Exceptional longevity in Okinawa: Demographic trends since 1975.

Demographers have studied the Japanese mortality pattern since Japan became the most longevous population worldwide, half a century ago. Nutrition and lifestyle were considered by epidemiologists, gerontologists and other scientists as the most important reasons explaining the Japanese superiority. In Okinawa, the mortality pattern is even more exceptional, but few demographers have pointed out this exception. Other scientists proposed different explanations - for example some genetic characteristics, less salt and more animal protein in the food, a mild climate, a higher level of activity, a better consideration of the oldest in the population and, globally speaking, a more traditional lifestyle. At the end of the 1980s, lower improvements of mortality among young adults were identified in Okinawa. In 2002, Okinawa fell from the 4th to the 26th place in the ranking of the 47 Japanese prefectures by male life expectancy. This has been considered by the population of Okinawa as a 'shock'. Our in-depth analysis of available life tables and associated mortality rates proves that the population of Okinawa is divided into two groups of generations: those born before World War II and those born after. The older generations clearly experience a highly favourable mortality pattern, whereas the younger generations show mortality levels that are definitively higher compared to mainland Japan. This contribution considers which factors may explain such a situation, including the plausible invalidation of the age of some oldest in the population. We plea for in-depth demographic age validation that will enhance all scientific findings so far and boost the exceptional longevity in Okinawa.

Is a plant-based diet effective to maintain a good psycho-affective status in old age? Results of a survey of a long-lived population from Sardinia.

BACKGROUND: Depression is common among the elderly, resulting in poor quality of life and elevated healthcare expenditure. Among other factors, dietary habits could also affect this condition, although the specific food patterns involved remain to be established. The present study aimed to assess the role of plant- versus animal-dominant foods consumption on the affective state of nonagenarians from a Sardinian population, Italy, well known for its longevity (Blue Zone). METHODS: Data, including demographic, education, anthropometric parameters, monthly income, and comorbidity were recorded and analyzed. Symptomatic depression was assessed using the Geriatric Depression Scale (GDS) during a comprehensive home geriatric assessment; nutritional status was evaluated by a validated food frequency questionnaire. RESULTS: A total of 200 elderly subjects living in the Sardinian Blue Zone (mean age 93.9 ± 3.9 years) participated in the study; symptomatic depression was present in 51% of the whole cohort and was more common among women. Multivariable logistic regression showed a significantly greater risk of depression in people consuming plantbased foods (OR = 1.42, 95% CI 1.04-1.93), whereas moderate animal-derived foods consumption was associated with a better affective state (OR = 0.79, 95% CI 0.62-0.98). CONCLUSIONS: These findings indicate that a more balanced diet, including animal-derived foods, instead of an exclusive plant-dominant diet, may be more appropriate in the elderly, and abstention from animal-based food intake should not be recommended in advanced age to prevent depression.

Diet and longevity in the Blue Zones: A set-and-forget issue?

The Blue Zones (BZs) are areas of the globe inhabited by exceptionally long-lived populations. They include the island of Okinawa in Japan, the island of Ikaria in Greece, the mountain area of the island of Sardinia in Italy, and the peninsula of Nicoya in Costa Rica. Their longevity is a relatively recent phenomenon that has been progressively investigated since the dawn of this century. Research efforts over the past two decades have sought to shed light on the factors associated with this longevity, as well as explore the possibility of lessons transferable to the general population. Among the features of BZ inhabitants, described in the literature, their eating habits hold a prominent place, as these have the advantage of being easily quantifiable and applicable on a larger scale. However, it is too often taken for granted that the mere fact of being documented in a long-lived population makes the diet a causal factor of that population's longevity; this is a claim which should be proven. Furthermore, it is implicitly assumed that a specific BZ diet is homogeneous and remains stable over time, whereas some evidence suggests the opposite. Therefore, this review summarizes our current knowledge of the BZ diets and discusses whether they can be considered as a paradigmatic example of healthy nutrition valid for anyone or, rather, a set of evolving food patterns that has offered benefits to a few specific communities in recent decades.

Does the trained immune system play an important role in the extreme longevity that is seen in the Sardinian blue zone?

