Age-related Death Research Articles

Inflammaging: The Next Challenge-Exploring the Role of Gut Microbiota, Environmental Factors, and Sex Differences.

The term 'inflammaging' has been coined to describe the chronic state of inflammation derived from ongoing cycles of tissue damage and the subsequent immune responses. This inflammatory status contributes to the decline of organs and physiological functions, accelerates the aging process, and increases the risk of age-related illnesses and death. During aging, the gut microbiota (GM) undergoes significant changes, including a decreased diversity of species, a decline in beneficial bacteria, and a rise in proinflammatory ones, resulting in persistent low-grade inflammation. Moreover, environmental factors, such as diet and medications, contribute to age-related changes in GM and immune function, preventing or promoting inflammaging. This narrative review aims to clarify the underlying mechanisms of inflammaging and to specifically investigate the influence of GM and several environmental factors on these mechanisms, while also exploring potential differences related to sex. Moreover, lifestyle and pharmacological interventions will be suggested to promote healthy aging.

Spatiotemporal Trends and Driving Factors of PM2.5-related Health Burden in Gansu Province, China from 2013 to 2020

To evaluate the spatiotemporal trends and drivers of PM2.5-related health effects in Gansu Province since the implementation of the Air Pollution Prevention and Control Action Plan, the latest global exposure mortality model （GEMM） was adopted to estimate the health burden attributable to PM2.5 in Gansu Province from 2013 to 2020. The factor decomposition method was used to further quantify the main causes of the long-term changes in deaths attributable to PM2.5 pollution. The results showed that from 2013 to 2020, the population-weighted PM2.5 concentration in Gansu Province decreased by 34.57%, and the proportion of people exposed to areas with an annual average PM2.5 concentration exceeding 35 μg·m-3 decreased significantly from 72.89% to 11.61%. Moreover, the number of attributable deaths in Gansu Province declined from 12 826 （95%CI： 7 840-17 408） in 2 013 to 9 814 （95%CI： 6 407-13 036） in 2020, indicating a decrease of 23.48%. Attributable deaths from stroke, chronic obstructive pulmonary disease, lung cancer, and lower respiratory infection declined, whereas deaths from ischemic heart disease increased by 12.11%. Notably, individuals aged 60 years and older accounted for more than 80% of all age-related deaths. The number of deaths attributable to PM2.5 in central and eastern Gansu Province was significantly higher than that in the Hexi region, and most regions showed a downward trend. The contribution of the total population, age structure, baseline mortality rate, and PM2.5 concentration to the change in PM2.5-related deaths was -1.26%, 16.16%, -9.84%, and -28.55%, respectively. Overall, population aging and a decrease in PM2.5 concentration were the main factors contributing to the increase and decrease in PM2.5-related deaths, respectively. The active clean air policies in Gansu Province have reduced the health burden caused by PM2.5 pollution, but with the trend of population aging, a significant reduction in PM2.5 concentration will be needed in the future to avoid more attributable deaths.

Specific analysis of PM2.5-attributed disease burden in typical areas of Northwest China.

Frequent air pollution events in Northwest China pose a serious threat to human health. However, there is a lack of specific differences assessment in PM2.5-related disease burden. Therefore, we aimed to estimate the PM2.5-related premature deaths and health economic losses in this typical northwest region, taking into account disease-specific, age-specific, and region-specific factors. We utilized the WRF-Chem model to simulate and analyze the characteristics and exposure levels of PM2.5 pollution in Gansu Province, a typical region of Northwest China. Subsequently, we estimated the premature mortality and health economic losses associated with PM2.5 by combining the Global Exposure Mortality Model (GEMM) and the Value of a Statistical Life (VSL). The results suggested that the PM2.5 concentrations in Gansu Province in 2019 varied spatially, with a decrease from north to south. The number of non-accidental deaths attributable to PM2.5 pollution was estimated to be 14,224 (95% CI: 11,716-16,689), accounting for 8.6% of the total number of deaths. The PM2.5-related health economic loss amounted to 28.66 (95% CI: 23.61-33.63) billion yuan, equivalent to 3.3% of the regional gross domestic product (GDP) in 2019. Ischemic heart disease (IHD) and stroke were the leading causes of PM2.5-attributed deaths, contributing to 50.6% of the total. Older adult individuals aged 60 and above accounted for over 80% of all age-related disease deaths. Lanzhou had a higher number of attributable deaths and health economic losses compared to other regions. Although the number of PM2.5-attributed deaths was lower in the Hexi Corridor region, the per capita health economic loss was higher. Gansu Province exhibits distinct regional characteristics in terms of PM2.5 pollution as well as disease- and age-specific health burdens. This highlights the significance of implementing tailored measures that are specific to local conditions to mitigate the health risks and economic ramifications associated with PM2.5 pollution.

