[Show abstract][Hide abstract] ABSTRACT: Irisin might play an important role in reducing the risk of obesity, insulin resistance, or several related diseases, and high irisin levels may contribute to successful aging. Thus, the irisin precursor (FNDC5) gene is a candidate to influence exceptional longevity (EL), i.e., being a centenarian. It has been recently shown that two single-nucleotide polymorphisms (SNPs) in the FNDC5 gene, rs16835198 and rs726344, are associated with in vivo insulin sensitivity in adults. We determined luciferase gene reporter activity in the two above-mentioned SNPs and studied genotype distributions among centenarians (n=175, 144 women) and healthy controls (n=347, 142 women) from Spain. We also studied an Italian [79 healthy centenarians (40 women) and 316 healthy controls (156 women)] and a Japanese cohort [742 centenarians (623 women) and 499 healthy controls (356 women)]. The rs726344 SNP had functional significance, as shown by differences in luciferase activity between the constructs of this SNP (all P≤0.05), with the variant A-allele having higher luciferase activity compared with the G-allele (P=0.04). For the rs16835198 SNP, the variant T-allele tended to show higher luciferase activity compared with the G-allele (P=0.07). However, we found no differences between genotype/allele frequencies of the two SNPs in centenarians versus controls in any cohort, and no significant association (using logistic regression adjusted by sex) between the two SNPs and EL. Further research is needed with different cohorts as well as with additional variants in the FNDC5 gene or in other genes involved in irisin signaling.
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Dental Research 10/2014; · 4.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AimThe 9p21 region has been pointed out by the genome-wide association studies as a hot spot for disease-associated variants. Most of the diseases linked with the locus are aging-related conditions, such us cardiovascular disease, diabetes and cancer. Centenarians are known to present a reduced risk and delayed onset for these conditions. Here, we aimed to assess if the 9p21 variants contribute to this protection by possibly altering basic aging mechanisms.Methods
We genotyped 15 tag single-nucleotide polymorphisms (SNP) along the CDKN2A/B/ANRIL locus in 1505 individuals. The participants were divided in three groups: centenarians, septuagenarians and young controls. Centenarians were 593 participants (age range 100–116 years, mean 105.9 years), septuagenarians were 434 volunteers aged between 69 and 71 years (mean 70.1 ± 0.9 years) and the 478 young controls were under the age of 50 years (range 14–50 years, mean 41.8 years). We genotyped the SNP rs1333049 in an additional sample of 231 coronary artery disease patients to confirm the 9p21 association.ResultsThe leading coronary artery disease-associated SNP rs1333049 was associated with coronary artery disease; however, none of the 9p21 SNP evaluated in the present study were associated with extreme longevity.Conclusions
Our findings suggest that the 9p21 disease-associated polymorphisms do not contribute to the life-long protection from cardiovascular and other age-related diseases observed in centenarians. It is likely that this protection is mediated by mechanisms different from the ones underlying the 9p21 association. Geriatr Gerontol Int 2014; ●●: ●●–●●.
Geriatrics & Gerontology International 10/2014; · 1.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Focal adhesion is critical for cell survival. The 'focal adhesion kinase' (FAK, or PTK2) is an important component of the human 'interactome' and thus a potential 'longevity-related protein'. Here we studied the association between two PTK2 gene SNPs (rs7843014, rs7460) and exceptional longevity (EL). Besides gaining insight into their functionality (by determining luciferase gene reporter activity), we studied the genotype/allele frequency of these two SNPs among three different cohorts: (i) Spanish centenarians (n=175, 100-111y, 144 women) and healthy controls (n=355, 20-50y, 284 women); (ii) Italian centenarians (n=79, 100-104y, 40 women) and controls (n=316, 29-50y, 156 women); and (iii) Japanese centenarians (n=742, 100-116y, 623 women) and healthy controls (n=499, 23-59y, 356 women). Both SNPs had functional significance, with the A-allele up-regulating luciferase activity compared to the other allele (rs7460 T-allele and rs7843014 C-allele, respectively). The A-allele of both SNPs was negatively associated with EL in the Spanish cohort [rs7460: odds ratio (OR) adjusted by sex=0.40 (95% confidence intervals (CI): 0.3, 0.6, P<0.001); rs7843014: OR=0.37 (95%CI: 0.3, 0.5), P<0.001]. The OR of being a centenarian if having the rs7460-TT genotype was 6.68 (95%CI: 4.1, 10.8, P<0.001). The rs7843014 CC genotype was also positively associated with EL [OR=7.58 (95%CI: 4.6, 12.3), P<0.001]. No association was however found for Italians or Japanese. Thus, two genotypes of the FAK gene, rs7460 TT and rs7843014 CC are possibly associated with lower gene expression, and might favor the likelihood of reaching EL in the Spanish population. Further research is needed to unveil the mechanisms by which FAK expression could maybe influence rate of aging.
