Cognitive Function of Centenarians and Its Influence on Longevity
Gondo, Yasuyuki, Poon, Leonard W., Annual Review of Gerontology & Geriatrics
High cognitive function has been asserted to be an important contributor to longevity in general and especially in extreme longevity. The goals of this chapter are to (a) examine evidence for this assertion in normal and pathological aging, (b) identify confounding and not well understood issues, and (c) suggest future research directions relating to causal factors of cognition on longevity.
REVIEW OF SUPPORTIVE EVIDENCE
Impact Among the General Population
The Terman Cohort Study, which examined the life course of intellectually gifted individuals, addressed the relationship between individual differences in cognitive function and mortality (Friedman & Markey 2003). At the beginning of the study (1921), researchers recruited 1,528 younger people with IQs of 135 and higher. These individuals were followed 7 decades until 1991. Total mortality rates of these gifted individuals were lower than those of the general U.S. population born at the same time.
Similarly, a recent series of studies that utilized intelligence test data collected more than 50 years ago reported positive relationships between childhood intelligence and mortality in middle and very old age (Batty, Deary, & Macintyre, 2006; Deary, Bastin, et al., 2006; Hart et al., 2005; Shenkin, Starr, & Deary, 2004; Whalley & Deary, 2001; Whalley et al, 2000). Data came from the Scottish Mental Survey of 11-year-old children performed in 1932. The researchers linked these test scores with public morbidity and mortality data and found that a higher test score in childhood was associated with longer survival.
A study of nuns also addressed the relationship between individual differences in cognitive function and mortality (Snowdon, Greiner, Kemper, & Nanayakkara, 1999). The researchers analyzed linguistic ability from the participants' autobiographies written in their younger ages (18-32 years old). Two scores of linguistic ability-grammatical complexity and idea densitywere analyzed to examine the association between cognitive performances and mortality The results showed that idea density had a negative association with the risk of mortality Individuals with performance in the lowest quartile had a 7-year shorter life span than the higher performance group.
Bosworth and Siegler (2002) reviewed nine studies that evaluated the relationship between terminal decline of cognitive function and death. Although they did not find a consistent relationship, they did find that the level of cognitive function is predictive of mortality Recent statistically sophisticated analyses with representative-sample longitudinal studies reported the same pattern (Ghisletta, McArdle, & Lindenberger, 2006; Rabbitt, Lunn, & Wong, 2006). What causes the association between cognitive ability and mortality in elders? Medical condition and vitality decline are strong candidates. Hassing and colleagues (2002) followed 446 participants aged 80 to 98 for 6 years and found that participants with a shorter remaining life span showed lower cognitive ability in the baseline survey However, this association was attenuated after medical conditions such as stroke and cardiovascular disease were considered. The lower cognitive ability associated with death may be triggered by a decline of physical function or vitality.
Impact Among Centenarians
Six centenarian studies addressed the impact of cognition on longevity (Gondo et al., 2006; Hagberg, 2006; Kliegel & Sliwinski, 2004; Poon et al., 2000; Samuelsson et al., 1997; Shimizu, Hirose, Arai, Gondo, & Wakida, 2001). The French centenarian study surveyed 800 centenarians and followed them for 8 years until 99% had died. Cognitive impairment measured by the short portable mental status questionnaire, a test similar to the Mini Mental State Examination (MMSE), significantly predicted survivorship as well as did residential condition, health status, activities of daily living (ADL), and independent activities of daily living (IADL). Because each variable was analyzed separately, the independent effect of cognitive function was unknown.
The positive influence of cognitive impairment on survivorship was reported in the Tokyo Centenarian Study (Shimizu et al., 2001). The Clinical Dementia Rating (CDR) score had a statistically significant influence on survival. This effect, however, disappeared after the clinical condition of the participants was controlled for. Another data set of the Tokyo Centenarian Study (Gondo et al., 2006) reported that the total functional status, evaluated by physical and cognitive function, had a stronger influence on 1-year mortality than did cognitive function (CDR rating, MMSE total score) alone. Because physical and cognitive functions are highly correlated in centenarians, a significant influence of cognitive impairment on survivorship may be reflected in the total functional status of the participants. However, the Swedish centenarian study (Samuelsson et al., 1997) reported an influence of cognitive function independent from that of physical function. The authors reported based on variety of cognitive measures-verbal understanding, digit span forward, and five-object test-that cognition had an influence on survivorship.