Villages in the island of Sardinia in the Mediterranean that display exceptional longevity are clustered within a defined mountainous region. Because of their unique location we hypothesize that these villages had a unique infectious disease exposure relevant to the observed successful longevity. These highland villages had a significant exposure to malaria in the first half of the 20th century after which malaria was eliminated due to vector control mechanisms. In addition, there is likely a high incidence of Helicobacter pylori infections among shepherds in Sardinia, the primary occupation of many living in the LBZ, as well as helminth infections among children. This suggests that individuals living in the LBZ had a unique infectious disease exposure. Specifically, we hypothesize that the continued high exposure of residents in the LBZ to these infectious agents prior to the 1950s lead to the generation of a uniquely trained (or imprinted) immune system. Once some of these diseases were eliminated in the latter half of the century, individuals within the LBZ were equipped with a trained immune system that was uniquely capable of not only responding effectively to common infections but also responding in a manner that maximized maintaining tissue health. In addition, there are lifestyle factors that also favor such a trained immune system. This hypothesis may help explain the slow progression of chronic immune mediated diseases as well as other chronic non-transmissible age-related diseases seen in the Sardinian LBZ and serve as a template for future studies that support or refute this hypothesis.

Centenarians exposed to the Spanish flu in their early life better survived to COVID-19.

BACKGROUND: Although it is known that mortality due to COVID-19 increases progressively with age, the probability of dying from this serious infection among the oldest-old population is little known, and controversial data are found in literature. METHODS: We examine the mortality by year and month of birth of Belgians who had turned 100 during the current COVID-19 pandemic and whose birth fell on the years around the end the First World War and the outbreak of the H1N1 "Spanish flu" pandemic. FINDINGS: The COVID-19 mortality of the "older" centenarians is significantly lower than that of "younger" centenarians, and this difference between the two groups reaches a maximum on August 1, 1918 as the discriminating cut-off date of birth. Having excluded the plausible impact of the end of WWI it becomes clear that this date corresponds to the time of reporting the first victims of the Spanish flu pandemic in Belgium. INTERPRETATION: In this study, the striking temporal coincidence between the outbreak of the Spanish flu epidemic and the birth of the cohorts characterized by greater fragility towards COVID-19 in 2020 strongly suggests a link between exposure to 1918 H1N1 pandemic influenza and resistance towards 2020 SARS-Cov-2. It can be speculated that the lifetime persistence of cross-reactive immune mechanisms has enabled centenarians exposed to the Spanish flu to overcome the threat of COVID-19 a century later.

Specific features of the oldest old from the Longevity Blue Zones in Ikaria and Sardinia.

Human longevity may be found in single individuals as well as in the population as a whole ("population longevity"). Longevity Blue Zones (LBZs), which are areas with an unusually high number of oldest old, have been identified in Sardinia and the Greek island of Ikaria. We compared the lifestyle, health status and some genetic markers of the LBZ populations with those of reference populations from Italy and Greece; the data were extracted from the GEHA database. In the LBZs, the proportion of individuals who never married or were married and still living with their spouse was significantly greater. Nonagenarians males and females with a high self‒perception of optimism and/or a high score for self-rated health were also found in larger proportions in LBZs. Among the variables with lower frequency were the proportion of the widowed, the percentage of subjects who had suffered a stroke and the frequency of Apoε4 and Apoε2 and the TT genotype of FOXO3A gene. Compared to behavioral and health indicators, the impact of genetic factors might be relatively less important in the LBZs. Nevertheless, further research is needed to identify potential epigenetic traits that might play a predominant role due to the interaction between genetics and the human and physical environments.

Description of Lifestyle, Including Social Life, Diet and Physical Activity, of People ≥90 years Living in Ikaria, a Longevity Blue Zone.

