Sci. Aging Knowl. Environ., 27 April 2005
Vol. 2005, Issue 17, p. pe11
[DOI: 10.1126/sageke.2005.17.pe11]

PERSPECTIVES

The Art and Science of Anti-Aging Therapies

John Q. Trojanowski, M. Kathryn Jedrziewski, Brad Johnson, and Linton A. Whitaker

The authors are at the Institute on Aging (J.Q.T., M.K.J., B.J., and L.A.W.), the Department of Pathology and Laboratory Medicine (J.Q.T. and B.J.), the Center for Human Appearance (L.A.W.), and the Department of Surgery (L.A.W.) at the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. E-mail: trojanow{at}mail.med.upenn.edu (J.Q.T.)

http://sageke.sciencemag.org/cgi/content/full/2005/17/pe11

Key Words: aging society • physical fitness • cognitive function • hormone replacement therapy • antioxidant • alcohol

Introduction

About 250 clinicians, scientists, and members of the Penn community convened on 18 and 19 March 2005 for a symposium at the University of Pennsylvania School of Medicine entitled the "The Art and Science of Anti-Aging Therapies: Convergence of Theory and Practice" (the full program is available here). The meeting was organized jointly by the Institute on Aging and the Edwin and Fannie Gray Hall Center for Human Appearance of the University of Pennsylvania School of Medicine and was most timely for a number of reasons. First, less than a year from now, members of the "baby boom" generation will begin turning 60 years old, and demographers estimate that by 2030, one in five people in the United States will be 65 years of age or older. Second, life expectancy has risen significantly in the 20th century, so that the elderly are an increasingly large segment of our population. Thus, the health care needs of a progressively aging population will continue to grow for decades.

Aging also should be very much on the minds of policy makers and government leaders because the social, medical, and economic changes wrought by this "demographic revolution" are likely to affect society quite dramatically in industrialized countries throughout the world. Not surprisingly, a steady stream of articles about our aging society and health issues related to aging appear in scientific journals and the popular press. Reflecting the concerns of many people about these issues, numerous products referred to as "anti-aging" medicines or therapies are being marketed, but many of them have no biological basis and their legitimacy or efficacy is suspect. In fact, two special issues (June and July) of The Journals of Gerontology in 2004 were dedicated to the topic of anti-aging medicines, which is among the top 10 subjects in geriatrics and gerontology (1). Although basic and clinical research on aging offers promising insights into this process as well as measures to ameliorate the physical and mental deterioration associated with aging, focusing attention on anti-aging poses the danger of branding aging as a disease. Thus, this symposium was designed to offer the medical community and the community at large an opportunity to make sense of these issues as well as to focus on the positive possibilities of living and enjoying a healthy life with advancing age. The program provided an overview of combined surgical, medical, and nonpharmacological approaches to promote healthy aging of the body and mind, as well as information about interventions, procedures, and therapies for aging well. The symposium also served as a forum for assessing the implications of the upcoming shifts in the population for those who treat and serve this population.

Highlights From the Meeting

Demographics

Caleb Finch (University of Southern California) provided an evolutionary and biological perspective on aging in organisms ranging from worms and flies to humans that was encyclopedic in scope, yet accessible to the general audience. This lecture enabled symposium attendees to appreciate the daunting scale of the demographic changes in the United States and other developed countries that are taking place now, setting the stage for subsequent presentations. For example, since the beginning of the 20th century, life expectancy in the United States has increased from <50 years to >76 years, while similar demographic shifts have occurred in nearly all other developed countries (see Tuljapurkar Perspective and Hoffmann Perspective). This extraordinary continuing extension of longevity is unprecedented in human history. However, although these advances in longevity are to be celebrated for their benefits to individuals and society, it is apparent that as increasing numbers of individuals live into the seventh decade and beyond, an ever larger percentage of the United States population will be at greater risk for developing aging-related disorders such as Alzheimer's disease (AD). AD is the most common cause of dementia in the elderly, affecting ~15 million people worldwide. The number of affected individuals in the United States and Europe is expected to triple by the year 2050 to 13.2 million and 16.2 million, respectively. Thus, although rare when first reported by Alois Alzheimer in 1906 (when life expectancy was only ~50 years), AD is becoming increasingly common. If effective treatments or preventive interventions for AD and other aging-related disorders are not discovered in the near future, the consequences to society on a global level could be worse than many natural disasters.

