Ó Springer 2006
Medicine, Health Care and Philosophy (2006) 9:87–96 DOI 10.1007/s11019-005-2668-7
Scientific Contribution Life extension research: An analysis of contemporary biological theories and ethical issues Jennifer Marshall Biomedical Ethics Unit, McGill University, 3647 Peel Street, Montreal, QC, H3A 1X1, Canada (Phone: +1-514-398-7406; Fax: +1-514-398-8349; E-mail:
[email protected])
Abstract. Many opinions and ideas about aging exist. Biological theories have taken hold of the popular and scientific imagination as potential answers to a ‘‘cure’’ for aging. However, it is not clear what exactly is being cured or whether aging could be classified as a disease. Some scientists are convinced that aging will be biologically alterable and that the human lifespan will be vastly extendable. Other investigators believe that aging is an elusive target that may only be ‘‘statistically’’ manipulatable through a better understanding of the operational principles of systems situated within complex environments. Not only is there confusion over definitions but also as to the safety of any potential intervention. Curing cell death, for example, may lead to cell cancer. The search for a cure for aging is not a clearly beneficial endeavour. This paper will first, describe contemporary ideas about aging processes and second, describe several current life extension technologies. Third, it analyses these theories and technologies, focusing on two representative and differing scientific points of view. The paper also considers the public health dilemma that arises from life extension research and examines two issues, risk/benefit ratio and informed consent, that are key to developing ethical guidelines for life extension technologies. Key words: biological aging, ethical issues, informed consent, life extension technologies, public health, risk/benefit ratio, theories of aging
Introduction Age, senescence, and youth are difficult terms to define precisely. They are states of being and/or processes that vary from individual to individual. The biological indicators of senescence are mostly nonexistent. For example, grey hair, which correlates about 0.7 with age, is still the closest biomarker we have for ageing. Currently, the most reliable biomarker for ageing is death (Holden, 2002). Life extension technologies and research into aging processes or age-related diseases inevitably focus on the deficiencies and deteriorations of old age. However, before we continue our quest for the Fountain of Youth, we should identify more clearly what we are fighting to prevent, and we should also determine whether aging should be classified as a disease. The scientific opinions and ideas about aging are as varied and abundant as those found in society in general. Biological theories have taken
hold of the popular and scientific imagination as pointing to a potential ‘‘cure’’ for aging. Some scientists believe that aging can be biologically altered and that the human lifespan can be vastly extended. Other investigators believe that aging is an elusive target that may only be ‘‘statistically’’ manipulated through a better understanding of the operational principles of systems situated within complex environments. Defining aging is only one important issue; another is the safety of potential interventions. Curing cell death, for example, may lead to cell cancer. The search for a cure for aging is not a clearly beneficial endeavour.
Theories of aging The many theories of aging attempt to explain why organisms grow old and to identify the aging processes that affect cells, organs, and biological
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systems. However, aging occurs at many different levels: social, psychological, physiological, morphological, cellular, and molecular (Fulop, 2000). Sociological and psychological aging differ from, but are connected to, the processes of biological aging. Aging is a subject that resonates throughout history and is discussed by many philosophers and spiritual leaders. However, biological or ‘‘pathological’’ aging, especially in wealthier countries, is a dominant research focus and is seen as the area of study that could potentially facilitate new therapeutic life extension technologies. This section starts with a brief examination of historical theories of aging followed with the many contemporary biological aging theories. Surprisingly, popular and social ideas about how to confront aging have remained essentially unchanged over time. In contrast, scientific theories have become increasingly reductionist, focusing on individual molecular biology and genetics. More recently, researchers have embarked upon a systems approach where genes, environment and chance are intricately involved in the aging process (Kirkwood, 2000). However, both social and scientific schools of thought share the many uncertainties that still exist with respect to the aging process. Historical
From Pythagoras to contemporary food and nutrition policies, the most important piece of advice on how to extend human life emphasizes the necessity of limiting the consumption of food and drink (Shapin and Martyn, 2000). Popular medical texts in the 16th and 17th centuries did little more than reflect moral and social norms as they advised how to live a healthy life and how to cure diseases (Brandt and Rozin, 1997). During the Scientific Revolution, one important gauge of the quality of reformed natural philosophical knowledge was its ability to produce a more effective medical practice that was capable of prolonging life (Shapin, 2000). Both Francis Bacon and Rene Descartes believed that if medicine were reestablished based on ‘‘proper philosophical principles,’’ humans could free themselves from the infirmities of old age. Descartes in particular believed that humans are provided with all things necessary to be preserved in perfect health to extreme old age but that we lack the knowledge of what these necessary things are (Shapin, 2000). Because the laws of mortality were not elucidated, medicine was action under uncertainty. Descartes’ recommendations amount to suggesting that we adhere to custom, exercise common sense, and have a healthy, moderate diet.
