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Nonagenarians and centenarians serve as successful examples of aging and extended longevity, showcasing robust regulation of biological mechanisms and homeostasis. Given that human longevity is a complex field of study that navigates molecular and biological mechanisms influencing aging, we hypothesized that microRNAs, a class of small noncoding RNAs implicated in regulating gene expression at the post‐transcriptional level, are differentially regulated in the circulatory system of young, middle‐aged, and nonagenarian individuals. We sequenced circulating microRNAs in Okinawan males and females <40, 50–80, and >90 years of age accounting for FOXO3 genetic variations of single nucleotide polymorphism (SNP) rs2802292 (TT ‐ common vs. GT ‐ longevity) and validated the findings through RT‐qPCR. We report five microRNAs exclusively upregulated in both male and female nonagenarians with the longevity genotype, play predictive functional roles in TGF‐β, FoxO, AMPK, Pi3K‐Akt, and MAPK signaling pathways. Our findings suggest that these microRNAs upregulated in nonagenarians may provide novel insight into enhanced lifespan and health span. This discovery warrants further exploration into their roles in human aging and longevity. [ABSTRACT FROM AUTHOR]

Isolated populations have advantages for genetic studies of longevity from decreased haplotype diversity and long-range linkage disequilibrium. This permits smaller sample sizes without loss of power, among other utilities. Little is known about the genome of the Okinawans, a potential population isolate, recognized for longevity. Therefore, we assessed genetic diversity, structure, and admixture in Okinawans, and compared this with Caucasians, Chinese, Japanese, and Africans from HapMap II, genotyped on the same Affymetrix GeneChip Human Mapping 500K array. Principal component analysis, haplotype coverage, and linkage disequilibrium decay revealed a distinct Okinawan genome-more homogeneity, less haplotype diversity, and longer range linkage disequilibrium. Population structure and admixture analyses utilizing 52 global reference populations from the Human Genome Diversity Cell Line Panel demonstrated that Okinawans clustered almost exclusively with East Asians. Sibling relative risk (λs) analysis revealed that siblings of Okinawan centenarians have 3.11 times (females) and 3.77 times (males) more likelihood of centenarianism. These findings suggest that Okinawans are genetically distinct and share several characteristics of a population isolate, which are prone to develop extreme phenotypes (eg, longevity) from genetic drift, natural selection, and population bottlenecks. These data support further exploration of genetic influence on longevity in the Okinawans.

Certain micronutrients are protective against cognitive decline. We examined whether there is any uniform pattern of circulating micronutrients cross--culturally that are associated with successful cognitive aging. For the U.S. sample, we used the stored serum/plasma of 115 participants, collected in Oregon, USA. The Okinawa sample consisted of 49 participants selected using similar inclusion criteria as the Oregon sample, from the Keys to Optimal Cognitive Aging Project. All participants were aged 85 years and older without cognitive impairment. We found that the Okinawan elders used fewer vitamin supplements but had similar levels of vitamin [B.sub.12] and [alpha]-tocopherol, lower folate and [gamma]-tocopherol, compared with Oregonian elders. That is, we did not find a uniform pattern of circulating micronutrients, suggesting that micronutrients other than those examined here or other lifestyle factors than nutrition could play an important role in achieving successful cognitive aging. Key Words: Oldest old--Circulating micronutrients--Healthy cognitive aging--Okinawa--Oregon. doi: 10.1093/gerona/glq124

Background. As elite representatives of the rapidly increasing 'oldest-old' population, centenarians have become an important model population for understanding human aging. However, as we are beginning to understand more about this important phenotype, another demographic group of even more elite survivors is emerging--so-called 'supercentenarians' or those who survive 110-plus years. Little is known about these exceptional survivors. Methods. We assessed the Okinawa Centenarian Study (OCS) database for all information on supercentenarians. The database includes dates of birth and year of death for all residents of Okinawa 99 years old or older and a yearly geriatric assessment of all centenarians who consented, enabling prospective study of age-related traits. Of 20 potential supercentenarians identified, 15 had agreed to participate in the OCS interview, physical examination, and blood draw. Of these 15, 12 (3 men and 9 women) met our age validation criteria and were accepted as supercentenarians. Phenotypic variables studied include medical and social history, activities of daily living (ADLs), and clinical phenotypes (physiology, hematology, biochemistry, and immunology). Results. Age at death ranged from 110 to 112 years. The majority of supercentenarians had minimal clinically apparent disease until late in life, with cataracts (42%) and fractures (33%) being common and coronary heart disease (8%), stroke (8%), cancer (0%), and diabetes (0%) rare or not evident on clinical examination. Functionally, most supercentenarians were independent in ADLs at age 100 years, and few were institutionalized before the age of 105 years. Most had normal clinical parameters at age 100 years, but by age 105 exhibited multiple clinical markers of frailty coincident with a rapid ADL decline. Conclusion. Supercentenarians displayed an exceptionally healthy aging phenotype where clinically apparent major chronic diseases and disabilities were markedly delayed, often beyond age 100. They had little clinical history of cardiovascular disease and reported no history of cancer or diabetes. This phenotype is consistent with a more elite phenotype than has been observed in prior studies of centenarians. The genetic and environmental antecedents of this exceptionally healthy aging phenotype deserve further study. Key Words: Supercentenarian--Longevity--Healthy aging--Phenotype--Okinawa--Japan.