This latter theme--the urgent need to plan now at state, federal, and global levels for a future in which large segments of the population are likely to live into the ninth decade of life--was emphasized by Daniel Perry (Alliance for Aging Research, Washington, D.C.). Although Perry emphasized many of the positive aspects of increased longevity due to medical and other advances in the past decades, he also noted alarming statistics that should serve as a clarion call for action: (i) 45% percent of the U.S. population, or 90 million people, had a chronic condition in 2000; (ii) care for people with chronic conditions consumes 78% of U.S. health care spending; (iii) in 2003, health care spending in the U.S. grew to $1.7 trillion; and (iv) in 2013, total health care spending in the United States is projected to reach $3.4 trillion, or almost one-fifth of the nation's total output. Perry pointed out that because of medical advances that have reduced aging-related morbidity and increased independence among elders, Americans have increasingly high expectations for aging in good health, and they are willing to invest in measures, including biomedical research, that will contribute to this aim. For example, he noted that (i) 78% of Americans would spend more on research to save billions on the cost of health care; (ii) 70% of Americans are willing to pay more for medicine and medical treatments if it would increase their chance of staying healthy and avoiding a nursing home; and (iii) 67% of Americans agree that unless cures and better treatments are discovered, there won't be enough hospitals, doctors, and equipment for the aging baby boom generation. Perry concluded by emphasizing that with continued planning and investments in research on aging, increasing numbers of people will be able to achieve their personal goal of healthy aging.

Physical fitness

How physical activity can promote healthy aging was discussed by Rebecca L. Craik and Kathleen Kline Mangione (Arcadia University, Glenside, Pennsylvania) in a presentation entitled "Staying Young by Keeping Fit: Exercise as Anti-Aging Therapy." Craik began by noting that biological aging is affected not only by genetics but also by environmental and lifestyle factors. For example, the cardiopulmonary, neuromuscular, and musculoskeletal systems have all been shown to respond to exercise; of these, the cardiovascular system is most responsive to exercise with advancing age.

Although we experience functional decline in each of these systems as we age, the rate of decline is similar whether we start at a high level of function or at a lower level. If people begin at a higher level of functioning, achieved through exercise, they build up a physiological reserve and will continue at a higher level of functioning as they age, as compared with nonexercisers. Data indicate that even competitive swimmers and runners reach an age at which, on average, their performance declines. Craik hypothesized that this decline could be a result of physical changes, such as the development of problems with the knee or hip, or decreased interest in the activity. Mangione then addressed the question of dose (that is, how much exercise is recommended). She noted that the Surgeon General, the Institute of Medicine, Healthy People 2010, and disease-specific organizations all make different recommendations on this point. Mangione said that we should strive for overload or performing beyond the level of normal activity. Exercising to the point of fatigue is the most efficient means of reaching fitness, although less exercise is also beneficial. For older adults, she recommended a program that included medical screening, an exercise prescription from experts, initial monitoring and tailoring, and a program for independent performance.

Cognitive function

Although the presentation by Marilyn S. Albert (Johns Hopkins University School of Medicine) came later in the symposium, it was the cognitive companion piece to the presentations by Kraik and Mangione. In her lecture, entitled "Maintain Your Brain While You Age--Pills Versus Puzzles?", she discussed the fact that we know there are changes in cognitive functioning as we age (see "All in Your Mind"), but we have not determined whether these changes are related to disease processes (see Thal Perspective and "When Does Normal Aging Become Abnormal?"). Memory function begins to decline, on average, in middle age. However, there is tremendous individual variability in memory performance. Other cognitive processes also show functional decline with age. Albert pointed to possible underlying causes for these age-related changes: (i) nerve cell loss throughout the brain, (ii) nerve cell loss in selective regions of the brain (see Nagahara Perspective and Gazzaley Perspective), and (iii) changes in mechanisms that impact on the function of the brain. She said that nerve cell loss in selective regions of the brain and changes in mechanisms impacting brain function were more likely to be underlying causes of declining cognitive function.