In 19th century United States, a new emphasis on health reform emerged. This movement emphasized hygiene and physical education, and the medical profession played a significant role in a new conception of life and aging (Hall, 2000). At the turn of the 20th century, researchers distinguished between ‘‘normal’’ and pathologic aging. Researchers were concerned that pathologic aging could be tied to the processes of industrialization, urbanization, an ‘‘unnatural’’ way of life, and imprudent dietetics (Martensen, 1995). Normal aging was witnessed in the longevity of persons living in ‘‘primitive’’ parts of Europe of the time. In the past, religious and philosophical thinkers also expounded on how to live a good life and on the role of the aged within the community. In traditional Chinese society, the experience of the oldest generation was valued highly, and the transmission of knowledge was regarded as vital to the community’s success (Levy, 1999). Taoism and Buddhism encouraged the desirable state of mindfulness that leads to timeless wisdom and imperviousness to the effects of aging (Hall, 2000). Confucianism elaborated that this mindfulness is most readily achieved with age (Levy, 1999). In traditional societies that practiced these religions, the elderly occupied a particular social status within the community. Currently, medicine and science define aging almost solely in biological terms, and old age is compared unfavorably to the vigor of youth. In the last century, physicians have told the story of old age largely in terms of physician interventions into the later stage of life (Davidow-Hirshbein, 2001). Medical researchers ignore the fact that old age has social and cultural implications beyond the biological. Current medical parlance categorizes the elderly in abstract or mechanical terms rather than descriptive or representative terms that would humanize the elderly. Biological
There are many theories of biological aging, most of which are not mutually exclusive. These theories can be divided into two categories: programmed aging and aging as a result of stochastic events. Programmed aging The theories of programmed aging explain that the aging process, like physical development, is ordered, ‘‘hard-wired’’ and that senescence is determined by changes in gene regulation (Partridge and Gems, 2002). This theory implies that there is a built-in genetic program that is activated
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at a certain stage of the life cycle, and which leads to death through a type of self-destruct mechanism in a variety of tissue or organ systems (Gershon and Gershon, 2000). Other programmed theories argue that biological clocks act through hormones to control the pace of aging or that a programmed decline in immune system functions leads to increased vulnerability to infectious disease and thus to aging and death (NIA, 2001). The aging process may be programmed at different levels; for example, aging can be understood as a genetic or cellular process (among others). Researchers now recognize that genes play a role in controlling development and pathological alterations (Fulop, 2000). Additionally, it is believed that many genes or a few key genes (depending on one’s theoretical sympathies) may also be related to lifespan (Fulop, 2000; Hekimi, 2003). Genetics researchers have uncovered longevity genes (age-1, clk, daf-2, sir-2) using yeast, nematode, and mouse models. It is hoped that these genes will represent fundamental aging mechanisms common across evolutionary lines and that the human genetic counterparts will be found and their roles elucidated. Telomeres are also thought to be a type of programmed aging at both the genetic and cellular level. Telomeres are DNA sequences at the end of chromosomes that shield vital genetic information from damage during cell division (NIA, 2001). Telomeres become progressively shorter each time the cell divides, which eventually leads to cell senescence and death. The enzyme telomerase keeps telomeres intact, and it is thought to play a role immortalizing these cells. It is believed that telomeres could serve as a genetic meter of the cell lifespan that halts cell proliferation (Fulop, 2000). This type of cellular senescence could be a possible defense against cancer development (Fagagna et al., 1999). Another phenomenon that is key to programmed cell senescence is the ‘‘Hayflick limit’’. After a certain number of divisions, cells enter a state of senescence in which they do not divide or proliferate and DNA synthesis is blocked (NIA, 2001). Gerontologists have found links between senescence and human life spans. Fibroblasts taken from 75-year-olds have fewer divisions remaining than cells from a child. Moreover, the longer a species’ lifespan, the higher its Hayflick limit (NIA, 2001). Aging as stochastic events Another group of theories postulates that aging is a result of stochastic events or that aging occurs as a
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result of random damage incurred and accumulated throughout the life of an organism (Gershon and Gershon, 2000). Damage to molecules and tissues accrue from many sources, including the by-products of metabolism, exposure to toxic agents, personal behavior and random events (Partridge and Gems, 2002). These theories are based on either a cell and tissue wear-and-tear type of process, the shortening of the life span due to an increase in the rate that oxygen is metabolized, the accumulation of cross-linked proteins that slow down bodily processes, the accumulation of damage caused by oxygen radicals, critical (‘‘error catastrophe’’) damage to mechanisms that synthesize proteins and the increase of genetic mutations with age causing deterioration and malfunction of cells (NIA, 2001). Summary These theories of aging represent two main themes. First, that aging is under genetic control and that cell senescence could be a defense against cancer development. According to this theme, once we understand genetics we will understand aging and could potentially develop drugs or therapies that would attack the aging process itself. Second, that aging represents the consequences of living. That is, certain hazards are faced throughout a lifespan that can lead to many types of damage that cause aging. This theme suggests that we could combat aging with a piecemeal, public healthoriented approach. Regardless of theory or theme, many investigators involved with aging research see aging processes as possibly open to manipulation.
