Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians.

Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1-3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.

Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians.

Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells (CD4 cytotoxic T lymphocytes [CTLs]) as a signature of supercentenarians. Furthermore, single-cell T cell receptor sequencing of 2 supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15 to 35% of the entire CD4 T cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, CD4 CTLs extracted from supercentenarians produced IFN-γ and TNF-α upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.

A Cultural Comparison of Personality Profiles of U.S. and Japanese Centenarians.

The purpose of this study was a cross-cultural examination of centenarians' personality through a person-centered approach to examine if there is a "resilient" personality profile consistent across cultures. Proxy reports information was obtained from family and close friends of 239 U.S. centenarians from the Georgia Centenarians Study and 272 Japanese centenarians from the Tokyo Centenarian Study. Latent profile analyses were conducted to identify personality profiles in centenarians from the United States and Japan. Two personality profiles were identified in both samples: a "resilient" personality profile and "nonresilient" personality profile. The "resilient" group had higher levels of positive personality traits with higher scores on agreeableness and extraversion and lower scores on neuroticism, conscientiousness, and openness. The "nonresilient" group had higher scores on neuroticism and lower scores on extraversion, openness, agreeableness, and conscientiousness. Fifty percent of U.S. centenarians and 65% of Japanese centenarians were in the "resilient" group.

Cardiovascular health and cognitive functioning among centenarians: a comparison between the Tokyo and Georgia centenarian studies.

ABSTRACTObjectives:Centenarians have survived into very late life, but whether they reach very old age in good health remains unclear. The purpose of this study was to compare the cardiovascular health status and cognitive functioning of centenarians in the United States with centenarians in Japan. DESIGN, SETTING, AND PARTICIPANTS: This cross-national design compared centenarians from the United States and Japan. The sample of U.S. centenarians was recruited from the Georgia Centenarian Study and included 287 centenarians. The sample of Japanese centenarians was recruited from the Tokyo Centenarian Study and included 304 centenarians. MEASUREMENTS: Cognitive functioning was assessed with a mental status questionnaire, and cardiovascular disease by a health history assessment, blood pressure, and selected blood parameters. RESULTS: The results suggest that Tokyo centenarians had lower disease experiences and BMI values, when compared to Georgia centenarians, but blood pressure was higher among Japanese centenarians. Lower levels of hemoglobin in Japanese centenarians and higher levels of C-reactive protein in Georgia were also found. The positive association of hypertension and albumin levels with cognitive functioning and the negative association of stroke occurrence with cognitive functioning were replicated in both countries. Differential effects were obtained for heart problems, BMI, and C-reactive protein (with positive effects for Tokyo centenarians, except for C-reactive protein). CONCLUSION: For extremely old individuals, some markers of cardiovascular disease are replicable across countries, whereas differential effects for cardiovascular health also need to be considered in cardiovascular health.

Characteristic glycopeptides associated with extreme human longevity identified through plasma glycoproteomics.

BACKGROUND: Glycosylation is highly susceptible to changes of the physiological conditions, and accordingly, is a potential biomarker associated with several diseases and/or longevity. Semi-supercentenarians (SSCs; older than 105 years) are thought to be a model of human longevity. Thus, we performed glycoproteomics using plasma samples of SSCs, and identified proteins and conjugated N-glycans that are characteristic of extreme human longevity. METHODS: Plasma proteins from Japanese semi-supercentenarians (SSCs, 106-109 years), aged controls (70-88 years), and young controls (20-38 years) were analysed by using lectin microarrays and liquid chromatography/mass spectrometry (LC/MS). Peak area ratios of glycopeptides to corresponding normalising peptides were subjected to orthogonal projections to latent structures discriminant analysis (OPLS-DA). Furthermore, plasma levels of clinical biomarkers were measured. RESULTS: We found two lectins such as Phaseolus vulgaris, and Erythrina cristagalli (ECA), of which protein binding were characteristically increased in SSCs. Peak area ratios of ECA-enriched glycopeptides were successfully discriminated between SSCs and controls using OPLS-DA, and indicated that tri-antennary and sialylated N-glycans of haptoglobin at Asn207 and Asn211 sites were characterized in SSCs. Sialylated glycans of haptoglobin are a potential biomarker of several diseases, such as hepatocellular carcinoma, liver cirrhosis, and IgA-nephritis. However, the SSCs analysed here did not suffer from these diseases. CONCLUSIONS: Tri-antennary and sialylated N-glycans on haptoglobin at the Asn207 and Asn211 sites were abundant in SSCs and characteristic of extreme human longevity. GENERAL SIGNIFICANCE: We found abundant glycans in SSCs, which may be associated with human longevity.

