The metabolic syndrome, IGF-1, and insulin action

Recent studies have shown that insulin and insulin-like growth factor (IGF)-1 signaling are involved in the control of ageing and longevity in model organisms. Based on these studies, genes involved in the insulin/IGF-1 signaling pathway are believed to play a role in longevity throughout evolution and could also be important in determining human longevity. However, human studies have yielded conflicting and controversial results. In human, defects in insulin receptor signaling cause insulin resistance and diabetes, and IGF-1 deficiency is associated with an increased risk of cardiovascular disease and atherosclerosis. Interestingly, insulin sensitivity normally decreases during aging; however, centenarians were reported to maintain greatly increased insulin sensitivity and had a lower prevalence of the metabolic syndrome as compared to younger subjects. Additionally, a longitudinal study revealed that insulin-sensitizing hormones, including leptin and adiponectin, were significantly associated with the survival of centenarians, indicating that an efficient insulin response may influence human longevity.     

Allele frequencies of +874T-->A single nucleotide polymorphism at the first intron of interferon-gamma gene in a group of Italian centenarians.

Ageing is characterized by a pro-inflammatory status which could contribute to the onset of major age-related diseases such as cardiovascular diseases, neurodegeneration, osteoarthritis and osteoporosis, and diabetes. Thus, it can be hypothesized that genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. We have studied the distribution of +874T-->A interferon-gamma (IFN-gamma) polymorphisms in a large number of Italian centenarians to evaluate if the two alleles might be differently represented in people selected for longevity. DNA samples were obtained from 174 Italian centenarians (>99 years old, 142 women and 32 men) and from 248 <60-year-old control subjects (90 women and 158 men) matched for geographical distribution. Polymorphisms at +874 were identified by using amplification refractory mutational system methodology. The +874T allele was found less frequently in centenarian women than in centenarian men or in control women whereas no significant differences were observed in the distribution of the two alleles between male or female controls. Allele frequencies in centenarian men were not found significantly different from male controls. Possession of the +874A allele, known to be associated with low IFN-gamma production, significantly increases the possibility to achieve extended longevity, suggesting that the pro-inflammatory status characteristic of ageing may be detrimental for successful ageing. The datum that the allele was significantly increased in female but not male centenarians seems to strengthen the idea that gender may be a major variable in the biology of the ageing process. However, the present data add another piece of evidence to the complex puzzle of genetic and environmental factors involved in controlling life span expectancy in humans. Thus, studies on cytokine gene polymorphisms may promise to individuate a complex network of trans-interactive genes able to influence the type and strength of responses to environmental stressors and as a final result, thereby conditioning individual life expectancy.     

Network analyses unveil ageing-associated pathways evolutionarily conserved from fungi to animals

The genetic roots of the diverse paces and shapes of ageing and of the large variations in longevity observed across the tree of life are poorly understood. Indeed, pathways associated with ageing/longevity are incompletely known, both in terms of their constitutive genes/proteins and of their molecular interactions. Moreover, there is limited overlap between the genes constituting these pathways across mammals. Yet, dedicated comparative analyses might still unravel evolutionarily conserved, important pathways associated with longevity or ageing. Here, we used an original strategy with a double evolutionary and systemic focus to analyse protein interactions associated with ageing or longevity during the evolution of five species of Opisthokonta. We ranked these proteins and interactions based on their evolutionary conservation and centrality in past and present protein–protein interaction (PPI) networks, providing a big systemic picture of the evolution of ageing and longevity pathways that identified which pathways emerged in which Opisthokonta lineages, were conserved, and/or central. We confirmed that longevity/ageing-associated proteins (LAPs), be they pro- or anti-longevity, are highly central in extant PPI, consistently with the antagonistic pleiotropy theory of ageing, and identified key antagonistic regulators of ageing/longevity, 52 of which with homologues in humans. While some highly central LAPs were evolutionarily conserved for over a billion years, we report a clear transition in the functionally important components of ageing/longevity within bilaterians. We also predicted 487 novel evolutionarily conserved LAPs in humans, 54% of which are more central than mTOR, and 138 of which are druggable, defining new potential targets for anti-ageing treatments in humans.