Given the individual variability in cognitive function, Albert posed the question, "Can we identify variations in lifestyle that predict maintenance of mental abilities with age?" Based on the many large, longitudinal, community-based studies that have been undertaken to look at this question, Albert presented the following results. Conditions or behaviors that affect the vascular system, such as diabetes, high serum cholesterol levels, obesity, and smoking show an association with reduced cognitive function, as do low levels of physical activity. Mental activity, measured both by years of formal education and the degree to which individuals participate in mentally stimulating activities, such as doing crossword puzzles and reading books, is also associated with better cognitive performance. Finally, psychosocial factors, like mood, social engagement, and feelings of self-worth, show an association with cognitive function. Albert noted that it is likely that the strongest effects are seen if multiple positive factors are present. Remarkably, recent data indicate that an enriched environment (that is, a large cage with a variety of toys and other equipment) can reduce amyloid deposits in animal models of AD (2) (see "Outrunning Alzheimer's Disease"), suggesting that neuropathology in the brain may respond to an enriched environment--at least in animal models. So given these results and those from other studies in human subjects, Albert said that controlled clinical trials are needed to extend these findings for the benefit of our aging population.

Steroid hormones

Anne Cappola (University of Pennsylvania School of Medicine) discussed how aging is accompanied by a decline in the concentration of several circulating hormones, including sex steroids and adrenal hormones, so it has been natural to hope that restoration of these hormones to youthful levels might help stave off undesirable aspects of aging (see Mobbs Perspective for an alternative view). Thus, in her talk entitled "Gonadal Steroids: Tonics or Toxins for Menopause and Andropause?", Cappola gave several reasons for pause in this line of thinking. She reviewed findings from the Women's Health Initiative randomized placebo-controlled trial of the risks and benefits of oral hormone replacement therapy (HRT: estrogen plus progesterone; ERT: estrogen alone) in postmenopausal women. Contrary to expectations, HRT was found to increase the risks of coronary heart disease and stroke, and this, coupled with the anticipated increase in breast cancer risk, outweighed benefits of reduced colorectal cancer and hip fracture risks (see "Weathering the HRT Storm"). ERT results were similar, but with no significant change in coronary risk. Furthermore, no significant protection from cognitive decline or dementia in women over the age of 65 was observed for those women on HRT. Although questions remain concerning possible benefits to select subpopulations of women or from different estrogen preparations, dosages, or routes of delivery, ERT is clearly not a panacea for aging women. For elderly men, clinical trials to examine the possible benefits of testosterone therapy, including improvements in strength, sexual function, and mood, are being considered, but will likely target select populations, given the clear risks of testosterone replacement, including prostate cancer.

Cappola also reviewed the DHEAge study, a 12-month randomized placebo-controlled study of the effects of replacement of the adrenal hormone dehydroepiandrosterone (DHEA; see Hornsby Review) in people aged 60 to 80 years (3). DHEA replacement had no effects on body composition or strength, although it resulted in some improvements in bone density, libido, and skin integrity in women over 70 years of age. Because DHEA is a natural substance, it is unregulated by the FDA, and Cappola pointed out that only half of over-the-counter preparations have doses of DHEA that are within 10 percent of the label's claim (and several have no DHEA at all). Clearly, many questions need to be addressed before we can fully realize any potential benefits of hormone replacements for the elderly.

Antioxidants

Although human-subject-oriented research is leading to new insights into pharmacological and nonpharmacological interventions to enhance health with aging, studies of animal models also are critical. Thus, this symposium included a presentation by the scientist and veterinarian Steven Zicker (Hill's Pet Nutrition) entitled "Antioxidants and Aging in Dogs--Lessons for a Dog's Older Best Friend." He provided encouraging data indicating that a diet rich in antioxidants might slow age-related cognitive decline. Like humans, many dogs experience decreased cognitive function with age, accompanied by physical changes in the brain, including cortical atrophy and beta-amyloid deposits. One theory posits that reactive oxygen species might contribute to these changes, in part by interfering with mitochondrial function. Zicker reported that food enriched for antioxidants (including vitamins E and C and beta-carotene), mitochondrial cofactors (lipoic acid and l-carnitine), and fruits and vegetables improved cognitive function in older beagle dogs, both in objective tests and in the perceptions of the dogs' owners (4). An enriched environment was also beneficial and had an additive effect with diet. Thus, it is possible to teach old dogs new tricks, and perhaps these old dogs will teach people new tricks for cognitive vigor as well.