Relationships between socio-clinico-demographic factors and global cognitive function in the oldest old living in the Tokyo Metropolitan area: Reanalysis of the Tokyo Oldest Old Survey on Total Health (TOOTH).

BACKGROUND: Despite a steady increase in life expectancy, a few studies have investigated cross-sectional correlates and longitudinal predictors of cognitive function, a core domain of the successful aging, among socio-clinico-demographic factors in the oldest-old exclusively. OBJECTIVES: The aims of this study were to examine socio-clinico-demographic characteristics associated with global cognition and its changes in the oldest-old. METHODS: We reanalyzed a dataset of cognitively preserved community-dwelling subjects aged 85 years and older in the Tokyo Oldest Old Survey on Total Health, a 6-year longitudinal observational study. This study consisted of (1) baseline cross-sectional analyses examining correlates of global cognition (n = 248) among socio-clinico-demographic factors and (2) longitudinal analyses examining baseline predictors for changes of global cognition in 3-year follow-up (n = 195). The Mini-Mental State Examination was used as a screening test to assess global cognition. RESULTS: At baseline, higher weights were related to higher cognitive function in the oldest-old. The baseline predictors of global cognitive decline in 3-year follow-up were higher global cognition, shorter education period, and lower sociocultural activities and lower instrumental activity of daily living, in this order. CONCLUSIONS: The present study suggests that it is crucial to attain higher education during early life and avoid leanness or obesity, participate in sociocultural cognitive activities during late life, and maintain instrumental activity of daily living to preserve optimal cognitive function in the oldest-old, which will facilitate developing prevention strategies for cognitive decline and promoting successful aging in this increasing population.

Physical, sensory, and cognitive functioning among centenarians: a comparison between the Tokyo and Georgia centenarian studies.

PURPOSE: The purpose of this study was to compare centenarians in the United States and Japan on sensory, cognitive, and physical functioning and to evaluate a model that tests the interrelationship between physical function, cognition, and sensory impairment in these two unique samples of the oldest old. METHODS: The sample of U. S. centenarians included 245 centenarians, the sample of Japanese centenarians included 304 centenarians. Sensory impairment was assessed by general assessments of vision and hearing, and physical function was assessed with six physical activities of daily living (i.e., eating, grooming, dressing, transporting, bathing, and walking). RESULTS: The results suggest that centenarians from the Georgia study showed higher levels of functioning in all domains when compared to the Tokyo sample. A structural equation model yielded stronger associations between cognitive and sensory function with physical function for the Tokyo sample. CONCLUSIONS: Functional differences may be due, in part, to different care patterns for the oldest old in the United States when compared to Japan.

Subjective well-being in centenarians: a comparison of Japan and the United States.