The Georgia Centenarian Study (Poon et al., 2000), which included only cognitively intact centenarians, examined predictors of number of days of survival past 100 years among 105 centenarians. They found cognition was one of four significant predictors. The other predictors were gender, fathers age of death, and nutrition sufficiency.
In summary, the data show that individuals with higher cognitive functions tend to live longer in the general population and among the oldest old, those age 85 and older. The literature also shows a level of mediating complexity between cognition and longevity that necessitates creative thinking and new research to better understand the relationships between cognition and longevity. First, a paradox exists between longevity and the high rate of dementia among centenarians. Is this a contradiction to the positive cognitionlongevity relationship? second, much variability exists in the neuropathology of the brain and cognitive functions among centenarians. Do different neuropathology and cognitive function relationships exist for the long-lived? Next, we review the literature on dementia and cognitive functioning among centenarians in the context of the cognition-longevity hypothesis.
REALITY OF COGNITIVE FUNCTION IN CENTENARIANS
Because centenarians are living in the final stage of the human aging process, describing their biological and behavioral status provides important information for conceptualizing the nature of human aging. In this sense, clarifying dementia prevalence in centenarian populations is important not only for political purposes of estimating social care costs in future longer-living societies but also for scientific purposes of conceptualizing the nature of the aging process. In short, the core question is whether the pathological aging process can be separated from the normal aging process or is part of it. With regard to brain aging, the question becomes whether the development of dementia can be seen as an extension of the normal aging process or as a separate pathological process. Does the development of dementia in old age appreciably shorten the life span of these individuals who could otherwise live a much longer life? There has long been debate on these issues (Hayflick, 2004; Holliday 2004), and we provide our perspectives in this review.
An exponential increase of dementia prevalence with age is a commonly observed phenomenon. At the ages of 65 to 69 years old, the prevalence of dementia is about 1.5%, but both prevalence and incidence rise to as high as 25% to 30% in the oldest old (Heeren, Lagaay Hijmans, & Rooymans, 1991; Ritchie & Kildea, 1995; Skoog, Nilsson, Palmertz, Andreasson, & Svanborg, 1993). If this increase in prevalence approaches 100% in the oldest old, such as centenarians, then dementia is inevitable. Such an increase would indicate that the development of dementia is part of the normal aging process, and the pathogenesis of dementia is simply a reflection of individual differences in the rate of aging of the brain. In contrast, if sufficient numbers of centenarians do not suffer from dementia, researchers could reject the hypothesis and conclude that the development of dementia is a pathological aging process separate from normal aging.
Table 8.1 lists studies that report dementia prevalence or the deterioration of cognitive function in centenarians. To date, only one study supports the first hypothesis by reporting 100% dementia in an assessment of community-dwelling centenarians (Blansjaar, Thomassen, & Van Schaick, 2000). The other studies, not all of them population based, reported 42% to 80% dementia prevalence (Akisaka, 2000; Andersen-Ranberg, Vasegaard, & Jeune, 2001; Asada et al., 1996; Beregi & Klinger, 1989; Choi et al., 2003; Gondo et al., 2006; Hagberg, Bauer Alfredson, Poon, & Homma, 2001; Inagaki, 1995; Karasawa, 1985; Powell, 1994; Ravaglia et al., 1999; Robine, Romieu, & Allard, 2003; Silver, Jilinskaia, & Perls, 2001; Sobel et al., 1995). A lower prevalence of 27% was reported in a Swedish study that included subjects only 100 years to 100 years and 6 months old and examined 70% of registered centenarians in the research region; however, after considering nonparticipants, the authors estimated a prevalence of 42% (Samuelsson et al., 1997).
