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COMMENTARY |
Division of Geriatric Medicine, Saint Louis University School of Medicine, and The Aging and Development Program, Department of Psychology, Washington University, St. Louis, Missouri.
Address correspondence to Herman T. Blumenthal, PhD, MD, 6203 Washington, St. Louis, MO 63130.
John Morley (1) provides an elegant historical account of efforts to extend the human life span and search for immortality. He provides a perspective that includes both myth and reality. To emphasize the fact that extended longevity has always been a human aspiration, his account extends from ancient times to current efforts. The desire to attain immortality is also reflected in the promise of an afterlife by our major religions. The extension of the life span of animals by caloric restriction has served as the model for studies applicable to humans, but since most humans would not be enticed by a life of semistarvation, the search is on for medications that would mimic caloric restriction. Several recent volumes (2–6) describe current efforts at life span extension. However, only two of these (2–5) consider the relevance of the aging-related diseases as a possible limiting factor. As several of these books have noted, when some of the investigators discover a medication that extends the life span in an animal, the American spirit of entrepreneurship takes over. They form a corporation, seek investors, and apply for a patent on the medication.
I would like to add an historical perspective that led to the formation of the Gerontological Society (now The Gerontological Society of America—the GSA). I had the good fortune, during the years that I worked toward the PhD and MD degrees (1936–1942) at Washington University, to study under the aegis of Leo Loeb and Edmund V. Cowdry, both of whom had a keen interest in studying aging. Loeb focused his interest on aging of the endocrine system, while Cowdry's interests were more global. I own a copy of the second edition of Cowdry's Problems of Aging. It contains a "Preface to the First Edition," in which he makes reference to two conferences. The first, jointly sponsored by the Union of Biological Societies and the National Research Council, was held at Woods Hole on January 25 and 26, 1937. The second conference, sponsored by the Committee on the Biological Processes of Ageing of the National Research Council, was held in Washington, D.C., on February 5, 1938.
These conferences not only provided the stimulus for the publication of Cowdry's Problems of Ageing but also to the formation of the Gerontological Society. (I have no information on how and when "ageing" became "aging.") A perusal of the chapter headings shows that both biological and pathological aspects of aging were discussed, and that there was a clear separation of the two. On the biological side, there were chapters by experts on aging in protozoa, invertebrates, vertebrates, and mammals, and there were a few chapters on the clinical aspects of what we now call "geriatrics." There were no discussions of extending the human life span.
When I joined shortly after my discharge from the military at the conclusion of World War II, two slogans dominated the discourse. The first was "Aging is not a disease," and it is reflected in the sectional divisions of the biological and medical sciences. This has not changed, although a perusal of issues of the Journals of Gerontology: Biological and Medical Sciences sections reveals that crossovers appear not infrequently. Disease in animals, and sometimes even in humans, can be found in the biological section and, conversely, the medical science section contains articles dealing with basic biological phenomena in humans. Morley's list of references attests further to such crossovers.
Over the protests of some biogerontologists, starting with Alzheimer's disease, there has been an increase in funding research on the aging-related diseases at the National Institute on Aging (NIA). Continuing further expansion in this direction, there is an online SAGE KE of Science item dated May 21, 2003, in which Mary Beckman announced the creation of two study sections at NIA: "a basic science section called Cellular Mechanisms in Aging and Development (CMAD) and a section of applied research called Aging Systems and Geriatrics (ASG)."
The second slogan was "To add life to years rather than years to life." The limited objective here was to make the years of late life a more positive experience. But it also reflected the fact that, beginning in the late 19th and extending well into the 20th century, there were attempts to extend human longevity, which were ultimately regarded as quackery. The last of these was Anna Aslan's "Gerovital." A clinic in Kansas offering such quackery became known as promoting "scrotum hokum." The objective of this second slogan was to eschew these older attempts at longevity extension in order to obtain respectability. It has largely succeeded in this endeavor, not only in the wide acceptance of the Journals of Gerontology, but also in the publication of articles on aging in such prestigious journals as Science, Nature, The New England Journal of Medicine, the Proceedings of the National Academy of Sciences, and The Lancet.
However, we are in danger of repeating history. We now have a National Academy of Anti-Aging Medicine, and an address by its president was titled "Making the quantum leap to human immortality in the year 2029." However, as Olshansky and colleagues have noted in a supplement to their Scientific American article (7), the strategy that such organizations actually promote to reduce undesirable effects of aging include a variety of hormonal applications with possible harmful side effects.
