Longevity

Perspectives Richard M. Friedenberg, MD

Longevity1 In the past, we have been told that life is finite. There is a beginning and a predictable end, which may vary in different individuals by some years. We knew that life may be terminated by disease at any age, but it was believed that eventually, we all succumb to senescence. It was always considered a remarkable achievement to be a centenarian, worthy of notice in newspapers and even a congratulatory letter from the president. However, the idea of a fixed limit to life was always questionable, since there is no known internal mechanism that automatically terminates life. In recent years, partly as a by-product of the identification of the human genome and the early success in gene manipulation, we are now told that there may be no finite end to life and that there may be no such thing as death by senescence (1). Our bodily systems attempt to preserve life, and aging occurs because of the accumulation of myriads of tiny faults (1). Death, then, is produced by treatable diseases and therefore could be preventable. Several decades in the future, the average life span might be as high as 110 or 115 years. For centuries, philosophers and physicians have searched for methods of extending life span without success. In

Index terms: Aging Perspectives Published online before print 10.1148/radiol.2233012153 Radiology 2002; 223:597– 601 1

From the Department of Radiological Sciences, University of California at Irvine Medical Center, Orange. Received January 14, 2002; accepted January 24. Address correspondence to the author, 18961 Castlegate Ln, Santa Ana, CA 92705 (e-mail: [email protected]).

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the 16th and 17th centuries, death was related to moral transgressions. Physicians and philosophers believed that Adam and Eve had been designed for immortality and that their deaths were the result of their moral transgression of eating from the tree of knowledge of good and evil (2). Despite this moral transgression, according to the Bible, Adam lived 930 years; his son Seth lived 912 years; and Methuselah set the biblical record of 969 years. The vigor of the human race appeared to diminish after this, with Abraham living just 175 years (2). Aging theories in the 16th and 17th centuries revolved primarily around moisture and heat (2,3). Living beings were obviously warm, and the warmer you were, the more vitality you had. Dying individuals were colder and drier and therefore closer to death. The comparison was made between the moist and supple flesh of a baby and the wrinkled, dry, and leathery skin of an old individual. It was believed that a longer life might be obtained by preventing the loss of heat and moisture, and this was attempted by applying ointments and oils to the skin and by limiting the intake of food, since food and drink required consummation of the body’s innate heat. The body had a limited supply of heat, and the more food you consumed, the more heat was required to consume the food. Shapin and Martyn, in their article “How to Live Forever, Lessons of History” (2), state that there were skeptics even in those days who questioned whether the practice was worth the price. Michel Du Montaigne, a philosopher of the time, was skeptical about the promises made by medical experts to prolong life. He believed the practice was not worth the price and said, “If you follow the advice of your physician, your life would be miserable. Rather than extend life and be miserable, live life and enjoy it” (2). Similarly, in George Bernard Shaw’s

preface to The Doctor’s Dilemma (4), he states, “Use your health even to the point of wearing it out. That is what it is for. Spend all you have before you die and do not outlive yourself. Do not try to live forever. You will not succeed.” Despite the wisdom of these philosophers, the search continued throughout the centuries for methods to increase longevity. Guttman (5), quoting the report of the Federal Interagency Forum titled “Older Americans 2000,” noted that persons born in 1960 have a life expectancy of about 70 years (67 years for men; 73 years for women), while for those born in 1997, the expected life span is 74 years for men and 79 years for women. Persons who reached the age of 85 in 1997 had 5.5 to 6.5 years of expected survival. Although heart disease is still the leading cause of death (40% for those over the age of 85), there has been approximately a one-third decrease in the rate of cardiovascular-associated lesions (3). Similarly, the percentage of disabled elderly has decreased as preventative medicine such as diet, vaccination, and mammography has improved. Cognitive function has also improved into older age. Among individuals between 65 and 69 years of age, fewer than 5% displayed moderate or severe memory impairment, which, as you might expect, increases to 36% at age 85. In Japan, the country whose citizens have the longest life span, the expectant life span is 75.9 years for men and 81.8 years for women (6). After reaching age 65, the expected life span is 16.2 and 19.9 years, respectively. The same numbers in the United States (5) are an expected life span of 74 years for men and 79 years for women, and after age 65, 14.9 and 19.1 years, respectively (7). The Framingham Heart Program estimated that by stopping smoking and correcting blood pressure, cholesterol, and obesity problems, those over the age of 65 could add up to 5 years of life expectancy (6). 597