Life extension technologies Life extension is a blanket term for personal health regimens, gene therapy, and a variety of other antiaging technologies (Heard, 1997). In the past, most life extension techniques took the form of advice about the benefits of a healthy diet and a modest lifestyle. Many religions and philosophies articulated good conduct and healthy living and further argued that one had a moral responsibility to live one’s life accordingly. There is still considerable emphasis on diet, exercise and healthy lifestyles in contemporary society. Currently, no treatments, drugs, or pills are known to slow ageing or extend life in humans (NIA, 2001). Yet, the idea that the lifespan can be extended has moved from being a fringe idea to a subject for serious research in genetics, endocrinology, and other biological sciences (Holden,
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2002). Based on the theories of aging, some researchers are hoping to uncover methods to decelerate the aging process, the onset of agerelated diseases, and inevitable death. A further explanation of the scientific motivations for extending life is not often embarked upon as if the technologies themselves define the exercise. Most potential life extension technologies concern genes and gene therapy, metabolic and hormonal regulation, and pharmaceuticals. However, it is clear from preliminary results, especially in the case of replacement hormone therapies, that not enough is known about aging systems and the effects of manipulating highly controlled regulatory mechanisms in humans. Aging is treated as pathology without any clear notion of what normal aging is. And we do not know whether these systems are clearly connected to aging per se. This section describes three areas of research that examine potential life extension technologies to present the ‘‘state-of-the-art’’ of anti-aging research in the public and private sector. Tumour suppressors and telomerase
Tumor suppressors and telomeres are elements that are being examined as possible senescence modifiers. Understanding how tumor suppressors exert their effects in cells and interact with other regulatory molecules may make it possible to increase the proliferative life span of key cell types in older persons (Fulop, 2000). Increased cell life span would have effects upon central processes such as wound healing and immune response, both of which are known to decline with aging as the proliferative ability of cells involved with these processes, under the control of tumor suppressors, decreases (Fulop, 2000). Researchers studying the function of telomeres and telomerase in the aging process believe it might be possible to avert old age by enabling cells to thrive beyond their scheduled time to die (NIA, 2001). Presently, researchers are investigating the possible therapeutic effects of the naturally occurring enzyme, telomerase, which is found in germ cells and in cancer cells. Caloric restriction and reactive oxygen species (ROS)
It was first observed in the 1930s, and repeatedly confirmed since, that caloric restriction (often called undernutrition without malnutrition) in the adult phase of life slows aging (Mangel, 2001). The reason that caloric restriction slows aging is not fully known, but it may be related to oxidative damage or other costs of metabolism (Mangel,
2001). ROS are short-lived toxic molecules produced in the mitochondria (known as the ‘‘powerhouse’’ of the cell) during regular cell metabolism. ROS have been implicated not only in aging but also in degenerative disorders, including cancer, atherosclerosis, cataracts, and neurodegeneration. Animals raised on restricted calorie diets have an increased life span because they produce fewer free oxygen radicals due to their lower metabolism and accumulate less damage to proteins, lipids, and DNA (mitochondrial and genomic) (Sudbery, 1999). It has also been suggested that there is a conserved survival mechanism, which is genetically triggered in times of scarcity, that results in slow aging (Hekimi and Guarente, 2003). Unraveling the molecular basis of such mechanisms in mammals is an important contemporary research objective. Currently, a company called GeroTech is developing a ‘‘calorie restriction mimetic,’’ which is a drug used to trick the body into starvation response with normal caloric intake (Holden, 2002). Researchers are also investigating ways to enhance enzymatic systems that reverse damage, to up-regulate scavengers of damaging agents and to render systems that generate damaging agents more parsimonious in their production (Jazwinski, 2002). Again, these potential interventions would be based on technologies that are not yet developed and are based mostly on research on yeast, nematodes and mice. Additionally, these therapies are based on the expectation that a universally shared system of specialized survival exists from yeast to humans. Hormone therapy