CROSS-COUNTRY VALIDATION OF ANTHROPOMETRIC AGE (ANTHROPOAGE) AS A MEASURE OF BIOLOGICAL AGING

Abstract Aging occurs at unique rates at an individual and population-level. In contrast to chronological age (CA), biological age (BA) is better at capturing functional decline and risk of age-related diseases, disability, and death. Nonetheless, it is still unclear how this phenomenon changes across adults from different races/ethnicities. We recently developed a BA metric using anthropometric measurements (AnthropoAge) in participants from NHANES-III. Here, we aim to validate AnthropoAge across countries and to determine whether it displays population-specific patterns using harmonized cohorts from the U.S. and Mexico from the Gateway to Global Aging Data Team, including the Mexican Health and Aging Study and the Health and Retirement Study. We found that AnthropoAge is a robust predictor of overall mortality risk in both American (AUROC=0.797; 95%CI 0.786-0.808) and Mexican (0.776; 0.740-0.812) adults, and this was consistent across multiple cutoffs of time. Notably, we found that the prediction improved in participants aged 50-75 years in comparison to older adults aged 75-100 years. AnthropoAge was also associated with number of comorbidities and disability in activities of daily living independently of CA. Finally, we observed marked changes of AnthropoAge and its acceleration across the years in both countries, with a significant interaction with Mexican ethnicity (beta for interaction: 0.2034; p=5.94E-05). AnthropoAge is a robust and reproducible measure of BA, however, new studies are required to decipher the heterogeneity of anthropometric aging in specific ethnicities and age categories.

Entropy Meets Physiology: Should We Translate Aging as Disorder?

Aging is characterized by an alteration of several physiological processes and biological pathways that leads to an increased susceptibility to age-related diseases and death. Normally, multipotential stem/progenitor cells may contribute to tissue homeostasis, and to minimize the age-depending DNA damage. Scientific research has demonstrated that aging induces several complex changes affecting even the mesenchymal stromal/stem cells (MSCs) ability to self-renew, differentiate, and immunomodulate the human tissues, causing further alterations in the local microenvironment. Cellular senescence can thus be considered as an overall response to several damages. Accordingly, aging seems to create the proper conditions to decrease the tissue's metabolic performance, and the cell-to-cell communication, resulting in a progressive tissue destruction; on the other hand, the MSCs functions appear to be severely reduced. This concise review summarizes the main alterations affecting the MSCs during aging, and it also explains the role of inflammation as a key player in age-related syndromes. The hypothesis is to suggest a parallelism between the thermodynamic concept of "entropy" and biological aging, speculating that both can increase within irreversible systems and both lead toward an irreversible disorder; so, the question is: should we translate aging as disorder?

Evaluation of potential aging biomarkers in healthy individuals: telomerase, AGEs, GDF11/15, sirtuin 1, NAD+, NLRP3, DNA/RNA damage, and klotho