Although the results indicate that dementia is not inevitable in centenarians, it is too early to make a conclusion about the dementia prevalence of centenarians at present. Recent meta-analysis pointed out the difficulty in estimating the dementia prevalence of centenarians because of the inconsistency of sample characteristics and assessment method adopted in each study (Calvert, Hollander-Rodriguez, Kaye, & Leahy, 2006).
In addition to these issues, we should consider age difference and gender difference of the cognitive ability among centenarians. In terms of the gender differences in cognitive ability, dementia prevalence was higher in women in most of the studies if researchers reported gender-separated dementia prevalence (Andersen-Ranberg, Vasegaard, et al., 2001; Beregi & Klinger, 1989; Choi et al., 2003; Gondo et al., 2006; Hagberg et al., 2001; Ravaglia et al, 1999; Robine et al., 2003; Sobel et al., 1995). Gender ratios in different studies might be an important factor in influencing the dementia prevalence. Another factor that could influence the prevalence rate is the distribution of the ages of the centenarians in a particular study. The Heidelberg Centenarian Study (Kliegel & Sliwinski, 2004) showed stability of cognitive function in a one-and-a-half-year period. The authors used a short version of the MMSE to assess the cognitive function of 36 participants (average age 100.2 years) and reported that only 9 (25%) participants showed a decline; the others were either stable (n = 22; 61%) or improved (n = 5; 14%). In contrast, a study of all centenarians (N = 47) in Yamanashi Prefecture, Japan, reported that all centenarians older than 104 years (n = 7) had dementia (Asada et al., 1996). One hundred years might not be old enough to be representative of the final stage of life.
In fact, Robine and Jagger (2003) estimated the age of 115 to be statistically appropriate for assessing the possibility of dementia-free aging and reported the cognitive function of seven supercentenarians (average age 116.9 years). Instead of clinical diagnosis, the researchers' criterion for absence of dementia was engagement in meaningful conversation. Six of the subjects had maintained cognitive ability until their final weeks of life. To date, only one study has systematically reported functional characteristics of supercentenarians (those who are 110 years and older), but cognitive function was not included (Schoenhofen et al., 2006).
Despite the higher dementia prevalence, research shows centenarians are cognitively superior to those who do not survive. Hitt, Young-Xu, Silver, and Perls (1999) reported that 89% of New England Centenarian Study participants were functionally independent at the age of 92 years, and 75% maintained the same functional level at the age of 95, in tests using IADL and ADL as measures of functional independence. They concluded that the "centenarians seem to either markedly delay or, in some cases, escape life-threatening disease such as cancer and Alzheimer's disease" (p. 652). This opinion raises some controversy because of the linear increase of hospitalization ratio in the \ elderly from their 80s to 100 years (Andersen-Ranberg, Schroll, & Jeune, 2001). Several studies indicate that the prevalence and incidence of Alzheimer's disease are decreased in nonagenarians in comparison with octogenarians (Kawas & Corrada, 2006; Ritchie & Kildea, 1995). Of these, the Cache County study reported an increase in the incidence of Alzheimer's disease up to the age of 90 and a decrease in the early 90s for men and in the late 90s for women (Miech et al., 2002). People who have survived to 90 might have some protective factor against dementia.
In summary, only a small number of the reported studies found dementia inevitable in all of the oldest old. Considering the average life span of 8 years after the onset of dementia and the lower incidence of dementia in nonagenarians, we could assume that a large number of individuals who survive to 100 could avoid dementia in their 10th decade of life. The reported evidence does not totally support the notion that dementia-free aging is possible, but we can conclude that some individuals enjoy dementia-free life at the age of 100. Centenarians might not avoid dementia throughout their life span, but they might develop it slowly. An unanswered question is whether late onset dementia for those with premorbid higher cognitive functions would preserve a longer life span.
