Position Statement on Human Aging

S. Jay Olshansky, Ph.D.
Leonard Hayflick, Ph.D.
Bruce A. Carnes, Ph.D.

In the past century a combination of successful public health campaigns, changes in living environments and advances in medicine have led to a dramatic increase in human life expectancy. Long lives experienced by unprecedented numbers of people in developed countries are a triumph of human ingenuity. This remarkable achievement has produced economic, political and societal changes that are both positive and negative. Although there is every reason to be optimistic that continuing progress in public health and the biomedical sciences will contribute to even longer and healthier lives in the future, a disturbing and potentially dangerous trend has also emerged in recent years. There has been a resurgence and proliferation of health care providers and entrepreneurs who are promoting antiaging products and lifestyle changes that they claim will slow, stop or reverse the processes of aging. Even though in most cases there is little or no scientific basis for these claims [1], the public is spending vast sums of money on these products and lifestyle changes, some of which may be harmful [2]. Scientists are unwittingly contributing to the proliferation of these pseudoscientific antiaging products by failing to participate in the public dialogue about the genuine science of aging research. The purpose of this document is to warn the public against the use of ineffective and potentially harmful antiaging interventions and to provide a brief but authoritative consensus statement from 51 internationally recognized scientists in the field about what we know and do not know about intervening in human aging. What follows is a list of issues related to aging that are prominent in both the lay and scientific literature, along with the consensus statements about these issues that grew out of debates and discussions among the 51 scientists associated with this paper.

Lifespan

Life span is defined as the observed age at death of an individual; maximum lifespan is the highest documented age at death for a species. From time to time we are told of a new highest documented age at death, as in the celebrated case of Madame Jeanne Calment of France who died at the age of 122 [3]. Although such an extreme age at death is exceedingly rare, the maximum life span of humans has continued to increase because world records for longevity can move in only one direction: higher. Despite this trend, however, it is almost certainly true that, at least since recorded history, people could have lived as long as those alive today if similar technologies, lifestyles and population sizes had been present. It is not people that have changed; it is the protected environments in which we live and the advances made in biomedical sciences and other human institutions that have permitted more people to attain, or more closely approach, their life-span potential [4] Longevity records are entertaining, but they have little relevance to our own lives because genetic, environmental and lifestyle diversity [5] guarantees that an overwhelming majority of the population will die long before attaining the age of the longest-lived individual.

Life Expectancy

Life expectancy in humans is the average number of years of life remaining for people of a given age, assuming that everyone will experience, for the remainder of their lives, the risk of death based on a current life table. For newborns in the U.S. today, life expectancy is about 77 years.6 Rapid declines in infant, child, maternal and late-life mortality during the 20th century led to an unprecedented 30-year increase in human life expectancy at birth from the 47 years that it was in developed countries in 1900. Repeating this feat during the lifetimes of people alive today is unlikely. Most of the prior advances in life expectancy at birth reflect dramatic declines in mortality risks in childhood and early adult life. Because the young can be saved only once and because these risks are now so close to zero, further improvements, even if they occurred, would have little effect on life expectancy [7-9]. Future gains in life expectancy will, therefore, require adding decades of life to people who have already survived seven decades or more. Even with precipitous declines in mortality at middle and older ages from those present today, life expectancy at birth is unlikely to exceed 90 years (males and females combined) in the 21st century without scientific advances that permit the modification of the fundamental processes of aging [10]. In fact, even eliminating all aging-related causes of death currently written on the death certificates of the elderly will not increase human life expectancy by more than 15 years. To exceed this limit, the underlying processes of aging that increase vulnerability to all the common causes of death will have to be modified.

Immortality

Eliminating all the aging-related [11] causes of death presently written on death certificates would still not make humans immortal [12]. Accidents, homicides, suicide and the biological processes of aging would continue to take their toll. The prospect of humans living forever is as unlikely today as it has always been, and discussions of such an impossible scenario have no place in a scientific discourse.