Hormone replacement therapies are anti-aging drug interventions that are currently in use, mostly in wealthy countries. These treatments are based on the belief that hormones control the pace of aging. The first hormone that was marketed and prescribed – in advance of credible scientific evidence – was estrogen replacement therapy (ERT). This therapy was touted as a treatment that would relieve the discomforts of menopause, and in some studies, it was found to slow bone thinning and protect from arteriosclerosis (Ettinger, 1998). Menopause was described as a ‘‘deficiency disease’’ that robbed women of their health, youth, femininity, and sexuality (Houck, 2003). In recent years in the United States, nearly 40% of postmenopausal women were prescribed ERT, while recently it was found that conventional hormone replacement increased the risks of breast
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cancer, heart attacks, strokes, and blood clots (Groopman, 2002). Testosterone therapy is referred to as a treatment for ‘‘male menopause’’. The hormone, which is administered to elderly men, is meant to reverse age-related complaints, such as weakened muscles, decreased sex drive, and decreased bone density (NIA, 2001). However, it is debatable whether the decline in testosterone levels is directly related to aging in men and whether the ‘‘normal’’ level of testosterone, based on the average level of testosterone in 20-year-old men, is an accurate standard for older men (Groopman, 2002). Another problem with testosterone therapy is that high levels of testosterone are linked to prostate cancer in men (NIA, 2001). It is questionable whether testosterone or estrogen replacement therapies are anti-aging drugs with physiology benefits or just marketing hype. Another potential drug target is growth hormone (GH), which is produced by the pituitary gland and appears to play a role in body composition and muscle and bone strength (Sudbery, 1999). It is not clear from the scientific literature whether high or low levels of this hormone are connected to long life. GH is being studied for its potential to strengthen muscle and bones and prevent frailty among older people (NIA, 2001). The anti-aging effects of GH therapy are typically observed after short-term treatment of patients with low plasma GH (Longo and Finch, 2003). However, chronically high GH levels increase the incidence of diseases, including cancer and kidney disease, in rodents. Chronically high GH levels also increase cardiovascular diseases and cancer in humans and increase the development of diabetes and glucose intolerance in older women and men (Longo and Finch, 2003). These hormone replacements (ERT, testosterone, and GH) are examples of therapies marketed as anti-aging treatments that target regulatory endocrine systems. However, an United States nationwide ERT trial of 1600 women was recently terminated when the therapy was linked to a 26% increase in invasive breast cancer and a significant increase in cardiovascular disease (Groopman, 2002). Analysis Increasingly, physicians and scientists are attempting to define aging and how it could be both improved and altered. Researchers attempting to develop life extension technologies focus on molec-
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ular biology or pathological aspects of aging, because these are the entities that can potentially be manipulated through drug or gene therapies. This research agenda continues regardless of the fact that many of these technologies and therapies are potentially dangerous and may not provide a good life or healthy aging. Since the structure of DNA was elucidated, a conception that life is molecular has evolved. From this point of view, aging could also be molecular and could be manipulated at the molecular level. However, how genetics and molecular biology inform the aging process at other levels, such as individual, population, societal is not clear. The following section examines a particular contemporary debate in the scientific literature and ends with a short discussion of several practical and ethical questions that arise from anti-aging research. What is the definition of aging?