Aging is a natural process of gradual decrease in physical and mental capacity. Biological age (accumulation of changes and damage) and chronological age (years lived) may differ. Biological age reflects the risk of various types of disease and death from any cause. We selected potential biomarkers of aging - telomerase, AGEs, GDF11 and 15 (growth differentiation factor 11/15), sirtuin 1, NAD+ (nicotinamide adenine dinucleotide), inflammasome NLRP3, DNA/RNA damage, and klotho to investigate changes in their levels depending on age and sex. We included 169 healthy volunteers and divided them into groups according to age (under 35; 35–50; over 50) and sex (male, female; male and female under 35; 35–50, over 50). Markers were analyzed using commercial ELISA kits. We found differences in values depending on age and gender. GDF15 increased with age (under 30 and 35–50 p < 0.002; 35–50 and over 50; p < 0.001; under 35 and over 50; p < 0.001) as well as GDF11 (35–50 and over 50; p < 0.03; under 35 and over 50; p < 0.02), AGEs (under 30 and 35–50; p < 0.005), NLRP3 (under 35 over 50; p < 0.03), sirtuin 1 (35–50 and over 50; p < 0.0001; under 35 and over 50; p < 0.004). AGEs and GDF11 differed between males and females. Correlations were identified between individual markers, markers and age, and markers and sex. Markers that reflect the progression of biological aging vary with age (GDF15, GDF11, AGEs, NLRP3, sirtuin) and sex (AGEs, GDF11). Their levels could be used in clinical practice, determining biological age, risk of age-related diseases and death of all-causes, and initiating or contraindicating a therapy in the elderly based on the patient’s health status.

Assessment of Frailty Index at 66 Years of Age and Association With Age-Related Diseases, Disability, and Death Over 10 Years in Korea

A frailty index has been proposed as a measure of aging among older individuals. However, few studies have examined whether a frailty index measured at the same chronologic age at younger ages could forecast the development of new age-related conditions. To examine the association of the frailty index at 66 years of age with incident age-related diseases, disability, and death over 10 years. This retrospective nationwide cohort study used the Korean National Health Insurance database to identify 968 885 Korean individuals who attended the National Screening Program for Transitional Ages at 66 years of age between January 1, 2007, and December 31, 2017. Data were analyzed from October 1, 2020, to January 2022. Frailty was defined using a 39-item frailty index ranging from 0 to 1.00 as robust (<0.15), prefrail (0.15-0.24), mildly frail (0.25-0.34), and moderately to severely frail (≥0.35). The primary outcome was all-cause death. Secondary outcomes were 8 age-related chronic diseases (congestive heart failure, coronary artery disease, stroke, type 2 diabetes, cancer, dementia, fall, and fracture) and disability qualifying for long-term care services. Cox proportional hazards regression and cause-specific and subdistribution hazards regression were used to examine hazard ratios (HRs) and 95% CIs for the outcomes until the earliest of date of death, the occurrence of relevant age-related conditions, 10 years from the screening examination, or December 31, 2019. Among the 968 885 participants included in the analysis (517 052 women [53.4%]), the majority were classified as robust (65.2%) or prefrail (28.2%); only a small fraction were classified as mildly frail (5.7%) or moderately to severely frail (1.0%). The mean frailty index was 0.13 (SD, 0.07), and 64 415 (6.6%) were frail. Compared with the robust group, those in the moderately to severely frail group were more likely to be women (47.8% vs 61.7%), receiving medical aid insurance for low income (2.1% vs 18.9%), and less active (median, 657 [IQR, 219-1133] vs 319 [IQR, 0-693] metabolic equivalent task [min/wk]). After adjusting for sociodemographic and lifestyle characteristics, moderate to severe frailty was associated with increased rates of death (HR, 4.43 [95% CI, 4.24-4.64]) and new diagnosis of all chronic diseases, including congestive heart failure (adjusted cause-specific HR, 2.90 [95% CI, 2.67-3.15]), coronary artery disease (adjusted cause-specific HR, 1.98 [95% CI, 1.85-2.12]), stroke (adjusted cause-specific HR, 2.22 [95% CI, 2.10-2.34]), diabetes (adjusted cause-specific HR, 2.34 [95% CI, 2.21-2.47]), cancer (adjusted cause-specific HR, 1.10 [95% CI, 1.03-1.18]), dementia (adjusted cause-specific HR, 3.59 [95% CI, 3.42-3.77]), fall (adjusted cause-specific HR, 2.76 [95% CI, 2.29-3.32]), fracture (adjusted cause-specific HR, 1.54 [95% CI, 1.48-1.62]), and disability (adjusted cause-specific HR, 10.85 [95% CI, 10.00-11.70]). Frailty was associated with increased 10-year incidence of all the outcomes, except for cancer (moderate to severe frailty adjusted subdistribution HR, 0.99 [95% CI, 0.92-1.06]). Frailty at 66 years of age was associated with greater acquisition of age-related conditions (mean [SD] conditions per year for the robust group, 0.14 [0.32]; for the moderately to severely frail group, 0.45 [0.87]) in the next 10 years. The findings of this cohort study suggest that a frailty index measured at 66 years of age was associated with accelerated acquisition of age-related conditions, disability, and death over the next 10 years. Measuring frailty at this age may offer opportunities to prevent age-related health decline.