Cognitive Function in Dementia-Free Centenarians
In contrast to the number of dementia prevalence studies, few studies assessed the cognitive ability of dementia-free centenarians. Most studies included both demented and cognitively normal centenarians as one group even when comparing cognitive ability with younger controls. The first wave of the Georgia Centenarian Study recruited only cognitively intact centenarians with cutoff points of MMSE ≥ 21 and Global Deterioration Scale ≤ 3 (Poon et al., 1992). These inclusion criteria took into account the lower MMSE scores owing to lower education levels and sensory deficits among the centenarians with no clinical signs of dementia. Thus, comparison of cognitive performance with younger controls (in their 60s and 80s) clarified the cognitive abilities of dementia-free centenarians. Holtsberg, Poon, Noble, and Martin (1995) compared item performance in the MMSE among centenarians and the younger controls. The total score of the centenarians was lower than that of the younger controls, the decline deriving mainly from the orientation items. Interestingly, although the scores of delayed recall and attention/ calculation dropped from age 60 (delayed recall 2.19; attention 4.25) to 80 (1.71 and 4.24, respectively) to 100 (1.39 and 3.81, respectively), the effect was not statistically significant. This result shows that memory performance of cognitively intact centenarians does not decline below the normal range of the younger elderly.
Higher-level cognition tests were also conducted. To assess intelligence function, Poon et al. (2000) performed the vocabulary, arithmetic, picture arrangement, and block design subtests from the Wechsler Adult Intelligence Scale Revised (WAIS-R). They also measured memory ability, primary and secondary memory by the paired association learning task, and tertiary memory by asking participants to name past U.S. presidents. They reported a decrease in each cognitive measure in centenarians. Decreases in crystallized intelligence and tertiary memory were evident. Among crystallized intelligence, the vocabulary subtest showed a precipitous drop. The Tokyo Centenarian Study (Inagaki & Gondo, 2003) also tested 12 cognitively intact centenarians (mean MMSE score = 23) by WAIS-R. Scores of digit symbol, block design, letternumber sequencing, and vocabulary tests were compared with those of 50to 80-year-old controls. Centenarians had lower scores in each test than the younger controls. A decrease in vocabulary was evident: The scores of all but one centenarian were below the expected score for 100 years extrapolated from the controls. Significant declines in crystallized intelligence and fluid intelligence were characteristic of the oldest subjects. A decline in verbal ability would not be avoidable in extremely old age. The Swedish centenarian study (Samuelsson et al., 1997) also compared verbal performance, reaction time, and memory of presumed dementia-free centenarians with those of younger controls and showed a decline in all scores.
The most remarkable characteristic of dementia-free centenarians is their ability in daily living tasks. The Georgia Centenarian Study (Poon et al., 1992) compared problem-solving abilities commonly faced in everyday settings at home and showed excellent maintenance of these abilities in centenarians. One unique study that focused on the autobiographical memory of centenarians (Fromholt et al., 2003) reported no difference between centenarians and octogenarians with regard to the number of recalled memories and the basic pattern of the frequency of memories at different ages. In particular, the lack of a decrease in recent memory in centenarians indicated that dementia-free centenarians have good episodic memory in everyday situations.
Because of the limited numbers of studies that assessed the cognitive abilities of dementia-free centenarians, we cannot present definitive characterizations. However, these studies indicate that centenarians have a sizable decline in cognitive ability, especially in fluid intelligence, even for centenarians who are free of dementia (Poon et al., 1992). Nevertheless, cognitively normal centenarians maintain their everyday cognitive abilities, such as problem solving and episodic memory embedded in the life context (Poon et al., 1992). The maintenance of environment-related cognitive function may be a key contributor to their longevity and survival.