‘‘Much of the confusion which has surrounded the biological concept of aging in the past is due to failure to establish a useable definition of aging and objective criteria through which the results of specific research can be evaluated’’ (Strehler, 1977). This section examines two points of view on aging from two recently published scientific articles. The first article, by Hekimi and Guarente (2003), raises the issue that aging is not programmed but is a centralized process that is genetically regulated. According to the second article by Jazwinski (2002), aging is a complex process with many independent causes and is not necessarily under genetic control. Medical records give the impression that aging is a collection of mostly independent degenerative processes that lead to disease and ultimately death. The authors, Hekimi and Guarente, suggest that although aging may appear to be multifactorial, findings in genetics research on simple organisms modulate this view. Single gene modifications in nematodes can dramatically increase lifespan. The magnitude of these effects suggests a central process of aging. The authors postulate that the central process is based on protection against reactive oxygen species (ROS), which researchers believe are linked to diabetes, Parkinson’s, Alzheimer’s, and cancer. Hekimi and Guarente discuss a particular gene, sir-2, that is thought to regulate an ‘‘aging pathway’’. Mammalian cells have a homologous sir-2 gene that is involved with damage-induced apoptosis or cell death. Over-expression of this gene renders cells
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resistant to apoptosis, thus, cells do not die and organs preserve their function. As with many of these genes, however, their manipulation could lead to cancer. Apoptosis is an important cellular mechanism employed to rid the organism of damaged cells, which could eventually become cancerous. Regardless of the potential dangers, Hekimi and Guarente foresee a future where aging can be genetically manipulated. Once scientists have control over genetics they will have (at least some) control over aging. According to Jazwinski, aging is a stochastic process; genes, environment and chance determine its course. This yields individuals who age slowly or quickly. Where genetic or environmental manipulations can affect the variability between individuals, their effect on a particular individual is indeterminate. Jazwinski suggests that linear thinking may be dangerous when it is applied to the interactive aging system. Chance events can have extraordinary consequences as they act on such systems. Jazwinski states that aging, as a non-linear dynamic process, can explain the effects of chance on aging and heterogeneity in life spans. Additionally, it may be impossible to pinpoint the limiting factor for longevity in any particular individual in the population. As the author states, this would be the biogerontologic equivalent of the uncertainty principle. As espoused by Jaswinski, an integrative approach based on systems biology may be essential to understanding biological aging. Reductionism seeks cause and effect among individual components of a biological system; whereas, an integrative approach asks questions about how a system functions without searching out the ultimate cause and effect among its components. The goal then is to understand the system’s operational principles and its responses to external forces. Thus, aging is complex and difficult to control, except perhaps in a statistical sense. Life span is not, therefore, fixed by ‘‘hard’’ programmed limits but by ‘‘soft’’ probabilistic limits, which are a result of genetic variance and stochastic accumulation of damage (Bonneux et al., 1998). This reasoning favors preventative strategies and a public health-oriented approach to age-related diseases over directed drug or gene therapies set against aging itself. Opportunities for slowing the rate of senescence can be sought by diminishing exposures to risk factors while working within an interdisciplinary systems approach. The following section takes the idea of a public health approach further and discusses the
practical and infrastructural needs of the elderly. Beyond biotechnological tinkering, researchers as well as policymakers need to consider these issues in order to effectively address the potentialities of extended human life spans. Public health, preventive strategies and aging
Currently, there is debate among gerontologists and social scientists about whether aged individuals will be increasingly healthy and require less expensive and invasive health care or will accumulate more chronic diseases and spend their old age in a disabled state. In either case, to encourage a healthy old age, a collaborative interdisciplinary approach that provides health and social services targeted to the elderly is essential (Cassel, 2001). For example, to encourage increasing numbers of healthy seniors, risks of deconditioning or malnutrition must be managed and drug regimens must be monitored. In the scenario of new and more numerous chronic diseases in old age, greater interventions and an efficient health care system will be important. Researchers have noted that disability in old age reflects a nation’s health care system, as well as, preventive health measures, rate of technological diffusion, advances in the treatment of acute and chronic diseases, social and political structures, and economic systems, to mention a few (Banks and Fossel, 1997). If a nation is poor or if disadvantaged individuals within rich countries do not have access to these services, it is likely that the disenfranchised will be disabled in their old age. If aging is simply biological or molecular, drug or other therapies will be sufficient to correct a faulty process or mutant gene. This may account for the popularity of a biologically focused explanation of aging since a ‘‘cure’’ for aging could be found through a ‘‘quick fix.’’ Yet, if we regard aging as a complex, multi-level process, it requires more than polypharmaceutical interventions to maintain health. This would mean a shift in attention from the development of drug or gene therapies to public health issues. However, the trend is to err on the side of caution when financing public services such as health and home care. This caution is exercised so that policymakers may avoid politically untenable tax hikes (Stipp, 1999). Such ignorance of changing demographics and the need for services leads to one to question the claim that the elderly will be increasingly healthy. An article by Laurie Garrett (2001) compares public health policies of the past to present-day ‘‘curative’’ medicine. Garrett explains that public