Comparative veterinary geroscience: mechanism of molecular, cellular, and tissue aging in humans, laboratory animal models, and companion dogs and cats.

Aging is the single most important cause of disease, disability, and death in companion animal species. Contrary to the common view of aging as mysterious and inevitable, it is more usefully understood as a set of complex but comprehensible and modifiable biological processes that are highly conserved across species. The purpose of this Currents in One Health manuscript is to describe key mechanisms of aging at the cellular and molecular level and the manifestations of these in the tissues of the musculoskeletal system, adipose, and the brain. The characteristics of these processes as identified in common laboratory animal models and in humans will be described and compared with the much more limited information available concerning aging in dogs and cats. This will highlight important targets for future research in these species. The consistent patterns across species in the hallmarks of aging and their manifestations at the level of tissues, organ systems, and individual animals signify potential targets for interventions to mitigate the negative health impacts of aging and extend both life span and health span (the period of life free of significant disease or disability). Further research to elucidate aging mechanisms in companion dogs and cats will eventually support development, testing, and implementation of clinical therapies to prevent and ameliorate age-related dysfunction, disease, and death.

Systemic innate immune response induces death of olfactory receptor neurons in Drosophila.

Neural functions are known to decline during normal aging and neurodegenerative diseases. However, the mechanisms of functional impairment owing to the normal aging of the brain are poorly understood. Previously, we reported that caspase-3-like protease, the protease responsible for inducing apoptosis, is activated in a subset of olfactory receptor neurons (ORNs), especially in Drosophila Or42b neurons, during normal aging. Herein, we investigated the molecular mechanism underlying age-related caspase-3-like protease activation and cell death in Or42b neurons. Gene expression profiling of young and aged fly antenna showed that the expression of antimicrobial peptides was significantly upregulated, suggesting an activated innate immune response. Consistent with this observation, inhibition or activation of the innate immune pathway caused delayed or precocious cell death, respectively, in Or42b neurons. Accordingly, autonomous cell activation of the innate immune pathway in Or42b neurons is not likely required for their age-related death, whereas the systemic innate immune response induces caspase-3-like protease activation in Or42b neurons; this indicated that the death of these neurons is regulated non-cell autonomously. We propose a possible link between the innate immune response and the death of olfactory neurons during normal aging.

New Computational Approaches to Aging Research

Aging is associated with numerous changes at all levels of biological organization. Harnessing this information to develop measures that accurately and reliably quantify the biological aging process will require systems biology approaches. This talk will illustrate how epigenetic data can be integrated with cellular, physiological, proteomic, and clinical data to model age-related changes that propagate up the levels—finally manifesting as age-related disease or death. I will also describe how network modeling and machine learning approaches (linear and non-linear) can be used to identify causal features in aging from which to generate novel biomarkers. Given the complexity of the biological aging process, modeling of systems dynamics over time will both lead to the development of better biomarkers of aging, and also inform our conceptualization of how alterations at the molecular level propagate up levels of organization to eventually influence morbidity and mortality risk.

Impact of an 8-Year Intensive Lifestyle Intervention on an Index of Multimorbidity.

