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The oldest-old (those aged ≥80 years) are the most rapidly growing age group globally, and are most in need of health care and assistance. We aimed to assess changes in mortality, disability in activities of daily living, and physical and cognitive functioning among oldest-old individuals between 1998 and 2008. We used data from the Chinese Longitudinal Healthy Longevity Study. Three pairs of cohorts aged 80–89 years, 90–99 years, and 100–105 years (in total, 19 528 oldest-old participants) were examined; the two cohorts in each pair were born 10 years apart, with the same age at the time of the assessment in the 1998 and 2008 surveys. Four health outcomes were investigated: annual death rate, Activities of Daily Living (ADL), physical performance in three tests and cognitive function measured by Mini-Mental State Examination (MMSE). We used different tests and multivariate regression analyses to examine the cohort differences. Controlling for various confounding factors, we noted that annual mortality among oldest-old individuals was substantially reduced between 0·2% and 1·3% in 1998–2008 compared with individuals of the same age born 10 years previously, and that disability according to activities of daily living had significantly reduced annually between 0·8% and 2·8%. However, cognitive impairment in the later cohorts increased annually between 0·7% and 2·2% and objective physical performance capacity (standing up from a chair, picking up a book from the floor, and turning around 360°) decreased anually between 0·4% and 3·8%. We also noted that female mortality was substantially lower than male mortality among the oldest-old, but that women's functional capacities in activities of daily living, cognition, and physical performance were worse than their male counterparts. Advances in medications, lifestyle, and socioeconomics might compress activities of daily living disability, that is, benefits of success, but lifespan extension might expand disability of physical and cognitive functioning as more frail, elderly individuals survive with health problems, that is, costs of success. National Natural Science Foundation of China, National Institute on Aging/National Institutes of Health, United Nations Funds for Population Activities.

A rapidly increasing proportion of people in high-income countries are surviving into their tenth decade. Concern is widespread that the basis for this development is the survival of frail and disabled elderly people into very old age. To investigate this issue, we compared the cognitive and physical functioning of two cohorts of Danish nonagenarians, born 10 years apart. People in the first cohort were born in 1905 and assessed at age 93 years (n=2262); those in the second cohort were born in 1915 and assessed at age 95 years (n=1584). All cohort members were eligible irrespective of type of residence. Both cohorts were assessed by surveys that used the same design and assessment instrument, and had almost identical response rates (63%). Cognitive functioning was assessed by mini-mental state examination and a composite of five cognitive tests that are sensitive to age-related changes. Physical functioning was assessed by an activities of daily living score and by physical performance tests (grip strength, chair stand, and gait speed). The chance of surviving from birth to age 93 years was 28% higher in the 1915 cohort than in the 1905 cohort (6·50% vs 5·06%), and the chance of reaching 95 years was 32% higher in 1915 cohort (3·93% vs 2·98%). The 1915 cohort scored significantly better on the mini-mental state examination than did the 1905 cohort (22·8 [SD 5·6] vs 21·4 [6·0]; p<0·0001), with a substantially higher proportion of participants obtaining maximum scores (28–30 points; 277 [23%] vs 235 [13%]; p<0·0001). Similarly, the cognitive composite score was significantly better in the 1915 than in the 1905 cohort (0·49 [SD 3·6] vs 0·01 [SD 3·6]; p=0·0003). The cohorts did not differ consistently in the physical performance tests, but the 1915 cohort had significantly better activities of daily living scores than did the 1905 cohort (2·0 [SD 0·8] vs 1·8 [0·7]; p<0·0001). Despite being 2 years older at assessment, the 1915 cohort scored significantly better than the 1905 cohort on both the cognitive tests and the activities of daily living score, which suggests that more people are living to older ages with better overall functioning. Danish National Research Foundation; US National Institutes of Health—National Institute on Aging; Danish Agency for Science, Technology and Innovation; VELUX Foundation.

If the pace of increase in life expectancy in developed countries over the past two centuries continues through the 21st century, most babies born since 2000 in France, Germany, Italy, the UK, the USA, Canada, Japan, and other countries with long life expectancies will celebrate their 100th birthdays. Although trends differ between countries, populations of nearly all such countries are ageing as a result of low fertility, low immigration, and long lives. A key question is: are increases in life expectancy accompanied by a concurrent postponement of functional limitations and disability? The answer is still open, but research suggests that ageing processes are modifiable and that people are living longer without severe disability. This finding, together with technological and medical development and redistribution of work, will be important for our chances to meet the challenges of ageing populations.

