Cognitive function in Japanese centenarians according to the Mini-Mental State Examination.

BACKGROUND/AIMS: We examined the effect of aging on cognitive function at the limit of human life expectancy by characterizing state of cognition in centenarians without clinical cognitive impairment. METHODS: Participants were 68 centenarians without cognitive impairment (Clinical Dementia Rating (CDR) 0), 96 controls 60 to 74 years old, and 46 controls 75 to 89 years old. We visited the places where centenarians were living and administered the Mini-Mental State Examination (MMSE) individually. Control subjects came to the assembly hall within their dwelling area, to be administered the MMSE. RESULTS: Mean total scores of centenarians (22.3) were lower than for either 60-74 (27.2) or 75-89 (26.2). Comparison of scores in each of five cognitive domains measured by MMSE showed a significant age-group effect upon orientation, memory, and attention. Centenarians' scores were lower than for younger groups in every domain except for the language and praxis, concentration, and for repetition. CONCLUSION: The centenarians' scores in memory and orientation declined as in earlier studies of normal aging. Centenarians' scores for attention and concentration differed from those in previous studies. The present result suggests that even primary memory is influenced by advanced age in centenarians, while ability to store information declines, ability to process is maintained.

Adipose endocrine function, insulin-like growth factor-1 axis, and exceptional survival beyond 100 years of age.

BACKGROUND: Observational studies have demonstrated similarities between the underpinning of frailty and biological features of centenarians, suggesting that adaptability to age-related multiple physiological decline may be a core component of successful aging. The aim of this study is to determine whether hormonal pathways potentially involved in energy homeostasis contribute to survival beyond 100 years of age. METHODS: We assessed a total of 252 centenarians (mean [standard deviation (SD)] age, 101.5 (1.8) years, range 100-108 years) using a complete set of biomarkers of adipose endocrine function and the insulin-like growth factor-1 (IGF-1) axis. Conventional risk factors at baseline were also assessed. The participants were followed up for all-cause mortality every 12 months by telephone contact. RESULTS: During 2253 days of follow-up, 208 centenarians (82.5%) died. The lowest tertile of leptin and the highest tertile of tumor necrosis factor-alpha were associated with higher mortality risk among centenarians after adjusting for age (per 6-month increase), sex, education, smoking, activities of daily living (ADL), cognitive function, and comorbidities (hazard ratio [HR] 1.6; 95% confidence interval [CI], 1.14-2.35; and HR 1.45; 95% CI, 1.00-2.08, respectively). The lowest tertiles of both IGF-1 and IGF binding protein 3 (IGFBP3) were also associated with increased mortality. The adipose risk score, indicating cumulative effects of adipokine dysregulation, was strongly associated with increased mortality risk; ADL; cognitive function; and levels of albumin, cholinesterase, high-density lipoprotein-cholesterol, C-reactive protein, interleukin 6, and IGF-1 at baseline. CONCLUSIONS: The results suggested that preservation of adipose endocrine function and the IGF-1 axis may be potentially important for maintaining health and function and promoting survival at an extremely old age.

Morbidity of Tokyo-area centenarians and its relationship to functional status.

BACKGROUND: Research in Western countries has shown most centenarians to be survivors with multiple comorbidities. However, Japanese centenarians' morbidity and its relationship to functional status has yet to be elucidated. The aim of this study is to clarify the association of morbidity with the physical and cognitive function of centenarians. We examined Tokyo-area centenarians to determine their kinds of morbidity profiles and how such morbidity related to their functional status. METHODS: We studied 302 centenarians living in Tokyo (101.2+/-1.8 years; 65 men, 237 women), and assessed their physical status, morbidity, and use of medication. Activities of daily living and cognitive function were also assessed using the Barthel Index and the Clinical Dementia Rating. RESULTS: More than 95% of the centenarians had chronic diseases. Both the physical and cognitive functions were significantly higher in men. The present and previous illnesses most frequently included hypertension, heart disease, stroke, fractures, and cataracts. Fractures were observed significantly more frequently in women. Diabetes mellitus was uncommon. The physical and cognitive function of centenarians with a history of stroke or fracture were particularly poor, whereas those centenarians with hypertension tended to show a high level of physical and cognitive function. CONCLUSIONS: Almost all centenarians had chronic diseases. Stroke and fracture were correlated with poorer function; therefore, we hypothesize that prevention of stroke and fracture might improve functional status in the oldest-old.

