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LIFE-EXTENDING BIOTECHNOLOGIES AND ANTI-AGING MEDICINE:

THE SCIENCE AND ETHICS OF TURNING BACK OUR BIOLOGICAL CLOCKS

By: Richard Haubner, Ph.D. and Ronald F. White, Ph.D.

College of Mount St. Joseph, Cincinnati, Ohio

INTRODUCTION

All living organisms are subject to the temporal limitations imposed by what is often referred to as a “biological clock.” This mechanism has been an implacable tyrant that relentlessly ushers in successive stages of biological existence: birth, maturation, reproduction, senescence, and ultimate death. For us human beings, those latter stages have always been accompanied by the timed onslaught of the so-called “diseases of aging,” including: Alzheimers Disease, Glaucoma, Heart Disease, Diabetes, Osteoporosis, and Cancer. Although biomedical researchers have developed treatments for many of these degenerative diseases, they have not been able to stop, or even slowdown the biological clock.However, new and promising research involving genes, telomeres, stem cells, and caloric restrictionmay soon lead to not only curesfor these seemingly intractable diseases, but perhaps even extend the maximum human lifespan.

Although, the stark, uncompromising reality of human mortality has always served as a prolific source of artistic, literary, and scientific inspiration, the moral question of whether we “ought” to passively accept this fate or not has always elicited heated debate.This essay will explore some of the very basic cultural, scientific, and moral aspects of the modern quest for immortality.

I. CULTURAL ATTITUDES TOWARD LONGEVITY

Back in 1966, Gerald Gruman observed that in Western culture, we can easily identify three broad themes that have endured over the centuries,which embody our most deeply rooted fascination with human longevity. They are the Antediluvian Theme, Hyperborean Theme, and the Fountain Theme (Gruman, Finley, Grant)

The Antediluvian Theme, which permeates the Old Testament genealogical record, documents the extraordinarily long lives of biblical characters, such as: Adam (930 years) Noah (950 years), and of course Methuselah (969 years). Although, Biblical longevity contradicts virtually everything we know about the evolutionary biology of the human species, the symbolism of these references reflects our longstanding fascination with extended human lifespans. Even today, our interest in extreme human longevity is reflected in the Guinness Book of World Records. Although, paled by Biblical standards, worldwide, there are at least ten authenticated super-centenarians alive today between the ages of 115 and 122 years.

The Hyperborean Themeembodies a collection of myths that refer to placeslocated somewhere “beyond the north wind,” where human beings enjoy long andhealthy livesfree from the ravages of disease, conflict, and work. Exemplars of this theme include references to places like Shangri-la, a mythical land of peace and tranquilityallegedly located somewhere in China, Nepal, or Tibet. In the nineteenth century, travelers described a similar paradise in southern Ecuador known as Vilcabamba, or the “valley of longevity.” Known even today for its extraordinarily large number of centenarians, scientists still study Vilcabamba hoping to uncover the unique environmental factors that contribute to the health and longevity of its inhabitants. (Leaf, 1973)The hyperborean myth still lurks in our cultural heritage as exemplified by the 1985 movie, “Cocoon,” which revived the vision of a place where older adults could go to live safe, enjoyable and illness-free lives. And of course, millions of Americans make their biweekly pilgrimage to health clubs and spas hoping to slow down their biological clocks.

The third theme is the Fountain Theme, which is based on the belief that there are substances in the world that we can ingest, bath in, or rub onto our skin that will either postpone senescence or expand human longevity. In the early sixteenth century, Ponce de Leon popularized this theme in his celebrated quest for the “Fountain of Youth.”Of course, Ponce de Leon never did find that magic fountain, but he did accidentally discover Florida, which ironically has become a modern-day Mecca for aging Americans. For better or worse, we can identify contemporary variations of the Fountain Theme nestled on the Internet, where entrepreneurs sell an astounding array of herbal remedies, vitamins, skin creams, dietary supplements,and other over-the-counter preparations that promise to restore the fading youth, vitality, and virility of the “baby boomer” generation.

Our longstanding fascination with stories of expanded human longevity remains deeply rooted in our culture via Biblical characters, mysterious places, and magical potions. But as our stories continue to sustain that vision of immortality, our biological clocks continue to tick away, and senescence and ultimate death still haunt the human condition. However, as we enter the twenty-first century, we can observe the early rumblings of a fourth themethat is beginning to appear in the pages of medical journals, newspapers, magazines, and stock reports. Let’s call it the Biotechnological Theme. It is rooted in the growing belief that scientific advances, especially in molecular biology, will inevitably lead to a radical increase in the maximum human lifespan.But is that something good?

Although the expansion of the human lifespan has been an enduring cultural theme, our oral and written documents also suggest a persistent ambivalence in regard to whether we actually “ought to” prolong human life beyond its natural boundaries. Again, Gruman observed two contrasting prescriptive attitudes toward life-extension: one negative the other affirmative. Apologism defends the belief that “extended life is neither possible nor desirable” (Gruman, Overall 16-21) It basically regards senescence and old age as inevitable natural phenomena. Apologists, therefore, aspire to “explain”human longevity, but resist any attempts to “control” it. Prolongevitism embraces the belief that the prolongation of human life is both possible and morally acceptable, if not morally required.