Long-lived individuals, such as centenarians, may harbor genetic or environmental advantages important for healthy aging. Populations with high prevalence of such individuals offer fertile ground for such research. However, precise phenotypes are required, particularly accurate age. Okinawa has among the world's highest reported prevalence of centenarians but, despite extensive study, no systematic validation of centenarian prevalence has been published. Therefore. we performed comprehensive age validation of a subset (8%) of the total centenarian population and assessed the reliability of the age registration system. Self-reported age was validated with several common methods and found to correlate well with documented age. Demographic methods, including assessment of age heaping, maximum age at death, centenarian proportions, and male to female ratios of centenarians indicate thai the age registration system is reliable. We conclude that the high reported centenarian prevalence in Okinawa is valid and warrants further study for its genetic and environmental correlates. Key Words: Longevity--Centenarian--Age Validation--Okinawa.

Prospective cohort study is conducted to test whether midlife biological, lifestyle, and sociodemographic risk factors are associated with overall survival and exceptional survival. The results have shown that avoidance of certain risk factors in midlife is associated with the probability of a long and healthy life among men.

Okinawa, an isolated island prefecture of Japan, has among the highest prevalence of exceptionally long-lived individuals in the world; therefore, we hypothesized that, within this population, genes that confer a familial survival advantage might have clustered. We analyzed the pedigrees of 348 centenarian families with 1142 siblings and compared sibling survival with that of the 1890 Okinawan general population cohort. Both male and female centenarian siblings experienced approximately half the mortality of their birth cohort-matched counterparts. This mortality advantage was sustained and did not diminish with age in contrast to many environmentally based mortality gradients, such as education and income. Cumulative survival advantages for this centenarian sibling cohort increased over the life span such that female centenarian siblings had a 2.58-fold likelihood, and male siblings a 5.43-fold likelihood, versus their birth cohorts, of reaching the age of 90 years. These data support a significant familial component to exceptional human longevity.

Consistent with the compression-of-morbidity hypothesis, several studies have reported that a significant proportion of centenarians delay or escape age-related diseases. Of those who live with such diseases for a long time, many appear to do so with better functional status than do younger persons who do not achieve extreme old age. The authors describe the first autopsy in an Okinawan-Japanese centenarian who escaped many age-related illnesses and delayed frailty toward the end of her very long life. Her late-life morbidity pattern is contrasted with that of white centenarians.

Energy restriction extends life span and lowers mortality from age-related diseases in many species, but the effects in humans are unknown. We prospectively examined this relationship in a large epidemiological study of Japanese-American men. We followed 1915 healthy nonsmokers, aged 45-68 years at study onset, for 36 years. Twenty-four-hour recall of diet was recorded at baseline, and follow-up was for all-cause mortality. After adjustment for age and other confounders, there was a trend toward lower mortality in the second quintile of energy intake, suggesting that men who consumed 15% below the group mean were at the lowest risk for all-cause mortality. Increased mortality was seen with intakes below 50% of group mean. Thus, we observed trends between low energy intake and reduced risk for all-cause mortality in humans until energy intake fell to less than half the group mean, consistent with previous findings in other species.

Abstract Ageing is a challenge for any living organism and human longevity is a complex phenotype. With increasing life expectancy, maintaining long-term health, functionality and well-being during ageing has become an essential goal. To increase our understanding of how ageing works, it may be advantageous to analyze the phenotype of centenarians, perhaps one of the best examples of successful ageing. Healthy ageing involves the interaction between genes, the environment, and lifestyle factors, particularly diet. Besides evaluating specific gene-environment interactions in relation to exceptional longevity, it is important to focus attention on modifiable lifestyle factors such as diet and nutrition to achieve extension of health span. Furthermore, a better understanding of human longevity may assist in the design of strategies to extend the duration of optimal human health. In this article we briefly discuss relevant topics on ageing and longevity with particular focus on dietary patterns of centenarians and nutrient-sensing pathways that have a pivotal role in the regulation of life span. Finally, we also discuss the potential role of Nrf2 system in the pro-ageing signaling emphasizing its phytohormetic activation.