The Washington Post
Navigation Bar
Navigation Bar

Related Items
On Our Site
  • Chapter One of Life Itself
  • Science Section
  • Horizon Section

  •   Microbes Are Immortal, So Why Aren't Humans?

    dna photo
    Martina Vortmeyer -- TWP
    By Boyce Rensberger
    Washington Post Staff Writer
    Wednesday, June 10, 1998; Page H01

    Why die? Why not live forever? Such questions have a naive, adolescent quality, but they address profound biological mysteries for which scientists have no good answers.

    The human body, like all multicelled organisms, grows up and then starts growing down, eventually to die. Why do we have to die? Why do we have to deteriorate as we grow old?

    After all, one-celled life forms don't have to suffer that fate. An amoeba or a bacterium lives for a time, aging in the sense that it becomes older. But eventually, it divides, yielding two newborn cells. Nothing has died. Molecules and structures that constituted the old microbe serve as templates for creation of molecules and structures of two young ones.

    If one-celled creatures can keep their internal structures intact and working indefinitely, why can't human cells do so? Biological evidence suggests that, if our cells remained in a condition as good as when we were young, our bodies would stay young and we, like the immortal protozoans, would never have to die.

    Does some biological inevitability catch up with us? Is it because of the most obvious difference between one-celled and many-celled organisms? Must we many-celled organisms die because of some necessity imposed by the fact of cells living in the large aggregates that make up our bodies?

    There is considerable evidence that multicelled organisms are fated to die at a roughly predictable time. Mice usually die before they are two or three years old. Elephants rarely make it past 50 or 60. Most humans are dead by 80 or 90 and virtually all by 120. The Galapagos tortoise appears to live to 150 or more with relative ease but never much beyond 175.

    At least since Aristotle, observations like these have led people to suppose that aging and death are built into the fundamental makeup of each species. The existence of single-celled creatures, let alone their immortality, was not known in ancient Greece. Just as offspring resemble parents in appearance, so they resemble them in life span.

    Still, the question remained: Do we age and die because our bodies are built to die, our deaths perhaps being necessary for the good of the species? Or do we die simply because our bodies break down after prolonged use, the species being indifferent to our fate? Put another way, is death required or optional?

    The answer could give hope that, if we tried hard to stay healthy, we could live forever. Or it could assure personal doom.

    In the 1920s, a clue seemed to emerge from experiments by Alexis Carrel, an American biologist at the Rockefeller Institute, now called Rockefeller University, in New York City. He established a culture of disembodied chicken cells that appeared to proliferate endlessly, generation after generation. The cell line was maintained for many years, far outliving the chicken that donated the cells.

    On the basis of this, Carrel asserted that cells were not programmed to die but were immortal and forever youthful, renewed at each division just as are one-celled organisms. He said that whatever made the whole chicken die -- and by extension, what made any multicellular organism die -- was that the organism's cells had changed into a specialized form, such as brain cells, muscle cells, heart cells and so on, that no longer could divide. When removed from the body, Carrel decided, some cells reverted to an embryonic form and recovered their ability to divide endlessly.

    We die, Carrel said, because our bodies contain so many specialized cells that they no longer can undergo the rejuvenating influence of cell division. Death, Carrel said, was the result of wear and tear within undividing cells that could not repair the damage.

    In the 1960s, that seemingly reasonable view came crashing down with one of the most puzzling discoveries in cell biology.

    Like amoebas, paramecia undergo "binary fusion," turning age into youth. Photo Researchers

    Leonard Hayflick, a cell biologist now at the University of California, San Francisco, found strong evidence that Carrel was wrong. Hayflick noticed that cell lines derived from normal (as opposed to cancerous) cells were not immortal. Over years of carefully controlled experiments, he showed that normal human cells can be grown in the laboratory for only about 40 to 60 rounds of cell division. The average was about 50.

    Then, although the cells looked perfectly healthy, they lost the ability to divide and died. The only cells Hayflick found that seemed to keep dividing endlessly were those from tumors. Cancer cells do appear to be "immortal." That's what makes them so lethal.

    What about Carrel's immortal chicken cells? Hayflick could not confirm Carrel's result. His own cultured chicken cell lines invariably became extinct after 15 to 35 rounds of cell division. Scientists now generally believe that Carrel's cell line was not really continuous. His method of feeding cells used serum prepared from chicken blood in a way that inadvertently included fresh chicken cells. The old cells, it now seems obvious, must have been dying but, unbeknownst to Carrel, were being replaced repeatedly with new cells.

    Hayflick's finding strongly suggested that the inevitability of death, and even a cellular form of aging, was built into each individual cell or, at least, built into cells from multicellular animals. Microbial cells are still immortal. No matter how well cared for the human cells are, if they are not cancer cells, they invariably die after an average of 50 divisions. Death seems programmed into our genes.