While, the moral debate has persisted for centuries, until recently, it has been mostly a hypothetical debate, promulgated primarily by science fiction writers. Given the new hope offered by the biotechnological theme, it now appears that the moral debate over the extended human longevity may soon have normative, “real life” implications. (Cohen and Kristol)

II. PROLONGEVITISM AND MODERN SCIENCE

The pursuit of prolongevitism via the biotechnological theme embraces the quest by scientists to develop theories that will enable sociologists and biologists to explain, predict, and control the human lifespan. Social scientists have already identified many of theenvironmental and social factors that profoundly influence human longevity.(Atchley, Morgan & Kunkel)We know, for example, that individuals can live longer by altering their lifestyles, which of course includes: eating right, exercising, reducing stress, driving carefully, and by not smoking. Communities can increase aggregate longevity by controlling air and water pollution, increasing access to health care, and by building safer highways. Although, there is much that can be done by both individuals and communities to advance longevity, lifestyle choices alone cannot halt the aging process. That’s because maximum human lifespans are determined by that biological clock.

The modern era of biological aging research begins with the pioneer work of Leonard Hayflick. (Hayflick, 1996) Back in 1961, Hayflick discovered that somatic cells divide a finite number of times before senescence and death take over. Although, the so-called “Hayflick Limit” is different for different kinds of cells and for different species, the basic idea is all living things seem to be subject to the dictates of a biological clock. Not all cells age. Germ cells and cancer cells do not age. Today, there are five major theories of why it is that we age: The Error Hypothesis, The Free Radical Hypothesis, The Cross-Linkage Theory, The Brain Hypothesis, and the Autoimmune Theory.(Fossel, 2003, 2004, Gavrilov 1996, Hall, Johnson, Klatz, Olshansky, Rose)

The quest for the “explanation” of natural events usually leads to the “prediction” and “control” of those events. Microbiologists can now explain many of the natural processes that are responsible for human senescence and mortality. Combined with advances in biomedical technology, it is not unreasonable to suppose that medical science will soon also be able to control the aging processes. As Michel Fossel put it: “There are two milestones in the story of aging: Len Hayflick’s proof that cells age, and the more recent discovery that they don’t have to.”(Fossel, 1996, p.3) This next section will outline some of the most promising lines of research into that may soon lead to a substantial increase in the maximum human lifespan.

III. SCIENTIFIC ADVANCES IN LONGEVITY:

WHAT’S OUT THERE AND WHAT’S NOT!

Currently, there are four promising areas of scientific research in the area of human longevity: genetics, caloric restriction, telomeres, and stem cells. With the exception of stem cell research, most of this research has targeted non-human research subjects, such as yeast, roundworms, fruit flies and mice.

A. GENETIC RESEARCH

In examining some of the advances in genetic research in solving the longevity puzzle, it is important to describe what genes are and what “longevity assurance genes” are and how those genes affect the organism. Genes are small pieces of DNA that determine an organism’s physical traits and personal characteristics and guide the physiological processes. Longevity assurance genes are variants of some genes that allow the organism to live longer. If an organism within a species inherits a longevity assurance gene, then that organism has the possibility of living longer and with a better quality of life than other organisms within the species that do not have the longevity assurance gene.

Twenty genes associated with longevity have been found in Baker’s yeast. (Jiang, Jaruga, Repnevskaya, 2000). And when caloric restriction occurs in yeast through reduction of sugar or amino acid content, life span increases. If the yeast is missing a specific longevity assurance gene, then the caloric restriction does not reduce life span (Sun, Kale, Childress, Pinswasdi, & Jazwinski, 1994). Another gene modifies the stress that yeast experiences under environmental conditions such as: heat, starvation, crowding and ultra violet light. (Jazwinski, 1996).

In genetic research the use of roundworms, C. elegans, has been very productive. The roundworm has a life span of 20 days, which is perfect for longevity research. (Arantes-Oliveira, Berman & Kenyon, 2003). Two genes were found that enhanced longevity. The first gene, when manipulated, increased the average life span of the roundworm by 65% and the maximum life span by 110%. The second gene, when activated, warded off physical stressors, such as ultra violet light, temperature, and light, which assisted in extending life (Tissenbaum & Guarente, 2001; Jiang et al., 2000; Parsons, 1996; Lithgow & Kirkwood, 1996; Dorman, Albinder, Shroyer, & Kenyon, 1995).