CHARACTERISTICS OF BRAIN-COGNITION RELATIONSHIP IN CENTENARIANS
Anatomical Reports of Centenarian Brains
Although the progression of pathological change in the brain is highly associated with behavioral expression in the Alzheimer's disease patient (Nagy et al., 1997), recent studies have shown a significant amount of variability between neuropathological changes and the expression of dementia symptoms clinically. Braak and Braak staging is a commonly used method of staging Alzheimer's disease pathology (Braak & Braak, 1991). Three stages are commonly reported: transentorhinal (I and II; clinically silent), limbic (III and IV; early stage), and neocortical (V and VI; fully developed). Haroutunian and colleagues (1998) examined the distribution of MMSE scores in older adults in each stage and found a positive linear trend among the normal and severe stages; however, the relationship between MMSE and Braak and Braak staging was ambiguous in individuals with moderate dementia. Similar findings were reported in nonagenarians and centenarians (Gold et al., 2000). Given these findings, an unanswered question is whether extreme longevity requires a neuroanatomically intact brain, dementia-free abilities, or both.
Three studies systematically examined both dementia expressions during the premorbid period and pathological diagnoses at the postmortem autopsy (Ding et al., 2006; Mizutani & Shimada, 1992; Silver, Newell, Brady, Hedley-White, & Perls, 2002). Mizutani and Shimada autopsied 27 centenarians, 11 of whom did not have dementia before death. Some degree of brain degeneration was observed in 8 of those 11 dementia-free centenarians, but there were no apparent anatomical changes in the brains of the 3 remaining. The researchers named those neuropathologically free and behaviorally dementia-free centenarians supernormal. The autopsies performed with the New England centenarian study (Silver et al., 2002) and the Aichi centenarian study (Ding et al., 2006) respectively reported 4 cases out of 14 and 4 cases out of 6 dementia-free centenarians that met the criteria of supernormal, with the remaining centenarians-although dementia-free at time of deathhaving brain neuropathology that pointed to pathological progression of dementia at autopsy. The Swedish centenarian study (Samuelsson et al, 1997) measured regional cerebral blood flow in 11 centenarians, only 1 of whom had observable dementia symptoms, and 70-year-old healthy controls. Two centenarians showed comparable blood flow as controls and 9 showed slight to moderate pathologic change. These results indicate the neuropathology of dementia-symptom-free centenarians could vary from a perfectly intact brain (labeled as supernormal) to some degree of pathology. These variations could be demonstrated in single-case studies.
Case Reports of Brain-Cognition Relationship
Case reports provide a vivid illustration of the characteristics of the behaviorbrain relationship in centenarians. One supernormal and three cognitive reserve centenarians are described. Sister Marcella is an example of a supernormal centenarian (Snowdon, 2003). She had an MMSE score of 28 and could correctly recall 8 out of 10 words in a delayed recall test before her death at the age of 100. In addition, she had perfect ADL and IADL scores. Her brain did not show any sign of abnormality by the pre death autopsy, and she had a Braak and Braak staging score of zero, an absence of neurofibrillary pathology.
In contrast, Sister Mary, who died at the age of 101 (Snowdon, 1997), is an example of an individual with excellent cognitive reserve. Her MMSE score was 27 points and she could correctly recall 5 out of 10 words in a delayed recall test. Her cognitive function was not as high as Sister Marcellas but was well preserved. Nevertheless, a large diffuse plaque in the neocortex and hippocampus, which is a characteristic of Alzheimer's disease, was observed by the autopsy.
Sister Matthia (Snowdon, 2003) is another example of an individual with excellent cognitive reserve. Although her test performance was not high, she maintained conversation ability to her last breath. She also had a pathological change in the brain (Braak and Braak stage IV). Another example is a 107year-old Japanese woman (Inagaki, 1995). She had problems with memory but maintained abstract thought and decision-making ability. She remained independent by her high ADL score and was diagnosed as not having dementia by the definition of Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III-R). However, the postmortem brain autopsy showed degeneration in the hippocampus region.