Women in almost all modern populations live longer than men. Research to date provides evidence for both biological and social factors influencing this gender gap. Conditions when both men and women experience extremely high levels of mortality risk are unexplored sources of information. We investigate the survival of both sexes in seven populations under extreme conditions from famines, epidemics, and slavery. Women survived better than men: In all populations, they had lower mortality across almost all ages, and, with the exception of one slave population, they lived longer on average than men. Gender differences in infant mortality contributed the most to the gender gap in life expectancy, indicating that newborn girls were able to survive extreme mortality hazards better than newborn boys. Our results confirm the ubiquity of a female survival advantage even when mortality is extraordinarily high. The hypothesis that the survival advantage of women has fundamental biological underpinnings is supported by the fact that under very harsh conditions females survive better than males even at infant ages when behavioral and social differences may be minimal or favor males. Our findings also indicate that the female advantage differs across environments and is modulated by social factors.

Mutations in the epigenetic modifier TET2 are frequent in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). Here, we investigate associations between TET2 mutations and DNA methylation in whole blood in 305 elderly twins, 15 patients with CCUS and 18 healthy controls. We find that TET2 mutations are associated with DNA hypermethylation at enhancer sites in whole blood in CHIP and in both granulocytes and mononuclear cells in CCUS. These hypermethylated sites are associated with leukocyte function and immune response and ETS-related and C/EBP-related transcription factor motifs. While the majority of TET2- associated hypermethylation sites are shared between CHIP and in AML, we find a set of AML-specific hypermethylated loci at active enhancer elements in hematopoietic stem cells. In summary, we show that TET2 mutations is associated with hypermethylated enhancers involved in myeloid differentiation in both CHIP, CCUS and AML patients. TET2 mutations are frequent in myeloid malignancies and in elderly individuals with or without cytopenia. Here, the authors analyse the association between TET2 mutations and methylation changes in healthy elderly twins and patients with cytopenia and compare them to those from leukemia.

Background High-income countries experienced unprecedented gains in life expectancy throughout the twentieth century. However, recent evidence suggests that these gains have slowed, especially at older ages. This paper focuses on recent trends in life expectancy and health in ageing populations in high-income countries. Methods We analysed mortality and health data from the Human Mortality Database and the Global Burden of Disease. Additionally, we reviewed recent literature to explore changes in life expectancy, health-adjusted life expectancy, physical and cognitive decline, and the impact of ageing on healthcare expenditure in countries with high life expectancies. Findings Although life expectancy continues to rise in high-income countries, the pace of improvement has slowed, especially among the oldest-old. While health-adjusted life expectancy has generally increased, the proportion of life spent in good health varies across countries, with notable differences in trends in physical and cognitive disabilities. In terms of economic implications, these findings highlight the importance of age and proximity to death as determinants of healthcare expenditures. Interpretation The deceleration in life expectancy gains, particularly among the oldest populations, raises important questions about future trends in longevity. As physical and cognitive health change in older ages healthcare systems will face new and diverse challenges. Understanding the role of ageing and time-to-death in shaping healthcare costs will be critical for anticipating future needs in high-income countries.