Geriatric Medicine versus Aging

Geriatric medicine is a critically important specialty in a world in which population aging is already a demographic reality in many countries and a future certainty in others. Past and anticipated advances in geriatric medicine will continue to save lives and help to manage the degenerative diseases associated with growing older [13,14], but these interventions only influence the manifestations of aging--not aging itself. The biomedical knowledge required to modify the processes of aging that lead to age-associated pathologies confronted by geriatricians does not currently exist. Until we better understand the aging processes and discover how to manipulate them, these intrinsic and currently immutable forces will continue to lead to increasing losses in physiological capacity and death even if age-associated diseases could be totally eliminated [15-20].

Antiaging Medicine

Advocates of what has become known as antiaging medicine claim that it is now possible to slow, stop or reverse aging through existing medical and scientific interventions [21-26]. Claims of this kind have been made for thousands of years [27], and they are as false today as they were in the past [28-31]. Preventive measures make up an important part of public health and geriatric medicine, and careful adherence to advice on nutrition, exercise and smoking can increase one’s chances of living a long and healthy life, even though lifestyle changes based on these precautions do not affect the processes of aging [32-33]. The more dramatic claims made by those who advocate antiaging medicine in the form of specific drugs, vitamin cocktails or esoteric hormone mixtures are, however, not supported by scientific evidence, and it is difficult to avoid the conclusion that these claims are intentionally false, misleading or exaggerated for commercial reasons [34]. The misleading marketing and the public acceptance of antiaging medicine is not only a waste of health dollars; it has also made it far more difficult to inform the public about legitimate scientific research on aging and disease [35]. Medical interventions for age-related diseases do result in an increase in life expectancy, but none have been proved to modify the underlying processes of aging. The use of cosmetics, cosmetic surgery, hair dyes and similar means for covering up manifestations of aging may be effective in masking age changes, but they do not slow, stop or reverse aging. At present there is no such thing as an antiaging intervention.

The scientifically respected free-radical theory of aging [36] serves as a basis for the prominent role that antioxidants have in the antiaging movement. The claim that ingesting supplements containing antioxidants can influence aging is often used to sell antiaging formulations. The logic used by their proponents reflects a misunderstanding of how cells detect and repair the damage caused by free radicals and the important role that free radicals play in normal physiological processes (such as the immune response and cell communication) [37-39]. Nevertheless, there is little doubt that ingesting fruits and vegetables (which contain antioxidants) can reduce the risk of having various age-associated diseases, such as cancer [40], heart disease [41,42], macular degeneration and cataracts [43,44]. At present there is relatively little evidence from human studies that supplements containing antioxidants lead to a reduction in either the risk of these conditions or the rate of aging, but there are a number of ongoing randomized trials that address the possible role of supplements in a range of age-related conditions [45-49], the results of which will be reported in the coming years. In the meantime, possible adverse effects of single-dose supplements, such as beta-carotene [50], caution against their indiscriminate use. As such, antioxidant supplements may have some health benefits for some people, but so far there is no scientific evidence to justify the claim that they have any effect on human aging [51-52].

Telomeres

Telomeres, the repeated sequence found at the ends of chromosomes, shorten in many normal human cells with increased cell divisions. Statistically, older people have shorter telomeres in their skin and blood cells than do younger people [53,54]. In the animal kingdom, though, long-lived species often have shorter telomeres than do short-lived species, indicating that telomere length probably does not determine life span [55-57]. Solid scientific evidence has shown that telomere length plays a role in determining cellular life span in normal human fibroblasts and some other normal cell types [588]. Increasing the number of times a cell can divide, however, may predispose cells to tumor formation [59-60]. Thus, although telomere shortening may play a role in limiting cellular life span, there is no evidence that telomere shortening plays a role in the determination of human longevity.

Hormones

A number of hormones, including growth hormone, testosterone, estrogen and progesterone, have been shown in clinical trials to improve some of the physiological changes associated with human aging [61,62]. Under the careful supervision of physicians, some hormone supplements can be beneficial to the health of some people. No hormone, however, has been proved to slow, stop or reverse aging. Instances of negative side effects associated with some of these products have already been observed, and recent animal studies suggest that the use of growth hormone could have a life-shortening effect [63-65]. Hormone supplements now being sold under the guise of antiaging medicine should not be used by anyone unless they are prescribed for approved medical uses.