As people age, they seek remedies to increase fitness and prolong life. Antiaging medicine revolves around hormones (estrogen, testosterone, and growth hormones), vitamins, and herbal supplements. Hormone levels decline with age, and the appropriate level for a 65-yearold is considerably less than that for a 25-year-old. The goal of antiaging medication is to restore the network of repair, and there are those who believe that hormone systems drive the maintenance and repair systems of the cells. These substances are administered to approximate what the body produces when it is functioning optimally. They believe it restores the antioxidant system to handle damages from oxidative stress (8). Those who believe in hormone therapy will usually treat those individuals in whom hormone levels fall below 50% of the expected level in a 25–30-year-old. Growth hormone therapy leads to a decrease in abdominal fat, an increase in lean muscle mass, a decrease in blood pressure, an increase in high-density lipoprotein, and a decrease in low-density lipoprotein; fasting insulin and glucose tolerance usually improve (9). They believe that it helps prevent coronary artery disease and diabetes. As for herbal and vitamin supplements, it has been estimated that 60% of the individuals in New York City over the age of 65 use them regularly (10). Most reports of the beneficial effects of herbal medication have been anecdotal, but controlled studies are now being conducted. So in essence, growth hormone, testosterone, estrogen, vitamins E and C, and herbal remedies are all in the package of antiaging medications. In 1996, the National Institutes of Health Consensus Conference concluded that the most modifiable risks are smoking, high blood pressure, high blood lipid levels, obesity, diabetes, and physical inactivity. They stated that all Americans should engage in regular physical activity for at least 30 minutes at a moderate intensity level every day of the week, since physical inactivity was considered a major risk for cardiovascular disease. About one in four adults, more women than men, currently live sedentary lifestyles, and another third are insufficiently active to achieve health benefits. This totals approximately 55% of the population (11) and occurs disproportionately more among Americans who are less educated and economically disadvantaged. Since 1900, the number of persons aged 65 and older has increased 11-fold, while the number of those younger than 65 has tripled (12). Between 1965 and 1995, the older population increased by 598

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82%, with one in eight Americans being older than 65, and those 85 and older (termed the oldest old) being the fastest growing segment of the U.S. population, reaching 31⁄2 million in 1994. Cassel (12) estimates that in 30 years, one in five Americans will be 65 years or older, and the number over the age of 85 may approach 9 million. At the time this article was written, the Social Security Administration reported approximately 65,000 centenarians, with only 5,000 being men. Cassel estimates that in 10 years, there will be well over 100,000 centenarians, and in 50 years, it may approach a million. In the United Kingdom, people over the age of 60 currently constitute a fifth of the population and will constitute a third by 2030. In the more developed countries as a group, by 2030 it is estimated that people 65 and older will constitute approximately 23% of the total population, and people 85 and older will constitute approximately 6% (12). There are many reasons for the increase in life expectancy, and these could be divided into environmental and genetic reasons. Among the environmental causes, medical progress would rank as number one. Such items as the reduction of premature death, the reduction of childbirth-related deaths, the eradication of serious infections, the decrease in deaths from cardiovascular-related diseases, the control of diabetes, and the improvement of surgical techniques have had a profound effect in that they increase the potential of individuals to attain older age. Other environmental factors include both behavioral and social changes. These include a decrease in smoking, the realization that diet and exercise decrease risk factors, and the establishment of Medicare in 1965, a major factor in providing treatment for elderly individuals. The major causes of death in the elderly are heart disease, cancer, and stroke, and the rates for each are about the same at they were in 1965; the major difference is that they are occurring at an older age (12). Therefore, we are not so much preventing these diseases as we are postponing them. Senescence in itself is not a cause of death, but a senescent cascade of diseases that occurs in the elderly may often be the cause of death. The object should be to postpone disease as long as possible and also to postpone the onset of disability, which will provide a shorter period of dependency before death. McMurdo (13) believes that by paying attention to three modifiable risk factors— cigarette smoking, body mass index, and exercise patterns—the onset