     

Fibroblast cultures from healthy centenarians have an active proteasome

Healthy centenarians represent the best example of successful ageing. Various studies have shown that centenarians have escaped the major age-associated diseases, they have several well-conserved immune parameters and at least one gene allele has been identified and linked with their increased longevity. During ageing there is an accumulation of oxidised proteins, a phenomenon that has been related to an impaired function of the 20S proteasome in aged cells. We have, therefore, analysed the expression and the proteolytic activity of the proteasome in centenarian cells. Four fibroblast cultures derived from healthy centenarians were studied and compared with cultures derived from adult donors of different ages. Analysis of several proteasome subunits RNA expression levels, determination of one peptidase activity and identification of oxidised proteins in these samples revealed that centenarian cultures have a functional proteasome. In addition, it was found that the centenarian cultures exhibit characteristics similar to the younger rather than the older control donors derived cultures in all three assays. These data indicate that centenarian cells may be different from elderly donors cells, thus opening up new dimensions for the identification and characterisation of factors that are linked with longevity.     

Does hereditary metabolic disease modulate senescence and ageing?

Hereditary metabolic diseases in the context of evolutionary biology elicit interesting questions about ageing and senescence: Will persons successfully treated for inborn errors of metabolism, age and die prematurely because of compromised longevity? Because some unhealthy longevity has its origins in germline and somatic mutational processes, and in an inability to withstand metabolic stress, are there lessons to be learned about senescence from hereditary metabolic disease? Why are ageing, senescence and death necessary for Homo sapiens and how do they happen? These questions form the theme upon which several variations are played during the course of this essay. The theory of the disposable soma recognizes genomic and environmental events, well-seasoned by Chance, as determinants of ageing and senescence. Together, they cause the somatic damage that results in death. Genomics will reveal genes involved in longevity, both healthy and unhealthy. There will be schedules of gene expression behind our life-history traits. As in the field of hereditary metabolic disease, analogous genetic enquiries about ageing can be formulated. For example, how will heterozygotes age? Will association studies in centenarians reveal 'longevity genes'? Will disparate longevity in sib pairs reveal genetic factors? If there are 'ageing' mutations, of what types and with what effects? Will these initiatives lead to healthier longevity? A deeper question yet remains: why has human biology invested so greatly in grandparenthood?     

Lipoproteins, vascular-related genetic factors, and human longevity

The relationships among lipoprotein metabolism, genetic vascular factors, vascular disease, and Alzheimer's disease suggest that the examination of centenarian populations in relation to certain genes or lipoprotein metabolism provide insights into human longevity. The findings on the higher frequency of the apolipoprotein E epsilon4 allele in middle-aged subjects than in centenarians were substantially confirmed. On the contrary, recent findings did not confirm previous data on increased prevalence of the high-risk angiotensin I converting enzyme D allele in French centenarians. The variability in the strength of association between angiotensin I converting enzyme polymorphism and longevity could be related to regional differences in angiotensin I converting enzyme D allele frequency in Europe recently showed, as also recently reported for apolipoprotein Eepsilon2 and epsilon4 allele in centenarians. Indeed some studies of lipoprotein profiles in centenarians have also had contradictory outcomes, with evidence of lower serum levels of high-density lipoprotein cholesterol, with higher high-density lipoprotein 2 cholesterol subfraction, larger high-density lipoprotein and low-density lipoprotein particle sizes, and higher lipoprotein(a) concentration in centenarians, which is apparently disadvantageous for human longevity. Elevated lipoprotein(a) serum levels, increasing the risk for cerebrovascular disease, may play a role in determining clinical Alzheimer's disease, but lipoprotein(a) elevation in centenarians, in the absence of other coronary artery disease risk factors, appears as a positive survival factor. In different populations, there are significant trends in the reduction of serum apolipoprotein E levels from apolipoprotein E epsilon2- to epsilon4-carriers and significant differences in serum apolipoprotein E levels with respect to age in epsilon4-carriers but only after adjustment for high-density lipoprotein cholesterol. While further studies are needed to confirm the possible role of apolipoprotein E concentration as putative longevity factor this paper provides an overview of many of the investigated vascular factors with respect to longevity.     