OBJECTIVE: The present study examined the cultural differences and similarities in the levels and predictors of subjective well-being in Japanese and American centenarians. METHOD: We analyzed data on cognitively intact Japanese (N = 59) and American (N = 125) participants from the Tokyo and Georgia Centenarian Studies, respectively. The Philadelphia Geriatric Center Morale Scale was used to measure subjective well-being, while sociodemographic, social, and health resources were assessed as potential predictors. RESULTS: The American participants reported higher scores on well-being (satisfaction with social relations and psychological comfort). However, cultural differences in the levels of well-being disappeared after we controlled for its predictors. The regression models revealed that health resources (cognitive function, hearing problems, and activities of daily living) were strong predictors of well-being in both countries. Social resources (living with others) were strongly associated with one dimension of well-being (attitude toward one's aging) among the Japanese participants. DISCUSSION: The findings support the existing lifespan and cross-cultural literature, indicating that declines in health impose certain limitations on adaptive capacity in oldest-old age irrespective of cultures, and that social embeddedness is valued in Eastern cultures. The authors speculate that cultural values, i.e. personal autonomy versus relational harmony, play an important role for well-being in oldest-old age.

Increased oxidative stress and coenzyme Q10 deficiency in centenarians.

Aging populations are expanding worldwide, and the increasing requirement for nursing care has become a serious problem. Furthermore, successful aging is one of the highest priorities for individuals and societies. Centenarians are an informative cohort to study and inflammation has been found to be a key factor in predicting cognition and physical capabilities. Inflammation scores have been determined based on the levels of cytokines and C-reactive protein, however, serum antioxidants and lipid profiles have not been carefully examined. We found that the redox balance of coenzyme Q10 significantly shifted to the oxidized form and levels of strong antioxidants, such as ascorbic acid and unconjugated bilirubin, decreased significantly compared to 76-year-old controls, indicating an increased oxidative stress in centenarians. Levels of uric acid, an endogenous peroxynitrite scavenger, remained unchanged, suggesting that centenarians were experiencing moderate, chronic inflammatory conditions. Centenarians exhibited a hypocholesterolemic condition, while an increase in the ratio of free cholesterol to cholesterol esters suggests some impairment of liver function. Serum free fatty acids and monoenoic acid composition, markers of tissue oxidative damage, were significantly decreased in centenarians, indicating an impairment in the tissue repair system. Despite an elevation of the coenzyme Q10 binding protein Psap, serum total coenzyme Q10 levels decreased in centenarians. This suggests a serious deficiency of coenzyme Q10 in tissues, since tissue levels of coenzyme Q10 significantly decrease with age. Therefore, coenzyme Q10 supplementation could be beneficial for centenarians.

Epistasis, physical capacity-related genes and exceptional longevity: FNDC5 gene interactions with candidate genes FOXOA3 and APOE.

BACKGROUND: Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of 'modifier genes', may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population. A total of 1565 individuals were studied, subdivided into 822 middle-aged controls and 743 centenarians. RESULTS: We found a FOXOA3 rs2802292 T-allele-dependent association of fibronectin type III domain-containing 5 (FDNC5) rs16835198 with EL: the frequency of carriers of the FOXOA3 rs2802292 T-allele among individuals with the rs16835198 GG genotype was significantly higher in cases than in controls (P < 0.05). On the other hand, among non-carriers of the APOE 'risk' ε4-allele, the frequency of the FDNC5 rs16835198 G-allele was higher in cases than in controls (48.4% vs. 43.6%, P < 0.05). Among carriers of the 'non-risk' APOE ε2-allele, the frequency of the rs16835198 G-allele was higher in cases than in controls (49% vs. 37.3%, P < 0.05). CONCLUSIONS: The association of FDNC5 rs16835198 with EL seems to depend on the presence of the FOXOA3 rs2802292 T-allele and we report a novel association between FNDC5 rs16835198 stratified by the presence of the APOE ε2/ε4-allele and EL. More research on 'gene*gene' and 'gene*environment' effects is needed in the field of EL.

Relationships of Muscle Echo Intensity with Walking Ability and Physical Activity in the Very Old Population.