of disability could be postponed by more than 5 years. Adapting such lowrisk habits can be associated not only with an increase in life span but also with an increase in health span. Another recognized risk factor for the elderly is hospitalization. Following hospitalization, 30% of adults older than 70 lose the ability to perform at least one of the activities of daily living, and 41% of these patients do not regain their lost function over the next 3 months (12). These negative effects of hospitalization must be combated with earlier mobilization and a team approach to rehabilitation of the patient. The other major factor affecting longevity has been genetic analysis, which has recently led to a revolution in aging research. Researchers are continually searching for genes that might influence life span. The underpinning of the genetics of aging relate to research conducted in fruit flies and nematodes (14). Fruit flies that exhibited the ability to reproduce late in their life spans were selectively bred over several generations, and this group showed extended longevity. This established the participation of genes in aging. Single genes were found to modulate life span in the worm Caenorhabditis elegans, a nematode that displayed increased life span and led to the first identification of a longevity gene named Age 1, which remains to be cloned. The relative importance of genetic influences on longevity was studied by Ljungquist et al (15) and Wilmoth et al (16), all from Sweden. Ljungquist et al (15) followed a large sample of identical and like-sexed fraternal twins together with a subsample of 1,734 twin pairs reared together and 130 twin pairs reared apart that were born between 1886 and 1990. Their results suggested that the genetic effect was small and that most of the variance in longevity was explained by environmental factors. Over the total age range examined, they believed that a maximum of about one-third of the variance in longevity was attributable to genetic factors, and the remaining variance was due to nonshared, individual, and specific environmental factors (15). Investigators who have analyzed trends of mortality in Sweden since 1861 concluded that of the total increase in maximum life span, the major portion was due to a decline in mortality above age 70 (16). Other factors in order of importance were the increase in number of individuals attaining old age, the increase in size of the birth cohorts, and the reduction in mortality before age 70. Friedenberg

Perls et al (17) suggest that extreme longevity—living 20–25 years longer than average—requires a genetic advantage. This might include a decrease in genes that are predisposed to disease, as well as the presence of genes that slow the process of aging and decrease the susceptibility to age-related diseases. Investigators who studied the siblings of centenarians identified a region on chromosome 4 in many of the siblings that was highly suggestive of a link to aging (18). It was suggested that there are probably other genes that have a similar effect and that there is probably a small total number, such as four to six genes, which have a major effect on longevity, although others believe that the number may be substantially higher (19). Over the past several years, the concept of a fixed limit to human longevity has become more questionable. Nearly every system in the body does its best to preserve life. Systems are not perfect, however, and aging occurs gradually from cellular changes that accumulate over time. Perhaps what we call senescence is the end result of accumulated cellular changes. I have addressed the question of longevity, but what about the quality of those extra years? Although Americans are living longer, is the quality of life becoming better or worse after age 65? Several investigators have approached this question in an attempt to assess the quality of life in elderly individuals (5,20,21). The Federal Interagency Forum on Aging, in their report titled “Older Americans 2000: Key Indicators of Well Being” (quoted by Guttman) (5), stated that older Americans are living longer, feeling better with less disability, and faring better economically. Black and Hispanic Americans are still lagging behind white Americans in this respect (5). Persons who reached the age of 85 in 1997 had 5.5– 6.5 years of expected survival. However, aging gradually leads to physical and mental deterioration. Heart disease is the leading cause of death, with cancer, stroke, chronic obstructive pulmonary disease, pneumonia, and diabetes as the next most frequent causes (3). Five of these six diseases are chronic and can produce severe disability. Arthritis affects more than half the population aged 70 and older, followed by hypertension (45%) and cancer (20%). In addition to physical disability, moderate or severe memory impairment increases with age. At age 65– 69, fewer than 5% of individuals display moderate or severe impairment (only 1% severe); however, by age 85, this increases to 36%. Depression is increasing and affects over 20% of those Volume 223

