Michiyo Takayama

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.

Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians.

To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8.6% variance explained) in (semi-)supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI) = − 0.795 (− 1.436 to − 0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.

Comparison of the levels of hepatocyte growth factor and vascular endothelial growth factor in aqueous fluid and serum with grades of retinopathy in patients with diabetes mellitus

AIMS To determine the relation between the stages of diabetic retinopathy (DR) and the levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in aqueous fluid and serum. METHODS Levels of HGF and VEGF in serum and aqueous humour obtained during ocular surgery were measured by enzyme linked immunosorbent assay in 58 diabetic patients with 32 non-diabetic patients (NDM) as controls. The patients with diabetes were classified into three groups according to the stage of DR: no DR (NDR; 15 cases), non-proliferative DR (NPDR; six cases), and proliferative DR (PDR; 37 cases). RESULTS No significant differences were found between any of the groups in serum concentrations of HGF or VEGF. The aqueous HGF levels increased with the stage of DR: NDM, median 397 pg/ml, range 133–930 pg/ml; NDR, 371 pg/ml, 142–1536 pg/ml; NPDR, 455 pg/ml, 162–1007 pg/ml; and PDR, 638 pg/ml, 187–2222 pg/ml. The aqueous VEGF levels in PDR (median 212 pg/ml, range 14–1216 pg/ml) were significantly higher than in NDM (105 pg/ml, 9–203 pg/ml), but aqueous HGF concentrations were unrelated to those of VEGF. CONCLUSION The results of the present study suggest that both HGF and VEGF present in the ocular tissues may play important roles in the progression of DR.

Denture Wearing during Sleep Doubles the Risk of Pneumonia in the Very Elderly

Poor oral health and hygiene are increasingly recognized as major risk factors for pneumonia among the elderly. To identify modifiable oral health–related risk factors, we prospectively investigated associations between a constellation of oral health behaviors and incident pneumonia in the community-living very elderly (i.e., 85 years of age or older). At baseline, 524 randomly selected seniors (228 men and 296 women; mean age, 87.8 years) were examined for oral health status and oral hygiene behaviors as well as medical assessment, including blood chemistry analysis, and followed up annually until first hospitalization for or death from pneumonia. During a 3-year follow-up period, 48 events associated with pneumonia (20 deaths and 28 acute hospitalizations) were identified. Among 453 denture wearers, 186 (40.8%) who wore their dentures during sleep were at higher risk for pneumonia than those who removed their dentures at night (log rank P = 0.021). In a multivariate Cox model, both perceived swallowing difficulties and overnight denture wearing were independently associated with an approximately 2.3-fold higher risk of the incidence of pneumonia (for perceived swallowing difficulties, hazard ratio [HR], 2.31; and 95% confidence interval [CI], 1.11–4.82; and for denture wearing during sleep, HR, 2.38; and 95% CI, 1.25–4.56), which was comparable with the HR attributable to cognitive impairment (HR, 2.15; 95% CI, 1.06–4.34), history of stroke (HR, 2.46; 95% CI, 1.13–5.35), and respiratory disease (HR, 2.25; 95% CI, 1.20–4.23). In addition, those who wore dentures during sleep were more likely to have tongue and denture plaque, gum inflammation, positive culture for Candida albicans, and higher levels of circulating interleukin-6 as compared with their counterparts. This study provided empirical evidence that denture wearing during sleep is associated not only with oral inflammatory and microbial burden but also with incident pneumonia, suggesting potential implications of oral hygiene programs for pneumonia prevention in the community.

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.

Maximum Occlusal Force and Physical Performance in the Oldest Old: The Tokyo Oldest Old Survey on Total Health

To elucidate the independent relationship between masticatory and physical performance in community‐living oldest old people (mean age ± standard deviation 87.8 ± 2.2, range 85–102).

Lipoprotein Metabolism in Japanese Centenarians: Effects of Apolipoprotein E Polymorphism and Nutritional Status

OBJECTIVES: To assess the complex interaction of apolipoprotein (apo) E polymorphisms and environmental factors on lipoprotein profile in centenarians.

Loss of protection by hypoxic preconditioning in aging Fischer 344 rat hearts related to myocardial glycogen content and Na+ imbalance

OBJECTIVES The objective of this study was to determine whether hypoxic preconditioning (HP) could lessen the myocardial increase in [Na+]i, thus protecting the aging myocardium against ischemia. BACKGROUND A decrease in ischemic tolerance with aging is associated with an accelerated increase in [Na+]i during ischemia. Ischemic preconditioning fails to protect the middle-aged and senescent myocardium against ischemia. METHODS Isolated hearts of young adult (12-week-old), middle-aged (50-week-old) and senescent (100-week-old) Fischer 344 rats were subjected to 25 min of ischemia with or without HP followed by 30 min of reperfusion. Left ventricular (LV) function, myocardial energy metabolites and [Na+]i were measured. RESULTS In the older groups, the recovery of LV function and high-energy phosphates (HEPs) was lower with an increased release of creatine kinase (CK) during reperfusion than in the young group. The increased [Na+]i at the end of ischemia was greater in the former groups than in the young group. HP decreased myocardial glycogen and lessened the increased [Na+]i in the young group, resulting in an improved recovery of LV function and HEPs, as well as decreased CK release. However, the levels of glycogen before HP in the older groups were higher than in the young group and its levels after HP were similar to that before HP in the young group. HP did not affect the [Na+]i, exacerbated CK release and inhibited the recovery of LV function and HEPs in the older groups. CONCLUSIONS HP failed to lessen the increased [Na+]i or to protect the aging hearts, probably due to the preexistence of increased glycogen level.

The Tokyo Oldest Old Survey on Total Health (TOOTH): A longitudinal cohort study of multidimensional components of health and well-being

BackgroundWith the rapid worldwide increase in the oldest old population, considerable concern has arisen about the social and economic burden of diseases and disability in this age group. Understanding of multidimensional structure of health and its life-course trajectory is an essential prerequisite for effective health care delivery. Therefore, we organized an interdisciplinary research team consisting of geriatricians, dentists, psychologists, sociologists, and epidemiologists to conduct a longitudinal observational study.Methods/DesignFor the Tokyo Oldest Old Survey on Total Health (TOOTH) study, a random sample of inhabitants of the city of Tokyo, aged 85 years or older, was drawn from the basic city registry. The baseline comprehensive assessment consists of an in-home interview, a self-administered questionnaire, and a medical/dental examination. To perform a wide variety of biomedical measurements, including carotid ultrasonography and a detailed dental examination, participants were invited to our study center at Keio University Hospital. For those who were not able to visit the study center, we provided the option of a home-based examination, in which participants were simultaneously visited by a geriatrician and a dentist. Of 2875 eligible individuals, a total of 1152 people were recruited, of which 542 completed both the in-home interview and the medical/dental examination, with 442 completed the in-home interview only, and another 168 completed self or proxy-administered data collection only. Carotid ultrasonography was completed in 458 subjects, which was 99.6% of the clinic visitors (n = 460). Masticatory assessment using a colour-changeable chewing gum was completed in 421 subjects, a 91.5% of the clinic visitors.DiscussionOur results demonstrated the feasibility of a new comprehensive study that incorporated non-invasive measurements of subclinical diseases and a detailed dental examination aiming at community-dwelling individuals aged 85 years or older. The bimodal recruitment strategy is critically important to capture a broad range of health profiles among the oldest old. Results form the TOOTH study will help develop new models of health promotion, which are expected to contribute to an improvement in lifelong health and well-being.Trial RegistrationThis study has been registered in the UMIN-Clinical Trial Registry (CTR), ID: UMIN000001842.

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.