The Quest for Pharmacological Immortality
December 29, 2001
Nothing sounds more unscientific, more starry-eyed and unrealistic, than the quest for immortality. But yet, as each year passes, a greater percentage of the very down-to-earth pharmaceutical industry is devoted to precisely this pursuit. The quest to beat death, to halt the apparently – but not necessarily – inevitable decline of the human mind and body with the progress of time.
Of course, the goal of eluding death long pre-exists science. It has taken hundreds of forms throughout history, pervading all cultures and eras. The ancient Chinese, for instance, had Taoist Yoga, a very complex discipline defining a life-long series of practices that, if adhered to precisely, purportedly resulted in physical immortality. Part of this teaching was that, by refraining from ejaculation for his entire life, a man could store his “essential energy” in a space by the top of his head, until he accumulated enough to create an eternal fetus that would grow into his deathless self. The modern variation of such ideas is less colorful but perhaps more likely to succeed: subtle biological and pharmaceutical research aimed at discovering the roots of aging, and creating chemical remedies.
The increasing number of elderly is one of the major trends in current demography. For instance, in 1950, only one in ten U.S. citizens was over the age of 65. Now the figure is about one in 8; and by 2030 it may be 1 in 5. There’s little doubt that the current human age record of 122 (Madame Jeanne Calment, who died in 1997) will soon be overturned. This ongoing increase in lifespan has been primarily due to a reduction in various deadly diseases, resulting from improved hygiene and medical care. But one thing our success at reducing disease has taught us is this: the real killer is not disease, but senescence. After a certain amount of time, the body’s microscopic parts just stop working, of their own accord, without the interference of any germs or viruses or cancerous mutations. This is the essential dark side of the human condition, and the focus of current scientific work on anti-aging. Scientists have a “short list” of biological and biochemical factors suspected to collectively underlie aging -- and for each of these likely culprits, there is a pharma firm or a maverick scientist working on the cure. It is entirely plausible that within decades – not centuries or millennia – pharmacological science will have made the very concept of getting old obsolete.
The Biology of Cell Senescence
A healthy body is not a constant pool of cells, but rather a hotbed of continual cellular reproduction. There are only a few exceptions, such as nerve cells, which do not reproduce, but simply persist throughout an organism’s lifespan, slowly dying off. In youth, newly formed cells outnumber dying cells; but then from about 25 on, then, things begin to go downhill, and the number of newly formed cells is less than the number of cells that die. Little by little, bit by bit, cells just stop reproducing.
The sad fact is that most types of human cells have a natural limit to the number of cell divisions they will undergo. This number, usually around 50 or so, is called the Hayflick limit, named after Leonard Hayflick, the researcher who discovered it in the mid-1960’s. Once a cell's Hayflick limit is reached the cell becomes senescent, and eventually it dies.
This may have the sound of inevitability about it – but things start to sound different when one takes a look at our one-celled cousins, such as amoebas and paramecia. These creatures reproduce asexually, by dividing into two equal halves – neither half sensibly classified as “parent” or “child.” This means that essentially, the amoebas alive today are the same ones alive billions of years ago. These fellows qualified for social security a rather long while ago, and yet they’re still alive today, apparently not having aged one bit – cells untroubled by the Hayflick limit. This nasty business of aging seems to have come along with multicellularity and sexual reproduction – a fascinating twist on the “sex and death” connection that has fascinated so many poets and artists.
Unlike in asexually-reproducing creatures, cells in multicellular organisms fall into two categories: germ-line cells which become sperm or egg for the next generation; and soma cells that make up the body. The soma cells are the ones that die, and the standard answer to “Why?” is “Why not?” The “disposable soma theory” argues that, in fact, our soma cells die because it’s of no value to our DNA to have them keep living forever. Throughout most of the history of macroscopic, sexually-reproducing organisms, immortal organisms would not have had an evolutionary advantage. Rather, there was an evolutionary pressure toward organisms that could evolve faster. And if a species is going to evolve rapidly, it’s valuable for it to have a relatively rapid turnover from one generation to the next.
There doesn’t seem to be any single cellular “grim reaper” process causing soma cell senescence. Rather, it would appear that there several distinct mechanisms, all acting in parallel and in concert.
There are junk molecules, accumulating inside and outside of cells, simply clogging up the works. And then there are various chemical modifications that impair the functioning of molecular components, such as DNA, enzymes, membranes and proteins. Of all these chemical reactions, oxidation has attracted the most attention, and various anti-oxidant substances are on the market as potential aging remedies. Another major chemical culprit is “cross-linking”: the occasional formation of unwanted bridges between protein molecules in the DNA – bridges which cannot be broken by the cell repair enzymes, interfering in the production of RNA by DNA. Cross-linkages in protein and DNA can be caused by many chemicals normally present in cells as a result of metabolism, and also by common pollutants such as lead and tobacco smoke.