    Even more compelling evidence emerged when Hayflick made the same observations on cells of other species. Mice, which live at most for three years, cannot keep their cells going in culture for more than 14 to 28 divisions. The venerable Galapagos tortoise has cells that keep dividing for 90 to 120 rounds. A species's life span appears related to the number of cell divisions its cells can sustain in culture.

    In a sense, these findings are most discouraging. They imply that, no matter how well we care for our bodies, we cannot extend our lives beyond a fixed limit. But that implication need not be as dismaying as it seems. It is not clear that we die because our cells reach the Hayflick limit.

    The evidence is in cells removed from old people for culturing. The human cells that live for about 50 cell divisions are fetal or newborn cells, often taken from umbilical cords or foreskins. Cells from people in their 80s or 90s typically live in culture for about 20 divisions. Most of us, it seems, die long before our cells reach the Hayflick limit. The implication is hopeful: Human cells may have the biological potential to carry us into our mid-100s.

    To this potential good news, however, scientists have found a discouraging caveat. Even in a healthy body, some cells -- including some of those most the crucial to survival -- no longer can enjoy the revitalizing benefit of dividing. Early in development, those cells committed themselves to specialized functions that make it architecturally impossible to divide again.

    This includes most muscle and nerve cells. Much of what the brain does when it learns is to extend processes that make contact with other brain cells. These wiring patterns among brain cells, one way that skills are retained and memories stored. If a nerve cell divided, it might renew itself as two, young cells but only after breaking connections needed to remember a fact or a skill. This process, happening billions of times, would create mental chaos.

    Still, biologists are puzzled as to why a cell that has ceased dividing must die. Why couldn't it just metabolize forever? Is a cell like a machine whose parts wear out? Or can cells replace worn-out parts with newly made ones?

    Or, is it possible that cells can replace only some broken parts, leaving other vital structures unrepairable?

    At least a dozen hypotheses have been advanced to explain how a cell might lose its capacity to live.

    One is that mutations occasionally hit the cell's genes and that, as the damage grows, so do the odds that vital genes are disabled. A liver cell might lose the ability to make an enzyme needed to perform a vital function for the body. As more such cells are damaged, the liver's efficiency declines with age. Without a minimally functioning liver, the rest of the body is doomed.

    Another school of thought blames the immune system, which gradually may lose control of itself and mistake parts of its own body for enemies. For example, evidence indicates that, as people grow older, their blood contains more and more antibodies shaped to bind not to invading microbes but to molecules and cells of one's self. As yet, however, no clear link has been made between types of auto-antibodies known to arise and diseases most common among the elderly.

    Yet another hypothesis is called "error catastrophe," which involves a healthy cell making a tiny error when reading the genetic code for a protein needed in the very process of reading the genetic code.

    Conceivably, every protein made by the flawed process would itself be flawed. A tiny initial error could mushroom quickly into a catastrophe, filling the cell with enzymes that couldn't produce the right reaction and protein building blocks that wouldn't fit together.

    Another theory invokes the fact that, when proteins are subjected to a certain amount of heat, they are deformed. The most familiar example is what happens to egg white, largely the protein albumin, in a frying pan. Living cells don't normally get that hot, but gentler heat can produce gentler gumming up of proteins.

    Like albumin, proteins essentially become welded as bonds form between molecules that are supposed to stay separate. Other proteins, when heated, "melt" into unusable shapes and can't be put right again.

    A related speculation blames the way glucose molecules can bind proteins, taking them out of service like two shoes with laces mischeviously tied together.

    Yet another theory of aging and death invokes a curious phenomenon in which an amino acid suddenly flips itself inside out, something like an umbrella caught in a gust of wind.

    Amino acids, like many other molecules, are not rigid but flexible within limits, continually jiggling and flexing. Sometimes, the forces that cause this motion combine randomly to make the atoms move more than usual. Then the molecule suddenly flips into a different but stable arrangement. As with the umbrella, the new shape may be functionally useless. If the amino acid happened to be in a vital protein when it flipped, the protein could be rendered useless.

    All of these theories have had advocates and enemies. None is fully accepted although there is room to think that any or several of them could be playing small roles in the aging and death of cells. Two additional hypotheses, however, have gained wider followings.

    One is the cellular equivalent of indigestion or, perhaps, terminal constipation.

    Occasionally, cells ingest substances that they cannot fully digest in their stomach-like organelles called lysosomes. This indigestible junk accumulates. Single-celled organisms eventually excrete this material, disgorging it in the cellular equivalent of defecation. One loss suffered by cells that are part of multicellular organisms, however, is the ability to do this -- and for good reason.

    Lysosomes contain caustic digestive enzymes that, if released, can damage cells. There seems to be no way for cells to unload lysosomes without exposing their neighbors to dangerous enzymes.