Probably the most important and impressive case report is that of Jeanne Calment, the longest-lived individual identified by the Guinness World Record (Robine & Allard, 1998, 1999). Calment died at the age of 122 years in 1997. She was examined by neuropsychological tests and brain CT scan when she was 118 years old (Ritchie, 1998). Prior to the 1998 examination, Calment was judged to have dementia owing to her lack of communication skills due to very poor vision and hearing. Her physician was one of a few persons who could communicate with her. Because of her poor hearing and vision, her physician spoke for the researcher, and stimuli were presented by touch. She showed no symptoms of depression and appeared emotionally stable. Although the neuropsychological test results showed lower scores than the younger (90 to 100 years) norm, her performance was diagnosed as normal. Interestingly, her performance in verbal secondary memory, logical memory, and verbal frequency score increased from the first visit to the third visit 6 months later. In addition, in her cognitive function, she was reported to be alert until the last week of her life (Robine & Jagger, 2003). One of the authors (Poon) visited Calment when she was 119 and presented her with a letter written in French from a Georgia centenarian, which was read to her by her physician. Calment understood the communication and responded graciously and appropriately by stating that "I am not alone after all!" Calment s CT scan showed marked atrophy in several brain regions except the frontal lobe. Recent brain imaging studies (Cabeza, Nyberg, & Park, 2005) have pointed out the involvement of the prefrontal cortex in cognitive reserve in older adults. The preserved frontal lobe might have helped maintain Calment s cognitive ability and her longevity.
In summary, it is clear that early-onset dementia could limit an individuals life span. At issue is whether late-onset dementia among the oldest old could shorten the life span and whether a neurologically intact brain and dementia-free behaviors at late life could further prolong the life span. We do not have answers to these questions at present. However, the literature seems to suggest four phenotypes of cognitive function among centenarians that may help to resolve the questions in the future: supernormal, cognitive reserve, late-onset dementia, and early-onset dementia.
The first two groups are dementia-free centenarians. Members of the supernormal group have no symptoms of brain pathology and higher scores for the usual cognitive tests. Centenarians who have no impairment in IADLs and can live independently are likely included in this group. Members of the cognitive-reserve centenarian group do not show behavioral dementia symptoms although they have pathological changes in the brain. They sometimes show a higher score in dementia screening tests but have difficulty with more complex tasks. They can handle everyday problems well and can communicate well. The autopsy results discussed above indicate a distinct frequency of supernormal and cognitive-reserve centenarians. Late-onset centenarians develop dementia in the 10th decade of life. Most centenarians are included in this category. The prevalence of dementia in centenarians is high, but many centenarians remain active in their 10th decade (Hitt et al., 1999). The findings seem to indicate that neuropathological development may be slow in centenarians. We hypothesize that there are very few centenarians with onset of dementia early in their lives, as it has been estimated that average life span after a diagnosis of dementia is 8 years. We suggest that it may be useful to categorize centenarians in these phenotypes and study their life spans to further understand the cognition-neuropathology-longevity relationships.
SUMMARY, CONCLUSIONS, AND NEW DIRECTIONS
This chapter began with a review that higher cognitive function is not only associated with low mortality in young and older adults but also days of survivorship after 100 years. A paradox to this relationship is that the prevalence of dementia is high among centenarians, because dementia tends to curtail the life span. We further reviewed the literature and found that neuropathological changes are positively related to dementia symptoms in normal and severe cases, while this relationship is more ambiguous among those with moderate dementia. We hypothesized that there may be four pheno types of neuropathology-cognitive function-longevity relationships among the oldest old. We suggest that the investigations of the relationships among the phenotypes and longevity may untangle the paradox and further our understanding between cognition and longevity.
To conclude this review, we introduce two plausible causal pathways that may mediate the cognitive-longevity relationship and also introduce several observations that could explain the cognition-longevity relationship apparent in centenarian studies.
Environmental Influence Model
The environmental model postulates that superior intelligence influences the overall environment of the individual, which leads to longer life span. The simplest scenario is that higher intelligence in early life results in higher educational attainment and that this superior knowledge results in healthier behavior and adoption of a lifestyle that can help to avoid cognitive decline and achieve longevity. On the basis of this notion, we hypothesize that centenarians have advantages over nonsurvivors in terms of all or some of these factors.