Caloric Restriction

The widespread observation that caloric restriction will increase longevity must be tempered with the recognition that it has progressively less effect the later in life it is begun [66], as well as with the possibility that the control animals used in these studies feed more than wild animals, predisposing them to an earlier death. Although caloric restriction might extend the longevity of humans, because it does so in many other animal species [67-69], there is no study in humans that has proved that it will work. A few people have subjected themselves to a calorically restricted diet, which, in order to be effective, must approach levels that most people would find intolerable. The fact that so few people have attempted caloric restriction since the phenomenon was discovered more than 60 years ago suggests that for most people, quality of life seems to be preferred over quantity of life. The unknown mechanisms involved in the reduced risk of disease associated with caloric restriction are of great interest [71] and deserve further study because they could lead to treatments with pharmacological mimetics of caloric restriction that might postpone all age-related diseases simultaneously.

Determining Biological Age

Scientists believe that random damage that occurs within cells and among extracellular molecules are responsible for many of the age-related changes that are observed in organisms [72-74]. In addition, for organisms that reproduce sexually, including humans, each individual is genetically unique. As such, the rate of aging also varies from individual to individual [75]. Despite intensive study, scientists have not been able to discover reliable measures of the processes that contribute to aging [76]. For these reasons, any claim that a person’s biological or "real age" [77] can currently be measured, let alone modified, by any means must be regarded as entertainment, not science.

Are There Genes That Govern Aging Processes?

No genetic instructions are required to age animals, just as no instructions on how to age inanimate machines are included in their blueprints [79-80]. Molecular disorder occurs and accumulates within cells and their products because the energy required for maintenance and repair processes to maintain functional integrity for an indefinite time is unnecessary after reproductive success. Survival beyond the reproductive years and, in some cases, raising progeny to independence, is not favored by evolution because limited resources are better spent on strategies that enhance reproductive success to sexual maturity rather than longevity [81]. Although genes certainly influence longevity determination, the processes of aging are not genetically programmed. Overengineered systems and redundant physiological capacities are essential for surviving long enough to reproduce in environments that are invariably hostile to life. Because humans have learned how to reduce environmental threats to life, the presence of redundant physiological capacity permits them and the domesticated animals we protect to survive beyond the reproductive ages. Studies in lower animals that have led to the view that genes are involved in aging have demonstrated that significant declines in mortality rates and large increases in average and maximum life span can be achieved experimentally [82-85]. Without exception, however, these genes have never produced a reversal or arrest of the inexorable increase in mortality rate that is one important hallmark of aging. The apparent effects of such genes on aging therefore appear to be inadvertent consequences of changes in other stages of life, such as growth and development, rather than a modification of underlying aging processes. Indeed, the evolutionary arguments presented above suggest that a unitary programmed aging process is unlikely to even exist and that such studies are more accurately interpreted to have an effect on longevity determination, not the various biological processes that contribute to aging. From this perspective, longevity determination is under genetic control only indirectly [86,87]. Thus, aging is a product of evolutionary neglect, not evolutionary intent [88-91].

Can We Grow Younger?

Although it is possible to reduce the risk of aging-related diseases and to mask the signs of aging, it is not possible for individuals to grow younger. This would require reversing the degradation of molecular integrity that is one of the hallmarks of aging in both animate and inanimate objects. Other than performing the impossible feat of replacing all of the cells, tissues or organs in biological material as a means of circumventing aging processes, growing younger is a phenomenon that is currently not possible.

Genetic Engineering

After the publication of the human genome sequences, there have been assertions that this new knowledge will reveal genes whose manipulation may permit us to intervene directly in the processes of aging. Although it is likely that advances in molecular genetics will soon lead to effective treatments for inherited and age-related diseases, it is unlikely that scientists will be able to influence aging directly through genetic engineering [92,93]. because, as stated above, there are no genes directly responsible for the processes of aging. Centuries of selective breeding experience (in agricultural, domesticated and experimental plants and animals) has revealed that genetic manipulations designed to enhance one or only a few biological characteristics of an organism frequently have adverse consequences for health and vigor. As such, there is a very real danger that enhancing biological attributes associated with extended survival late in life might compromise biological properties important to growth and development early in life.