The use of fruit flies in genetic research on longevity has also been very productive. Fruit flies are excellent subjects for longevity studies because of their short life spans. The drosophilia melangaster fly has a life span of 10 days and the Mediterranean fly has a life span of 60 days. MacKay (1998) found two important results in her studies. First, she found a gender difference among the flies in the way the genes were expressed with regard to longevity. Second, groups of flies assigned to different environments had different rates of longevity. (Dye, 2004). Michael Rose, an evolutionary biologist at University of California, Irvine, is working in the area of breeding rather than the manipulation of gene expression. His latest research is the discovery of late-life mortality plateaus. This discovery indicates that as one gets older that chance of dying increases until around age 90 when the mortality rate levels out. This means that if an individual reaches 105, then the chances of dying are no more than that of a 95 year old. Through breeding of fruit flies, Rose is trying to reduce the mortality rate plateau to a younger age. The results of his work show that through breeding, fruit flies live 100% longer and, as the process of breeding continues, he is projecting 200% increase in life expectancy. (Rose) This could have implications life span extension in humans (Veggeberg, 1992).

A promising area in genetic research related to longevity is the utilization of drugs to extend the lives of fruit flies (Ainsworth, 2004). The drug, PBA, switches on numerous genes, one of which is the gene responsible for anti-aging effects (Kang, Benzer, & Min, 2002). Another important endeavor with fruit flies is the identification of an aging gene. This gene, dubbed the INDY gene in homage to Monty Python and the Holy Grail, was identified by Rogina, Reenan, Nilsen, and Helfand (2000). This gene is associated with how the body stores energy. The research examined the relationship among metabolism, caloric restriction and longevity. In the fruit fly study, when this gene was manipulated, life span was almost doubled (National Institute on Aging, 2000). An understanding of this gene can have an influence on human longevity.

A number of research studies were done on the longevity of mice. In one study, a gene was found that was responsible for protecting and repairing genes damaged by oxygen free radicals (Moskovitz, Yim, & Chock, 2002). Another study found a gene that was a regulator of the life span in mammals. Mice have two copies of this gene. When one copy of the gene was removed, life span increased 33% among female mice and 16% among male mice. Also, mice with a single copy of this gene were more resistant to oxidative stress (Holzenberger, M., Ducos, B., & Dupont, J., 2003). Other studies were done on hormones and reproduction in mice as well as other animals (Carey, Lido, Harshman, Zhang, Muller, Partridge, and Wang, 2002; Cargill, Care, Muller, & Anderson, 2003).

Recently, researchers examined human centenarians to determine why these individuals live extremely long lives and why diseases such as heart disease, stroke, cancer, Alzheimer’s disease and other diseases associated with age are either postponed or do not occur at all. In their studies they discovered a region on Chromosome 4 where the exact gene or genes is located, and it is this gene or group of genes that is believed to be responsible for extreme longevity. Once the specific genes in this area are identified in the centenarians, then interventions can be developed to address longevity and chronic disorders affecting many adults in the older age category (Puca, Daly, Brewater, Matisse, Varrett, Shea-Drinkwater, Kang, Joyce, Nicoli, Benson, Kunkel, & Perls, 2001).

B. CALORIC RESTRICTION RESEARCH

Numerous studies on caloric restriction have been done with yeast, worms, flies and especially with rats and mice with excellent results. Those animals that were on calorie restricted diets lived longer than those who were on normal diets and unrestricted diets. In 1986, Weindruch, Walford, Fligiel, and Guthrie (1986) conducted a study related to dietary restriction of mice. It was found that the groups of mice with restricted diets demonstrated a 35-65% increase in life span, and were more energetic and less susceptible to tumors. Restricted diets provide support for anti-aging as suggested by other studies (Su-Ju, Kaeberlein, Andalis, Sturtz, Defossez, Culotta, Fink, and Guarente, 2002; Bluher, Kahn, & Kahn, 2003). In another study related to food restriction, Bluher and his colleagues (2003) wanted to find out whether or not a reduction in fat mass among mice without caloric restriction enhances longevity. They used mice that were missing the fat-specific insulin receptor. These animals had reduced fat mass and were protected against obesity, even though their food portions were normal. Mean life span increased approximately 134 days or about 18%. The results of the study indicated that it was leanness not food restriction that was a key factor to longevity (Bluher, Kahn, & Kahn, 2003).

Since the late 1980’s the National Institute on Aging has been conducting caloric restriction research on Monkeys. Although, the research is ongoing, it is apparent that monkeys that are fed 30% less food are much healthier and have about half the death rate of monkeys that eat as much as they like. Although, few American’s would be willing or able to sustain such a harsh dietary regimen, researchers believe that they will soon be able to develop a pill that would physiologically restrict the body’s ability to process calories. (Lane)

C. TELOMERE RESEARCH

Telomeres are specialized segments of DNA found on the tips of the chromosomes. They serve as a cap for the chromosome, preventing it from attaching to the ends of other chromosomes. Each time the cell divides, telomeres shorten. To reduce the telomere reduction process, the protein, telomerase can be used. This protein can re-lengthen the telomere. It was found that telomere length is a predictor of longevity and physical health of the individual over 60. People with shorter telomeres did not live as long as those individuals with longer telomeres.