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health works on behalf of the community while placing special attention to the poorest, where disease most frequently arises. The curative model, on the other hand, is an individualized medical model that is costly and fails to address the fundamental roots of ill health. Additionally, in Europe and North America, spending is skewed toward massive outlays for end-stage disease intervention, while basic health needs go unmet. Illnesses are not monitored, especially for those who are uninsured, so there is greater disability. Thus, the search for a cure for aging through an anti-aging magic bullet, while considered by some to be scientifically possible, is likely politically and socially irresponsible. Developing drugs to control some aspects of the aging process does not guarantee a healthy old age for all. Presently, we have little information about the aging process and the ability of current or future interventions to alter this process, and appear to be socially unready for anti-aging technology. If society decides that life extension is an important social agenda, we will require interventions that are not limited to drugs for individuals, but consist of other public health strategies. An ethical framework?
Is it possible to proceed with moral confidence into applied aging research? If we are to develop guidelines, we must reach consensus on the direction of this research and amass greater knowledge of the aging systems. As mentioned above, genetic and cellular systems are part of larger systems beyond any particular individual. These processes are not well understood and may be part of human defences against cancer development or other diseases. In this way is it possible to have too much life? Juengst (2002) asks whether ‘‘anti-aging research can ever be conducted ethically with human subjects’’. Issues around the ability to assess risks and informed consent are not easily resolved in this setting. However, there have been calls to commence clinical trials to increase knowledge and to test the safety and efficacy of particular anti-aging interventions (Butler, 2000; de Grey et al., 2002; Miller, 2002). This section discusses two issues that are important considerations when assessing clinical trials: risk/benefit ratio and informed consent in the aging research context. Risk/benefit ratio The benefits of anti-aging research range from a ‘‘compressed morbidity,’’ where lives would be free
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from chronic disease and end quickly at the limit of the human lifespan, to ‘‘decelerated aging,’’ where the pace of human aging would slow, to ‘‘arrested aging,’’ where we would have complete control over the basic biological processes of aging (Juengst et al., 2003). If aging processes are multi-factorial, the only method of control is through piecemeal interventions. Preventing age-related decline this way is considered inadequate and may only prolong senescence. However, the multi-factorial approach to aging could conceivably lead to greater health and disease prevention. Rather than simply attempting to prolong life, this approach looks at whole systems. Those who believe that aging is a single process, which is best addressed at the basic biological level (genetically and/or pharmaceutically), believe that an aging treatment could be found ‘‘in one swoop’’ (Gems, 2003). Yet, this reductionist view of aging does not take the complexity of individual health into consideration. Drugs that could manipulate the biological aging process could not control all non-biological aspects of an individual’s health. While individuals may grow increasingly older, they may not necessarily be healthier. Additionally, ‘‘we can be certain that there is no way of avoiding in the end some form of rationing for the elderly’’ (D. Callahan quoted in Glannon, 2001, pp. 160–161). Thus, while the benefit of this research is an increased lifespan, the risk may be that there is no guarantee of health. In this respect, ‘‘extending the human life span simply may be putting off the inevitable and not making us collectively any better off than we are within a normal lifespan’’ (Glannon, 2001). Furthermore, anti-aging research could itself be unsafe. As witnessed in the administration of hormone replacement therapies to human subjects, the commencement of treatment for a largely undeciphered aging process can lead to disturbing results. Anti-aging treatments of this sort have, for many decades, been linked to cancer. Should researchers feel confident to recruit subjects for anti-aging clinical trials? The aging process is likely life-long. It does not emerge at the age of 65, and it may, in fact, begin in utero (Kirkwood, 1997; Grimley-Evans, 2000). Thus, where do we target anti-aging treatments; when should they begin, and who are the most likely subjects for research trials? Anti-aging research also carries potential societal risks. The ‘‘benefit’’ of research is not usually enjoyed by any one individual, but in the form of enhanced scientific knowledge enjoyed by society (Freedman et al., 1992). However, in the case of anti-aging research, it is not clear whether society is