Rejuvenation Research 06/2014; · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The ApoE gene is associated with the risk of Alzheimer or cardiovascular disease but its influence on exceptional longevity (EL) is uncertain. Our primary purpose was to determine, using a case-control design, if the ApoE gene is associated with EL. We compared ApoE allele/genotype frequencies among the following cohorts: cases (centenarians, most with 1 + major disease condition; n = 163, 100-111y) and healthy controls (n = 1039, 20-85y) from Spain; disease-free cases (centenarians; n = 79, 100-104y) and healthy controls (n = 597, age 27-81y) from Italy; and cases (centenarians and semi-supercentenarians, most with 1 + major disease condition; n = 729, 100-116) and healthy controls (n = 498, 23-59y) from Japan. Our main findings were two-fold. First, the ε4-allele was negatively associated with EL in the three cohorts, with the following odds ratio (OR) values (adjusted by sex) been found: 0.55 (95% confidence interval (CI): 0.33, 0.94), P = 0.030 (Spain); 0.41 (95%CI: 0.18, 0.99), P = 0.05 (Italy); and 0.35 (95%CI: 0.26, 0.57), P < 0.001 (Japan). Second, although no association was found in the Spanish cohort (OR = 1.42 (95%CI: 0.89, 2.26), P = 0.145), the ε2-allele was positively associated with EL in the Italian (OR = 2.14 (95%CI: 1.18, 3.45), P = 0.01) and Japanese subjects (OR = 1.81 (95%CI: 1.25, 2.63), P = 0.002). Notwithstanding the limitations of case-control designs, our data suggest that the ApoE might be a candidate to influence EL. The ε4-allele appears to decrease the likelihood of reaching EL among individuals of different ethnic/geographic origins. An additional, novel finding of our study was that the ε2-allele might favor EL, at least in the Italian and Japanese cohorts.
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression.
Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E-deficient mice (ApoE(-/-)/Angptl2(-/-)) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE(-/-) mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (ApoE(-/-)/Tie2-Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell-derived nitric oxide. Conversely, Angptl2(-/-) mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis.
Endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.
Arteriosclerosis Thrombosis and Vascular Biology 02/2014; · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to compare the most important life events reported by U.S. and Japanese centenarians. This study included a population-based sample of 239 U.S. centenarians from the Georgia Centenarian Study and 304 Japanese centenarians from the Tokyo Centenarian Study. Two open-ended life events questions were categorized and grouped into different life event domains. Several cross-tabulations were computed to investigate culture and gender differences in most important life event domains. Next, four configural frequency analyses were conducted using Neuroticism, Extraversion, and the first most often mentioned life event domain for each sample (i.e., marriage and historical life events). Results suggest that events related to marriage were the most frequent important event domains mentioned by U.S. centenarians. The Japanese sample was more likely to report historical events. Men from the U.S. were more likely to report events related to work and retirement compared to U.S. women, and U.S. women reported events related to family as the most important life events when compared to U.S. men. Japanese women considered events related to marriage, death and grief as the most important life events when compared to Japanese men. In addition, Japanese men reported events related to work and retirement as the most important life events. A cross-cultural difference was found in life events: U.S. centenarians were more likely to mention positive experiences related to marriage and children, whereas Japanese centenarians reported mostly negative and traumatic experiences such as historical, death/grief, and work/retirement events.
