Wear and Tear Theory

The body's metabolism produces waste regularly. The majority of bodily waste is expelled through breathing, urine, feces, and sweat. The most easily disposable waste is composed of small molecules like urea, carbon dioxide, and electrolytes. Proteins and nucleic acids, which are made up of larger molecules, need to be broken down before being used as fuel or excreted. Special digestive enzymes are present in the cells that break down damaged or unnecessary proteins and nucleic acids. However, it is tough to get rid of the waste resulting from cross-linking and other unusual reactions that have taken place at the cellular level, particularly when they involve protein. The molecular compounds formed from these reactions are generally quite large, not particularly soluble, and hard to break down. Most damaged or cross-linked proteins are broken up by intracellular protein-digesting enzymes, known as proteases, to be pooled together into manageable groups. It has been shown that low-energy proteases tend to produce larger clumps of molecular waste. For discarding large pieces of waste, cells have lysosomes, which are special organelles, effectively membrane sacks containing concentrated levels of powerful digestive enzymes.

No matter how many waste disposal methods the body has, some kinds of bodily wastes build up with age. When neurons from the brains of different aged animals are studied under the microscope, there is a remarkable difference depending on the sample's age. There are unusual yellowish deposits in the cytoplasm of old neurons. These deposits are lipofuscin, an age-related pigment found in several different tissues types of older people and animals. Age pigments, while visible, seem to have no particular useful function. They are there because they are generally insoluble by-products of various pathological and physiological processes that are difficult to break down. While they take up quite a bit of space and are not chemically threatening, they can interfere with normal cellular functions by their mere presence.

The most studied as well as the most common form of age pigment is lipofuscin. As we get older, lipofuscin accumulates in most tissues, but the heart, the muscular system, and the brain are particularly hard hit. Thus, lipofuscin has traditionally been thought of as a fairly innocuous by-product of aging. However, there is now proof that lipofuscin can be a major contributor to aging as well as age-related illnesses.

The buildup of lipofuscin is associated with other components of aging: free radicals and cross-linking in particular. Lipofuscin has been proved to be a result of free radical damage to certain biological membranes. Lipids (which are fatlike composites that are key parts of the cell membrane) are very vulnerable to attack by oxygen free radicals; this process is known as peroxidation. Lipid peroxides react with other lipids and proteins, creating large and insoluble clusters. The cells then attempt to break down these insoluble clusters using lysosomes and proteases, but this isn't always successful. The buildup of cross-linked molecular waste that cannot be processed turns into lipofuscin deposits. It seems that the largest buildup of lipofuscin happens in the cells that burn the largest amounts of energy and don't often divide. The more fuel used (oxidized), the more free radicals are produced, and the more cross-linked excess is formed. We do not understand why cells that divide regularly do not have as large of the buildup of lipofuscin. One theory is that the proteases and lysosomes are more active in cells that divide a lot.

The neurons (brain cells), heart, and skeletal muscles are the three kinds of cells that do not divide. The buildup of lipofuscin seems to add to the age-related slowdowns of these tissues. All cellular processes require a regular flow of nutrients and other molecules in and out of the cells. The tissue can be damaged by lipofuscin because it physically blocks the regular flow between cells, thereby reducing the supply of fuel and structural units and slowing the elimination of wastes. The level of lipofuscin can exceed 50% of cellular capacity, which will, in turn, slow the normal traffic of the molecules. There is a clear relationship between the severity of dementia and congestive heart failure and the level of lipofuscin present in the neurons and the heart muscle cells accordingly.

One study showed that when the lipofuscin was introduced into the cells of a young person, they reacted in the same manner as if they had come from a much older person. In controlled conditions, fibroblasts can be forced to engulf large amounts of pigments. This forced lipofuscin can rapidly stop cellular division and cause the fibroblasts to act as though they are from an older person. This shows that lipofuscin accumulation is not random but indeed contributory issues in age-related problems.

Lipofuscin accumulation can be affected by many factors. Processes that promote the formation of free radicals or inhibit the body's antioxidant defenses can, as a result, raise the level of lipofuscin deposits. Stress is the most common irritant. Stress increases the metabolic rate of the nervous system, the heart, and the skeletal muscles, thereby cause a higher number of free radicals to be produced. Another key factor in the speed of lipofuscin accumulation is the activity of cellular proteases.

Lipofuscin is not the only age-related waste pigment; there are others as well. Ceroid is a waste pigment that is linked to low levels of fat-soluble antioxidants. Another waste pigment is amyloid which is related to autoimmune disease. Large accumulations of amyloid can lead to kidney or heart failure. Beta-amyloid plays a major role in Alzheimer's.

Current research has proven that it is possible to retard the buildup of age-related pigments. The best way to do this is to improve the antioxidant defenses and to lower exposure to stress. Lipid soluble antioxidants like vitamin E and lipoic acid block lipid peroxidation and slow down lipofuscin and ceroid buildup. Raising levels of carbohydrate tolerance can also reduce the number of cross-linking reactions, which in turn slows the accumulation of pigment deposits. Reducing levels of inflammation can also slow down the buildup of age pigments. Weight reduction can also be effective.

Certain neuroactive drugs and nutrients have been proved to lower the level of deposits of lipofuscin and ceroid in the brain. For example, Meclofenoxate and Deanol have effectively reduced lipofuscin buildup in the neurons of multiple species, including monkeys, pigs, and rodents. It seems that both of these drugs work because they contain dimethylaminoethanol (DMAE). DMAE is a nutrient present in small amounts in fish and other foods and is available in supplement form in health food stores. DMAE has been proven to improve memory, learning ability, and concentration. Research has also shown that DMAE could increase the life span of rodents. However, we still do not understand why DMAE and its by-products cause the deposits of age pigments to shrink in neurons. One reason might be that they activate proteases and lysosomes, thereby creating extra intercellular water, leading to more efficient waste disposal. We still need to wait and see if long-term use of DMAE in humans can increase longevity and reduce lipofuscin buildup.