The potential association between level of education and age-related cognitive decline remains an open question, partly because of a lack of studies including large subsamples with low education and follow-up intervals covering a substantial part of the adult lifespan. To examine cognitive decline assessed by a comprehensive clinical test of intelligence over a 35-year period of follow-up from ages 50 to 85 and to analyze the effect of education on trajectories of cognitive decline, including the effects of selective attrition. A longitudinal cohort study with a 35-year follow-up of community dwelling members of the Glostrup 1914 cohort. The study sample comprised 697 men and women at the 50-year baseline assessment and additional participants recruited at later follow-ups. Verbal, Performance, and Full Scale IQs were assessed using the Wechsler Adult Intelligence Scale at ages 50, 60, 70, 80, and 85. To be able to track cognitive changes between successive WAIS assessments, all IQs were based on the Danish 50-year norms. Information on school education was self-reported. The association between education and cognitive decline over time was examined in growth curve models. Selective attrition was investigated in subsamples of participants who dropped out at early or later follow-ups. The trajectories for Verbal, Performance, and Full Scale IQ showed higher initial cognitive performance, but also revealed steeper decline among participants with a formal school exam compared to participants without a formal exam. Verbal IQ showed the largest difference in level between the two educational groups, whereas the interaction between education and age was stronger for Performance IQ than for Verbal IQ. In spite of the difference in trajectories, higher mean IQ was observed among participants with a formal school exam compared to those without across all ages, including the 85-year follow-up. Further analyses revealed that early dropout was associated with steeper decline, but that this effect was unrelated to education. Comprehensive cognitive assessment over a 35-year period suggests that higher education is associated with steeper decline in IQ, but also higher mean IQ at all follow-ups. These findings are unlikely to reflect regression towards the mean, other characteristics of the employed test battery or associations between educational level and study dropout.

FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 ( OSER1 ), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased ATP production, and altered transcription of mitochondrial genes. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging. FOXO transcription factors are known to promote longevity via effects on transcriptional targets. In this study, the authors identify OSER1 as an evolutionarily conserved target of FOXO. OSER1 expression improves resistance to oxidative stress, supports mitochondrial function, and extends lifespan across multiple species.

Population aging will pose huge challenges for healthcare systems and will require a promotion of positive attitudes towards older people and the encouragement of careers in geriatrics to attract young professionals into the field and to meet the needs of a rapidly growing number of old-aged patients. We describe the current demographic profile of hospital care use in Denmark and make projections for changes in the patient profile up to 2050. The Danish population in 2013 (N = 5.63 million) was followed up for inpatient and emergency admissions recorded in Danish hospitals in 2013 using population-based registers. We combined age- and sex-specific hospital care use in 2013 with official population estimates to forecast the profile of hospital days up to 2050 with respect to age and sex. The total number of hospital days per year is projected to increase by 42% between 2013 and 2050, from 4.66 to 6.72 million days. While small changes are projected for the population aged 0-69, the largest change is projected to occur for the population aged 70+. The 2013 levels were 0.82 and 0.93 million days for men and women aged 70+, respectively. By 2050, these levels are projected to have reached 1.94 and 1.84 million days. While the population aged 70+ accounted for 37.5% of all days in 2013, its contribution is projected to increase to 56.2% by 2050. Our study shows one possible scenario for changes in the hospital days due to population aging by 2050: Assuming no changes in hospital care use over the forecast period, the absolute contribution of individuals aged 70+ to the total hospital days will more than double, and the relative contribution of persons aged 70+ will account for nearly 60% of all hospital days by 2050, being largest among men.

Weighing risks and benefits of postmenopausal hormone therapy (HT) has proven a balancing act. We aimed to investigate the association between HT and mortality before and after the 2002 publication from the Women’s Health Initiative (WHI) study. This publication found that the risk of using HT outweighted the benefits, and thus it caused a marked reduction in systemic HT user prevalence. The 2002 WHI publication may also have caused a change in the subsequent HT user profile, as HT is no longer recommended in the prevention of chronic diseases. This cohort study included two populations followed from 1995: A 5% random sample of female singletons from the Danish general population (n = 52,388) and a sample of Danish female twins (n = 15,261). HT use was evaluated in 1995, 2000, 2005, and 2010. The association between HT, education, and mortality was investigated and controlled for potential unobserved familial confounding in a within-pair analysis. Singletons aged 56–75 using systemic HT in 2000 had a lower mortality compared to non-users (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.78–0.89). In 2005, the mortality was like that of the background population for this age group (HR 1.02, 95% CI 0.94–1.11). Recently postmenopausal twins showed a similar tendency. Systemic HT users, who had switched to local HT by 2005, had a substantially lower mortality than non-users (HR ranging from 0.42 to 0.67 depending on age group). In conclusion, we found that the prevalence of systemic HT use declined after 2002, and systemic HT users’ mortality changed from lower before 2002 to similar to that of the background population after 2002. This indicates that the healthiest users decided to either drop systemic HT or switcted to local HT, as recommendations changed following the WHI publication.