[Show abstract][Hide abstract] ABSTRACT: Prevention of disability is a major challenge in aging populations; however, the extent to which physical independence can be maintained toward the limit of human life span remains to be determined.
We examined the health and functional status of 642 centenarians: 207 younger centenarians (age: 100-104 years), 351 semi-supercentenarians (age: 105-109 years), and 84 supercentenarians (age: >110 years). All-cause mortality was followed by means of an annual telephone or mailed survey.
Age-specific disability patterns revealed that the older the age group, the higher the proportion of those manifesting independence in activities of daily living at any given age of entry. Multiple logistic regression analysis identified male gender and better cognitive function as consistent determinants of physical independence across all age categories. In a longitudinal analysis, better physical function was significantly associated with survival advantage until the age of 110. However, mortality beyond that age was predicted neither by functional status nor biomedical measurements, indicating alternative trajectories of mortality at the highest ages.
These findings suggest that maintaining physical independence is a key feature of survival into extreme old age. Future studies illuminating genetic and environmental underpinnings of supercentenarians' phenotypes will provide invaluable opportunities not only to improve preventive strategies but also to test the central hypotheses of human aging.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 11/2013; · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The rs1333049 (G/C) polymorphism located on chromosome 9p21.3 is a candidate to influence extreme longevity owing to its association with age-related diseases, notably coronary artery disease (CAD). We compared allele/genotype distributions of rs1333049 in cases (centenarians) and controls (younger adults, without (healthy) or with CAD) in two independent cohorts: Spanish (centenarians: n = 152, 128 women, 100-111 years; healthy controls: n = 343, 212 women, age <50 years; CAD controls: n = 98, 32 women, age ≤65 years) and Japanese (centenarians: n = 742, 623 women, 100-115 years; healthy controls: n = 920, 511 women, < 60 years; CAD controls: n = 395, 45 women, age ≤65 years). The frequency of the "risk" C-allele tended to be lower in Spanish centenarians (47.0 %) than in their healthy (52.9 %, P = 0.088) or CAD controls (55.1 %, P = 0.078), and significant differences were found in genotype distributions (P = 0.034 and P = 0.045), with a higher frequency of the GG genotype in cases than in both healthy and CAD controls as well as a lower proportion of the CG genotype compared with healthy controls. In the Japanese cohort, the main finding was that the frequency of the C-allele did not differ between centenarians (46.4 %) and healthy controls (47.3 %, P = 0.602), but it was significantly lower in the former than in CAD controls (57.2 %, P < 0.001). Although more research is needed, the present and recent pioneer findings (Rejuvenation Res 13:23-26, 2010) suggest that the rs1333049 polymorphism could be among the genetic contributors to exceptional longevity in Southern European populations, albeit this association does not exist in the healthy (CAD-free) Japanese population.
[Show abstract][Hide abstract] ABSTRACT: Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non-centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta-analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population.
[Show abstract][Hide abstract] ABSTRACT: Introduction : The Centenarian Studies Network (CSN) is a group of 7 centenarian studies and associated scientists from the USA (Ashkenazi Jewish and New England Centenarian Studies), Australia, Sardinia, Japan, Spain and Italy.
Method : Investigators from the CSN will provide 10 minute presentations according to the following topics: The ideal phenotype panel for the study of exceptional survival: 1) Health related behaviors (Nir Barzilai) 2) Neuropsychological and MRI assessment (Perminder Sachdev & Charlene Levitan) 3) Demographic study (Gianni Pes) 4) Physical, functional and biochemical assessment (Nobu Hirose) Genetic findings: 1) GWAS meta-analysis (Paola Sebastiani) 2) micro-RNA findings (Jose Vina) 3) Cross-ethnic comparisons (Gil Atzmon) 4) Functional variants and possible pathways (Annibale Puca)
Results : Results for the above 8 topics will be presented.