Replacing Body Parts

Suggestions have been made that the complete replacement of all body parts with more youthful components could increase longevity. Though possible in theory, it is highly improbable that this would ever become a practical strategy to extend length of life. Advances in cloning and embryonic stem cell technology may make the replacement of tissues and organs possible [94-99] and will likely have an important positive impact on public health in the future through the treatment of age-related diseases and disorders. But replacing and reprogramming the brain that defines who we are as individuals is, in our view, more the subject of science fiction than science fact.

Lifestyle Modification and Aging

Optimum lifestyles, including exercise and a balanced diet along with other proven methods for maintaining good health, contribute to increases in life expectancy by delaying or preventing the occurrence of age-related diseases. There is no scientific evidence, however, to support the claim that these practices increase longevity by modifying the processes of aging.

Concluding Remarks

Since recorded history individuals have been, and are continuing to be, victimized by promises of extended youth or increased longevity by using unproven methods that allegedly slow, stop or reverse aging. Our language on this matter must be unambiguous: there are no lifestyle changes, surgical procedures, vitamins, antioxidants, hormones or techniques of genetic engineering available today that have been demonstrated to influence the processes of human aging [100,101]. We strongly urge the general public to avoid buying or using products or other interventions from anyone claiming that they will slow, stop or reverse aging. If people, on average, are going to live much longer than is currently possible, then it can only happen by adding decades of life to people who are already likely to live for 70 years or more. This "manufactured survival time" [102] will require modifications to all of the processes that contribute to aging--a technological feat that, though theoretically possible, has not yet been achieved. What medical science can tell us is that because aging and death are not programmed into our genes, health and fitness can be enhanced at any age, primarily through the avoidance of behaviors (such as smoking, excessive alcohol consumption, excessive exposure to sun, and obesity) that accelerate the expression of age-related diseases and by the adoption of behaviors (such as exercise and a healthy diet) that take advantage of a physiology that is inherently modifiable [103].

We enthusiastically support research in genetic engineering, stem cells, geriatric medicine and therapeutic pharmaceuticals, technologies that promise to revolutionize medicine as we know it. Most biogerontologists believe that our rapidly expanding scientific knowledge holds the promise that means may eventually be discovered to slow the rate of aging. If successful, these interventions are likely to postpone age-related diseases and disorders and extend the period of healthy life. Although the degree to which such interventions might extend length of life is uncertain, we believe this is the only way another quantum leap in life expectancy is even possible. Our concern is that when proponents of antiaging medicine claim that the fountain of youth has already been discovered, it negatively affects the credibility of serious scientific research efforts on aging. Because aging is the greatest risk factor for the leading causes of death and other age-related pathologies, more attention must be paid to the study of these universal underlying processes. Successful efforts to slow the rate of aging would have dramatic health benefits for the population by far exceeding the anticipated changes in health and length of life that would result from the complete elimination of heart disease, cancer, stroke and other age-associated diseases and disorders.

Authors and Endorsers

Dr. Olshansky is Senior Research Scientist and Professor at the School of Public Health, University of Illinois at Chicago. Dr. Hayflick is Professor of Anatomy at the University of California at San Francisco. Dr. Carnes is Assistant Professor of Geriatric Medicine at the University of Oklahoma. Drs. Olshansky and Carnes are also coauthors of The Quest for Immortality (Norton, 2001), a book-length antidote to anti-aging hype.

