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Centenarians

CENTENARIANS

Old age is often viewed as a time of disability and loss. Shakespeare captured it in Act II, Scene 7 of As You Like It : "Last scene of all,/ That ends this strange eventful history,/ Is second childishness and mere oblivion,/ Sans teeth, sans eyes, sans taste, sans everything." Centenarians often prove these dismal lines wrong, and demonstrate that the compression of morbidity hypothesis (that it is possible for most of us to live a long, healthy life) may be true.

The word "centenarian" is derived from the Latin for "of a hundred," and refers to someone who has lived to be one hundred years of age or older. The term "supercentenarian" refers to people 105 years and older. The number of centenarians in developed countries has doubled every decade since the 1960s. This is related to the dramatic decline in mortality rates seen in developed countries worldwide.

Age verification

Whenever centenarians are studied, there must be a process in place to verify their reported age. In the 1960s and 1970s there were many reports of extremely long-lived populations in a number of places, including Georgia in the Caucasus and Vilcabamba, Ecuador. Some individuals claimed to be up to 180 years old. When these claims were investigated in further detail, proof of age was not available. Detailed life histories, with discussion of historical events in relationship to what age the person was at that time, were inconsistent. Dr. Thomas Perls, a geriatrician at Harvard University, and colleagues developed a rigorous age verification protocol for use in the New England Centenarian Study. They prefer a birth or baptismal certificate, or if these are not available, a passport or military certificate issued many years before. Other records, such as a family Bible, are also acceptable. Multiple supporting documents are preferred over a single document.

The longest proven life span for a human is 122 years, for Jeanne Calment, a woman who died in Arles, France, in 1997. Her age was carefully validated. She was a model of health most of her life, and lived alone until the age of 110. The longest verified life span for a male was that of Christian Mortensen, a Danish man who emigrated to the United States; he died in 1998 at the age of 115.

Epidemiology of centenarianism

Several research teams have attempted to estimate the prevalence of centenarianism, that is, the proportion of the population who are one hundred years and older. Since the number of centenarians is growing much faster than the total population, the prevalence of centenarianism will likely increase in the coming decades. Among the population-based studies with rigorous age verification conducted in the 1990s, the prevalence ranged from 38 per million total population (in Sweden) to 135 per million (in Sardinia). Census-based studies give larger prevalences, but there are concerns that, at these extreme ages, the census data may not be accurate.

These data are all from Western nations. The limited population-based data from other countries suggest that centenarian prevalence is much lower in non-Western nations. This will likely change as these countries experience the demographic shift that has already occurred in the West, the transition from predominantly young to predominantly older populations.

Mortality rates increase exponentially with age; that is, one's chance of dying is higher in each successive year of one's life, and the rate of increase also rises each year. This is known as the Gompertz Law of Mortality. Centenarians, however, do not comply with this law. At around age ninety the rate of increase seems to slow, and at age 110 mortality rates actually decline. Figure 1 illustrates this. Note that the y-axis is logarithmic. The black line is the exponential increase predicted by the Gompertz Law. The red line is the actual observed data, from Japan and western Europe. The blue line is the equation that best fits the mortality data at all ages; the green line provides the best fit for those 105 and older.

Characteristics of centenarians

The bulk of centenarians are women. At any age women have a greater life expectancy than men, and by the time one reaches one hundred, the sex ratio is four women to one man. The one place where this does not seem to be the case is the island of Sardinia, where the ratio is two women to one man. This finding is not yet explained, though the fact that Sardinia has had a relatively closed gene pool for thousands of years raises the possibility that Sardinians carry a sex-specific gene that promotes longevity. Among supercentenarians the sex ratio is five women to one man.

Many centenarians continue to function independently. In the New England Centenarian Study, 40 percent of centenarians were completely independent, and close to 90 percent had been independent ten years earlier, at an average age of ninety-two (see figure 2). In the Italian Centenarian Studies, with close to four hundred subjects, about 25 percent were in perfect health. Another 30 percent were in relatively good health. Interestingly, males who live this long do very well compared to females, making up 30 percent of those in perfect health but only 15 percent of those in poor health.

Centenarians escape many of the common diseases associated with aging. Cancer, heart disease, and diabetes are all less common in centenarians than in seventy- or eighty-year-olds. One important aging-related disease is dementia. The incidence and prevalence of dementia increase exponentially with aging but, as with other diseases, many centenarians do not suffer from dementia. Between 40 percent and 60 percent of subjects in studies from Europe, the United States, and Japan were diagnosed with dementia. The others were cognitively normal. When brain tissue from centenarians without dementia is examined, it often does not show any of the changes typically associated with Alzheimer's disease or stroke. These data show that common aging-related diseases are not inevitable, and it is possible to live into very late life and remain well. Serenity may be a personality characteristic of centenarians. Several of the studies found that many of their subjects were easygoing and relaxed.

The metabolic state of centenarians is paradoxical. Several groups have found that healthy, functional centenarians have metabolic characteristics that are commonly associated with disease, such as unfavorable cholesterol profiles, with high concentrations of harmful substances such as triglycerides and low-density lipoprotein cholesterol (LDL-C) and low concentrations of the beneficial high-density lipoprotein cholesterol (HDL-C). They also have high levels of proinflammatory cytokines such as interleukin-6, and high levels of prothrombotic substances. Several theories try to explain these paradoxical findings. Among them is Claudio Franceschi and colleagues' Inflamm-Aging. Inflamm-Aging hypothesizes that aging is due to environmental stresses, particularly inflammatory ones, and that people who live very long, healthy lives may have one, or both, of two characteristics. Either they avoid these stresses, which is unlikely, or, more likely, they have a particular mix of genes (their genotype) that is robust and can minimize the negative effects of the inflammation. A similar theory is François Schächter's Compensatory Adaptation, which suggests that centenarians have a genotype which allows them to better resist internal or external stresses that would cause disease in an individual with a less favorable genotype.