Alcohol

At the close of the opening day of this conference, guests were treated to a lecture by R. Curtis Ellison, the champion of the use of wine and alcohol in maintaining good health, who gave a presentation entitled "Wine and a Healthy Lifestyle."�As chief of Preventive Medicine and Epidemiology and director of the Institute on Lifestyle and Health at Boston University's School of Medicine, Ellison certainly has the credentials to support his claim that the daily, moderate use of alcohol has profound health benefits that can lead to a longer life.�Although this may come as a surprise to some, Ellison pointed out that the concept is not new.�At one time, throughout the world, alcohol was an important part of most medical therapies.�Today, in much of Europe, daily alcohol consumption is the norm and is supported by both physicians and scientists.�Although the mores in the United States have prevented daily drinking from becoming a part of our culture, its health benefits have been proven.�In fact, the landmark Framingham Heart Study clearly shows that abstinence from alcohol (along with high cholesterol levels, high blood pressure, and cigarette smoking) is one of the four major risk factors for heart disease--a fact that, according to Ellison's talk, was suppressed by the U.S. government, which was more interested in temperance than health.�The truth is that daily, moderate use of alcohol reduces the risk of heart disease by 50%. However, the benefits of alcohol do not end in the heart.�Ellison listed a multitude of other health benefits (supported by a host of other studies) gained by the use of wine and alcohol: a decrease in cerebral vascular disease (stroke rate reduced by 30 to 50%), congestive heart failure, diabetes, osteoporosis, infectious disease, obesity, and even cognitive diseases such as AD and dementia.�Ultimately, these benefits lead to an overall reduction in mortality of nearly 25%. Although the dangers of excessive alcohol consumption are well known, Ellison has successfully made a case for the moderate use (0.5 to 2 drinks per day) of alcohol.�Following his five-part recipe for a healthy lifestyle--no tobacco, staying lean, a diet low in animal fat and high in fiber and whole grains, regular exercise, and moderate, daily alcohol consumption--will increase the likelihood of a healthier and longer life.

Interventions and ethics

Interwoven with the presentations summarized above were a fascinating, even spellbinding series of presentations on cosmetic and surgical approaches to maintaining a healthy appearance with advancing age. Although several of these lectures had a technical focus on the most state-of-the-art surgical techniques used in the Center for Human Appearance, the personal and psychological importance of appearance to individuals as they age was emphasized by the presentation entitled "Physical Appearance in Daily Life: Youthfulness Equals Beauty; Aging Equals What?" by David B. Sawer (Center for Human Appearance, University of Pennsylvania School of Medicine). However, it was clear in the closing presentation by Arthur Caplan (Center for Bioethics, University of Pennsylvania School of Medicine), that the notion of taking active measures to promote healthy aging is fraught with considerable controversy from a bioethics perspective. Caplan's lecture was entitled somewhat tongue-in-cheek "The Ethics of Being Forever Young," but given his inimitable lecture style as well as the current national debate on feeding tubes and the right to die, he quickly cut straightaway to discussion of the most challenging religious, political, and ethical dilemmas we face now in our rapidly aging society. Interestingly, Caplan's conclusions about how to move forward in dealing with these dilemmas echoed many of the points made by Perry: Investment in biomedical research can pave the way for improving the health of the increasing numbers of Americans who will live into their eighth or ninth decade and beyond in the coming years, whereas providing equitable access to health care services for all will take us a considerable distance toward ensuring that this is done in an ethical manner.

Concluding Remarks

This symposium could not address all of the critical issues of the day on this topic, but it did cover a considerable portion of this uncharted territory, leaving the audience with the understanding that the aging of our society is a demographic revolution that will change life as we know it in a very short time. Progress in aging-related research has benefited people living today, such that they can expect to live healthier lives as they age than their predecessors. The symposium stressed the importance of pursuing activities and dietary habits that are health promoting throughout life, especially in the second half of life. Thus, investment in biomedical research should be complemented by efforts to increase public awareness about lifestyles and habits that individuals can adopt so that they age in the healthiest manner possible.


April 27, 2005
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Citation: J. Q. Trojanowski, M. K. Jedrziewski, B. Johnson, L. A. Whitaker, The Art and Science of Anti-Aging Therapies. Sci. Aging Knowl. Environ. 2005 (17), pe11 (2005).








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