The Position Statement on Human Aging has been endorsed by Robert Arking, Allen Bailey, Andrzej Bartke, Vladislav V. Bezrukov, Jacob Brody, Robert N. Butler, Alvaro Macieira-Coelho, L. Stephen Coles, David Danon, Aubrey D.N.J. de Grey, Lloyd Demetrius, Astrid Fletcher, James F. Fries, David Gershon, Roger Gosden, Carol W. Greider, S. Mitchell Harman, David Harrison, Christopher Heward, Henry R. Hirsch, Robin Holliday, Thomas E. Johnson, Tom Kirkwood, Leo S. Luckinbill, George M. Martin, Alec A. Morley, Charles Nam, Sang Chul Park, Linda Partridge, Graham Pawelec, Thomas T. Perls, Suresh Rattan, Robert Ricklefs, Ladislas (Leslie) Robert, Richard G. Rogers, Henry Rothschild, Douglas L. Schmucker, Jerry W. Shay, Monika Skalicky, Len Smith, Raj Sohal, Richard L. Sprott, Andrus Viidik, Jan Vijg, Eugenia Wang, Andrew Weil, Georg Wick and Woodring Wright. Drs. Olshansky and Carnes received funding for this work from the National Institute on Aging. The position paper was previously published in Scientific American Magazine and the Journal of Gerontology: Biological Sciences.