Type 2 diabetes mellitus and obesity are sometimes described as conditions that accelerate aging. Multidomain lifestyle interventions have shown promise to slow the accumulation of age-related diseases, a hallmark of aging. However, they have not been assessed among at-risk individuals with these two conditions. We examined the relative impact of 8 years of a multidomain lifestyle intervention on an index of multimorbidity. Randomized controlled clinical trial comparing an intensive lifestyle intervention (ILI) that targeted weight loss through caloric restriction and increased physical activity with a control condition of diabetes support and education (DSE). Sixteen U.S. academic centers. A total of 5,145 volunteers, aged 45 to 76, with established type 2 diabetes mellitus and overweight or obesity who met eligibility criteria for a randomized controlled clinical trial. A multimorbidity index that included nine age-related chronic diseases and death was tracked over 8 years of intervention delivery. Among individuals assigned to DSE, the multimorbidity index scores increased by an average of .98 (95% confidence interval [CI] = .94-1.02) over 8 years, compared with .89 (95% CI = .85-.93) among those in the multidomain ILI, which was a 9% difference (P = .003). Relative intervention effects were similar among individuals grouped by baseline body mass index, age, and sex, and they were greater for those with lower levels of multimorbidity index scores at baseline. Increases in multimorbidity over time among adults with overweight or obesity and type 2 diabetes mellitus may be slowed by multidomain ILI. J Am Geriatr Soc 68:2249-2256, 2020.

Assessment of aging processes in individual dynamics of health and work capacity indicators

The purpose of the review is to identify the effects of natural aging processes and accompanying age-related diseases on the personal labor potential of a person in modern conditions of socio-economic development. Personal labor potential is subject to the processes of natural biological aging. Improvements in living conditions and advances in health care lead to an increase in the proportion of the elderly in the population structure, but these same processes can reduce the rate of individual aging, the risks of age-related diseases and death. The aging process reduces overall viability, which is accompanied by an increased risk of age-related chronic diseases. For these diseases, personal risk levels should be assessed, and preventive measures should be taken in a timely manner. There are risk markers for various diseases that increase in frequency with age, as well as markers of increased overall mortality. The assessment of individual aging is based on indicators of biological age, which should be considered to assess personal labor potential.

Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver.

Accumulating somatic mutations have been implicated in age-related cellular degeneration and death. Because of their random nature and low abundance, somatic mutations are difficult to detect except in single cells or clonal cell lineages. Here, we show that in single hepatocytes from human liver, an organ exposed to high levels of genotoxic stress, somatic mutation frequencies are high and increase substantially with age. Considerably lower mutation frequencies were observed in liver stem cells (LSCs) and organoids derived from them. Mutational spectra in hepatocytes showed signatures of oxidative stress that were different in old age and in LSCs. A considerable number of mutations were found in functional parts of the liver genome, suggesting that somatic mutagenesis could causally contribute to the age-related functional decline and increased incidence of disease of human liver. These results underscore the importance of stem cells in maintaining genome sequence integrity in aging somatic tissues.

Increased nuclear permeability is a driver for age-related motoneuron loss.

Sarcopenia is the loss of skeletal muscle mass with age, the precise cause of which remains unclear. Several studies have shown that sarcopenia is at least partly driven by denervation which, in turn, is related to loss of motor nerve cells. Recent data suggests degradation of the nucleocytoplasmic barrier and nuclear envelope transport process are contributors to nerve loss in a number of neurodegenerative diseases. Having recently shown that important components of the nuclear barrier are lost with advancing age, we now ask whether these emergent defects accompany increased nuclear permeability, chromatin disorganization and lower motoneuron loss in normal ageing, and if so, whether exercise attenuates these changes. Immunohistochemistry was used on young adult, old and exercised mouse tissues to examine nucleocytoplasmic transport regulatory proteins and chromatin organization. We used a nuclear permeability assay to investigate the patency of the nuclear barrier on extracts of the spinal cord from each group. We found increased permeability in nuclei isolated from spinal cords of old animals that correlated with both mislocalization of essential nuclear transport proteins and chromatin disorganization, and also found that in each case, exercise attenuated the age-associated changes. Findings suggest that the loss of nuclear barrier integrity in combination with previously described defects in nucleocytoplasmic transport may drive increased nuclear permeability and contribute to age-related motoneuron death. These events may be significant indirect drivers of skeletal muscle loss.