Childhood intelligence has been identified as an initial predictor of longevity (Backman & MacDonald, 2006; Deary, Whiteman, Starr, Whalley & Fox, 2004), and educational attainment could be used as a proximal variable in a centenarian study because it is a factor representative of total cognitive functional ability (Darigues, Letenneur, Helmer, Lewden, & Chene, 2003). To the authors' knowledge, only the Tokyo Centenarian Study has characterized the educational attainment of centenarians among matching birth cohort populations (Gondo, Hirose, & Masui, 2004). Figure 8.1 shows the school rate of participants in the Tokyo Centenarian Study and the corresponding rate for the same birth cohort for the nation as a whole. It can be seen that the school ratio was fairly high in centenarians. Because of the social circumstances in Japan, this higher rate among centenarians might have been influenced by the economic condition of their parents rather than the cognitive ability of the participants in early life. However, even if this were the case, higher educational attainment could have contributed to the development of intelligence and the brain, which in turn could have been a protective factor against cognitive decline (Stern, 2002). At the same time, the ratio of smokers among the Tokyo Centenarian Study participants was lower than that among the age-matched cohort (Gondo et al., 2006). This may indicate that higher educational attainment contributes to the acquisition of knowledge about health-related behavior.
An active lifestyle as well as engaging in complex work is also an important predictive factor of cognitive ability (Schooler & Mulatu, 2001; Schooler, Mulatu, & Oates, 1999). The Heidelberg Centenarian Study examined the influence of education, occupation, and late life cognitive involvement on the cognitive status of centenarians (Kliegel, Zimprich, & Rott, 2004). That study adopted participants of retirement age engaging in four activitiesbalancing their checkbook, learning a foreign language, domestic travel, and foreign travel-as indices of cognitive involvement. The results revealed that educational attainment influenced the cognitive ability of the participants. In addition, although late life cognitive involvement was influenced by educational attainment, it had an independent influence on the cognitive ability of centenarians. It could be postulated that the environment in late life is as important as early education for maintenance of cognitive performance, even in centenarians. The same logic could be applied to test the relationship between cognition and mortality.
Common Biological Factor Model
Contrary to the environmental influence model, the Common Biological Factor model assumes the presence of a common biological factor that has a direct influence on both cognitive function and longevity. A genetic factor could be a strong candidate. Historically, studies of twins have provided evidence that a certain amount of global cognitive function evaluated by intelligence tests is heritable at a younger age. Recently, this notion was expanded to old age (Deary, Spinath, & Bates, 2006). Identification of candidate genes that could influence cognitive ability or cognitive decline would make it possible to examine the association between genetic factors and cognitive function or longevity in the elderly. In fact, several candidate genes are reported to have an association with both cognitive function in the elderly and longevity.
The apolipoprotein E (APOE) gene is well known to be a strong risk factor for Alzheimer's disease. APOE has three common alleles-s2, s3, and s4-and is related to lipoprotein metabolism. Carriers of the s4 allele are at higher risk of Alzheimer's disease. Possession of the s4 allele is related to poor performance in tests of global cognitive ability (MMSE or IQ test), episodic memory, and executive function (Deary, Whitman, Pattie, & Starr, 2004; Greenwood, Lambert, Sunderland, & Parasuraman, 2005). Carriers of the s4 allele are rare among centenarians (Blanche, Cabanne, Sahbatou, & Thomas, 2001; Gerdes, Jeune, Ranberg, Nybo, & Vaupel, 2000; Lindpaintner et al., 1995). Possession of the s4 allele is a risk factor for both dementia and death. Recently, a study of Ashkenazi Jewish centenarians reported an association between the cholesterol ester transfer protein (CETP) gene and mortality and cognitive function (Barzilai, Atzmon, Derby, Bauman, & Lipton, 2006). The frequency of the W genotype of the CETP gene increased according to age. Individuals who possessed the W genotype had higher cognitive function in quasi-centenarians (Barzilai et al., 2006). Although the frequency in centenarians has not yet been reported, the Klotho gene has also been shown to be associated with cognitive function (Deary et al., 2005) and also human life span (Arking et al., 2002).