References

  1. Workshop Report, Is There an Antiaging Medicine? International Longevity Center, Canyon Ranch Series; New York, 2001.
  2. U.S. General Accounting Office. "Antiaging Products Pose Potential for Physical and Economic Harm." Special Committee on Aging, GAO-01-1129. September 2001.GAO-01-1129
  3. Allard M, Lebre V, Robine JM., Calment J. Jeanne Calment: From Van Gogh’s time to ours: 122 extraordinary years. W.H. Freeman & Co.: New York; 1998.
  4. Carnes BA, Olshansky SJ, Grahn D. Continuing the search for a law of mortality. Popul Dev Rev. 1996;22(2):231-264.
  5. Finch C, Kirkwood TBL. Chance, Development, and Aging. Oxford University Press; 2000.
  6. Anderson RN. United States life tables, 1998. National Vital Statistics Reports. 2001;48:1-40.
  7. Olshansky SJ, Carnes BA, Cassel C. In Search of Methuselah: Estimating the upper limits to human longevity. Science. 1990;250:634-640.
  8. Demetrius L, Ziehe M. The measurement of Darwinian fitness in human populations. Proc R Soc Lond B Biol Sci. 1984;B222:33-50.
  9. Demongeot J, Demetrius L. La derivé demographique et la selection naturalle: étude empirique de la France (1850-1965). Population. 1989;2:231-248.
  10. Olshansky, S.J., Carnes, B.A., Désesquelles, A. 2001. Prospects for Human Longevity.  Science 291 (5508):1491-1492.
  11. Carnes BA, Olshansky SJ. A Biologically Motivated Partitioning of Mortality. Exp Gerontol. 1997;32:615-631.
  12. Hayflick L. How and why we age. Exp Gerontol. 1998;33:639-653.
  13. Cassel CK, Cohen HJ, Larson EB, Meier DE, Resnick NM, Rubenstein LZ, Sorensen LB. (Eds.). Geriatric Medicine. New York: Springer; 2001.
  14. Evans JG, Williams FT. (Eds) Oxford Textbook of Geriatric Medicine. Oxford University Press, Oxford; 2001.
  15. Hayflick L. How and Why We Age. 1994. Ballantine Books: New York.
  16. Medina J. The Clock of Ages. Why We Age – How We Age – Winding Back the Clock. 1996. Cambridge University Press.
  17. Gosden R. Cheating Time: Science, Sex, and Aging. 1996. W.H. Freeman & Co.: New York.
  18. Bailey AJ. Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev. 2001;122:735-755.
  19. Bailey AJ, Sims TJ, Ebbesen EN, Mansell JP, Thomsen JS, Moskilde L. Age-related changes in the biochemical and biomechanical properties of human cancellous bone collagen: Relationship to bone strength. Calcif Tis Res. 1999;65:203-210.
  20. Wick G, Jansen-Durr P, Berger P, Blasko I, Grubeck-Loebenstein B. Diseases of aging. Vaccine. 2000;18:1567-1583.
  21. Chopra D. Grow younger, live longer: 10 steps to reverse aging. Harmony Books: New York; 2001.
  22. Klatz R. Grow young with HGH: The amazing medically proven plan to reverse aging. Harper Perennial Library; 1998.
  23. Brickey MP. Defy aging: Develop the mental and emotional vitality to live longer, healthier, and happier than you ever imagined. New Resources Press; 2000.
  24. Carper J. Stop aging now!: The ultimate plan for staying young and reversing the aging process. Harper perennial Library; 1996.
  25. Null G, Campbell A. Gary Null's ultimate anti-aging program. Broadway Books; 1999.
  26. Pierpaoli W, Regelson W, Colman C. The melatonin miracle. Simon and Schuster: New York; 1995.
  27. Gerald J. Gruman, A history of ideas about the prolongation of life. Trans Amer Phil Soc. 1966;56(9):1-102.
  28. Austad S. Why we age: What science is discovering about the body's journey through life. John Wiley & Sons: New York; 1999.
  29. Holliday R. Understanding ageing. Cambridge University Press; 1995.
  30. Arking R. Biology of aging: Observations and principles, 2nd edition. Sinauer Associates, Sunderland, MA.; 1998.
  31. Arking R. The Biology of aging: What is it and when will it become useful? Infertility and Reproductive Medicine Clinics of North America. 2001;12:469-487.
  32. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980;303:130-135.
  33. Rogers RG, Hummer RA, and Nam CB. Living and dying in the USA: Behavioral, health, and social differentials of adult mortality. Academic Press; 2000.
  34. Olshansky SJ, Carnes BA. The quest for immortality: Science at the frontiers of aging. Norton: New York; 2001.
  35. Miller R. Extending life: Scientific prospects and political obstacles. Milbank Q. 2002;80(1):155-74.
  36. Harman D. Aging: A theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298-300.
  37. Robert L, Labat-Robert J. Aging of connective tissues: from genetic to epigenetic mechanisms. Biogerontology. 2000;1:123-131.