Patterns of VTE Treatment with Noac in Cancer Patients - Results of the Prospective Dresden Noac Registry (NCT01588119)

Background: Until recently, patients with cancer associated thrombosis (CAT) were predominantly treated with low-molecular weight heparin (LMWH) but trial data and updated guidelines suggest that direct oral anticoagulants (DOAC) may represent feasible and convenient oral alternatives. However, most data supporting this relate to 6-12 months outcomes only and long-term data in this setting are scarce Aims: To evaluate the effectiveness and safety of CAT treatment with DOAC in daily care. Patients and methods: From the multicentric Dresden NOAC Registry, long-term outcomes of a subgroup of CAT patients (active or recent cancer, defined as cancer therapy within 5 years prior to thrombosis) receiving CAT therapy with DOAC were evaluated, based on prospectively collected data and centrally adjudicated outcome events. Results: Of the 1667 VTE patients enrolled in the registry until 30th June 2019, 186 patients (11.2%) were identified to have CAT (mean age 67.3 years; 61.3% male). At enrolment, cancer was reported as active in 97 (52.2) cases and recent in 89 (47.8) cases. Solid malignancies were diagnosed in 163 (87.6%) cases were, the remaining 23 (12.4%) cases were hematologic malignancies; table 1; figure 1). Of the 97 cases with active malignancies, 43.3% had metastatic disease. CAT treatment consisted of rivaroxaban in 80 (43.0%) patients, 66 (35.5%) received edoxaban and 40 (21.5%) apixaban. During follow-up (mean 27.8 months, range 0.5 - 88.6), 14 patients experienced recurrent VTE events (7.5 %; incidence rate 3.5/100 pt. years) of which 4 occurred during DOAC treatment and 10 after discontinuation or during prolonged (&amp;gt;3d) DOAC interruption (figure 2a). During DOAC exposure (within 3 days of last intake), major bleeding occurred in 15 patients (8.1%; incidence rate 5.9/100 pt. years; figure 2b) and presented as gastrointestinal (GI) bleeding in 7, intracranial bleeding in 3 and in other bleeding manifestations in 5 cases. For 34 patients with GI cancer, the incidence rate for major bleeding was 13.3/100 pt. years and all four major bleedings in this group presented as upper GI bleed. 40 patients died during FU (21.5%; incidence rate 9.4/100 pt. years). Causes of death included terminal malignant disease (n=22), infection (n=6), fatal bleeding (n=4), age related death (n=3), fatal cardiovascular event (n=3), and other reasons (n=2). Conclusions: Our results now contribute long-term data of DOAC treatment for CAT. Incidence rates of recurrent VTE and major bleeding were consistent with the results from recent randomized trials in CAT. Most VTE recurrences occurred after interruption or discontinuation of DOAC, which indicates the importance of continued therapy especially for patients with active cancer. On-treatment rates of major bleeding were comparable for patients with recent or active cancer, indicating a need for an individualized risk-benefit assessment, especially since patients with recent cancer were at lower risk for VTE recurrence. Our findings of higher major bleeding rates in patients with GI cancer (both active and recent) is in line with the observations in randomized trials and supports guidelines recommendations, cautioning against DOAC use in CAT patients at high risk for bleeding, such as GI cancer patients. Disclosures Marten: Daiichi Sankyo: Honoraria; Bayer HealthCare: Honoraria. Tittl:Daiichi Sankyo: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding.

NOAC Therapy Is Also Effective and Safe in Patients Older Than 80 Years — Results of the Prospective Dresden NOAC Registry (NCT01588119)