A cross-sectional observational study was conducted to describe the lifestyle of people ≥90 years, living in Evdilos or Raches, two municipalities of the Greek island of Ikaria, classified a longevity blue zone. The 71 participants were interviewed and underwent the Mediterranean Islands study food frequency questionnaire (MEDIS-FFQ) and the international physical activity questionnaire (IPAQ). The frequency of social contacts was daily for 77.9% of participants, weekly for 16.1%, and monthly for 5.9%. Most participants (90.0%) believed in God, and 81.4% took part in religious events. A total of 62.0% attended Panigiria festivals. Access to primary health care was considered difficult in the past for 66.2% of participants, while 22.1% felt that it remained difficult at the time of the survey. The level of adherence to the Mediterranean diet was 62.7% (61.6% in women and 64.0% in men). Physical activity levels were moderate or high for 71.8% of participants (59.5% of women and 85.3% of men). In conclusion, the participants had a very high level of family solidarity, social interaction and physical activity. The results concerning the Mediterranean diet are less convincing. It would be interesting to study the impact of these factors on the longevity of the oldest old aged people living in Ikaria.

Evolution of the Dietary Patterns Across Nutrition Transition in the Sardinian Longevity Blue Zone and Association with Health Indicators in the Oldest Old.

Health and longevity in humans are influenced by numerous factors, including lifestyle and nutrition. However, the direct relationship between lifetime eating habits and functional capacity of the elderly is poorly understood. This study investigated the dietary changes across nutrition transition (NT) in the early 1960s, in a population located in the Sardinia island known for its longevity, dubbed as "Longevity Blue Zone" (LBZ), as well as the relationship between the dietary patterns and a panel of health indicators. A total of 150 oldest-old participants (89 women and 61 men, age range 90-101 years) living in the LBZ were recruited. Participants were interviewed using validated questionnaires to assess the consumption frequency of common food items, as well as the correlation with self-rated health, comorbidity, affective and cognitive level, physical mobility, disability and anthropometric parameters. Differences between subgroups were evaluated using the Mann-Whitney U test for independent samples or the Wilcoxon signed-rank test for paired samples. Correlation analysis was performed by calculating the Spearman correlation coefficient, separately in males and females. Compared to the pre-NT epoch, the consumption of meat, olive oil and fresh fruit slightly increased, while the consumption of lard, legumes and vegetables decreased. A significant association was found between increased olive oil intake across NT and self-rated health (ρ = 0.519), mobility (ρ = 0.502), improved vision (ρ = -0.227) and hearing (ρ = -0.314); increased chicken meat intake and performance in activities of daily living (basic activities of daily living: ρ = 0.351; instrumental activities of daily living: ρ = 0.333). Instead, vegetable consumption showed low correlation with health indicators. A mild increase in meat intake, mostly pastured poultry, is associated with better physical performance in the Sardinian LBZ elders, suggesting that a supply of protein may have been crucial to maintaining adequate functional capacity.

Assessment of the Health Status of the Oldest Olds Living on the Greek Island of Ikaria: A Population Based-Study in a Blue Zone.

OBJECTIVE: To describe the demographic characteristics, socio-economic status, functional status (autonomy, strength), and health status (cognitive and thymic functions, cardiovascular risk factors, and nutritional status) of the oldest olds living on the Greek island of Ikaria. We also try to explain the longevity observed in this population. METHODS: A cross-sectional observational study of people aged 90 and over living in both municipalities of north-western Ikaria (Evdilos and Raches) was conducted over one year, from October 21, 2012 to October 21, 2013. The participants were interviewed (medical history), had a brief clinical examination, and underwent standardized geriatric assessments including the Geriatric Depression Scale (GDS-15), the Mini-Mental-State Examination (MMSE), the Activities of Daily Living (ADL), the Instrumental ADL (IADL), and an assessment of grip strength. RESULTS: Seventy-one persons (37 females, 34 males), aged 94.1 years on average, were interviewed at their homes. Seven percent were current smokers (females 5.4%, males 8.8%). Hypertension was diagnosed in 70.4% of participants, diabetes in 19.7%, hypercholesterolemia in 12.7%, and obesity in 17.2%; 66.0% of the population had one chronic disease or more. The mean score for the GDS-15 scale was 3.7/15.0, 23.7/30.0 for the MMSE, 4.0/6.0 for the ADL, and 4.2/8.0 in females and 3.6/5.0 in males for the IADL. Grip strength was 17.0 kg in females and 26.5 kg in males. CONCLUSIONS: This study provides an overview of the socio-demographic and medical characteristics of the oldest olds living in a longevity Blue Zone.