  38. Fülöp Jr T, Douziech N, Jacob MP, Hauck M, Wallach J, Robert L. Age-related alterations in the signal transduction pathways of the elastin-laminin receptor. Pathol Bio. 2001;49:339-348.
  39. Labat-Robert J. Cell-matrix interactions, alterations with aging and age associated diseases. A review. Pathol Bio. 2001;49:349-352.
  40. World Cancer Research Fund. American institute for cancer research. Food, nutrition and the prevention of cancer: A global perspective; 1997.
  41. Tavani A, La Vecchia C. Beta-carotene and risk of coronary heart disease. A review of observational and intervention studies. Biomed Pharmacother. 1999;53(9):409-416.
  42. Hu FB, Willett WCJ. Diet and coronary heart disease: findings from the Nurses’ health study and health professionals’ follow-up Study. Nutr Health Aging. 2001;5(3):132-138.
  43. Van Duyn MA, Pivonka EJ. Overview of the health benefits of fruit and vegetable consumption for the dietetics professional: selected literature. Am Diet Assoc. 2000;100(12):1511-1521.
  44. Christen WG. Antioxidant vitamins and age-related eye disease. Proc Assoc Am Physicians. 1999;111(1):16-21.
  45. MRC/BHF Heart Protection Study Collaborative Group. MRC/BHF heart protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J. 1999;20:725-741.
  46. Manson JE, Gaziano M, Spelsberg A, et al for the WACS Research Group: A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women. Rationale, design, and methods. Ann Epidemiol. 1995;5:261-269.
  47. Egan DA, Garg R, Wilt TJ, et al for the ADMIT Investigators: Rationale and design of the arterial disease multiple intervention trial (ADMIT) Pilot Study. Am J Cardiol. 1999;83:569-575.
  48. The Age-Related eye disease research group: The age-related eye disease study (AREDS): Design implications. AREDS Report No. 1. Control Clin Trials 1999;20:573-600.
  49. Tikellis G, Robman LD, Harper CA, et al. The VECAT study: methodology and statistical power for measurement of age-related macular features. Ophthalmic epidemiology. 1999;6:181-194.
  50. Paolini M, Abdel-Rahman SZ, Cantelli-Forti G, Legator LS. Chemoprevention or Antichemo- prevention? A salutary warning from the Beta-Carotene experience. J Natl Cancer Inst. 2001;93(14):1110-1111.
  51. Morley AA, Trainor KJ. Lack of an effect of vitamin E on lifespan of mice. Biogerontology. 2001;2:109-112.
  52. de Grey ADN. Noncorrelation between maximum life span and antioxidant enzyme levels among homeotherms: implications for retarding human aging. J Anti-Aging Med. 2000;3:25-36.
  53. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 1990;345:458-460.
  54. Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA 1994;91:9857-9860.
  55. Hemann MT, Greider CW. Wild-derived inbred mouse strains have short telomeres. Nucleic Acids Res 2000;28:4474-4478.
  56. Kakuo S, Asaoka K, Ide T. Human is a unique species among primates in terms of telomere length. Biochem Biophys Res Commun. 1999;263(2):308-14.
  57. Holliday R. Endless quest. Bioessays. 1996;18(1):3-5.
  58. Bodnar AG, Ouellette M, Frolkis M, et al. Extension of life span by introduction of telomerase into normal human cells. Science. 1998;279:349-352.
  59. Wang J, Hannon GJ, Beach DH. Risky immortalization by telomerase. Nature 2000;405:755-756.
  60. de Lange T, Jacks T. For better or worse? Telomerase inhibition and cancer. Cell 1999;98:273-275.
  61. Rudman D, Feller AG, Nagraj HS, et al. Effects of growth hormone in men over 60 years old. N Eng J Med. 1990;323:1-6.
  62. Gallagher JC. Role of estrogens in the management of postmenopausal bone loss. Rheum Dis Clin North Am. 2001;1:143-
  63. Wolf E, Kahnt E, Ehrlein J, et al. Effects of long-term elevated serum levels of growth hormone on life expectancy of mice: Lessons from transgenic animals. Mech Ageing Dev. 1993;68:71-87.
  64. Bartke A, Brown-Borg H, Mattison J, et al. Prolonged longevity of hypopituitary dwarf mice. Exp Gerontol. 2001;36:21-28.
  65. Coschigano KT, Clemmons D, Bellush LL, and Kopchick JJ. Assessment of growth parameters and life span of GHR/BP gene disrupted mice. Endocrinology. 2000;141:2608-2613.
  66. Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science. 1992;215(4538):1415-8.
  67. Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Charles C. Thomas. Springfield, IL.; 1988.
  68. Harrison DE, Archer JR. Natural selection for extended longevity from food restriction. Growth Dev Aging. 1989;53:3-6.
  69. Duffy PH, Seng JE, Lewis SM, et al. The effects of different levels of dietary restriction on aging and survival in the Sprague-Dawley rat: implications for chronic studies. Aging Clin Exp Res 2001;13:263-272.