Background: Non-vitamin-K-antagonist oral anticoagulants (NOACs) have rapidly become a cornerstone in anticoagulant therapy. However, anticoagulated patients older than 80 years represent an especially challenging population, since their thromboembolic and bleeding risks are excessively high and chronic kidney disease is common, making treatment decisions even more complicated. As a consequence, long-term safety data for this specific population are needed.Patients and methods: Using data from DRESDEN NOAC, a prospective regional registry in Germany in which patients with oral anticoagulation undergo prospective follow-up (FU) by quarterly phone interviews, we assessed rates of thromboembolic and bleeding outcomes in patients older than 80 years, based on centrally adjudicated events using standard outcome definitions.Results: Until 30th November 2017, 3984 patients were enrolled into the registry (53% male, mean age 70.2 years), including 935 patients aged ≥ 80 years (487 [52.1%] received rivaroxaban, 198 [21.2%] apixaban, 165 [17.6%] edoxaban and 85 [9.1%] dabigatran, respectively). Indication for anticoagulant therapy was atrial fibrillation (AF) in 752 (80.4%) cases, venous thromboembolism (VTE) in 179 (19.1%), and other indications in 4 (0.4%) cases. This subset of patients had a mean age of 84.2 years (range 80-100y) and 406 (43.4%) patients were male (Table 1).During a mean follow-up of 970.7 ± 642.2 days (mean NOAC exposure 815.3 ± 644.5 days) an intention-to-treat (all events counted) analysis of all very old patients demonstrated an event rate for the composite endpoint of stroke, TIA, systemic embolism or VTE of 1.0/100 patient-years (95% CI 0.8 - 1.2). In AF patients, the rate for stroke, TIA, systemic embolism was 1.0/100 patient-years (95% CI 0.8 - 1.2) and in VTE patients, the rate for recurrent DVT or PE in VTE patients was 0.4/100 patient-years (95% CI 0.2 - 0.7).In the on-treatment analysis (only on-treatment events counted), the corresponding event rates were 0.7/100 patient-years (95% CI 0.5 - 0.9) for the composite endpoint, 0.7/100 patient-years (95% CI 0.5 - 0.9) for stroke, TIA, systemic embolism in AF patients, and 0.1/100 patient-years (95% CI 0.01 - 0.3) for recurrent VTE in VTE patients, respectively. The overall rate of ISTH major bleeding was 1.0/100 patient-years (95% CI 0.8 - 1.2), with numerically higher rates in SPAF patients (1.2/100 patient-years; 95% CI 0.9 - 1.5) compared to VTE patients (0.4/100 patient-years; 95% CI 0.2 - 0.7).255 patients died during FU (2.2/100 patient-years; 95% CI 2.0 - 2.5), of which 120 deaths occurred during or within 3 days after last intake of NOAC (1.3/100 patient-years; 95% CI 1.1 - 1.6). Most common causes of death were fatal cardiovascular event (n= 86; consisting of 20 cases of acute coronary syndrome, 19 ischaemic strokes, 17 VTE, 2 systemic embolism and 123 cases of other cardiovascular deaths such as worsening of chronic heart failure, or unexplained deaths ruled as potentially related to cardiovascular events) and age related death (n= 79), followed by sepsis/infection (n= 40), terminal malignant disease (n= 26), fatal bleeding (n= 11) and other causes (n= 13).Overall, after 1800 days of FU, approximately 80% of this very old population were outcome-free survivors, as indicated by the Kaplan Meier curve (figure1).Conclusions: During long-term FU of more than 2.5 years, this very old population of NOAC recipients demonstrated low rates of cardiovascular or major bleeding complications during active NOAC therapy. Approximately one quarter of the study population died during follow-up, with cardiovascular events being the leading cause of death. Only 11 fatal bleeding events were observed; however, most of the 58 fatal thromboembolic events occurred after anticoagulation was discontinued. This indicates that continued anticoagulation with NOACs may result in a beneficial risk-benefit ratio also in very old patients. [Display omitted] DisclosuresBeyer-Westendorf:Bayer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding. Marten:Bayer: Honoraria; Daiichi Sankyo: Honoraria.

Endurance exercise prevents high-fat-diet induced heart and mobility premature aging and dsir2 expression decline in aging Drosophila.

High-Fat-Diet (HFD)-induced obesity is a major contributor to heart and mobility premature aging and mortality in both Drosophila and humans. The dSir2 genes are closely related to aging, but there are few directed reports showing that whether HFD could inhibit the expression dSir2 genes. Endurance exercise can prevent fat accumulation and reverse HFD-induced cardiac dysfunction. Endurance also delays age-relate functional decline. It is unclear whether lifetime endurance exercise can combat lifetime HFD-induced heart and mobility premature aging, and relieve the harmful HFD-induced influence on the dSir2 gene and lifespan yet. In this study, flies are fed a HFD and trained from when they are 1 week old until they are 5 weeks old. Then, triacylglycerol levels, climbing index, cardiac function, lifespan, and dSir2 mRNA expressions are measured. We show that endurance exercise improves climbing capacity, cardiac contraction, and dSir2 expression, and it reduces body and heart triacylglycerol levels, heart fibrillation, and mortality in both HFD and aging flies. So, lifelong endurance exercise delays HFD-induced accelerated age-related locomotor impairment, cardiac dysfunction, death, and dSir2 expression decline, and prevents HFD-induced premature aging in Drosophila.