Association of endemic goitre and exceptional longevity in Sardinia: evidence from an ecological study.

This study aims to test the hypothesis that a high prevalence of endemic goitre, considered as a proxy measure for subclinically reduced thyroid function in the population, is geographically associated with exceptional longevity. Using historical data available for 377 Sardinian municipalities in the first half of the twentieth century, we performed an ecological study to investigate the geographic distribution of goitre and its spatial association with demographic indicators of population longevity. This analysis was conducted by using both conventional ordinary least square and geographically weighted regression models to take into account spatial autocorrelation and included other longevity-associated factors previously identified in Sardinia. The spatial analysis revealed that the goitre rate (p < 0.0001), the proportion of inhabitants involved in pastoralism (p = 0.016), the terrain inclination (p = 0.008), and the distance from the workplace as a proxy for physical activity (p = 0.023) were consistently associated with population longevity at an aggregated level in the 377 municipalities. Within the limits of an ecological study design, our findings support the existence of a significant association between high goitre prevalence and increased probability to survive into old age. The present study confirms previous results and is consistent with animal studies and epidemiological surveys in other long-lived areas known as Blue Zones. Potential mechanisms underlying this association need to be further investigated.

Analysis of Physical Activity Among Free-Living Nonagenarians From a Sardinian Longevous Population.

Physical activity was identified as a major determinant of longevity. Using wearable accelerometers, we evaluated energy expenditure (EE), including resting- (REE) and total-energy expenditure (TEE), physical activity level (PAL), percentage of PAL ≥ 3 metabolic equivalent tasks (METs), number of steps, resting index (RI%) and sleep patterns in 44 free-living nonagenarians (27 men) residing in a Sardinian village famous for its longevous population. The average REE and TEE recorded were 1275 ± 163 kcal/day and 2284 ± 543 in the men and 952 ± 108 kcal/day and 1810 ± 302 in the women, respectively. The average PAL was 1.8, and the percentage of physical activity >3 METs was greater than 40%. A significant negative correlation (p < 0.05) between disability and PAL was found among the women. This study provides evidence that nonagenarians from the longevous population of Sardinia show excellent physical functionality indexes. Their longevity might result, at least in part, from their ability to stay physically fit during aging.

Why were Sardinians the shortest Europeans? A journey through genes, infections, nutrition, and sex.

Since ancient times the Mediterranean island of Sardinia has been known for harboring a population with an average body height shorter than almost every other ethnic group in Europe. After over a century of investigations, the cause(s) at the origin of this uniqueness are not yet clear. The shorter stature of Sardinians appears to have been documented since prehistoric times, as revealed by the analysis of skeletal remains discovered in archaeological sites on the island. Recently, a number of genetic, hormonal, environmental, infective and nutritional factors have been put forward to explain this unique anthropometric feature, which persisted for a long time, even when environmental and living conditions improved around 1960. Although some of the putative factors are supported by sound empirical evidence, weaker support is available for others. The recent advent of whole genome analysis techniques shed new light on specific variants at the origin of this short stature. However, the marked geographical variability of stature across time and space within the island, and the well-known presence of pockets of short height in the population of the southern districts, are still puzzling findings that have attracted the interest of anthropologists and geneticists. The purpose of this review is to focus on the state-of-the-art research on stature, as well as the factors that made Sardinians the shortest among Europeans.

Fertility History, Children's Gender, and Post-Reproductive Survival in a Longevous Population.