Why some people live to be one hundred

The characteristics of healthy centenarians suggest that they are not examples of delayed or slow aging. Rather, healthy centenarians have experienced an aging process different from that of the general population. James Vaupel's heterogeneity of frailty hypothesis supports this, showing that very long-lived groups follow different trajectories of aging, compared to short- or average-lived populations. Genetics are likely an important factor in becoming a healthy centenarian. T. T. Perls's group in Boston, among others, has shown that centenarianism clusters in families. Unfortunately, when the association between specific human genes and longevity has been investigated, the results have often been inconsistent. The best candidates are mitochondrial genes; the gene for tyrosine hydroxylase, an enzyme involved in cellular respiration; and possibly the apolipoprotein E, a protein involved in cholesterol metabolism and function. Studies in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans demonstrate that genes involved in the insulin signaling pathway exert an important effect on longevity.

This may be one of the mechanisms through which caloric restriction promotes longevity. No such effects of the insulin signaling pathway have yet been identified in humans, however. What is shared by these candidate genes is an involvement in gene-environment interactions, allowing an individual to suffer less harm from environmental stressors than others without one of these beneficial genotypes, in keeping with the Inflamm-Aging and Compensatory Adaptation theories. These genes do not seem to slow an aging clock, if such a clock exists in humans. Other investigators wonder if extreme longevity is caused by the absence of genotypes that promote disease; evidence for this is lacking as of 2001.

Women with fewer children seem to live longer. Observational data from humans support this, and studies with nematodes and insects also demonstrate that less fertile individuals live longer. This may be an example of one theory of aging at work, George Williams's Antagonistic Pleiotropy. Antagonistic pleiotropy holds that some genes which may be beneficial (in this case, genes that cause one to be reproductively successful) are harmful later in life, leading to disease or accelerated aging. Conversely, genes that are detrimental early in life (and so make one less successful at reproduction) may be beneficial in late life, promoting longevity. The data from insects support the latter explanation more so than the former.

Good genes are not likely the only reason explaining the achievement of long, healthy lives. A number of childhood factors, including parental literacy, a stable home life, and good childhood health promote longevity. Higher educational achievement and socioeconomic status are beneficial. Not smoking and maintaining a healthy weight are also important.

What centenarians can tell us

Although centenarians, who have lived through changes most people can only imagine, can teach us much about the past, history is not the only thing that can be learned from them. The study of centenarians can provide new perspectives on several unsolved puzzles of humans and human biology. For example, why do people age, and how do they age? What can be done to help more people live longer, healthier lives? What will the future look like, when there is a much larger proportion of very old, possibly very frail, people in the population? What adaptations will families, society, and public policy need to undergo to deal effectively with this aging population?

Chris MacKnight

See also Compression OF Morbidity; Genetics, Longevity Assurance; Genetics, Parental Influence; Life Expectancy; Life Span Extension; Longevity, Selection; Oldest Old.

BIBLIOGRAPHY

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Franceschi, C.; BonafÈ, M.; Valensin, S.; Olivieri, F.; de Luca, M.; Ottaviani, E.; and de Benedictis, G. "Inflamm-aging: An Evolutionary Perspective on Immunosenescence." Annals of the New York Academy of Sciences 908 (2000): 244254.

McMurdo, M. E. T. "A Healthy Old Age: Realistic or Futile Goal?" British Medical Journal 321 (2000): 11491151.

Perls, T. T.; Bochen, K.; Freeman, M.; Alpert, L.; and Silver, M. H. "Validity of Reported Age and Centenarian Prevalence in New England." Age and Ageing 28 (1999): 193197.

Ritchie, K. "Mental Status Examination of an Exceptional Case of Longevity: J. C. Aged 118 Years." British Journal of Psychiatry 166 (1995): 229235.

SchÄchter, F. "Human Genetics '98: Causes, Effects, and Constraints in the Genetics of Human Longevity." American Journal of Human Genetics 62 (1998): 10081014.

SchÄchter, F. "Genetics of Survival." Annals of the New York Academy of Sciences 908 (2000): 6470.

Tuljapurkar, S.; Li, N.; and Boe, C. "A Universal Pattern of Mortality Decline in the G7 Countries." Nature 405 (2000): 789792.

Vaupel, J. W.; Carey, J. R.; Christensen, K.; Johnson, T. E.; Yashin, A. I.; Holm, N. V.; Iachine, I. A.; Kannisto, V.; Khazaeli, A. A.; Liedo, P.; LOngo, V. D.; Zeng, Y.; Manton, K. G.; and Curtsinger, J. W. "Biodemographic Trajectories of Longevity." Science 280 (1998): 855860.

Westwendorp, R. J. G., and Kirkwood, T. B. L. "Human Longevity at the Cost of Reproductive Success." Nature 396 (1998): 743746.

Wilmoth, J.; Skytthe, A.; Friou, D.; and Jeune, B. "The Oldest Man Ever? A Case Study of Exceptional Longevity." Gerontologist 36 (1996): 783788.

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