This study investigated the relationships between muscle echo intensity (EI), physical activity (PA), and functional mobility in 108 Japanese (88-92 years). We measured EI and muscle thickness (MT) at the midpoint of the anterior superior iliac spine and patella using B-mode ultrasound. Light and moderate-to-vigorous PA (LPA and MVPA) were assessed with a triaxial accelerometer. The timed up and go (TUG) test was used to measure for functional mobility. EI, but not MT, was significantly associated with both TUG scores (ß = 0.17, p = .047) and MVPA (ß = -0.31, p = .01) when adjusted by potential confounders. However, association between EI and TUG disappeared after adjusted for MVPA. Meanwhile, MVPA was significantly associated with TUG scores independent of EI (ß = -0.35, p < .001). Although EI of anterior thigh muscles might be a weaker predictor of functional morbidity than MVPA, it is a noninvasive and practical approach for assessing muscle quality in the very old.

ICC-dementia (International Centenarian Consortium - dementia): an international consortium to determine the prevalence and incidence of dementia in centenarians across diverse ethnoracial and sociocultural groups.

BACKGROUND: Considerable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium - Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary aim is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups. METHODS: Studies focusing on individuals aged ≥95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress. DISCUSSION: General challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of'abnormal' in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments.

Association between maximum occlusal force and 3-year all-cause mortality in community-dwelling elderly people.

BACKGROUND: Among the very elderly, poor oral health reduces life expectancy. In this study, differences in the magnitude of the maximum occlusal force (MOF) in the very elderly were examined in terms of effects on all-cause mortality in a 3-year follow-up. METHODS: We evaluated 489 community-living elderly individuals aged 85 years or older. MOF was measured using an occlusal force measuring device, and participants were classified into three groups according to gender- and dental status-sensitive tertiles. Demographic variables, cognitive, physical function, psychological status, oral health, comorbidity, and blood chemistry factors were assessed. One-way analyses of variance, χ (2) tests, and the Kruskal-Wallis test were used for statistical analyses. The relationship between MOF tertiles and 3-year all-cause mortality was examined using a multivariate Cox model analysis after adjusting for confounding factors. RESULTS: MOF tertiles were significantly associated with cognitive impairment, number of teeth, limitations on chewable foods, handgrip strength, timed up-and-go test, and diabetes mellitus. During the follow-up period, 74 subjects died. Subjects with the highest MOF had a significantly lower mortality rate than other groups (log rank P  =  0.031). In the univariate Cox model, MOF tertiles were independently associated with a lower risk of death (HR = 0.69, 95 % CI = 0.51-0.91). Even after adjusting for various confounders in the multivariate Cox model (Model 1), MOF was independently associated with a lower risk of death (HR = 0.67, 95 % CI = 0.50-0.91). In model 2, we added handgrip strength as a confounder and found that the HR for MOF was attenuated (HR = 0.73, 95 % CI = 0.54-0.99), but still statistically significant. CONCLUSIONS: In a cohort of the very elderly, MOF was independently associated with all-cause mortality after adjusting for various health issues. Moreover, this independent association remained after a further adjustment for handgrip strength; however, the HR was attenuated. This suggests that MOF and handgrip strength may share a common mechanism of a general decrease in muscle strength, possibly sarcopenia, which is a significant cause of mortality in the very old.

Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression.

OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.

Examination of important life experiences of the oldest-old: cross-cultural comparisons of U.S. and Japanese centenarians.

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.

[Functional status, morbidity, and mortality of centenarians].

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.

Status and physiological significance of circulating adiponectin in the very old and centenarians: an observational study.