With the foregoing as background, my commentary is intended to direct attention to two issues. First, what impact will the extension of the life span have on the prevalence of disease in the oldest-old? Second, what are the societal consequences of life-span extension?
The first of these issues involves the relationship between biological and pathological aging. In this regard, the separation of the two is a matter of contention. On the one hand, in two almost identical publications, Olshansky and colleagues (7,8) argue that it is necessary to make a clear separation between those deficits attributable to innate or biological aging and the causes of the aging-related diseases. They evidently view the latter as deriving from exogenous causes, and see their link to biological aging as one in which biological defenses against these diseases, such as the competence of the immune system, undergo an aging-related deterioration.
As Morley notes, many of those engaged in longevity extension studies attribute the extension in animals to free-radical inhibition based on Harman's 1957 introduction of the free radical concept of aging. But in a 1961 publication, Harman (9) states: "Mutation, cancer and aging are attributed basically to the side-effects of endogenously formed free radicals." Thus, he provides a direct link between biological (stochastic) aging and cancer.
My own view, as reflected in several essays (10–12), is that the relationship between biological aging and the aging-related diseases is a more complex one than the separation posited by Olshansky and colleagues. It holds that there is no single formula connecting the two. The two may connect causally in different ways. It is asserted that different pathogenetic pathways can lead to the same phenotypic disease. For example, a disease of the juvenile period can be of congenital or hereditary origin. The same phenotypic disease can emerge in the postreproductive period associated with late-acting genetic mutations, lifestyle practices, or exposure to environmental mutagens, as well as in the senescence period when it derives directly from biological aging, as posited by Harman for cancer.
One of the criteria used by Olshansky and colleagues to distinguish biological aging from the aging-associated diseases is that of universality (i.e., that biological aging is present in everyone who lives long enough), and that there is no single disease that complies with this criterion. While there also may be some manifestations of biological aging that do not comply with the requirement of universality, there are some diseases that may. There appears to be an unbroken link between biological aging and the aging-associated diseases, particularly cancer, in the caloric restriction and other animal models that extend the life span (13–15). Folkman and Kalluri (16) make the following observation regarding the universality of cancer in humans.
"It has been estimated that more than one-third of women aged 40 to 50, who did not have cancer-related disease in their life-time, were found at autopsy with in situ tumours in their breast. But breast cancer is diagnosed in only1% of women in this age range. Similar observations are also reported for prostate cancer in men. Virtually all autopsied individuals aged 50 to 70 have in-situ carcinomas in their thyroid gland, whereas only 0.1% in this age group are diagnosed with thyroid cancer during this period of their life. ... The most likely answer is our body's inherent capacity to prevent the majority of these in situ tumours from recruiting their own new blood supply, thus preventing further growth owing to a lack of oxygen and nutrients. In the absence of a new supply of blood vessels by a process known as angiogenesis, an in situ tumour can remain dormant indefinitely."
By combining three autopsy studies by Ishii and Sternby (17–19) with one by Klatt and Meyer (20), we arrived at a total of 55 centenarians. The prevalence of cancer in these 55 centenarians is 40%. The cancers are sufficiently disseminated to be the cause of death. Moreover, amyloidosis may also meet the criterion of universality in the oldest-old humans and other mammals (21).
Now to the second objective of this commentary—the societal consequences of human life-span extension. If we apply the caloric restriction model to a human population, with a possible maximum increase in life expectancy to about 150 years, the result would be a disproportionate increase in the population of the aged along with a decline in the birth rate. Since the caloric restriction model does not eliminate the aging-associated diseases but only postpones them, the prevalence of the aging-related diseases would be about the same that we have today.
The possibility that another strategy for life-span extension may emerge with the ongoing genomic revolution has also been considered (22). In it, Martin (23) is cited as expressing the opinion that life span is limited by a large number of disease-associated genetic loci deriving largely from randomly acquired sporadic mutations. Because of their stochastic origin, identifying these loci on a population basis is beyond the capacity of the genome project.
But we are already seeing a demographic shift in the direction of the oldest-old as a consequence of advances in preventive and therapeutic medicine. It has been projected (24) that, by 2050, our health care system will have to accommodate a population in which approximately 70 million Americans will be older than age 65 years, and approximately 50 million will be older than age 85. Centenarians will number about 300,000.
It is beyond the scope of this commentary to describe the effects of these demographic changes on Social Security and Medicare. That's a subject the social sciences should address.
References
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