Greek centenarians: assessment of functional health status and life-style characteristics

Centenarians represent an intriguing model for ageing studies, since they demonstrate extreme longevity by definition, and at the same time a proportion of them have aged successfully. Here, we present data from the first nationwide study on Greek centenarians concerning their functional health status and life-style characteristics. We have identified 489 individuals (77% women) born in 1900 or before who were still alive between the years 2000 and 2002. Socio-demographic characteristics, activities of daily living (ADLs), living conditions, dependence on other people, former and current diseases and health disorders, current medication, nutrition and personal habits were recorded for every subject. Interestingly, only 2% of Greek centenarians lived in nursing homes, while the majority lived with their family or relatives. Furthermore, 6% were free from severe health disorders, autonomous (based on simple criteria for ADLs) and also leading an active social life, and hence may be considered as being in optimal condition. This group of centenarians may serve as a valuable source of information on genetic, environmental, and psychosocial determinants of successful ageing.     

Does a retrograde response in human aging and longevity exist?

The retrograde response (RR) is a compensatory mechanism by which mutant strains of yeast are able to cope with mitochondrial DNA (mtDNA) impairments by up-regulating the expression of the stress-responder nuclear genes and significantly increasing lifespan. Starting from the observation that both mtDNA variability and Tyrosine hydroxylase (THO, stress-responder gene) variability are correlated with human longevity, we asked ourselves whether mechanisms similar to RR may exist in humans. As a first investigative step we have analyzed the distribution of the mtDNA inherited variants (haplogroups) according to THO genotypes in three sample groups of increasing ages (20-49 years; 50-80 years; centenarians). We found that the mtDNA haplogroups and the THO genotypes are associated randomly in the first group, while in the second group, and particularly in the centenarians, a non-random association is observed between the mtDNA and nuclear DNA variability. Moreover, in centenarians the U haplogroup is over-represented (p=0.012) in subjects carrying the THO genotype unfavorable to longevity. On the whole these findings are in line with the hypothesis that longevity requires particular interactions between mtDNA and nuclear DNA and do not exclude the possibility that an RR has been maintained throughout evolution and it is present in higher organisms.     

Cloning of differentially expressed genes in skin fibroblasts from centenarians

Normal human fibroblasts undergoing serial passaging have been extensively used to identify genes linked with aging. Most of the isolated genes relate to growth retardation signals and the failure of homeostasis that accompanies aging and senescence. In contrast, there is still limited knowledge regarding the nature of the genes that influence positively the rate of aging and longevity. Healthy centenarians represent the best example of successful aging and longevity. Studies using samples from these individuals have proved very valuable for identifying a variety of factors that contribute to successful aging. The aim of the current work was to take advantage of skin fibroblast cultures established from healthy donors including centenarians in order to clone differentially expressed genes in centenarians. First, we demonstrate that centenarian derived cultures follow the typical Hayflick curve and they enter senescence after serial passaging. Application of differential screening techniques in minimally passaged cultures of four control donors of different ages (18–80 years old) and four centenarians has resulted in the cloning of six differentially expressed genes in centenarians. Four of the cloned genes, namely adlican, KBL, EST 38 and EST 39, were over-expressed in centenarians, while VDUP1 and OCIF were down-regulated in the same samples. We have also compared the expression levels of two representative cloned genes in cultures of human embryonic and adult fibroblasts to establish potential links with replicative senescence. Interestingly, VDUP1 was found over-expressed in late passage cells, while EST 39 was down-regulated in the same cultures. Thus our work demonstrates that a combination of the use of both biopsies derived cells and classical in vitro cells passaging will facilitate the better understanding of the biology of aging and longevity.Normal human fibroblasts undergoing serial passaging have been extensively used to identify genes linked with aging. Most of the isolated genes relate to growth retardation signals and the failure of homeostasis that accompanies aging and senescence. In contrast, there is still limited knowledge regarding the nature of the genes that influence positively the rate of aging and longevity. Healthy centenarians represent the best example of successful aging and longevity. Studies using samples from these individuals have proved very valuable for identifying a variety of factors that contribute to successful aging. The aim of the current work was to take advantage of skin fibroblast cultures established from healthy donors including centenarians in order to clone differentially expressed genes in centenarians. First, we demonstrate that centenarian derived cultures follow the typical Hayflick curve and they enter senescence after serial passaging. Application of differential screening techniques in minimally passaged cultures of four control donors of different ages (18–l80 years old) and four centenarians has resulted in the cloning of six differentially expressed genes in centenarians. Four of the cloned genes, namely adlican, KBL, EST 38 and EST 39, were over-expressed in centenarians, while VDUP1 and OCIF were down-regulated in the same samples. We have also compared the expression levels of two representative cloned genes in cultures of human embryonic and adult fibroblasts to establish potential links with replicative senescence. Interestingly, VDUP1 was found over-expressed in late passage cells, while EST 39 was down-regulated in the same cultures. Thus our work demonstrates that a combination of the use of both biopsies derived cells and classical in vitro cells passaging will facilitate the better understanding of the biology of aging and longevity.     