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over the age of 85. Disability, defined as a limitation of one of the activities of daily living, affected over 7 million individuals (21% of the population) in 1994 (3). In a different study, next of kin were asked to report on the use of hospitalization and nursing home services in a large number of deceased individuals who were aged 65 years and older in 1986. Results were compared with those of a similar group who were aged 65 years and older in 1993. They noted that women used substantially fewer hospital and nursing home services in the last year of life in 1993 versus 1986, and men aged 85 and older had a decline in nursing home stays. The authors of this study concluded that men and women over the age of 85 experienced a better overall terminal quality of life in 1993 than in 1986 (20). A third study included 1,741 University of Pennsylvania alumni whose initial data were accumulated in 1986 at an average age of 68 and who were then assessed between 1987 and 1994 at the average age of 75. Investigators concluded that persons with better health habits survived longer and that disability was postponed and compressed into a few years at the end of life. This was not as noteworthy for those with poor health habits (21). The overall impression is that the elderly population, in addition to living longer, is living a better quality of life than that of their predecessors some generations ago. Much of this relates to environmental changes that have produced better health habits and that seem to postpone the onset of disability, compressing it into the last years of life. Life span appears to be determined by the interplay between environmental and genetic factors. We can understand the effect of environmental factors, but how does genetic background influence longevity? Are there specific genes that increase longevity, or is longevity primarily influenced by the genetic predisposition to develop certain age-related diseases? The answer to this question may not be decided for many years. Some authors believe that the main thrust is a genetic predisposition to develop diseases, allowing some individuals to either delay or escape diseases associated with aging (22). Even with a genetic predisposition, however, there is considerable variability among individuals with the same genetic background as to when the disease becomes manifest. For example, the gene for polycystic kidney disease may be present in members of a given

family, but some members of the family may manifest the disease at age 22 and others may not manifest the disease until their 60s. Holloszy (23) defines aging at the cellular level as a progressive deterioration of structure and function that occurs over time. Primary aging refers to the deterioration of structure and function as a direct result of the aging process. Secondary aging is that caused by diseases and environmental factors. Improvement or slowing of secondary aging can be defined as an increase in average life span, while slowing of primary aging results in an increase in maximal life span. Holloszy believes that there is a genetic predisposition to develop age-related diseases. He estimates that in mammals, the genetic factor accounts for only about 35% of the interspecies variance in longevity. The rate of primary aging is probably genetically determined by the effectiveness of mechanisms that act to maintain structural integrity of cells in tissues. These include protecting DNA against free radical damage, repairing damaged DNA, and providing protection against the development of malignancies. He believes that the genotypes that are known to enhance longevity in humans do so with their influence on disease development. The achievements of genetics in the analysis of aging in mammals are less impressive than in other organisms. So far, to our knowledge, no genotype has been discovered that slows the aging process in humans, although it has been discovered in mice (24), nematodes, and fruit flies (14). In 1990, there were 4 million people aged 85 and older, the so-called oldest old. It is estimated that there will be 40 million in 2040. Vaillant and Mukamal (25) believe that it is not that individuals are living longer, but that more people are living to age 65. The life span of an 85-year-old man has increased by only 1.2 years, from 4 years in 1900 to 5.2 years in 1987. Therefore, the increase in number of oldest old people directly relates to more people reaching 65 years of age. Both environmental and genetic factors have probably contributed to the fact that elderly individuals report less disability, and 40% of those over the age of 85 remain fully functional. By using a global definition of successful aging, Vaillant and Mukamal (25) note that in the Berlin Aging Study Cohort (26), at age 75, 80% of the study population were still considered in good health, cognitively fit, active, and involved in life, or in average health, still independent, and Longevity

