2
Biological Research, Medical Advances, and Ethical Considerations

The first session of the symposium examined links between scientific advances in biology and medicine and healthy aging. How can the healthy life span be increased, either by a longer life span that is healthy or by an existing life span made healthier? What advances have been made in understanding the underlying biology of aging? What are the challenges to caring for people as they become more frail? And at the end of life, what is the appropriate amount of health care? What ethical dilemmas arise when trying to determine the amount of health care that society should provide?

EXTENDING THE LIFE SPAN

Richard A. Miller

Geriatrics Center

University of Michigan


Richard Miller addressed biological research on the life span by proposing to ask a hypothetical 50-year-old: Would you rather spend the next 30 years turning into an 80-year-old, or would you like to stay 50 years old for 30 years, and only then resume aging? Miller is convinced that remaining 50 is not only preferable but also possible.

In some laboratory animals, including animals that function as humans do, the life span can be extended by 40 percent. The animals whose aging has been slowed are healthy, vigorous, and cognitively intact, with strong



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 5
2 Biological Research, Medical Advances, and Ethical Considerations T he first session of the symposium examined links between scientific advances in biology and medicine and healthy aging. How can the healthy life span be increased, either by a longer life span that is healthy or by an existing life span made healthier? What advances have been made in understanding the underlying biology of aging? What are the challenges to caring for people as they become more frail? And at the end of life, what is the appropriate amount of health care? What ethical dilemmas arise when trying to determine the amount of health care that society should provide? EXTENDING THE LIFE SPAN Richard A. Miller Geriatrics Center Uniersity of Michigan Richard Miller addressed biological research on the life span by propos- ing to ask a hypothetical 50-year-old: Would you rather spend the next 30 years turning into an 80-year-old, or would you like to stay 50 years old for 30 years, and only then resume aging? Miller is convinced that remaining 50 is not only preferable but also possible. In some laboratory animals, including animals that function as humans do, the life span can be extended by 40 percent. The animals whose aging has been slowed are healthy, vigorous, and cognitively intact, with strong 

OCR for page 5
 GRAND CHALLENGES OF OUR AGING SOCIETY immune systems at ages that would be the equivalent of 80 to 130 years in humans. They are not disease-ridden. Indeed, at death, the incidence of most diseases in these animals is below the norm. The possibility of extending longevity and delaying late-life diseases as a group has tremendous implications not only for a longer healthy life span but also for research budgets. Years would be added to an average person’s life span as the result of finding cures for cancer, heart disease, stroke, and diabetes. However, none of these hypothetical cures separately, and not even all of them together, would generate the increase in life span that would result from slowing the aging process. Concen - trating resources on research on slowing the aging process would yield much greater dividends than dispersing the resources among different diseases. Furthermore, while cures for these various late-life diseases remain hypothetical, increasing the life span of animals is already routinely accomplished in laboratories, via at least two diets (including radical caloric restriction) and five gene mutations. The next step is to devise more palatable pharmacological methods to achieve these results. An intermediary research agenda involves the study of worms and flies that use the same gene to extend their life span, the study of cells from bats and birds that live on average three times longer than mammals of the same size, and comparisons of people to shorter lived marmosets. Research should also take advantage of what biologists have discovered regarding stress resistance pathways, developmental “switches,” and long-lived mouse mutants. Such research could lead to the development of antiaging drugs, a reasonable therapeutic means for human beings to slow the aging process. Nonetheless, basic research on the biology of longevity and the aging process receives very little funding. For example, the National Institutes of Health now directs 0.06 percent of its funds to this topic. Why is that the case? Obstacles to this research are largely political rather than sci- entific. Popular pseudoscience on extending longevity has damaged the public image of serious work in the field. In addition, aging is generally viewed as inalterable, so researching how to change it is seen as futile. Furthermore, each of the late-life diseases has a separate lobby to build social awareness, gain media attention, raise money, and pursue research funds. The market is another arena of difficulty. Although current research is promising, drugs that will actually slow aging cannot be tested in time, Miller noted, “to show a profit within a chief executive officer’s lifetime.” Also, drugs that purport to slow aging are already on the market and, although ineffectual, are profitable. Politically, “Add life to years” is an acceptable slogan, while slowing aging is not. Finally, in terms of science