Effect of rosuvastatin 5-20mg on triglycerides and other lipid parameters in Japanese patients with hypertriglyceridemia.

To evaluate the potential dose effect of rosuvastatin on triglyceride (TG) levels in Japanese hypertriglyceridemic patients, we randomized 154 patients with TG levels of >or=200 and <800 mg/dL to 8 weeks of treatment with rosuvastatin 5, 10 or 20mg once daily; bezafibrate 200mg twice daily; or placebo. Compared with placebo, TG was reduced by 30.1% with rosuvastatin 5mg, 30.1% with 10mg and 32.3% with 20mg (all p

Functional status of centenarians in Tokyo, Japan: developing better phenotypes of exceptional longevity.

BACKGROUND: Centenarians are sometimes said to be representative of lifelong healthy aging. Whether they are, in fact, examples of healthy aging remains a subject of debate. The existence of heterogeneity in functional status has been reported repeatedly in previous studies of centenarians. However, there is as yet no standardized classification system with which to describe their functional phenotype. METHODS: As part of a dynamic cohort study, we studied 304 centenarians (65 men and 239 women) living in Tokyo. Their functional status (sensory, physical, and cognitive), which we used to represent their phenotype, was assessed and subsequently classified by standard assessment methods (simple questionnaire, Barthel index, Mini-Mental State Examination, and the Clinical Dementia Rating, respectively). RESULTS: We classified participants into 4 categories according to their functional status. Only 5 (2%) were classified as "Exceptional," with all of their functions graded as excellent, and 56 (18%) were "Normal," exhibiting maintenance of fine cognitive and physical functions. One hundred sixty-seven (55%) were "Frail," exhibiting impairment of either cognitive or physical functions, and the remaining 76 (25%) were "Fragile," exhibiting deterioration of both physical and cognitive functions. CONCLUSIONS: The relationships between biochemical marker, mortality rates, lifestyle, and functional phenotypes demonstrated by this classification method indicate that the system is reliable to address the functional status of extremely old persons. Thus, this framework would be a useful tool for exploring the factors that contribute to exceptional longevity as well as those that help to maintain the functional status of the extremely old population.

Contribution of an affect-associated gene to human longevity: prevalence of the long-allele genotype of the serotonin transporter-linked gene in Japanese centenarians.

Negative affect such as depression and anxiety has been reported to be associated with morbidity and mortality, and polymorphisms of the serotonin transporter (5HTT) gene may be associated with such affect disorders. Hypothesizing that 5HTT gene polymorphisms could influence human longevity via negative affect; we compared the polymorphic variation of the 5HTT gene between 265 Japanese centenarians and control subjects. In addition, we evaluated the relationships between the 5HTT genotype and the physical, cognitive, and biologic status of centenarians, as indicated by the Barthel Index, the Mini-Mental State Examination, and serum albumin concentration, respectively. The frequency of the l/l genotype and the l allele was significantly greater in centenarians than in younger control subjects, particularly women. A significant effect of the 5HTT genotype on serum albumin concentration was observed in both sexes. Although, there was sex optionality, the l allele may carry a longevity advantage possibly through behavioral mechanisms.

Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways.

Recent studies have demonstrated a significant association between mutations in genes involved in the insulin/IGF1 signaling pathway and extension of the life span of model organisms. In this study which compared 122 Japanese semisupercentenarians (older than 105) with 122 healthy younger controls, we examined polymorphic variations of six genes which are involved in insulin/IGF1 signaling. These genes were FOXO1A, INSR, IRS1, PIK3CB, PIK3CG, and PPARGC1A. We investigated the possible association of each gene locus and longevity by haplotype-based association analyses using 18 SNPs from public databases and the published literature. One INSR haplotype, which was comprised of 2 SNPs in linkage disequilibrium, was more frequent in semisupercentenarians than in younger controls.

Blood type B might imply longevity.