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satisfied with life. At age 95, this level of health was maintained by only 30%. Two of the most important psychosocial predictors of successful aging were high level of education and having an extended family network. After age 30, our ability to recall proper names steadily declines, but such anomia does not predict dementia. In 1948, the World Health Organization defined health not as the absence of illness but as the presence of physical, mental, and social well-being (27). Investigators in study at Harvard University followed two socially diverse cohorts of adolescents, one a college group and the other a core city group, until they became great-grandfathers (25). They were all males from the United States, and all were white. The college cohort reached every stage of disability and death about 10 years later than did the core city group. At age 65, 25% of the core city group were dead, and 20% were disabled. At age 75, 27% of the college men were dead, and 14% were disabled. Obviously, education, which includes a certain degree of affluence and access to health, made a substantial difference. Predictor variables change over time. Serum cholesterol level, for example, may be important in the young, but in the elderly cohorts after age 70, it may not be a general risk factor (25). Shortened ancestral longevity is a risk factor for people who die before the age of 60, but it may not be a risk after that age (25). What effect will longevity have on health care costs? In the United States, people 65 years of age or older are projected to increase from 13% of the population in 2000 to 20% by 2030 because of the aging of the baby boom generation and increased longevity (28). As the 85year-old population increases, they are more likely to require nursing home care, and currently, Medicaid pays about half of the total costs of nursing home care in the United States. As might be expected, as the age at death increases, the proportional expenditure for acute care decreases and that for nursing home care increases. On the basis of Medicare data, Spillman and Lubitz (28) state that the total projected expenditure for all services from the age of 65 years until death in 1996 dollars was $164,505 per person. Of this amount, the bulk was for Medicare ($105,342) and for nursing home care— care not covered by Medicare ($34,205). Nursing home costs increase with patient age. Average nursing home costs were $12,000 for those who died at age 75 and $64,000 for those who died at 600

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age 90. Nursing home costs surpass Medicare costs for persons older than 97 years. The authors estimate that for all individuals born in 1950 who turn 65 in 2015, health care costs in 1996 dollars will be 73% higher than the combined expenditures for individuals who turn 65 in 2000. This assumes that Medicare rates remain the same and that insurance coverage remains more or less the same. The most important factor is the higher number of persons projected to reach age 65 in 2015. It is estimated that 47% of persons who reach age 65 in 2015 will survive to age 85. Throughout this article, I have tried to establish two different but intimately related concepts. The first is the increase in longevity, and although the projections that I have quoted are all individual concepts, there is no doubt that there will be real increases in the future. It is possible that average life span will increase to 90 or 95 years in the next few generations and that 5%–10% of the population may reach the century mark. The second related concept is the quality of life, and this is much more difficult to project. Even if death is not related to senescence but is due always to disease, and if increased longevity is related to the delay of onset of diseases, will most of the individuals older than age 90 be confined to wheelchairs, perhaps with severely diminished cognitive qualities? Perls et al (29), reporting on a population of 460, 829 in a New England centenarian study, noted that 8,856 (1.9%) were older than age 85, and among them, 46 were verified centenarians, a ratio of one per 10,000. Of this group, 61% were in nursing homes. He projected that by 2000, there may be as many as 100,000 centenarians worldwide. In addition to physical disabilities, the incidence of dementia appears to increase dramatically with age. In one study, dementia has been reported in 1% of the population at age 65, increasing to 47% by age 85 (30). Investigators in a Canadian study noted that the prevalence of dementia rose from 40% among those 90 –94 years old to 59% among those 95–99 years old (31). There have been insufficient data on those over 100 years old. Rose (32) believes that although we may delay death, we will not be able to markedly delay, beyond what has already been accomplished, the decline in physiologic function. He believes that people will live longer but will not enjoy much more of a robust old age than their counterparts of previous generations.