Sex-specific longevity associations defined by Tyrosine Hydroxylase–Insulin–Insulin Growth Factor 2 haplotypes on the 11p15.5 chromosomal region

By studies in centenarians, it was recently found that an STR marker of the Tyrosine Hydroxylase (TH, 11p15.5) gene is associated with human longevity. The aim of the present study was to continue the exploration of the 11p15.5 chromosomal region in human longevity by analyzing two additional RFLP markers, which lie in the Insulin (INS) and Insulin Growth Factor 2 (IGF2) genes. Both the genes, which are localized downstream TH, are indeed good candidates in longevity, as ascertained on the basis of laboratory studies in experimental models. Neither INS nor IGF2 markers did reveal association with longevity. Nevertheless, linkage disequilibrium analyses showed sex-specific longevity associations defined by both TH–INS and TH–IGF2 haplotypes. On the whole, the results reinforce the involvement of the chromosomal region spanning from TH to IGF2 loci in controlling the longevity phenotype in humans.     

Biology and Genetics of Human Longetivity

Abstract. Human longevity is a multifactorial trait, which includes a network of genes combined with strong environmental factors. Biological and clinical characteristics of human beings are the result of the interaction between genes and the environment. Until about 1950 centenarians were quite rare in low-mortality countries. Since then the number has more than doubled every 10 years and even the number of 105+ year old people is now increasing. This proliferation of centenarians is mainly a result of the decrease in oldest-old mortality and probably due to changes of lifestyle and health care. Although studies of Danish twin pairs seem to indicate that genetic influence on human lifespan is only moderate, several gene loci contribute to longevity. Data are evident from the Italian Centenarian Study for apoproteinB, tyrosine hydroxylase and mitochondrial DNA loci among others studied (superoxide dismutases, ie. SOD1 and SOD2, poly(ADP-ribose)polymerase and thyroid peroxidase). The data from the Danish Centenarian Study confirm the findings from the studies of French and Finnish centenarians on apolipoprotein E genotype with a higher frequency of epsilon-2 and lower frequency of epsilon-4. However, the apoE genotype seems not to be a key determinant of exceptional longevity: in 105+ year olds the epsilon-4 allele was found in 4 out of 19 persons. Italian centanarians have a paradoxically marked hypercoagulability as demonstrated also by genetic markers. Also the von Willebrand factor was increased independently of the blood group. Studies on such atherosclerosis risk factors as lipoprotein(a) and homocysteine revealed that these two parameters may be high in Italian centenarians, but their genetic control possibly attenuates with age, and environmental factors may play a major role in the oldest-old persons. Also interaction among genes is possible. All these studies suggest that longevity is a phoenomenon depending on multiple genetic and environmental factors. Further studies are needed for a better understanding of the complex interactions which allow people to reach a very old age.     

Inflammation,genetic background and longevity

Ageing is an inexorable intrinsic process that affects all cells, tissues, organs and individuals. Due to a diminished homeostasis and increased organism frailty, ageing causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. Actually, it is characterized by a state of reduced ability to maintain health and general homeodynamics of the organism. A large part of the ageing phenotype is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status of ageing, “inflamm-ageing”. It is strictly linked to immunosenescence, and on the whole they are the major contributory factors to the increased frequency of morbidity and mortality among elderly. Inflamm-ageing is compatible with longevity; even if centenarians have an increased level of inflammatory mediators in comparison to old subjects and they are very frail, they also have high level of anti-inflammatory cytokines together with protective genotypes. Actually, data on case control studies performed in Italian centenarians suggest that a pro-inflammatory genotype is unfavourable to reach extreme longevity in good health and likely favours the onset of age-related diseases such as cardiovascular diseases and Alzheimer’s disease, the leading causes of mortality and disability in the elderly. However, many associations between gene variants and longevity have been found only in Italian population. This should not be unexpected, since ageing and longevity are complex traits resulting not only and not exclusively from genetics, but rather from the interactions between genetics, environment and chance.     

Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE)

Gender accounts for important differences in the incidence and prevalence of a variety of age-related diseases. Considering people of far advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In the present investigation, we report data from a nationwide study on Italian centenarians (a total of 1162 subjects), and from two studies on centenarians living in two distinct zones of Italy, i.e., the island of Sardinia (a total of 222 subjects) and the Mantova province (Northern Italy) (a total of 43 subjects). The female/male ratio was about 2:1 in Sardinia, 4:1 in the whole of Italy, and about 7:1 in the Mantova province. Thus, a complex interaction of environmental, historical and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. Gender differences in the health status of centenarians are also reported, and an innovative score method to classify long-lived people in different health categories, according to clinical and functional parameters, is proposed. Our data indicate that not only is this selected group of people, as a whole, highly heterogeneous, but also that a marked gender difference exists, since male centenarians are less heterogeneous and more healthy than female centenarians. Immunological factors regarding the age-related increase in pro-inflammatory status, and the frequency of HLA ancestral haplotypes also show gender differences that likely contribute to the different strategies that men and women seem to follow to achieve longevity. Concerning the different impact of genetic factors on the probability of reaching the extreme limits of the human life-span, emerging evidence (regarding mtDNA haplogroups, Thyrosine Hydroxilase, and IL-6 genes) suggests that female longevity is less dependent on genetics than male longevity, and that female centenarians likely exploited a healthier life-style and more favorable environmental conditions, owing to gender-specific cultural and anthropological characteristics of the Italian society in the last 100 years.     

Functionally significant insulin-like growth factor I receptor mutations in centenarians

Rather than being a passive, haphazard process of wear and tear, lifespan can be modulated actively by components of the insulin/insulin-like growth factor I (IGFI) pathway in laboratory animals. Complete or partial loss-of-function mutations in genes encoding components of the insulin/IGFI pathway result in extension of life span in yeasts, worms, flies, and mice. This remarkable conservation throughout evolution suggests that altered signaling in this pathway may also influence human lifespan. On the other hand, evolutionary tradeoffs predict that the laboratory findings may not be relevant to human populations, because of the high fitness cost during early life. Here, we studied the biochemical, phenotypic, and genetic variations in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls and demonstrated a gender-specific increase in serum IGFI associated with a smaller stature in female offspring of centenarians. Sequence analysis of the IGF1 and IGF1 receptor (IGF1R) genes of female centenarians showed overrepresentation of heterozygous mutations in the IGF1R gene among centenarians relative to controls that are associated with high serum IGFI levels and reduced activity of the IGFIR as measured in transformed lymphocytes. Thus, genetic alterations in the human IGF1R that result in altered IGF signaling pathway confer an increase in susceptibility to human longevity, suggesting a role of this pathway in modulation of human lifespan.     

Genetics of aging: lessons from centenarians

Aging is a universal phenomenon that affects nearly all animal species. It can be considered as the product of an interaction between genetic, environmental and lifestyle factors, which in turn influence longevity that varies between and within species. Several studies have been focused in healthy centenarians, because these exceptional individuals represent the best example of successful aging. These studies have shown that centenarians have escaped the major age-associated diseases, they have well conserved several immune parameters, and at least one gene allele has been identified and linked with longevity. In parallel, studies at cellular level have identified several genes that influence, positively or negatively, normal replicative in vitro life-span. The ability of these genes to regulate aging in vitro, in conjunction with the telomeres shortening hypothesis have raised the intriguing question of the existence of a molecular clock that counts and thus may modulates human aging and longevity. This review article will discuss these issues, focusing in the nature of the genetic factors that associate with these phenomena.     

