Aging theories cover the genetic, biochemical, and physiological properties of a typical organism, as well as the way these properties change with time. Genetic theories deal with speculations regarding the identity of aging genes, accumulation of errors in the genetic machinery, programmed senescence, and telomeres. Biochemical theories are concerned with energy metabolism, generation of free radicals, the rate of living, and the health of mitochondria. Physiological theories deal almost entirely with the endocrine system and the role of hormones in regulating the rate of cellular senescence.
Error catastrophe theory
Running a cell is a complex affair. RNA and proteins have to be synthesized on a regular basis to maintain and run the cell’s machinery.Production of proteins, either for enzymes or structural materials, occurs in a two-step process: transcription of the gene to produce mRNA, followed by translation of the message to produce the protein. For cells that are actively dividing, a third step, replication of the DNA, precedes the other two. Errors can occur all along the way; when they do, defective genes, mRNA, and proteins are produced. The error catastrophe theory, first proposed in the 1960s, suggests that over time, the number of errors build up to a catastrophic level leading to the death of the cell and, possibly, the entire organism.
Soon after this theory was proposed, many scientists conducted experiments that attempted to force a buildup of errors to see how the cells would cope with it. Bacteria were grown on medium containing defective amino acids to maximize the error frequency of protein synthesis. Similar experiments were conducted on fruit flies (Drosophila melanogaster) and mice, both of which were given food containing defective amino acids. To everyone’s surprise, these experiments had no effect on the bacteria’s or animal’s health, vigor, or life span. Somehow the cells were able to avoid an error catastrophe. Today scientists understand why those experiments failed: Cells have elaborate repair systems and strategies that detect and destroy defective molecules. If a defective protein is synthesized, it is quickly broken down and replaced with a normal copy. Only in cases where the repair systems have been damaged would an error catastrophe occur (e.g., Werner’s syndrome).
In its original formulation, the error catastrophe theory focused on protein synthesis, which apparently can tolerate a high error frequency. Consequently, many scientists began to wonder if errors in the genome, or possibly a defective regulation of the genes, might be responsible for the aging process. After all, cells avoid an error catastrophe at the translational level because they can always try again with a fresh mRNA from a good gene. But if the genes themselves are damaged, or programmed for senescence, the outcome would be a gradual decline in cell vigor and the eventual death of the organism.
Genes and programmed aging
Are humans programmed to get old? If so, is it like the program that guides our development from a single fertilized egg to a multicellu-lar organism? Or is aging the unfortunate side effect of adaptations that make it possible for us to have and protect our offspring? Many gerontologists believe that aging is a matter of evolutionary neglect, rather than design.
However life spans evolved, it is clear that our genes have the final say in how long an individual will be on the stage. Even though flies and humans are constructed from the same kinds of cells (eu-karyotes), one animal lives two weeks, the other 80 years. If those eukaryotes had remained free-living, as their protozoan ancestors have done, they would live for millions of years.
The genes in a multicellular organism appear to be regulating life span for the good of the cell community as a whole. The size of the community, the animal’s intelligence, the number of offspring, and the pressure the animal experiences from its predators, are all taken into account. The final life span seems to be a balance of all these forces, and given these forces may be the best deal the organism can hope for. There would be no point to nature’s producing a fruit fly that could live a thousand years since their predators eat them all in a matter of days. Scientists might try producing a fly that could live that long, but what in the world would an animal with that level of intelligence do for all that time? This is not just a whimsical point. There is a very strong correlation between longevity and the weight of the brain: "Smart" animals usually live longer than "dumb" animals.
The goal of gerontologists is to try to get a better understanding of the covenant between the genes, the organism, and the environment. Whether intended by evolution or not, many genes are directly responsible for an animal’s life span. These genes may be exerting their effects through inappropriate behavior (that is, they are turning on or off at the wrong time) or through a mutation that eventually damages the protein product.
Damage at the gene level reinvokes the error catastrophe theory, but many experiments have failed to establish a role for genetic (or somatic) mutations in cell senescence. This is because the cell can detect and repair DNA damage as easily as it deals with errors in translation, and those repair systems remain intact long after the animal shows visible signs of age.
The inappropriate expression of certain genes as a major cause of aging is only now being addressed in a comprehensive way. With the sequence of the human genome now at hand, it will soon be possible to screen for the expression of all human genes, in every tissue and organ of the body. When this job is complete (and it will be as big a job as the genome project itself) researchers will finally have an idea of which genes are responsible for the human life span.
Although scientists have not identified the genes controlling our life span, there is a genetic element called a telomere that clearly regulates the replicative life span of human cells in culture. A telomere is a simple DNA sequence that is repeated many times, located at the tips of each chromosome. Telomeres are not genes, but they are needed for the proper duplication of the chromosomes in dividing cells. Each time the chromosomes are duplicated, the telomeres shrink a bit, until they get so short the DNA replication machinery can no longer work. This occurs because the enzyme that duplicates the DNA (DNA polymerase) has to have some portion of the chromosome out ahead of it. Much like a train backing up on a track, DNA polymerase preserves a safe distance from the end of the DNA, so it does not slip off the end. Telomeres also provide a guarantee that genes close to the ends of the chromosomes have been replicated. DNA polymerase stalls automatically whenever it gets too close to the end of the chromosome, permanently blocking the ability of the cell to divide. When this happens, the cell is said to have reached replicative senescence.