Conclusion : Centenarian studies must pool their rare resources if they can expect to produce large enough samples for robust findings and it is essential that genetic studies attempt to replicate and compare each other’s results. In addition, this Centenarian Studies Network includes a multidisciplinary group of clinicians, geneticists, molecular biologists, and biostatisticians to effectively deal with the complexity of the many genetic and environmental factors that contribute to exceptional longevity.
The 20th IAGG Congress of Gerontology and Geriatrics, Seoul, Korea; 06/2013
[Show abstract][Hide abstract] ABSTRACT: Longevity phenotype in humans results from the influence of environmental and genetic factors. Few gene polymorphisms have been identified so far with a modest effect on lifespan leaving room for the search of other players in the longevity game. It has been recently demonstrated that targeted disruption of the mouse homolog of the human angiotensin II type 1 receptor (AT(1)R) gene (AGTR1) translates into marked prolongation of animal lifespan (Benigni et al., J Clin Invest 119(3):524-530, 2009). Based on the above study in mice, here we sought to search for AGTR1 variations associated to reduced AT(1) receptor protein levels and to prolonged lifespan in humans. AGTR1 was sequenced in 173 Italian centenarians and 376 younger controls. A novel non-synonymous mutation was detected in a centenarian. Two polymorphisms in AGTR1 promoter, rs422858 and rs275653, in complete linkage disequilibrium, were significantly associated with the ability to attain extreme old age. We then replicated the study of rs275653 in a large independent cohort of Japanese origin (598 centenarians and semi-supercentenarians, 422 younger controls) and indeed confirmed its association with exceptional old age. In combined analyses, rs275653 was associated to extreme longevity either at recessive model (P = 0.007, odds ratio (OR) 3.57) or at genotype level (P = 0.015). Significance was maintained after correcting for confounding factors. Fluorescence activated cell sorting analysis revealed that subjects homozygous for the minor allele of rs275653 had less AT(1)R-positive peripheral blood polymorphonuclear cells. Moreover, rs275653 was associated to lower blood pressure in centenarians. These findings highlight the role of AGTR1 as a possible candidate among longevity-enabling genes.
[Show abstract][Hide abstract] ABSTRACT: This response letter addresses two points raised by le Bourg when discussing our previous paper entitled "Exploring the impact of climate on human longevity". First, the arguments explaining the accuracy of the numbers of centenarian in Okinawa are developed, and second the composition and healthfulness of the traditional Okinawan diet are described as well as the changes in dietary pattern and their impact on longevity.
[Show abstract][Hide abstract] ABSTRACT: Objective: Japan is one of the world’s eminent longevity countries. The most important problem for elderly people is maintenance of their health condition. It is important to be able to maintain excellent oral function to achieve a healthy long life and to improve QOL. This research examines the influence that improvement of QOL by the mouth function exerts on the state of the whole body among oldest old people resident of Tokyo metropolitan-area.
Method: A total of 407 people, over 85 years old were participated in this study (male; 189, female; 218, age; 85-102 years, mean age; 87.7 years). A questionnaire assessing socio-demographic information, health history, oral health-impact profile and number of natural teeth was used. Self-perceived impact of oral health on quality of life was observed using The Geriatric Oral Health Assessment Index (GOHAI).
Result: The median GOHAI was 56.0 (51.0-58.0). We classified GOHAI scores on the basis of quartile, and put clinical oral health measures, socioeconomic and general health factors in it and compared it between the 4 groups. Then the significant difference was observed in the number of remaining teeth, maximum occlusal force and chewable food index which are oral health measures, and dental care past 1 year. Further, also in ADL, there was a significant difference between 4 groups.
Conclusion: The results suggested that the score of the oldest old's GOHAI related to the oral health states and general health factors. Further the more score of GOHAI was high, the more leading healthy life was suggested.