Another common factor is medical condition. The study by Hassing and colleagues (2002) provided support for the notion that medical condition could be a common factor affecting both cognitive decline and death. The New England centenarian study reported that centenarians have a pheno type characterized by low morbidity and high vitality. Ninety percent of centenarians were reportedly active at the age of 90 (Hitt et al., 1999), and 62% were either free of disease or showed delayed pathogenesis at the age of 80 (Evert, Lawler, Bogan, & Perls, 2003). These characteristics of centenarians indicate that avoidance of disease is a common factor for both protection against cognitive decline and achievement of longevity.
Because both genetic and environmental factors are thought to be associated with cognitive phenotypes in centenarians, it is premature and simplistic to describe lifelong trajectories in terms of each phenotype. However, exploration of these factors or trajectories would contribute to a better understanding of the secret of longevity, and therefore some speculation on this issue has been provided in this final section.
In supernormal centenarians who maintain excellent cognitive function with no brain impairment, genetic factors are undoubtedly important. Although there is little evidence for the association of specific genes with brain pathology, possession of APOE 84 is reported to be associated with the pathological progression of Alzheimer's disease (Yip et al., 2005). Supernormal centenarians might possess a good set of genes for brain protection, and these might contribute to longevity. Focusing on this phenotype might be a good strategy for identifying longevity-related genes. The cognitive reserve centenarians would not only be another excellent target sample for identifying longevity-related genes but also for evaluating environmental factors that facilitate cognitive maintenance. Pathological change may be a cofactor in this phenotype; protective environmental factors might have a stronger influence than late-onset or early-onset phenotype.
This review has shown that cognitive function influences human longevity throughout life. However, the cognition-longevity relationship is likely a complex phenomenon mediated by genes, environment, and their interactions. (Especially gender difference in cognitive function is a large paradox with regard to this phenomenon.)
Further studies to examine the association between the cognition phenotype of centenarians with the features of autopsied brains, linked to data on gene polymorphism, environmental factors, and their interaction will help to clarify and reveal the nature of the cognition-longevity relationship demonstrated by centenarian studies. Finally, cognition is only one piece of the puzzle, and the size of that piece relative to the whole picture is unclear. In the Terman study, Friedman and Markey (2003) demonstrated that health-related behavior, psychological adjustment, personality, and social relationships were important predictors of mortality among the participants, even though they had a higher IQ and tended to live longer than the population average. Integration of these emotional aspects and genetic factors with cognitive ability will help to construct the whole picture of longevity.
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Leonard W. Poon, PhD, DPhiL, he, is professor of public health in the Department of Health Policy and Management, professor of psychology in the Department of Life Span Developmental Psychology, chair of the faculty of gerontology, and director of the Institute of Gerontology at the University of Georgia. He is also the director of the Georgia Geriatric Education Center. Dr. Poon is the principal investigator of the Georgia Centenarian Study, which was funded by the National Institute of Mental Health (1988-1992, 1992-1997) and the National Institute on Aging (2001-2008). He is the founder and executive director of the International Centenarian Consortium since 1994. Aside from his primary interests of functional, cognitive, and behavioral correlates of longevity and adaptation, his research includes normal and pathological changes of memory with age, early detection of dementia, and the impact of exercise and activities on cognitive functions among older adults. Dr. Poon is a fellow of the Gerontological Society of America, the American Psychological Association, the American Psychological Society, and the Association for Gerontology in Higher Education.
Yasuyuki Gondo, PhD
Human Welfare Research Team
Metropolitan Institute of
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Publication information: Article title: Cognitive Function of Centenarians and Its Influence on Longevity. Contributors: Gondo, Yasuyuki - Author, Poon, Leonard W. - Author. Journal title: Annual Review of Gerontology & Geriatrics. Volume: 27. Publication date: January 1, 2007. Page number: 129+. © Springer Publishing Company 2008. Provided by ProQuest LLC. All Rights Reserved.