All biological characteristics of living organisms are presumed to have arisen through the processes of genetic variation and natural selection - evolution. For most of our evolutionary history, new genes have arisen by modification of existing genes. When a new gene variant arises by the process of mutation, a decision has to be made to keep it or discard it. That decision is made on the basis of whether or not a particular variant increases the reproductive success of the organism in which it arises. Does it increase that organism’s ability to pass on its DNA to the next generation? If so, it will spread through the individual’s offspring, over time, to the rest of the species. If not, it will likely disappear in short order.

It is easy to see how this process of natural selection works for traits like increased physical vigor, better eyesight, or brighter plumage for attracting mates. But how do we explain the existence of aging and death? This question has long puzzled evolutionary biologists. How could something so clearly contrary to the interests of the individual organism have evolved? As individuals get older, their ability to find mates, reproduce and, where necessary, care for offspring, are all seriously impaired by aging. So how could genetic variants promoting aging ever have been selected in evolution?

This mystery is compounded by the fact that, in the wild, most animals do not live long enough to experience serious aging. They die from disease or predation long before they become noticeably old; for most species, elderly individuals can only be found in zoos or laboratories. That means that the very thing natural selection is supposed to act upon rarely ever shows up in nature. Yet, if kept in zoos or labs, they definitely do age. Where did the genes responsible for aging come from?

To get around these conceptual problems, scientists came up with a very clever hypothesis. Suppose a new genetic variant of an existing gene were to arise that functioned perfectly well to do its assigned job while the individual is young but, when the individual gets older, this same gene begins to have a negative effect on the individual’s ability to survive. By the time natural selection picks off individuals carrying this gene, they will already have passed it on to their offspring. Hence the gene’s negative effect will be "invisible" to evolution; such genes are beyond the reach of natural selection!

There are genes in humans that could fit this description. The classic model, pointed out some fifty years ago, is the gene for Huntington’s disease. This is a disease caused by a defect in a single gene. We do not know what the normal gene does, but inheritance of a single "bad" copy of this gene results in development of a disorder that is uniformly lethal. But this disorder usually sets in only after about 35-40 years of age. That is ample time for the affected individual to have passed on the gene to his or her offspring. Some of the genes involved in Alzheimer’s disease, and genes predisposing to certain cancers, could also fit into this category.

This proposal was greeted with relief by physicians and scientists who studied aging, and has become embedded as part of what is commonly called "the evolutionary theory of aging." However, recent advances in molecular biology suggest that this theory is wrong. According to the evolutionary theory, aging genes should accumulate randomly in different species over evolutionary time. But a study of the genes underlying aging and programmed death in the simplest unicellular eukaryotes, such as Paramecia and yeast, all the way through human beings, shows that these genes are remarkably similar in every species. Aging genes from humans, for example, can function to replace the equivalent aging genes in yeast, and vice-versa.

It is now clear that aging as it occurs in humans reflects a process that was already in place in our evolutionary ancestors several billion years ago. The first forms of life on earth were the prokaryotes, represented today by the highly successful bacteria that inhabit every conceivable biological niche on the planet. The prokaryotes were and are effectively immortal, in the sense that they never age. They die for many accidental reasons, but never from growing old. The prokaryotes gave rise to the more complex eukaryotes, some forms of which ultimately evolved into mammals and human beings.

It is in the eukaryotes that we first see aging and compulsory death. The earliest eukaryotes were, like their bacterial forebears, unicellular. They divide continuously throughout their lifespan. But unlike bacteria, eukaryotic cells have a limited lifespan, based on the number of times they have divided. Even if they are not starved, eaten, or killed by other means, they gradually grow old and will die when they reach their replicative limit.

This had not happened before in evolution. But we see this same form of "replicative senescence" in many human cells. Astonishingly, many of the genes responsible for replicative senescence in eukaryotes that evolved a billion or more years ago are still present in human beings today. And they cause a form of cellular aging and death virtually identical to that seen in Paramecia and yeast. If cells such as fibroblasts are removed from our bodies and placed in culture, they divide rapidly at first, but then age and eventually stop dividing, just like unicellular eukaryotes.

This presents a major challenge for the evolutionary theory of senescence. If aging genes arose randomly in various life forms across evolutionary time, why are so many of them identical?

The answer to this question requires a deeper understanding of the origin of phenomena like replicative senescence. Virtually all the damage in aging eukaryotic cells, including the damage that causes them to stop dividing, can be accounted for by something called oxidative stress. Oxygen is incredibly toxic; its breakdown products within the cell - called oxygen radicals - are responsible for the vast majority of symptoms underlying cellular senescence and organismal death.