Genetic interaction with temperature is an important determinant of nematode longevity.

SummaryAs in other poikilotherms, longevity in C. elegans varies inversely with temperature; worms are longer‐lived at lower temperatures. While this observation may seem intuitive based on thermodynamics, the molecular and genetic basis for this phenomenon is not well understood. Several recent reports have argued that lifespan changes across temperatures are genetically controlled by temperature‐specific gene regulation. Here, we provide data that both corroborate those studies and suggest that temperature‐specific longevity is more the rule than the exception. By measuring the lifespans of worms with single modifications reported to be important for longevity at 15, 20, or 25 °C, we find that the effect of each modification on lifespan is highly dependent on temperature. Our results suggest that genetics play a major role in temperature‐associated longevity and are consistent with the hypothesis that while aging in C. elegans is slowed by decreasing temperature, the major cause(s) of death may also be modified, leading to different genes and pathways becoming more or less important at different temperatures. These differential mechanisms of age‐related death are not unlike what is observed in humans, where environmental conditions lead to development of different diseases of aging.

Age-Related Changes in Morphometric Parameters of Hippocampal Neurons in Humans

Age-related changes in the hippocampus (HPO) lead to derangements of all types of memory and changes in emotional reactions. The aim of the present work was to study morphometric measures of neurons in the human HPO during aging. Specimens were obtained at autopsy of 43 people of both genders, aged 21–92 years, divided into four age groups. Specimens were stained with cresyl violet to detect neurons. Neurons were counted per unit area in the pes hippocampi in sections of intrinsic hippocampal fields CA1 and CA3 and the dentate gyrus, with measurement of neuron body profile field areas. Aging was found to be associated with heterochronous loss of nerve cells in the human HPO, this process occurring at different intensities in the midpart and the pes. The extent of age-related death of nerve cells in the human HPO increases in the direction dentate gyrus ⟶ field CA3 ⟶ field CA1. Most parts of the HPO showed compensatory increases in neuron profile field areas from 36 to 74 years, followed by a decrease in subjects more than 75 years old.

Impact of rotavirus vaccination on child mortality, morbidity, and rotavirus-related hospitalizations in Bolivia

BackgroundThe public health impact of rotavirus vaccination in countries with high child mortality rates remains to be established. The RV1 rotavirus vaccine was introduced in Bolivia in August 2008. This study describes the trends in deaths, hospitalizations, and healthcare visits due to acute gastroenteritis (AGE) and in rotavirus-related hospitalizations, among children <5 years of age, during the pre- and post-vaccination periods. MethodsData were obtained from the National Health Information System to calculate vaccine coverage and AGE-related health indicators. Trend reductions in the main health indicators were examined using the pre-vaccine period as baseline. The effect of vaccination on the epidemiology of rotavirus-related AGE was assessed using data from the active surveillance hospitals. ResultsCompared with the 2001–2008 pre-vaccine baseline, the mean number of rotavirus-related hospitalizations was reduced by 40.8% (95% confidence interval (CI) 21.7–66.4%) among children <5years of age in the post-vaccine period (2009–2013). Reductions were most pronounced in children <1year of age, eligible for vaccination. The mean proportions of AGE-related deaths, AGE-related hospitalizations, and AGE-related healthcare visits during 2009–2014 were reduced by 52.5% (95% CI 47.4–56.3), 30.2% (95% CI 23.5–36.1), and 12.9% (95% CI 12.0–13.2), respectively. The greatest effect in reduction of AGE-related deaths was found during the months with seasonal peaks of rotavirus disease. Over the post-vaccine period, changes in rotavirus epidemiology were observed, manifested by variations in seasonality and by a shift in the mean age of those with rotavirus infection. ConclusionsThe significant decrease in main AGE-related health indicators in children <5years of age after the introduction of rotavirus vaccine provides evidence of a substantial public health impact of rotavirus vaccination in Bolivia, as a measure for protecting children against AGE.