Analysis of HLA-DRB1, DQA1, DQB1 haplotypes in Sardinian centenarians

Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA-DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1 *15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a role in the association to diseases. Hence, we have evaluated, by amplification refractory mutation system/polymerase chain reaction (ARMS-PCR) the HLADQA1 and HLA-DQB1 allele frequencies in 123 centenarians and 92 controls from Sardinia to assess whether the association to HLA-DRB1 *15 allele may be due to the other genes involved in the HLA-DR,DQ haplotypes. The frequencies of HLA-DQA1, DQB1 haplotypes were not significantly modified in centenarians. Nevertheless by evaluating the frequency of DRB1 *15 linked haplotypes, we observed a not significant increase in centenarians of HLA-DQA1 *01, DQB1 *05 and HLA-DQA1 *01,DQB1 *06 haplotypes. These data suggest that these haplotypes might have a role in determining life span expectancy and longevity.     

Association Between Social Factors of Health Ageing and Longevity: Determinants of the Longevity Index (LI) in OECD Countries

This study estimates the longevity index (LI) of centenarians and elucidates the influence of correlates of social factors as healthy ageing on the LI of centenarians in countries of the Organisation for Economic Co-operation and Development (OECD). The data for the analysis of centenarians in the selected 18 OECD countries were obtained from the population censuses conducted by the National Statistical Offices of these member countries. This study utilized the demographic databases of centenarians from the above countries to calculate the following parameters: the proportion between the centenarians and the total population. Although significant positive correlations were found between the LI of centenarians and social factors such as health expenditure as a percentage of the gross domestic product (HGDP), and public expenditure on health (PH) and dependency expenditure ratio (DR), negative correlations were found between the LI of centenarians and social factors such as, suicide rates in both genders (SR), suicide rates in women (SRW), and occupational injuries (OI). Finally, the LI predictors were used to form a model of healthy ageing, with higher HGDP as health expenditure, and higher DR as dependency expenditure, and lower SRW as risk of life, including lower OI as labor injuries (R ²?=?0.909, P?=?0.023). The findings imply that an aged society plays an important role in ensuring the continued longevity of older people; therefore, the governments of OECD countries must strengthen their preventive social programmers and increase their existing support services for the elderly through increased financing of the health sector.     

Discovery of functional gene variants associated with human longevity: opportunities and challenges

Age is a major risk factor for many human diseases. Extremely long-lived individuals, such as centenarians, have managed to ward off age-related diseases and serve as human models to search for the genetic factors that influence longevity. The discovery of evolutionarily conserved pathways with major impact on life span in animal models has provided tantalizing opportunities to test the relevance of these pathways for human longevity. Here we specifically focus on the insulin/insulin-like growth factor-1 signaling as a prime candidate pathway. Coupled with the rapid advances in ultra high-throughput sequencing technologies, it is now feasible to comprehensively analyze all possible sequence variants in candidate genes segregating with a longevity phenotype and to investigate the functional consequences of the associated variants. A better understanding of the functional genes that affect healthy longevity in humans may lead to a rational basis for intervention strategies that can delay or prevent age-related diseases.     

Distributions of ACE and APOE polymorphisms and their relations with dementia status in Korean centenarians

BACKGROUND: Genetic polymorphisms of angiotensin-converting enzyme (ACE) and apolipoprotein E (APOE) have been reported to be associated with human longevity and dementia in the elderly. However, whether such putative longevity genes exert the same effects on different ethnic groups living in different environments is not well known. METHODS: We investigated the distributions of the ACE and APOE genotypes and their relations with dementia status in Korean centenarians by cross-sectional study. A total of 103 centenarians (13 men and 90 women, mean age 102.4 +/- 2.6 years) were included in this study. The allele frequencies of the genes were compared with those of two control groups: 7232 apparently healthy adults (4100 men and 3132 women) of mean age 48.5 +/- 9.6 years for the ACE genotyping, and 6435 adults (5008 men and 1427 women) of mean age 50.7 +/- 7.9 years for the APOE genotyping. The dementia status of the centenarians was assessed by clinical psychologist using the Clinical Dementia Rating (CDR) score. RESULTS: The frequencies of genotypes and alleles of the ACE and APOE genes of the centenarians were not significantly different from those of the control groups. There was a lack of association between presence of the D allele on the ACE gene and dementia status. However, the frequency of the epsilon4 allele of the APOE gene was significantly higher in centenarians with dementia than in centenarians without definitive dementia (9.1% versus 1.5%, p <.05). CONCLUSIONS: These results suggest that neither the ACE nor the APOE gene is significantly associated with longevity in the Korean population, but that the APOE epsilon4 allele is still related with dementia even at age 100 and older.