Oxygen was only a trace element in the earth’s atmosphere when prokaryotic life forms emerged from the primordial soup. It became a significant element only when certain bacteria began splitting water to create energy, releasing molecular oxygen in the process. Doubtless this new gas was lethal for many of the relatives of these bacteria, but some of them cleverly learned to use this very oxygen by combining it with food to generate energy, in a process we ourselves use to this day. To help cope with the resulting oxygen radicals, they evolved a number of antioxidant defenses, particularly enzymes like superoxide dismutase and catalase.

As eukaryotic life forms began to spread across the planet, they faced the same problem in dealing with oxygen. But rather than developing their own means of using oxygen for energy, and defending themselves against the consequences, they simply engulfed some of the smaller bacteria that had already learned how to deal with oxygen, and put them to work. We can see the fossil remnants of these bacteria in our cells today. They are the mitochondria, which we use to extract usable forms of biological energy from food and molecular oxygen. We also inherited some of the genes for antioxidant enzymes from these bacteria, although we developed a few more on our own.

The mitochondria remain today the principal source of oxygen radicals in all of the cells of our bodies. These radicals can damage virtually every molecule of which our bodies are made. The most important molecule, from an aging standpoint, is DNA. Damage to DNA triggers a number of alarms in cells that can shunt them into a pathway of rapid senescence or even death. Cells try to prevent DNA damage in the first place by neutralizing oxygen radicals through antioxidant enzymes and other inherent defense mechanisms. They can also use substances taken in through the diet, such as the antioxidant Vitamins A, C and E. If DNA nevertheless suffers oxidative damage, there are powerful DNA repair systems to restore it to its original state.

But all of these systems decline with age, and that in itself is part of the natural aging process. Molecular damage caused by oxygen radicals accumulates, and at some point the cells - and ultimately the organism composed of these cells - can no longer function. Usually the organism becomes so weakened by diminished cellular function that it succumbs to external disease or gets eaten by a predator. But in longer lived species like ourselves, if all else fails the individual may die from total physiological collapse - "old age", if you will.

As with replicative senescence, the genes responsible for the generation of oxygen radicals, as well as the repair and prevention of oxidative damage, were already present in the very earliest eukaryotes, and have changed very little over evolutionary time. Thus it wasn’t necessary for senescence and death to evolve in eukaryotes; the whole process was inherited from our prokaryotic ancestors, and has changed very little since then. We end up with the important insight that the genes involved in aging were not selected by evolution to cause aging after all; they went with the territory when the decision to use oxygen for energy generation was made - several billion years ago!

The impact of some of these ancient genes on aging in humans can be seen in inherited aging diseases like Werner’s syndrome. This is a type of disorder called a progeria, in which humans race through the aging process at a greatly accelerated pace. Individuals with Werner’s syndrome reach old age in their forties. In other progerias, such as the Hutchison-Gilford syndrome, individuals go through the aging process and die before they are twenty. Although none of the progerias displays every single aspect of aging, each of them results in the development of a substantial portion - as many as a third - of the features of aging.

The genetic variant that causes Werner’s syndrome was recently isolated and characterized. It involves a defect in a single gene that codes for a DNA helicase, an enzyme that unwinds DNA in preparation for replication or repair. It is thought likely that defects in this enzyme interfere with a cell’s ability to repair damage to DNA. As mentioned earlier, the ability to repair DNA declines with age, and is thought to be a major contributor to aging. Individuals with Werner’s syndrome may have a decreased ability to repair DNA damage from birth. Working backward from humans, Dr. Leonard Guarente at MIT recently isolated the Werner’s gene in yeast. Remarkably, mutations in this gene cause an accelerated aging syndrome in yeast, which are separated from humans by at least a billion years of evolutionary time!

The study of aging intersects in unsuspected ways with cutting edge research ina wide range of fields. If, as scientists now believe, aging is largely caused by an increasing burden of unrepaired damage to our DNA, what will we see in Dolly, the sheep that gained fame in 1997 as the first truly cloned mammal? Dolly was cloned by removing the DNA-containing nucleus from a mammary gland cell taken from a six-year-old sheep, and transferring it to an unfertilized egg (which is zero years old) taken from another sheep. This hybrid egg was then implanted into the uterus of yet a third sheep, where it proceeded to direct successfully the construction of an entire new sheep - Dolly. If we believe that the age of an animal is a reflection of the aging of its DNA, what age is Dolly? The nuclear DNA that directed her complete development was six years old. Does Dolly begin life at age six, in terms of cumulative DNA damage? Will she die prematurely from a form of artificial "pre-aging"?