    As long as cells can divide and regain full size, they repeatedly dilute the amount of accumulated junk. But specialized cells in the body lose this option. More and more useless stuff piles up.

    Consider nerve cells, which will not have divided since childhood and may be many decades old. Most of the cell will be young because its internal renewal processes -- breaking down old organelles and enzymes in the lysosomes and making new ones -- will have recycled most organelles.

    Even in a 70-year-old brain cell, most organelles will be no more than a few weeks old. But the one exception to this continuing renewal is the brown, indigestible debris that accumulates in the lysosomes. Cell biologists call it lipofuscin.

    The lipofuscin theory of cell aging is that, as the gunk accumulates, cells become less and less able to recycle their other molecules and structures. Lysosomes are essential to that process because they break down the old hardware of life, reducing it to its raw materials, which then are reused for new construction. A lysosome jammed with lipofuscin could not supply raw materials for cell renewal.

    The other theory of aging and death that has earned respectful adherents involves entities called free radicals. These are not political revolutionaries at large but atoms and molecules with a high propensity to bind to another atom or molecule.

    Free radicals can be produced in cells when radiation, including light, strikes certain molecules, fragmenting them. Heat can have a similar effect, as can some toxins.

    Whatever the cause, the result is an atom or molecule with an unpaired electron. Since an atom's electrons must exist in balanced pairs for the molecule to be stable, such entities are highly reactive and "want" to acquire another electron. Most free radicals have a powerful propensity to bind to some other atom or molecule, even if that one is happily stable, or even to break apart another molecule to steal an electron.

    This wouldn't be so bad if the process stopped there. A healthy cell could compensate easily for the loss of a molecule now and then. But what often happens is a chain reaction. As the first free radical rips apart some law-abiding molecule to satisfy its chemical drives, it leaves fragments that themselves become free radicals. A chain reaction that went unstopped could easily destroy the life-sustaining structures within a cell and replace them with uselessly mangled molecules.

    Fortunately, cells have ways of protecting themselves from free radical damage. One is a special enzyme that unradicalizes the free radicals, sometimes by causing two free radicals to bind with each other. As long as the cell is well supplied with this enzyme, called superoxide dismutase, it is relatively well protected against free radical damage.

    As with all the protective mechanisms of life, however, they can fail. Or the rate of free radical chain reactions can simply outrun the rate of the protective reactions.

    Ironically, one of the most potent free radicals is oxygen. It reacts vigorously with a wide variety of atoms and molecules, from iron (to make rust) to hemoglobin (from which it, fortunately, is liberated to supply cells) to the reactions within cells where oxygen is used to "burn" carbohydrate molecules to release their stored energy. The cellular enzymes that interact with oxygen are, of course, usually very good about keeping the radical under control.

    Biochemists have long known that it is possible to quench the electron thirst of a free radical with another molecule called an antioxidant. These are molecules that carry a surplus electron and can give it to a free radical, be it oxygen or any other, without themselves becoming something harmful to the cell. This has led to speculation that, if cells were well supplied with antioxidants, they would be better protected against damage by free radicals.

    Intriguingly, vitamins C and E are antioxidants. Vitamin E is used as a food additive to retard rancidity, which is simply the oxidation of food. One study found that people with vitamin E deficiency have cells with increased amounts of lysosome-stuffing lipofuscin. Another, even more tantalizing, found that mice fed extra vitamin E lived longer than those on an ordinary diet.

    It is possible, however, that life extension in this study was not a result of vitamin E but of the fact that the mice lost weight on the diet. It is known that low-calorie diets -- nutritionally balanced but just barely meeting the needs of the animal -- extend life spans.

    While studies like these have led people to take vitamin supplements, antioxidants clearly cannot stop aging and cell death altogether. Cell cultures fed extra vitamin E still died when they reached the Hayflick limit. But, of course, since most people apparently die decades before they reach the Hayflick limit, antioxidant supplements still might be useful in maintaining structural integrity of cells until that limit is reached.

    Although accumulation of lipofuscin and the related effects of free radical damage are perhaps the leading hypotheses to account for aging and death, scientists have reached no broad consensus. Quite possibly, we age and die because of a combination of some of these processes and others unknown. Living cells are so extraordinarily complex, thousands of different chemical processes being needed to maintain the structures that make life, that any number of things could go wrong and kill a cell.

    Still, we know that free-living, single-celled organisms need never die. They are as complex as any of our cells but able to repair the ravages of time. Cell division for them would seem to be a fountain of youth. Pass through it, and you never die.

    But when single cells banded together hundreds of millions of years ago to form multicelled organisms, each cell had to subordinate its freedom to the good of the community. Each also surrendered its immortality. Refraining from dumping lysosomal wastes was one evidence of those sacrifices. Its price may have been gradual destruction of any given cell's ability to renew its parts indefinitely.