Background: High levels of circulating adiponectin are associated with increased insulin sensitivity, low prevalence of diabetes, and low body mass index (BMI); however, high levels of circulating adiponectin are also associated with increased mortality in the 60-70 age group. In this study, we aimed to clarify factors associated with circulating high-molecular-weight (cHMW) adiponectin levels and their association with mortality in the very old (85-89 years of age) and centenarians. Methods: The study included 812 (women: 84.4%) for centenarians and 1498 (women: 51.7%) for the very old. The genomic DNA sequence data were obtained by whole-genome sequencing or DNA microarray-imputation methods. Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate regression analyses were used to evaluate cHMW adiponectin characteristics and associated factors. All-cause mortality was analyzed in three quantile groups of cHMW adiponectin levels using Cox regression. Results: The cHMW adiponectin levels were increased significantly beyond 100 years of age, were negatively associated with diabetes prevalence, and were associated with SNVs in CDH13 (p=2.21 × 10-22) and ADIPOQ (p=5.72 × 10-7). Multivariate regression analysis revealed that genetic variants, BMI, and high-density lipoprotein cholesterol (HDLC) were the main factors associated with cHMW adiponectin levels in the very old, whereas the BMI showed no association in centenarians. The hazard ratios for all-cause mortality in the intermediate and high cHMW adiponectin groups in very old men were significantly higher rather than those for all-cause mortality in the low-level cHMW adiponectin group, even after adjustment with BMI. In contrast, the hazard ratios for all-cause mortality were significantly higher for high cHMW adiponectin groups in very old women, but were not significant after adjustment with BMI. Conclusions: cHMW adiponectin levels increased with age until centenarians, and the contribution of known major factors associated with cHMW adiponectin levels, including BMI and HDLC, varies with age, suggesting that its physiological significance also varies with age in the oldest old. Funding: This study was supported by grants from the Ministry of Health, Welfare, and Labour for the Scientific Research Projects for Longevity; a Grant-in-Aid for Scientific Research (No 21590775, 24590898, 15KT0009, 18H03055, 20K20409, 20K07792, 23H03337) from the Japan Society for the Promotion of Science; Keio University Global Research Institute (KGRI), Kanagawa Institute of Industrial Science and Technology (KISTEC), Japan Science and Technology Agency (JST) Research Complex Program "Tonomachi Research Complex" Wellbeing Research Campus: Creating new values through technological and social innovation (JP15667051), the Program for an Integrated Database of Clinical and Genomic Information from the Japan Agency for Medical Research and Development (No. 16kk0205009h001, 17jm0210051h0001, 19dk0207045h0001); the medical-welfare-food-agriculture collaborative consortium project from the Japan Ministry of Agriculture, Forestry, and Fisheries; and the Biobank Japan Program from the Ministry of Education, Culture, Sports, and Technology.

Centenarians have a diverse gut virome with the potential to modulate metabolism and promote healthy lifespan.

Distinct gut microbiome ecology may be implicated in the prevention of aging-related diseases as it influences systemic immune function and resistance to infections. Yet, the viral component of the microbiome throughout different stages in life remains unexplored. Here we present a characterization of the centenarian gut virome using previously published metagenomes from 195 individuals from Japan and Sardinia. Compared with gut viromes of younger adults (>18 yr) and older individuals (>60 yr), centenarians had a more diverse virome including previously undescribed viral genera, such as viruses associated with Clostridia. A population shift towards higher lytic activity was also observed. Finally, we investigated phage-encoded auxiliary functions that influence bacterial physiology, which revealed an enrichment of genes supporting key steps in sulfate metabolic pathways. Phage and bacterial members of the centenarian microbiome displayed an increased potential for converting methionine to homocysteine, sulfate to sulfide and taurine to sulfide. A greater metabolic output of microbial hydrogen sulfide in centenarians may in turn support mucosal integrity and resistance to pathobionts.

Epigenetic profile of Japanese supercentenarians: a cross-sectional study.