The story is even slightly more complex. There are two kinds of DNA in cells - nuclear DNA, and mitochondrial DNA. Mitochondrial DNA is left over from the bacteria imported into our cells to help process oxygen, but it is still used by our cells for a variety of purposes. Damage to mitochondrial DNA is thought to be a key element in the aging of cells. But inheritance of mitochondrial DNA is different from the inheritance of nuclear DNA. Mitochondrial DNA comes only from the mother, as part of her egg; sperm contribute no mitochondria to the newly formed individual. So Dolly has old nuclear DNA, and fresh, new mitochondrial DNA from the egg into which the old nucleus was implanted. Which DNA will determine her age? Or will the nuclear DNA be somehow "rejuvenated" by the fresh egg, making her birth age and age in terms of cellular senescence the same? These are intriguing questions, the answers to which will have important implications for both ends of life: embryonic development and old age.

Another recent discovery with potential implications for aging is related to something called telomeres. Telomeres are special structures that "cap" each end of our chromosomes so that they don’t stick to one another. Because of the way DNA is replicated, short stretches of these telomeres are lost from the end of each chromosome every time a cell divides. In many single-cell eukaryotes that divide extensively as a normal part of their life cycle, there is a special enzyme called telomerase that can restore the telomeric ends to chromosomes. However, telomerase is either absent or found at extremely low levels in most adult cells in higher organisms.

It has been proposed that telomeres could be an important part of an internal "clock" mechanism that could account for replicative senescence. With each round of cell division, more and more of the protective telomeric cap is lost from each chromosome, until at some point chromosomes begin to clump together. Exposed regions of DNA in these abnormal chromosomes could activate damage control systems that either shunt cells into the senescent state, or cause them to die.

Telomeres can actually be observed to shorten throughout the lifespan of human cells as they age. Telomeres are also significantly shorter in Hutchison-Gilford and Werner’s syndrome patients compared to age-matched controls. But telomeres in cancer cells are kept in good working condition; cancer cells have somehow managed to activate their telomerase! It has thus been proposed that the normal absence of telomerase activity in adult animal cells may be a critical barrier to the development of tumors.

Until very recently there was some doubt about whether telomere shortening is a primary cause of replicative senescence, a result of replicative senescence, or simply an intriguing coincidence. But any doubts about the role of telomeres in human replicative senescence were laid to rest in an experiment reported in the journal Science in early 1998. Normal human cells with the standard human replicative potential were transfected with a gene that activates telomerase, and then grown in culture. At the time of the report, the cells receiving the telomerase-activating gene had lived half again as long as untreated cells, and showed no signs of slowing down. They were also "younger" looking in terms of cellular morphology, and the ability to adhere properly to the culture plates. The consensus at this point is that they have almost certainly escaped replicative senescence; they have likely become immortal.

There will doubtless be advantages in being able to reactivate telomerase in cells that ordinarily do not divide. A commonly cited example is in the case of burn victims. The best skin for transplanting onto burns is the victim’s own skin, and in the case of small burns this is entirely feasible and works well. In the case of massive burns, the victim simply doesn’t have enough skin. There have been attempts to grow some of an individual’s skin cells in vitro for reimplantation to a burn site, but this has not been terribly successful because of the slow and ultimately limited growth potential of normal skin cells in culture. If telomerase were reactivated in some of these cells, we could well see the growth of sufficient cells to provide clinically useful amounts of a patient’s own skin. The problem, of course, is how to stop the cells from continuing to grow once the burn site has been completely filled in. This is not beyond technical possibility, but great care would have to be taken to assure that cancer did not develop.

When the telomerase story broke, it was touted by some of the media as a possible key to human immortality. Simply find a way to switch telomerase on in our cells and, like the cells in culture, they (and we) will live forever. But remember that the cells in culture were all dividing vigorously; like tumor cells, they had overcome the natural barrier to unlimited proliferation. The likely outcome of turning on telomerase in all of our cells would not be immortality in the sense we might dream of, but the the eventual development of massive and uncontrollable tumors.

Beyond that, we must remember that the majority of cells in the body do not divide, and for those cells replicative senescence is not a likely cause of aging in the first place. It is not at all obvious at present that reactivating telomerase in those cells would have any impact on aging of the tissues they make up. But this must be explored, and it will; current views could be wrong, in ways we cannot yet perceive. Could we rejuvenate those cells in our bodies that do divide, by reactivating telomerase? Possibly, if we could find a way to prevent them from becoming cancerous. But even if we could achieve that, aging in our other tissues - if it proves not to involve telomerase - would very likely proceed on schedule, and it is not clear that our overall rate of aging would be seriously altered. Nevertheless, the importance of the ability to manipulate a major component of cellular senescence cannot be over-exaggerated, and we will all want to follow this story closely as it develops.