OCR for page 5
 BIOLOGICAL RESEARCH, MEDICAL ADVANCES, AND ETHICAL CONSIDERATIONS as a profession, most scientists depend on funding, and there is very little funding for research on the biology of aging. And while young scientists are attracted to the latest technological advances, little of that is involved in this research. Standing apart from these cultural, social, economic, political, and professional obstacles is the considerable scientific chal - lenge of curing aging. “To be honest,” Miller admitted, “it’s not that easy to cure.” What are the key questions to be addressed in the biology of aging and extending the healthy life span? Miller put two research questions at the forefront: 1. Why do some species live longer than others? 2. How can important cells be made stress resistant with drugs? To characterize the scientific consensus, controversy, and ignorance on the biology of aging, a parallel may be drawn from the history of infectious disease. The study of how to slow the aging process is at about the same stage as the study of infectious disease after Edward Jenner pio - neered a vaccine against smallpox, but before Louis Pasteur, John Snow, and Robert Koch documented why the vaccine worked and developed the germ theory of disease. That is, in efforts to slow the aging process, scien - tists can already intervene, but they do not know how that intervention works, if it is safe, or how to make it as safe and efficacious as possible. “In general,” Miller summarized, “we have a lot of controversy, a growing consensus, and too much ignorance at this stage.” A further puzzle is how to reframe the possibility of slowing the aging process as an acceptable, endorsable, and respectable endeavor. Acknowl- edging that this remains a distant goal, Miller coined a term for the gen- eral prejudice in this area: “gerontologiphobia.” This prejudice includes the fear of what antiaging medicines (if they were ever invented) might do to society, despite the evidence that a pharmacologically extended life span would add healthy, active, disease-free years to life. THE BIOLOGY OF FRAILTY Linda P. Fried Mailman School of Public Health Columbia Uniersity Much new research exists on the underlying biology of frailty. Clini - cal components of frailty include declines in mobility, strength, balance, motor processing, cognition, nutrition, endurance, and physical activity. A core feature is loss of muscle mass or sarcopenia. There is mounting

OCR for page 5
 GRAND CHALLENGES OF OUR AGING SOCIETY evidence of a multisystem physiological dysregulation in frailty, includ- ing not only sarcopenia but also inflammation, decreased heart rate vari - ability, altered clotting processes, altered insulin resistance, anemia, and altered neuroendocrine axis. People who manifest frailty have disruptions of multiple systems at the physiological level and perhaps at much deeper molecular and genetic levels. Many of these systems affect each other, creating a biological safety net that provides reserves and resilience. In frailty, multisystem dysregulation and interactions may result in loss of physiological networking and mutual regulation, loss of reserves, and decreased homeostatic regulation. A spiral of deterioration is established as decreased physiological reserves and resilience lead to functional decline, culminating in disability or death. The understanding of frailty has changed significantly over the past 20 years. Fried identified six points of a new consensus: (1) frailty is an aging-associated phenomenon, (2) frailty carries a high risk of adverse outcomes for the individual (e.g., mortality), (3) the risk is evidenced under conditions of stress (e.g., hospitalization), (4) frailty may have to do with an underlying vulnerable physiological state, (5) the severity of frailty occurs along a continuum with implications for the opportunities for prevention, and (6) frailty may be associated with multisystem reduc - tion in reserve capacity1 (even to the threshold of clinical failure). The consensus view is that frailty is better understood as background vulnerability rather than a foreground presenting disease, and it has a physiological or biological basis. There is also some divergence among researchers working on frailty. Some see it as the vulnerability or loss of reserves that results from the sum of all the health problems an individual may have, including coexisting impairments, symptoms, and diseases, not necessarily related to each other. Others view frailty as its own medi- cal syndrome with an identifiable clinical presentation. In this perspec - tive, which Fried shares, frailty results from physiological impairments. Frailty is an independent, distinct, clinically recognizable condition. It is not a single disease, nor is it associated with just one disease. It is neither comorbidity nor multimorbidity. It predicts disability but is not a disabil - ity. Frailty may have a primary relationship to the biology of aging and also seems to be associated with a number of specific diseases that have inflammation as a component (e.g., HIV, congestive heart failure, chronic obstructive pulmonary disease, diabetes, obesity). Understanding frailty is essential because it appears to be a chronic 1 Reserve capacity refers to the ability of a physiological system (e.g., cardiac, respiratory) to maintain vital functions in the face of external stresses. Frailty is a likely result of aggre - gate loss of reserves in multiple systems.