IADR/AADR/CADR General Session and Exhibition 2013; 03/2013
[Show abstract][Hide abstract] ABSTRACT: Prevention or postponement of age-related diseases and functional limitation is the key component of successful aging. We studied centenarians, a model for successful aging in terms of functional status and morbidities. Vast majority of centenarians had chronic disease such as hypertension (63.6%) , heart disease (28.8%) , stroke (15.9%) , fragile fracture (46.4%) , and few centenarians were free from any chronic diseases. Male centenarians had better physical function than female counterparts. Stroke and fragile fracture had negative impacts on their functional status, but hypertension was paradoxically associated with better physical function. When we looked at mortality beyond 100 years of age, physical function, but not morbidity profile had significant impact on their mortality. These results raised a notion that age-related frailty or diminution of functional reserve may be the major cause both for physical disability and poor prognosis of centenarians. Previous results from our study suggested that stability of energy homeostasis, in which neuroendocrine system has a key role, may be important to maintain physical function at the extreme old age.
[Show abstract][Hide abstract] ABSTRACT: Objective: To examine whether habitual dietary intake of marine-origin n-3 polyunsaturated fatty acids (MOPUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with functional mobility in the community-dwelling oldest old, 85 years or older, who are at high risk for physical disability. Design: A cross-sectional study. Setting: A community-based survey conducted at university research center or home-based. Participants: Four hundred seventeen (189 men, 228 women) out of 542 participants in the baseline examination of the Tokyo Oldest Old Survey on Total Health, a community-based ongoing longitudinal study among the oldest old living in the center of Japan. Measurements: Habitual dietary intake of MOPUFA was assessed by the brief-type self-administered diet history questionnaire (BDHQ), and functional mobility was assessed by the Timed Up and Go test. Plasma inflammatory biomarkers (C-reactive protein, interleukin-6 and tumor necrosis factor-α) were measured. We evaluated the cross-sectional association between habitual intake of MOPUFA and functional mobility using multivariate logistic regression analysis. Prior to the analysis, validation of BDHQ in this study was confirmed among 190 participants (96 men, 94 women) based on the EPA and DHA concentrations in the erythrocyte membrane phospholipids as reference. Results: Moderate correlation between estimated dietary intake of EPA/DHA and concentration of EPA/DHA in the erythrocyte membrane phospholipids was obtained (Spearman's r=0.29-0.58, p<0.01). Multivariate logistic regression analysis revealed that a lower habitual intake of EPA+DHA was significantly associated with poor functional mobility in men but not in women (OR (95%CI) per 1 SD increase of EPA+DHA intake; 0.55 (0.33-0.91), 0.88 (0.59-1.32), men and women respectively). Conclusions: Habitual intake of MOPUFA was associated with functional mobility in community-dwelling oldest old men.
The Journal of Nutrition Health and Aging 01/2013; 17(1):82-9. · 2.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Induced pluripotent stem cell (iPSC) technology can be used to model human disorders, create cell-based models of human diseases, including neurodegenerative diseases, and in establishing therapeutic strategies. To detect subtle cellular abnormalities associated with common late-onset disease in iPSCs, valid control iPSCs derived from healthy donors free of serious late-onset diseases are necessary. Here, we report the generation of iPSCs from fibroblasts obtained immediately postmortem from centenarian donors (106- and 109-years-old) who were extremely healthy until an advanced age. The iPSCs were generated using a conventional method involving OCT4, SOX2, KLF4, and c-MYC, and then differentiated into neuronal cells using a neurosphere method. The expression of molecules that play critical roles in late-onset neurodegenerative diseases by neurons differentiated from the centenarian-iPSCs was compared to that of neurons differentiated from iPSCs derived from familial Alzheimer's disease and familial Parkinson's disease (PARK4: triplication of the α synuclein gene) patients. The results indicated that our series of iPSCs would be useful in neurodegeneration research. The iPSCs we describe, which were derived from donors with exceptional longevity who were presumed to have no serious disease risk factors, would be useful in longevity research and as valid super-controls for use in studies of various late-onset diseases.
PLoS ONE 07/2012; 7(7):e41572. · 3.53 Impact Factor