The aim of the present study was to investigate the association between blood groups and life expectancy. We compared frequencies of ABO blood group in 269 centenarians (persons over 100 years) living in Tokyo and those in regionally matched controls (n=7153). Frequencies of blood types A, O, B, and AB in centenarians were 34.2, 28.3, 29.4, and 8.2%, respectively, while those in controls were 38.6, 30.1, 21.9, and 9.4%, respectively. Blood type B was observed more frequently in centenarians than in controls (chi(2)=8.41, P=0.04). This tendency also was true in comparison between centenarians and 118 elderly old individuals of the 7153. Approximate one-third of the centenarians were free from serious diseases such as malignancy. However, blood types were not associated with such medical records. Our findings suggest that blood type B might be associated with exceptional longevity. Responsible mechanisms need to be investigated.

Association analysis of the SHC1 gene locus with longevity in the Japanese population.

The SHC1 gene encodes a signaling and transforming protein that has been implicated in the aging process in worms and mammals. In this study we examined 230 Japanese centenarians and 180 healthy younger controls and looked at the SHC1 locus as a candidate region that may be associated with longevity. We identified 12 single nucleotide polymorphisms (SNPs) within a 10-kb region encompassing the entire SHC1 gene from the DNA of 30 centenarians and 24 healthy younger controls. Five SNPs, including three nonsynonymous sites, lay within coding elements, six were located within introns, and one was in the 3' untranslated region. All of these SNPs were relatively rare, with a minor allele frequency of less than 5% in our subjects. A pairwise linkage disequilibrium analysis using the r2 statistic showed that two of the SNP pairs are in tight linkage disequilibrium at this locus. We investigated the possible association of SHC1 with longevity using association analyses with allelotypes and haplotypes but found that the SNPs identified in SHC1 had no impact on longevity for Japanese centenarians.

Dietary patterns and further survival in Japanese centenarians.

We have previously reported that centenarians (persons > or = 100 y old) in Tokyo prefer dairy products. Dietary preferences may be associated with longevity. The aim of the present study was to investigate the relationship between dietary patterns and further survival in centenarians. During 1992-1999, we examined the dietary practices of 104 centenarians (29 men and 75 women; mean age, 100.3 +/- 0.9 y) who lived in the Tokyo metropolitan area. Dietary patterns were classified by kappa-means cluster analysis. As clinical co-variables, we considered activities of daily living, cognitive function, nutritional status, presence of important disease, gender, and age at the time of the initial survey. Survival data were recorded yearly until 2001, and then tested with Kaplan-Meier analysis and the log rank statistic. Four dietary patterns were identified: a pattern preferring vegetables (n = 33), a pattern preferring dairy products (n = 26), a pattern preferring beverages (n = 10), and a pattern preferring cereals (n = 35). No clinical variables differed between the four dietary patterns. In 2001, 28 centenarians were still alive. The survival rate for those preferring dairy products was the highest of the four dietary patterns; in particular, being significantly higher than the pattern preferring beverages (p = 0.048). A dietary pattern preferring dairy products was associated with increased survival in Tokyo-area centenarians.

Deficiency of choresteryl ester transfer protein and gene polymorphisms of lipoprotein lipase and hepatic lipase are not associated with longevity.

Cholesteryl ester transfer protein (CETP) is one of the key proteins in reverse cholesterol transport (RCT). The role of CETP in atherosclerosis remains controversial. In this study we investigated the associations between polymorphisms of CETP (mutations in intron 14 and exon 15, and Taq1B), hepatic lipase (C-514T), lipoprotein lipase ( PvuII and HindIII), and ATP-binding cassette transporter 1 (R219K) loci and longevity in 256 centenarians and 190 healthy younger controls. Although heterozygous CETP deficiency and the B2 allele of the Taq1B polymorphism was consistently associated with higher HDL-C concentrations both in centenarians and controls, the allelic frequencies of those polymorphisms did not differ between the two groups. The allelic frequencies of other gene polymorphisms in RCT were not different between the two groups. Centenarians with lipoprotein lipase P(-/-) genotype had significantly higher HDL-C concentration than those with P(-/+) or with P(+/+), in contrast, there was no such a relationship among controls. In stepwise multiple regression analysis, serum albumin, CETP deficiency and lipoprotein lipase PvuII genotype were independently associated with HDL-C in centenarians. Sex, CETP deficiency, and the Taq1B genotype were also independently associated with HDL-C; however, lipoprotein lipase PvuII genotype had no significant effect on their HDL-C in controls. In conclusion, we observed that CETP deficiency and other gene polymorphisms in RCT have no impact on longevity for Japanese centenarians.