The question of whether mothers' fertility history influences their post-reproductive survival has been addressed frequently in the scientific literature. Using data from Villagrande Strisaili, Sardinia, where longevity is higher than anywhere else in Europe, we analyzed the relationship between the fertility pattern of mothers who survived past age 50 (n = 539) and their post-reproductive lifespan. We find that, after adjustment for potential confounders (mothers' birth cohort, survival of spouse), the mothers who on average delivered their children later displayed a reduced mortality risk (‒2.9 percent for each additional year), supporting previously reported findings. We also find that a male-skewed offspring ratio was associated with decreased mortality risk of mothers, with longer survival of mothers who delivered their sons above age 35 (p = 0.005), a result not found for daughters. So far, no biological explanation has been suggested for the positive effect of delivering sons later in life. We conjecture that in our dataset stronger nonbiological factors such as gender-specific sociocultural and economic factors may have masked the negative effect reported in other populations, for which a biological explanation was proposed.

Centenarians' Marital History and Living Arrangements: Pathways to Extreme Longevity.

OBJECTIVES: Mortality risk for older persons is associated with marital status and living arrangements, for example, living alone, with a spouse, with others but without a spouse, or in a collective household. This study analyzed the marital history and living arrangements of centenarians with the aim of identifying which trajectories are associated with reaching an advanced age. METHOD: Original longitudinal register-based data for 3,000 Belgian centenarians born between the years 1893 and 1903 were used to reconstruct their marital history and living arrangements during their later life (from age 60 to 100). RESULTS: The marital history and living arrangements for male and female centenarians were strikingly different after they reached the age of 60. From age 60 to 100, male centenarians lived twice as long with their wife as female centenarians did with their husband. Female centenarians lived alone for more than half of their lives. Male centenarians had younger wives and female centenarians had older husbands than non-centenarians. More than half of the widowers remarried and did so with a woman who was generally more than 10 years younger. Most centenarians ended their life in a nursing home but entered it very late in life. DISCUSSION: In very old age, living with a spouse is beneficial for men but not for women, for whom living alone is more advantageous than living with a spouse. This study compares the marital history and living arrangement trajectory of centenarians with people who did not live as long to determine associated mortality risks confirming that men are often not able to live by themselves, whereas women seem to have few problems to manage on their own.

The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific.

To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.

Description of extreme longevity in the Balearic Islands: Exploring a potential Blue Zone in Menorca, Spain.

AIM: We aimed to determine whether there was a Blue Zone, an area characterized by extreme longevity, in Menorca, Spain. METHODS: We explored official statistics of the Balearic Islands, Spain, and calculated life expectancy from 1991 to 2009, by sex and island, among other demographic estimators. RESULTS: The life expectancy at birth in Menorca reached a peak in 2007 with 82.3 years, but since 2001 in females and 2007 in males, it plateaued and then descended. The percentage of centenarians in Es Migjorn Gran was 0.17% in 2001, only because of the 0.33% male contribution, and it returned to within the average Balearic rates. There is no record of any other surviving centenarian after 2006 in Es Migjorn Gran. Results obtained with other demographic indices are confirmatory. CONCLUSIONS: It appears there was no extreme longevity or Blue Zone in Es Migjorn Gran and the surrounding villages in Menorca.

Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.

Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006.

This study investigated the relationship between individual height and survival at older ages among conscripts born between 1866 and 1915 in an inland village of Sardinia, Italy. Individual age at death was related to military height measurement at age 20. Differential longevity of conscripts at older ages was investigated through the comparison of age-specific mortality rates and life expectancy estimates. Results indicated that short conscripts (<161.1 cm) generally had higher survival rates than their tall peers (≥ 161.1 cm). At 70 years of age, tall peers were expected to live two years less than short conscripts. Biological mechanisms were examined in relation to the greater longevity of shorter people.

A population where men live as long as women: villagrande strisaili, sardinia.

Usually women live longer than men and female centenarians largely outnumber male centenarians. The findings of previous studies identifying a population with a femininity ratio close to 1.0 among centenarians in the mountainous region of Sardinia was the starting point of an in-depth investigation in order to compare mortality trajectories between men and women in that population. The exceptional survival of men compared to women emerges from the comparison with similar Italian data. Age exaggeration for men has been strictly excluded as a result of the age validation procedure. The discussion suggests that besides biological/genetic factors, the behavioral factors including life style, demographic behavior, family support, and community characteristics may play an important role. No single explanation is likely to account for such an exceptional situation and a fully integrated multidisciplinary approach is urgently needed.