We have unquestionably increased the quality of life for individuals under the age of 90 by means of social and environmental factors discussed previously. It may be more difficult to avoid the physical and mental deterioration of those older than 90 years. Aging research promises marked progress, but this has not been matched by equal progress in improving quality of life. Prolonged infirmity may be the fate of most of those older than 90 years. In the Berlin aging study, only 30% of those older than 90 years were in reasonable health (26). If this continues, we will not have accomplished much. We would all like to live as long as possible, but we must balance this with the quality of life obtainable. Disease and death will be with us forever. The interpretation of the quality of life will vary between individuals, but if we cannot improve it, what have we really accomplished by extending life? Those focused on prolonging life through genetic and environmental research must also focus on improving the quality of those added years to make their work meaningful. References 1. Kirkwood TB. Where will it all end? Lancet 2001; 357:576. 2. Shapin S, Martyn C. How to live forever: lessons of history. BMJ 2000; 321:1580 – 1582. 3. Gruman GJ. A history of ideas about prolongation of life: the evolution of prolongevity hypothesis to 1800. Trans Am Phi Soc 1966; 56. 4. Shaw GB. The doctor’s dilemma. London, England: Penguin, 1957; 86 – 87. 5. Guttman S. Older Americans 2000. Geriatrics 2000; 55:63– 69. 6. Fraser GE, Shavlik DJ. Ten years of life. Arch Intern Med 2001; 161:1645–1652. 7. Bulletin of the Metropolitan Life Insurance Company. 1992; 73:10 –15. 8. Sohal RS, Weindrach R. Oxidative stress, caloric restriction and aging. Science 1996; 273:60 – 61. 9. Luddington AV. Anti-aging medicine: interview with Joseph M. Raffaele and Ronald Livesay. Geriatrics 2000; 55:37– 46. 10. Butler RM, Fossel M. Pan CX, et al. Antiaging medicine. Geriatrics 2000; 55:38 – 43. 11. Physical activity and cardiovascular health. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. JAMA 1996; 276:241–246. 12. Cassel CK. Successful aging: how increased life expectancy and medical advances are changing geriatric care. Geriatrics 2001; 56:35–39. 13. McMurdo MET. A healthy old age: realistic or futile goal? BMJ 2000; 321:1149 – 1151. 14. Jazwinski SM. Longevity, genes and aging. Science 1996; 273:54 –59. 15. Ljungquist B, Berg S, Lanke J, et al. The effect of genetic factors for longevity: a Friedenberg

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comparison of identical and fraternal twins in the Swedish twin registry. J Gerontol A Biol Sci Med Sci 1998; 53:M441– M446. Wilmoth JR, Deegan LJ, Lundstrom H, Horiuchi S. Increase in maximum lifespan in Sweden. Science 2000; 289:2366 – 2368. Perls TT, Bubrick E, Wager CG, et al. Siblings of centenarians live longer (letter). Lancet 1998; 351:1560. Puca AA, Daly MJ, Brewster SJ, et al. A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proc Natl Acad Sci U S A 2001; 98:10505–10508. Maugh TH. Gene study seeks secret of long life. The Nation 2001; Aug 28:sect A-1. Liao Y, McGee DL, Cao G, Cooper RS. Quality of the last year of life of older adults: 1986 vs 1993. JAMA 2000; 283: 512–518.

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Vita AJ, Terry RB, Hubert HB, Fries JF. Aging, health risks, and cumulative disability. N Engl J Med 1998; 338:1035– 1041. Larkin M. Centenarians point the way to healthy ageing. Lancet 2000; 353:1074. Holloszy JO. The biology of aging. Mayo Clin Proc 2000; 75(suppl):S3–S9. Bartke A, Coschigano K, Kopchick J, et al. Genes that prolong life: relationships of growth hormone and growth to aging and life span. J Gerontol A Biol Sci Med Sci 2001; 56:B340 –B349. Vaillant GE, Mukamal K. Successful aging. Am J Psychiatry 2001; 158:839 – 847. Baltes PB, Mayer K, eds. The Berlin aging study. Cambridge, England: Cambridge University Press, 1999. World Health Organization. World Health Organization handbook of basic documents. 5th ed. Geneva, Switzerland: World Health Organization, 1952; 3–20.

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Spillman BC, Lubitz J. The effect of longevity on spending for acute and chronic long term care. N Engl J Med 2000; 342: 1409 –1415. Perls TT, Bochen K, Freeman M, et al. Validity of reported age and centenarian prevalence in New England. Age Ageing 1999; 28:193–197. Silver MH, Jilinskaia E, Perls TT. Cognitive functional status of age confirmed centenarians in a population based study. J Gerontol B Psychol Sci Soc Sci 2001; 56:P134 –P140. Ebly EM, Parhad IM, Hogan DB, Fung TS. Prevalence and types of dementia in the very old: results from the Canadian Study of Health and Aging. Neurology 1994; 44: 1593–1600. Rose MR. Can human aging be postponed? Sci Am 1999; 281:106 –111.

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