OCR for page 5
 BIOLOGICAL RESEARCH, MEDICAL ADVANCES, AND ETHICAL CONSIDERATIONS progressive process in 90 percent of older adults. Prevention, particularly in the early stages, is therefore a great concern. There are a variety of ways to screen for early vulnerability to frailty at four levels: (1) phe - notype, (2) preventing attendant risk, (3) physiological dysregulation, and (4) molecular and genetic causes. Because frailty is a multisystem phenomenon, key risk factors will probably affect multiple systems. Effec- tive interventions are also likely to affect many systems simultaneously. Intervening on only one level (phenotype, physiological, or molecular) may not be a meaningful alteration. As Fried observed, “We’ve done lots of single-strand silver-bullet type interventions over the years, which actually didn’t yield results.” Three categories of interventions are under evaluation. Interventions at the first level, phenotype, include ways to increase physical activity and social engagement by redesigning community opportunities and environ- ment. Maintaining physical activity ensures functioning on many levels, from muscle mass and strength to regulating mitochondrial function and energy production. Intervention to encourage and facilitate physical activity could be very cost-effective. Social engagement is also essential. Building a sense of meaning and usefulness and countering isolation is likely to play a role in preventing frailty and disability. Experience Corps, which puts older volunteers into public elementary schools, is a form of social engagement in which both physical and cognitive activities are embedded. A second category of interventions under evaluation addresses moments of risk. Careful attention is warranted to redesigning hospitals and rethinking hospitalization, as hospitals are virtual stress tests for frail individuals. Screening procedures, for example before surgery or certain therapies or treatments, are also relevant. Current research indicates that screening for frailty is a much more specific predictor of poor postopera- tive outcome than any other screening measure. The third category of interventions under evaluation work on the physical characteristics of frailty. These include nutritional supplemen - tation, such as with protein enhancement or selenium. In a pilot study, the hormone ghrelin appears to significantly increase both body weight and the level of growth hormones in frail older women. Anti-inflamma - tories may also be an effective intervention. All of these affect multiple systems. Many research questions remain. Fried identified four areas of research in frailty science with great potential to enhance healthy aging: 1. Understand frailty as a key risk factor for disability and loss of independence. This would include establishing standardized meth-

OCR for page 5
0 GRAND CHALLENGES OF OUR AGING SOCIETY ods for screening and devising strategies for prevention of frailty at early stages. 2. Explore primary and secondary frailty, particularly seeking under- lying processes that are intermediate, in common (e.g., inflammato- ries), or final common pathways. A related area of study is whether prevention of chronic diseases and obesity would also prevent frailty. 3. Undertake deeper study of the biology of vulnerability, including systems biology of homeostasis and reserves. 4. Pursue clinical implications, including redesigning care to be more effective and less costly, with attention to reducing risks in the built environment and the provision of palliative care. It is important to think about public health for an aging society. In frailty prevention, public health approaches are likely to be the most effective. Housing and neighborhoods could be redesigned to minimize isolation and optimize access. Programs such as Experience Corps can also have large impacts, as older adults maintain physical and cognitive activity, make meaningful and valued contributions, and extend their pro- ductivity. Large-scale public health interventions of this sort would affect physiology at many different levels and would furthermore be sustain - able in ways that laboratory interventions are not. They are sustainable because they are meaningful, they make a difference, and they are fun. Therefore people sign up and stay—which is not the case for many physi- cal exercise interventions. They also bring in people at high risk and are cost-effective. A final advantage of large-scale public health interventions is that they confer social benefit on everyone. As Fried concluded, “If we can redesign societal approaches so that they are both great for people as they get older and great for society because they help bring the wisdom and experience of an aging population to bear on unmet social needs, then we could have a new kind of social compact.” ALLOCATING SCARCE HEALTH CARE RESOuRCES Daid B. Reuben Multicampus Program in Geriatric Medicine and Gerontology Uniersity of California, Los Angeles The provision of health care services in the United States falls into three categories: (1) what we can do, (2) what we do indeed do, and (3) what we should do. The category of “can do” is driven by technology and science and is characterized by the perspective that more is always better. Large invest -

OCR for page 5
 BIOLOGICAL RESEARCH, MEDICAL ADVANCES, AND ETHICAL CONSIDERATIONS ments have yielded large returns, including improved control of disease, prevention of some disease, and lengthened life expectancy. These large returns have come at a high price. Providing dialysis, for example, which became a defined Medicare benefit in 1973, costs $23 billion per year for the current 422,000 beneficiaries. Implantable cardiac defibrillators, a defined Medicare benefit since 2005, cost $28,000 for each of the approxi - mately 500,000 eligible individuals, for a total of $13.5 billion. Many more such costly procedures are to come, especially for the older adults who are becoming a larger proportion of the population. The second category, the “do indeed do,” refers to health care as it is generally practiced. It is driven by providers and patients and shaped by such factors as availability, access, insurance, practice patterns, and patient/provider choices. While the procedures and tests of conventional health care do not carry price tags comparable to those of dialysis or defi - brillators, taken as a whole they sum to very large expenditures. However, despite substantial expenditures, the U.S. health care system exhibits poor performance on quality measures. People in America also have a poorer health status compared with those in other nations. The third category is the “should do.” What should be done in health care is a matter of personal, societal, and ethical values. Little money is invested in determining the proper limits of health care because of the difficulty of the task, the lack of ownership of this challenge, and the potential for public backlash. Because the issue of determining the proper limits of health care is avoided, people are left with a system in which what they can do eventually becomes what they do indeed do. The refusal to address the proper limits of health care raises ques- tions of distributive justice and the fair allocation of resources across society. In general, the guiding principle in the United States has been that resources are spent to benefit the most people. Nonetheless, costly sophis- ticated care is often provided to individuals while the needs of many are neglected. For example, the cost of a bed in an intensive care unit for a week ($16,800) can be compared with the annual cost of health insur- ance for a family of four ($12,700). This is similar to the case of a trapped miner for whom immense resources are spent on rescue, when society is not willing to invest in making the mineshaft safer in the first place. If the country continues in this manner, health care costs will become com - pletely unaffordable. Garrett Hardin’s well-known 1968 essay, “The Tragedy of the Com- mons,” describes the dilemma of multiple individuals acting indepen - dently in their own self-interest and thereby destroying a shared limited resource, through no intent of their own and against their own long-term interest. Hardin’s metaphor is the common pastureland on which each herder sends an additional cow, resulting in overgrazing. It is in the inter-

