The Zen of Science

Who wants to live forever? 
By Marc Ringel, MD

      I suspect some of the readers of this magazine do. I'm going to explain in this column the basic biology of aging and why, for the foreseeable future, you should not plan on living much longer than eight or 10 decades. 

      Thankfully, most of us probably gave up our illusions of physical invulnerability and immortality sometime after adolescence, which is why as adults we're at least a little careful, even when we rockclimb or party. Though I don't personally believe in angels, I frequently take solace in the art nouveau picture of heavenly creatures hovering above little children as they negotiate a bridge over a little stream, the sort of bridge whose undersides are inhabited by trolls and other dangers. In my mind, I replace the toddlers' sweet faces with those of my teenagers and they're not walking, they're driving. I know how dangerous it can be to feel invulnerable and immortal. I attribute my own survival beyond that developmental stage to a good share of dumb luck (or angelic protection).

      But I digress. The point is that as adults we learn, sooner or later, that our physical bodies will not live forever. There are almost as many different ways to deal with this undeniable fact of life as there are different spiritual practices. Some would say that the whole reason for religion is to help humans cope with death. Which is good, because (I'm speaking as a physician now) it really, really is inevitable. 

      Let's start with some basic science. Apoptosis is the process by which cells grow old and die. Every higher animal, from housefly to human, starts life as a single cell, the union of an egg and a sperm. That cell can produce any other kind of cell needed to construct a whole organism. One little DNA package, wrapped up in the cell nucleus, contains instructions and the potential to make brain, heart, skeleton, intestines, kidneys, lungs, blood-everything it takes to construct an individual. As the cell divides and its descendents differentiate, they lose their ability to make different types of tissues, called pleuripotency. Once committed to a specific destiny a bone marrow cell that produces white cells, for example, can no longer produce red cells too. 

      Differentiation occurs in a stepwise fashion throughout life. Take the example of the progression from a single fertilized egg, from the ultimate pleuripotent cell which can produce every type of tissue; to cells that make only blood; to cells that make only white blood cells; to only antibody producing plasma cells; to single cells that can secrete only a single antibody from among millions. As cells differentiate they progressively narrow the range of tissue types they can make. It's as if the trailing edge of the blueprint rolls up from behind as the construction plan encoded in an organism's DNA is accomplished, making the earlier stages of the plan inaccessible.

      In 1961, Hayflick and Moorhead reported on their experiments with a wide variety of mammal cell types. They demonstrated that cells go through about 50 divisions over the course of their development from fertilized egg to the last cell in a line, and then they die. The upper bound on cell divisions came to be known as the Hayflick limit, the ultimate determinant of longevity. Fifty doublings produces 250 total cells (more than a million billion, 1 followed by 15 zeroes), plenty of cells for a lifetime, but far short of enough to last forever. With each division a cell is exposed to errors in copying and dividing its DNA. After about 50 divisions the cell has accumulated enough errors to dictate that, instead of dividing to produce a daughter cell, it just dies. 

      Life is a dynamic process. While alive, at any age, an organism never stops growing. Some tissues turn over very rapidly. Humans must make millions to billions of new blood cells, skin cells, and intestinal lining cells every day. Bone marrow, skin, and intestinal crypts contain incessantly active stem cells which generate new tissue. When these cells are poisoned the organism suffers immediately, which explains why so many cancer patients become anemic, lose their hair, and suffer from diarrhea as a result of their chemotherapy.

      If you can understand why the drugs that treat cancer cause these side effects you can gain a lot of insight into why our bodies don't live forever. There are just two types of cells that escape the Hayflick limit: reproductive cells, which can trace their genealogy back continuously through a couple of billion years of evolution, and cancer cells, which, by definition have lost controls on their growth and will continue multiplying as long as the organism that spawned them survives. Stem cells, which keep dividing actively throughout life, have the least controls on their growth. Most of today's chemotherapeutic agents are designed to kill rapidly multiplying cells, which, unfortunately, means wiping out many normal stem cells, with the side-effects outlined above. (There are other strategies for targeting malignant cells more narrowly, but these efforts are still in their infancy).

      Less rapidly growing tissues are, by and large, less susceptible to chemotherapy side-effects. There is a huge range of growth activity in adult tissues, with blood, skin and intestinal cells at the high end and brain cells, which hardly ever divide after childhood (just ask my teens about their parents), at the other. 

      Not being able to divide and regenerate can certainly present a medical dilemma. The cells we lose to apoptosis in every tissue, including muscles, heart, kidneys, joint cartilage, explain the physical decline that comes with aging. Parkinson's disease, the result of losing specific brain tissue that controls movement, is an example of the problem that non-regenerating tissue presents to the patient whose neural cells can never reconstitute that area of the brain. A promising experimental approach to treating Parkinson's disease involves implantation of nervous system stem cells from human embryos. It is hoped that the introduced cells can differentiate into needed brain tissue. Embryonic tissue has the further advantage of provoking less of a transplantation rejection reaction because undifferentiated cells have not yet developed the cell markers on their surfaces that alert the immune system to the presence of a foreign biologic agent. (Note: Federal support for embryonic stem cell research has been put on hold by the Bush administration. Though unused microscopic human embryos grown in a test tube for infertile couples are the usual source of such cells, the endeavor has been tagged by some in the anti-abortion movement with the same homicidal epithets applied to late term abortions.)

      Undoubtedly, medical science will gradually learn how to replace a number of aging tissues. But it will be a long, long time, if ever, before it can reverse the fundamental link between differentiation and growth in all multi-cellular organisms. If you understand this, you will understand why it is you're not going to live forever. Mortality, mediated by apoptosis and the Hayflick limit, is the price we pay for the controlled growth that maintains our structure. Sure, it would be handy to grow a new arm like a starfish does after it's lost one, but then you couldn't have the wonderful, complex, differentiated limb that comes with the standard human package. And, being able to regenerate whole limbs would leave us a whole lot more prone to developing cancer out of all these pleuripotent cells that would have to lurk about into adulthood.

      In my November/December piece in Nexus, I plan to discuss what health goals make the most sense for individuals and their society once they've accepted that there are pretty firm limits on lifespan, a topic my fellow aging baby boomers and I need to come to grips with.