As time passes, signalling pathways and genetic regulatory networks within cells can be altered for the worse, due to subtle changes in cellular chemistry. The repair mechanisms that would normally correct such errors appear to slow down over time. “Telomeres,” the ends of chromosomes, seem to get shorter each time a cell divides, causing normally suppressed genes to become activated and impair cell function. And finally, the brain processes that regulate organism-wide cell behavior decline over time, partly as a result of ongoing cell death in the brain.
The really frustrating thing about all these phenomena is that none of them are terribly different from other processes that naturally occur within cells, and which cells seem to know quite well how to cure and repair. It would seem that cells have just never bothered to learn how to solve these particular problems that arise through aging, because there was never any big evolutionary advantage to doing so. We may well die, not because it would be so hard to engineer immortal cells, but because it was not evolutionarily useful to our DNA to allow us to live forever.
Chasing the Immortality Pill
Curing old age is one kind of speculative research that modern capitalist society seems relatively willing to fund.
For instance, Larry Ellison, the controversial 55-year-old chief executive of Oracle, is the largest single supporter of anti-aging research, with $20 million per year committed. He may be the second-richest man in the world, but he’s smart enough to realize that “you can’t take it with you” – and he’s deploying his wealth strategically with this in mind. He makes no bones about his motivations. ``Death has never made any sense to me,” he says. “How can a person be there and then just vanish, just not be there? … Death makes me very angry. Premature death makes me angrier still.”
Much of the funding for anti-aging research, though, comes not from immortality-obsessed visionaries, but from stolid biotech firms concerned with curing particular diseases. As it turns out, most of the factors underlying aging are also connected to various particular medical conditions. This dual focus drives the R&D of dozens of pharma firms. For instance, Centaur Pharmaceuticals discovers and develops new drugs for various diseases involving ischemia and inflammation, which its scientists believe will also have general anti-aging properties. Geron focuses on telomere shortening and cell death, with applications both to anti-aging and to cancer. Human Genome Sciences works on understanding signal transduction pathways – how they work, why they fail and how to repair and redirect them – a quest which, if successful, will have myriad applications.
Perhaps the most advanced work in the field is going on at a company called Alteon Inc. Alteon has picked up a train of research begun in the early 1900’s, regarding the formation of complexes between sugars and the amino acids of proteins. At first these complexes were found to cause the toughening and discoloration of food observed during the cooking process and after prolonged storage. It was later determined that these same structures were part of a new biochemical pathway in which permanent glucose structures were formed on the surface of proteins. These structures -- "Advanced Glycosylation Endproducts" or A.G.E.’s -- were seen to interact with adjacent proteins to form pathological links between proteins, called A.G.E. crosslinks. And these crosslinks seem to play a critical role in diabetes, as well as in the Hayflick limit of various human cells. Alteon is currently testing medication that promises to prevent this crosslinking from occurring.
Long Life Through Caloric Restriction
But even Alteon’s drugs aren’t yet on the market. If one wants to live as long as possible, what can one do right now?
The most promising, immediately applicable anti-aging work has to do not with pills but with caloric restriction. There is increasing evidence that if you eat about 70% of what you’d ordinarily want, you’ll live a lot longer. You need to eat a healthy diet, rich in vitamins and proteins, but low in calories.
This has been tested extensively in various nonhuman mammals. For instance, mice normally don’t live over 39 months, but caloric restriction has produced mice with 56 months lifespan. This corresponds proportionally to a 158 year-old human. And these long-lived mice aren’t old and crusty -- they’re oldster/youngsters, keen-minded, strong-bodied and healthy. Studies on monkeys are currently underway, though this naturally will take a while, due to monkeys’ relatively long lives.
Why does caloric restriction work? It increases the ability of the body to repair damaged DNA, and it decreases the amount of oxidative (free radical) damage in the body. It increases the levels of repair proteins that respond to stress, it improves glucose-insulin metabolism, and for some reason, not fully understood, it delays age-related immunological decline as well. Basically, many of the well-known mechanisms of senescence set in more slowly if the body has to process less food over its lifetime. Of course, it’s not yet demonstrated that caloric restriction will do for humans what it’s done for other animals, but none of the researchers involved with the work seems to have much doubt. The relation of this line of thinking with anti-aging pharmacology has yet to be investigated – it may well be there are medications that work most effectively in coordination with a caloric restriction diet.
The Immortality Pill is not yet available, alas. The pharma Fountain of Youth is not yet upon us. But the first batch of serious anti-aging medications is coming soon to a pharmacy near you. Funded by a mixture of visionaries and pragmatists, biochemists, geneticists and pharmacologists are going to chip away at the problem of cell senescence, bit by bit, gene by gene, biochemical process by biochemical process, year after year, decade after decade. And with each new drug and each new dietary recommendation they produce, the average human lifespan will get longer and longer. No end is in sight. The process of scientific advance may be too slow to save us from dying -- but for our grandchildren, or great-great-grandchildren, “old age” may well be something they read about in the history books, along with black plague and syphilis, an ailment of the past.