OCR for page 5
 GRAND CHALLENGES OF OUR AGING SOCIETY est of each herder to put as many cows as possible on the land, even to the point of damaging it, since the herder receives all the benefit of the additional cows. The damage, however, is shared by the whole group. There are many parallels with individual overuse of common health care resources. According to Hardin’s earlier analysis, problems characterized by the tragedy of the commons (such as overpopulation) have no technical solutions. Hardin argued that appeals to individual conscience or altru - ism will also not be effective and that some sort of coercion is required. Coercion can take the form not of force, but of laws and standards, a new and clear shared understanding, in Reuben’s view, “of what is permissible and what is not permissible.” In health care, this would consist of some form of reallocation of health care resources. What might this look like? In terms of Reuben’s three categories, restricting what we can do is not a feasible step. The impressive and costly interventions in this category have strong public support and have provided large benefits to improving health. Furthermore, they offer the promise of hope to individuals and their families and are therefore dif - ficult to withdraw. And systemically, they are the livelihood of many scientists and physicians who have a vested interest in providing them. Thus, restricting what we can do is not apt to happen. Defining the limits of what we should do is imperative but also unlikely. This task is inherently messy, involving cultures and religions, and often putting individual interests counter to societal interests. Defin - ing the limits of what we should do in health care requires courage and leadership, and neither is coming, either from government or from health care providers. Therefore, focus might best be put on what we do indeed do. Gov- ernment, medical experts, and ethicists can use their moral authority to establish a system of allocating health care resources. Doing so will involve some degree of moral hazard. If health care services are too read- ily available, they may be overused. But if access to health care services is excessively restricted, then failure to access early preventive care will result in more costly health problems later. A well-designed regime for allocating health care resources would move society off the path toward bankruptcy and ensure distributive jus- tice in health care. It would be a welcome means to deny unrestrained use of health care in futile situations. Providing an illustration from his own practice, Reuben mentioned the case of an elderly individual with severe dementia and metastatic breast cancer being kept in an intensive care unit for 130 days at the insistence of her family. In another similar instance involving a patient in intensive care for many weeks, Reuben sought to convince the family to allow the patient to be transferred. His efforts to

OCR for page 5
 BIOLOGICAL RESEARCH, MEDICAL ADVANCES, AND ETHICAL CONSIDERATIONS discuss prognosis and palliative care options were cut short, however, by a statement of the patient’s relative: “Our family believes in miracles.” Such individual situations, in a larger context that permits and pays for whatever interventions can be done, makes for a health care system that violates distributive justice and generates unsustainable costs. Responding to questions, Reuben acknowledged that the overuse of medical care and technology is not only patient-driven. In the current system, with payment based on procedures performed rather than health outcomes achieved, doctors have incentives to do too much. There may be an overuse of costly tests and technology, but an underuse of more cost- effective interventions. Different approaches will be needed to address patient-driven and physician-driven overuse of health care. One type of solution is needed when a patient’s family demands a ventilator for the last 90 days of life, whereas a different solution is needed when physicians who are making a profit doing procedures continue to order costly tests and interventions. A defined system for allocating health care resources would address only direct costs of health care, and not the substantial indirect economic impact of lost productivity of patients and their infor- mal caregivers. Reuben closed with a three-part research agenda: 1. What methods are most effective in communicating choices at the individual patient/provider level? 2. How can technical solutions reduce the need for tough societal decisions (e.g., present the case to a panel without having the patient or patient’s representative in the room)? 3. How can science inform decision making about resource allocation?

OCR for page 5