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prepared for an increase in the number of elderly. It has been estimated that for every year of extra life expectancy, people spend an average of 9.6 months (80%) in a disabled state (Cassel, 2001). If the aging model is a multifactorial one, how much is disability in old age expected to change without increased interventions via social and health services? As mentioned above, the worldwide trend has been to cut back on these services. If this trend continues, the only people who could maintain health in old age would be the wealthy. If the aging model is a single target, using drugs to slow down or arrest aging, this could create a whole other set of problems, which are discussed in detail elsewhere (Callahan, 1994; Glannon, 2002; PCBE, 2003). Focusing attention on finding the magic bullet – drug or gene – cure for aging diverts attention from other forms of research and other ways of approaching health problems in old age. Funding and resources may be diverted from public health initiatives and systems biology research. Additionally, should resources be spent on life-extension in a world divided into rich and poor nations and unequal access to health care? Should we not pay attention to these inequalities before we consider conducting anti-aging clinical trials? Although some might insist on the value of delaying the onset of chronic diseases associated with aging and increasing longevity, there are many others who have wretched lives and who experience considerable pain and suffering while they are alive. What comes to mind here are people in developing countries with short, miserable lives due largely to social and economic conditions of extreme poverty (Glannon, 2001).
Is there a risk that this type of research is aimed more exclusively at those who are healthy and financially secure? This research may be more useful if it focuses on the general population and ways in which greater numbers of people may improve their lives. Informed consent The fears that surround aging, illness, and death help fuel an anti-aging alternative remedy industry. Concerns about the potential disabilities associated with biological aging drive life extension research. The aged may also fear the social stigma that is increasingly placed on them. Over-emphasis on youth and the lack of meaningful occupation for elderly women and men lead to psychological difficulties (Davidow-Hershbein, 1999; Houck, 2003).
These apparent fears raise concerns about potential clinical trial participants and their ability to assess the risks of anti-aging research. It is believed that unrealistic expectations could lead to possible exploitation of trial subjects by researchers (Juengst, 2002), and the Research Ethics Board (REB) makes decisions for individuals in a protective, paternalistic fashion. The kind of protection required for life extension and aging research has been compared to the types of safeguards needed for terminally ill patients recruited to Phase I/II trials (Juengst, 2002). According to the Canadian Tri-Council policy statement on ethical conduct for research involving humans, these types of situations ‘‘may distort the perceptions by patients and their families, as well as by researchers, of the balances between the harms and benefits of the research...[this] can further stress the duty of researchers to maximize the benefit and minimize harm to subjects’’. One way to minimize harm is to subject these types of trials to the highest scrutiny. In addition, consent forms would have to list all potential risks (as mentioned in the previous section) and would have to provide a section explaining the reasons for the increased surveillance of these types of trials.
Conclusion There are many theories, ideas, and opinions about aging. Biological theories have taken hold of the scientific and popular imagination as possible ‘‘cures’’ for aging. However, what is being cured has not been defined. Some scientists are convinced that aging can potentially be manipulated through drug and/or gene therapies. Other investigators believe that aging is an elusive target that may only be ‘‘statistically’’ engineered through a whole systems approach. There is confusion over both definitions and the safety of potential interventions. Curing cell death, for example, may lead to cell cancer. So, while preventing the diseases of aging may seem a laudable goal, curing aging is not as clearly beneficial. Beyond pharmaceutical interventions, social and health services will be needed to assure the well being of the elderly whether or not the aging process is elucidated. Current trends do not indicate that spending will increase in these services. What seems more likely is that individualized medicine based on searches for costly drug ‘‘cures’’ will continue to be the model we follow. Ethical frameworks for clinical research are difficult to establish given this climate. Many believe that
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extending the human lifespan at all costs is desirable. It is difficult to argue against ‘‘the mythic power of rejuvenation [where] almost any risks fade away, including, ironically, the risk of death’’ (Juengst, 2002). Given the complications, risks, and lack of services, embarking on clinical trials at this stage could be premature. It is important to exercise the highest caution regarding the research methods and to re-examine the goals of anti-aging investigations.
Acknowledgements The author is grateful for the support of Dr. Kathleen Glass, editing support from Kak Wilhelm and funding from Genome Quebec.
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