    Even if that were found to be the root cause of cellular aging and death and hence the death of the whole organism, a mystery remains. Why do mice die after two or three years while humans live many decades longer? Are our cells that different? They must be.

    To Leonard Hayflick, this suggests a different approach to the riddle of mortality. The question, he says, is not "why do we age?" but "why do we live as long as we do?"

    The principles of evolutionary biology suggest an answer. To ensure survival of the species, individuals need live only long enough to see that their offspring are well launched on their own lives.

    Consider the salmon, whose young need no help from their parents. Once the adult salmon swim upstream and spawn, they die. The salmon species has no further need of those particular individuals. The spark of salmon life has been passed in egg and sperm to a new generation.

    Indeed, Alfred Russel Wallace, the co-discoverer with Charles Darwin of natural selection, once argued that parents who lived too long eventually would compete with their young for resources. Survival of the young, once properly reared, thus may be improved if the old sacrifice by dying.

    Wallace thought that the time of death might be a trait programmed into the species by evolution as if it were a pattern of coloration or a body shape. If he is correct, the Hayflick limit may be evidence that time of death is programmed. It comes very late under the ideal conditions of cell culture in the laboratory.

    Perhaps it arrives sooner amid the natural conditions of the body because of various adverse effects inflicted by other cells living in close proximity. Since timing of the cell-division cycle differs among tissues, some cells in vital organs may be on a fast track and may reach their Hayflick limit before cells in other tissues. But those other tissues will be doomed nonetheless when the fast-track cells give out.

    Mammals need longer parental care than salmon. The newborn mouse must be suckled for a few weeks and then trained in the ways of mouse society. Parent mice must be strong and healthy enough to live through this period. To do so, they must have cellular mechanisms that can repair damaging effects of age for at least that long.

    But once the young are launched, a matter of weeks in the mouse, the species no longer needs the parents. Mice typically die after only about two years. There is no evolutionary pressure for mice to live any longer. Natural selection can favor a longer life span only if that result somehow favors survival of the next generation carrying those genes.

    Humans, requiring very lengthy parental care, could not have evolved if their cells aged and died as quickly as those of mice. Even if one remembers that virtually all of human evolution occurred when our species lived as small bands of hunters and gatherers, a child still would benefit from having living parents until perhaps the teenage years, This means that parents live at least until, say, 30.

    Since at least two children must reach reproductive age for each couple and given infant mortality rates in those days, this might well mean that the parental generation should stay biologically fit until perhaps 40. So why do humans live well past this age? There might also be a premium on living still longer if the wisdom and knowledge of the elderly benefited survival of the family. The respect accorded old people in many traditional human societies may be a relict sign that our species evolved by depending on wisdom of the elderly.

    Hayflick suggests that evolution has favored humans whose cells can keep their internal structures intact long enough to launch the next generation and that, if we live longer than that, we are simply coasting on reserve capacity built into the system.

    In other words, evolution has guaranteed us cells that can live in a multicellular organism perfectly well until we reach what is known as middle age. Then our cells slowly start falling apart.

    Cells deteriorate in the course of living. But they can be repaired like new as long as they can keep building new structures to replace the old, as long as they keep capturing new nonliving matter in the form of food, water and air and organizing it into correct patterns and shapes.

    They can keep doing this as long as free radical damage has not crippled vital enzymes and structures and as long as the lipofuscin buildup has not clogged their lysosomes' abilities to help recycle materials needed to rebuild.

    When most human beings die, however, not all of our cells necessarily die. A very select few, perhaps not more than one, two or three, often find immortality. These are the sex cells, sperm and eggs that have joined to begin constructing a new generation of human being.

    These cells possess the spark of life received from our parents and carry it forward to our children. The sex cells relay life to swarms of new cells that will build another human body. And, eventually, a few of the cells from that next generation will pass the torch to yet another.

    So, after all, the immortality of the single-celled still is in us. The grand architectures of our 60 trillion-celled bodies are but contrivances of the sex cells bent on sustaining their immortality. From an evolutionary perspective, our bodies are merely machines whose purpose is to convey the sex cells into their selfish futures. As generations of biologists have noted, "a chicken is an egg's way of making another egg."

    The society of cells that is the human body, it turns out, is ruled by an immortal autocrat -- the molecular architecture that is the essential core of life, the structural integrity of the genes and of other intracellular machinery that must be preserved and transmitted to a new generation.

    The structures bequeathed to the fertilized egg by a mother and a father serve as templates for the manufacture of copies needed in all cells of the new embryo.

    In a sense, then, the parts of us that are not sex cells are expendable hardware whose job is finished when their precious cargo is safely transmitted to a new generation.

    Adapted from Life Itself: Exploring the Realm of the Living Cell by Boyce Rensberger. Published by Oxford University Press.

    © Copyright 1998 The Washington Post Company

    Back to the top

    Navigation Bar
    Navigation Bar