BACKGROUND: Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline. METHODS: In this cross-sectional study, we enrolled Japanese non-centenarians (eligible participants aged 20-80 years) from the Tohoku Medical Megabank Community-Based Cohort Study and centenarians and supercentenarians (aged 101-115 years) from the Tokyo Centenarian Study and the Japanese Semi-supercentenarian Study. We assessed participants' whole-blood DNA methylation profiles and then developed sex-specific and non-specific first-generation epigenetic clocks by elastic net regression, calculated individuals' epigenetic ages, and assessed their age acceleration. We also screened for age-related CpG sites in non-centenarians by epigenome-wide linear regression analyses and ANOVA. We subsequently investigated which CpG sites in centenarians and supercentenarians had DNA methylation patterns following the age-related findings obtained from non-centenarians and which did not. We further characterised CpG sites with hypermethylation or hypomethylation in the centenarians and supercentenarians using enrichment and protein-protein interaction network analyses. FINDINGS: We enrolled 421 non-centenarians (231 [55%] women and 190 [45%] men; age range 20-78 years), recruited between May 20, 2013, and March 31, 2016, and 94 centenarians and supercentenarians (66 women [70%] and 28 [30%] men; age range 101-115 years), recruited between Jan 20, 2001, and April 17, 2018. Non-sex-specific epigenetic clock showed the highest accuracy (r=0·96) based on which centenarians and supercentenarians had negative epigenetic age acceleration. Epigenome-wide association analyses further showed that centenarians and supercentenarians had younger-than-expected epigenetic states (DNA methylation profiles similar to those of non-centenarians) for 557 CpG sites enriched in cancer-related and neuropsychiatric-related genes, whereas these individuals had advanced (or older) epigenetic states for 163 CpG sites represented by genes related to TGF-ß signalling, which is involved in anti-inflammatory responses and known to contribute to healthy ageing. INTERPRETATION: These results indicate that exceptionally healthy longevity depends not only on maintaining young epigenetic states but also on advanced states of specific epigenetic regions. FUNDING: The Japan Agency for Medical Research and Development, KDDI Research, and Keio University. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Clinical course of the longest-lived man in the world: A case report.

BACKGROUND AND OBJECTIVE: Supercentenarians, people who have reached 110 years of age, represent an ultimate model of human longevity. We have conducted research from both biomedical and psychosocial perspectives to clarify the factors that contribute to healthy longevity. The current study described the clinical course of the oldest lived man in the world. METHODS: Kimura Jiroemon, who is the verified oldest man in recorded history, lived for more than 116 years. We conducted a longitudinal investigation including physical and psychological assessments, blood data, and electrocardiogram (ECG) from the age of 111 and obtained medical data such as computed tomography (CT) images during the course of hospitalizations in the last year of his life. RESULTS: At the age of 111, Jiroemon was almost independent regarding activities of daily living. Additionally, his Philadelphia Geriatric Center Morale Scale score was 15/17, indicating high psychological well-being. His biological data included first-degree atrioventricular (AV) block on ECG; mild decreases of hemoglobin (11.6 g/dL), hematocrit (36.2%), and albumin levels (3.5 g/dL); and elevated serum cystatin C levels (1.32 mg/L), indicating potential dysfunction of the renal and electrical conduction systems. He then lived without fatal illness until the age of 115 years. At this age, he lost consciousness, and his ECG revealed complete AV block. At the first hospitalization for intensive examination, his doctor recommended implanting a cardiac pacemaker, but he and his family declined. On December 12, 2012, his condition rapidly worsened, and he was hospitalized twice for heart failure because of AV block. On May 11, 2013, he lost consciousness after breakfast, and he was hospitalized for the fourth time. He was diagnosed with pneumonia and heart failure based on his chest CT findings and elevated brain natriuretic peptide levels (160 pg/mL), and died on June 12, 2013 at the age of 116. CONCLUSIONS: Despite having no cardiovascular risk factors throughout his life, Jiroemon developed heart failure from potential heart and kidney dysfunction, suggesting that aging of the cardiorenal system was the ultimate pathology of the oldest man in the world. His clinical course represents a model of both suppression of morbidity and extreme longevity. Comprehensive health and longevity research studies from physical and psychological aspects are required.