscin is the most common age-related waste pigment, there are others. One is ceroid, a cousin of lipofuscin associated with low levels of fat-soluble antioxidants. Another is amyloid, a pigment associated with some autoimmune diseases. Large amyloid deposits may cause life-threatening conditions, such as heart or kidney failure. Beta-amyloid (a type of amyloid) plays a key role in Alzheimer's disease.

Research shows that it may be possible to slow down the accumulation of age-related pigments. The first step is to improve antioxidant defenses and reduce exposure and vulnerability to stress. Due to their ability to block lipid peroxidation, lipid soluble antioxidants, such as vitamin E and lipoic acid, are especially important in slowing down the accumulation of lipofuscin and ceroid. Improving carbohydrate tolerance reduces the rate of cross-linking reactions and, therefore, slows down the growth of age pigment deposits. Reducing inflammation tends to slow down the accumulation of age pigments as well. So does weight reduction in overweight individuals.

Some neuroactive drugs and nutrients were shown to reduce deposits of lipofuscin and ceroid in the brain. In particular, meclofenoxate and Deanol (dimethylaminoethanol p-acetamidobenzoate) were shown to reduce lipofuscin deposits in neurons in several animal species, including rodents, pigs and monkeys. It appears that the activity of both these drugs is due to dimethylaminoethanol (DMAE), which is a part of their structure. DMAE is a nutrient found in small quantities in fish and some other foods, and available over the counter in health food stores. Similarly to the above drugs, DMAE was shown to improve various cognitive activities, such memory, concentration and learning. In some studies, DMAE was found to increase the life span of rodents. It is still unclear how DMAE and its derivatives shrink the deposits of age pigments in neurons. One possibility is that they activate proteases and lysosomes and increase the amount of intracellular water, which leads to accelerated waste disposal. Whether long-term DMAE supplementation in humans increases longevity or reduces the accumulation of lipofuscin remains to be determined.


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