  70. Journal of Gerontology: Biological Sciences. 2001;56,3: entire issue.
  71. Masoro EJ. Dietary restriction: current status. Aging Clin Exp Res 2001;13:261.
  72. Hayflick L. The Future of aging. Nature. 2000;408:267-269.
  73. Morley AA. The somatic mutation theory of ageing. Mut Res. 1995;338:19-23.
  74. Odagiri Y, Uchida H, Hosokawa M, Takemoto K, Morley A, Takeda T. Accelerated accumulation of somatic mutations in the senescence-accelerated mouse. Nat Genet. 1998;19:117-118.
  75. Carnes BA, Olshansky SJ. Heterogeneity and its biodemographic implications for longevity and mortality. Exp Gerontol. 2001;36:419-430.
  76. Workshop Report, Biomarkers of Aging: From Primitive Organisms to Man. International Longevity Center – Canyon Ranch Series, New York, NY.; 2001.
  77. Roizen M. RealAge: Are you as young as you can be? Cliff Street Books; 1999.
  78. Roizen M, La Puma J. The RealAge diet: Make yourself younger with what you eat. Cliff Street Books; 2001.
  79. Hayflick L. The Future of aging. Nature. 2000;408:267-269.
  80. Miller RA. Kleemeier award lecture: are there genes for aging? J Gerontol A Biol Sci Med Sci. 1999;54(7):B297-307.
  81. Kirkwood TBL. Evolution of aging. Nature. 1977;270:301-304.
  82. Johnson TE. Aging can be genetically dissected into component processes using long-lived lines of Caenorhabditis elegans. Proc Natl Acad Sci. USA. 1987;84:3777-3781.
  83. Johnson TE. Increased life span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science. 1990;249:908-912.
  84. Vaupel JW, Carey JR, Christensen K, et al. Biodemographic trajectories of longevity. Science. 1998;280:855-859.
  85. Johnson TE, Wu D, Tedesco P, Dames S, Vaupel JW. Age-specific demographic profiles of longevity mutants in Caenorhabditis elegans show segmental effects. J Gerontol Bio Sci. 2001;56:B331-339.
  86. Hayflick L. How and Why We Age. 1994. Ballantine Books: New York.
  87. Demetrius L. Mortality plateaus and directionality theory. Proc R Soc Lond B; 2001,268:1-9.
  88. Olshansky SJ, Carnes BA, Butler RA. If humans were built to last. Sci Am; 2001.
  89. Carnes BA, Olshansky SJ, Gavrilov L, Gavrilova N, Grahn D. Human longevity: nature vs. nurture—fact or fiction. Perspect Biol Med. 1999;42(3):422-441.
  90. Robert L. Cellular and molecular mechanisms of aging and age related diseases. Pathol Oncol Res. 2000;6:3-9.
  91. Robert L. Aging of the vascular wall and atherosclerosis. Exp Gerontol. 1999;34:491-501.
  92. Rattan SIS. "Gene therapy for aging: mission impossible?" Hum Reprod Gen Ethics. 1997;3:27-29.
  93. Rattan SIS. "Is gene therapy for aging possible?" Ind J Exp Biol. 1998;36:233-236.
  94. Stem Cells: Scientific Progress and Future Research Directions. Department of Health and Human Services. June 2001.
  95. Stem Cells and the Future of Regenerative Medicine. Committee on the Biological and Biomedical Applications of Stem Cell Research, Board on Life Sciences National Research Council, Board on Neuroscience and Behavioral Health, Institute of Medicine. National Academy Press, 2002.
  96. Cardiomyocytes Induce Endothelial Cells to Trans-Differentiate into Cardiac Muscle: Implications for Myocardium Regeneration. G. Condorelli et al. in Proceedings of the National Academy of Sciences USA, Vol. 98, No. 19, pages 10733-10738; September 11, 2001.
  97. Heart Regeneration in Adult MRL Mice. J. M. Leferovich et al. in Proceedings of the National Academy of Sciences USA, Vol. 98, No. 17, pages 9830-9835; August 14, 2001.
  98. Segregation of Human Neural Stem Cells in the Developing Primate Forebrain. V. Ourednik et al. in Science, Vol. 293, pages 1820-1824; September 7, 2001.
  99. A Genome-Wide Scan for Linkage to Human Exceptional Longevity Identifies a Locus on Chromosome 4. A. A. Puca in Proceedings of the National Academy of Sciences USA, Vol. 98, No. 18, pages 10505-10508; August 28, 2001.
  100. Living to 100: Lessons in Living to Your Maximum Potential at Any Age. Thomas T. Perls, et al. Basic Books, 1999.
  101. Time of Our Lives: The Science of Human Aging. Tom Kirkwood. Oxford University Press, 1999.
  102. Confronting the Boundaries of Human Longevity. S. J. Olshansky, B. A. Carnes and D. Grahn in American Scientist, Vol. 86, No. 1, pages 52-61; 1998.
  103. Aging, Health Risks, and Cumulative Disability. A. J. Vita, R. B. Terry, H. B. Hubert and J. F. Fries in New England Journal of Medicine, Vol. 338, No. 15, pages 1035-1041; April 9, 1998.

This article was posted on August 27, 2004.