Telomeres. A telomere is a simple DNA sequence, located at the tips of each chromosome, that is repeated many times. Telomeres are not genes, but they are needed for the proper duplication of the chromosomes in dividing cells.
The telomeres in human fibroblasts are long enough to permit about 50 rounds of DNA replication. That is, the cell can divide about 50 times in culture. This is often referred to as the Hayflick limit, after Leonard Hayflick, the scientist who was the first to notice that normal cells cannot divide indefinitely in culture. Cancer cells, on the other hand, can divide indefinitely, and from them scientists isolated an enzyme called telomerase that restores the telomeres after each cell division. If the telomerase gene is added to normal fibroblasts, they are no longer bound by the Hayflick limit and can divide indefinitely, like an immortal cancer cell. The transformation of normal fibroblasts with the telomerase gene was conducted for the first time in 1998 at the Geron Corporation, a biotechnology company. The results generated a tremendous amount of excitement, for they seemed to imply that reversal of replicative senescence would be followed very quickly by the reversal of the aging process. Scientists at Geron began talking about human life spans of several hundred years.
Experiments since have shown, however, that while telomerase can block replicative senescence in cultured cells, it has little to do with the life span of the animal as a whole. Indeed, some animals with long life spans have short telomeres and negligible telomerase activity, while other animals with short life spans have long telomeres and active telomerase. This is not surprising if one remembers that most cells in an animal’s body are post-mitotic; they stop dividing soon after the individual is born. So the life span of the individual made from those cells cannot be regulated by the length of the telomeres.
This theory takes a pragmatic approach to the regulation of life span. Simply put, it claims that if you are going to live fast and hard, your life will be short. The engine in a race car, run at full throttle, is lucky to last a full day. On the other hand, engines that are driven carefully, at modest RPMs, can last for 10 to 20 years and may even log 200,000 miles (321,868 km). Of course, if you buy a new car, park it in a garage, and rarely drive it, it will last even longer. This theory is not concerned with the underlying mechanism of aging, but simply advocates repair or replacement of body parts as they wear out, much in the way one deals with a broken-down car.
Of course, some body parts, such as our brain and muscles, cannot be replaced, and if anything serious happens to them, it would likely be fatal. The rate-of-living theory tries to deal with senescence by adopting a preventive strategy, involving a reduction in activity level and caloric intake. These strategies have been tested in house-flies, mice, and rats with some success.
Houseflies normally live one month in laboratory conditions, that is, in a large cage where they are fed and protected from their predators. If they are kept in tiny cages, no bigger than a teacup, their flight activity is severely restricted, and as a consequence, their life span is more than doubled. Caloric restriction has the same effect, but is most likely due to the forced reduction in flight activity, due to a lack of energy. Raising mice or rats in confined quarters to lower their activity level has no effect and may even reduce the life span because of the stress that it causes in these animals. Caloric restriction, however, can increase a rat’s life span by 50 to 60 percent.
Researchers at the University of Wisconsin, led by Drs. Ricki Colman and Richard Weindruch, have recently completed a 20-year experiment in which rhesus monkeys were raised on a low-calorie diet (30 percent fewer calories per day). Compared to a control group that received a standard diet, the experimental group has shown a dramatic reduction in the incidence of diabetes, heart disease, neurological disorders, and cancer. Moreover, the low-calorie group looks younger and healthier than the control group, with slim physiques and smooth glossy coats. In terms of survival, Weindruch estimates that the life span of the experimental group will be extended by 10 to 20 percent. This is not as dramatic as the results for mice and rats, but it does suggest that a calorie-restricted diet could extend the human life span as well.
The role of free radicals is closely related to the rate-of-living theory and was originally proposed in the 1950s. Free radicals are molecules that have an unpaired electron, which makes them very reactive. One of the most important, the oxygen free radical, is a toxic exhaust produced by mitochondria during the very important metabolic process of oxidative phosphorylation. This process produces the ATP that cells need to survive. The oxygen free radical can remove an electron from virtually any molecule in the cell, including DNA, RNA, proteins, and the lipids in the cell membrane. When it does so, it triggers a chain reaction of destabilized molecules reacting with other molecules to form new free radicals and a variety of potentially dangerous compounds. Many gerontologists believe free radicals are directly responsible for cellular senescence and the aging of the animal as a whole.
But cells do not give free radicals a free rein. A special enzyme, called superoxide dismutase (SOD), neutralizes oxygen free radicals as they are produced. Gerontologists in favor of the free radical theory maintain that SOD does not neutralize all of the free radicals, and that the damage is done by those that escape. Alternatively, aging may reduce the efficiency of SOD, such that the amount of free radicals increases gradually with age. An anti-aging remedy, consisting of a regular diet of antioxidants (chemicals that inactivate free radicals) such as vitamin E or vitamin C, has been proposed. Many experiments have been conducted on mice and rats to test this remedy, but with limited success. The most recent study, conducted in 2008 at the University College London, used the nematode C. elegans to test the free radical theory. The UCL team, led by Drs. Ryan Doonan and David Gems, genetically modified a group of nematodes to permanently reduce their levels of free radicals. According to the theory, the experimental group should have had a much longer life span than the controls, but the results failed to show such a difference. The researchers concluded that oxidative damage is not a major driver of the aging process.