Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design.

Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first preclinical trial in a relevant middle-aged nonhuman primate (NHP) model to allow estimation of the main translatable effects of the senolytic combination dasatinib (D) and quercetin (Q), with and without caloric restriction (CR). A multi-systemic survey of age-related changes, including those on immune cells, adipose tissue, the microbiome, and biomarkers of systemic organ and metabolic health are reported. Age-, weight-, sex-, and glycemic control-matched NHPs (D + Q, n = 9; vehicle [VEH] n = 7) received two consecutive days of D + Q (5 mg/kg + 50 mg/kg) monthly for 6 months, where in month six, a 10% CR was implemented in both D + Q and VEH NHPs to induce equal weight reductions. D + Q reduced senescence marker gene expressions in adipose tissue and circulating PAI-1 and MMP-9. Improvements were observed in immune cell types with significant anti-inflammatory shifts and reductions in microbial translocation biomarkers, despite stable microbiomes. Blood urea nitrogen showed robust improvements with D + Q. CR resulted in significant positive body composition changes in both groups with further improvement in immune cell profiles and decreased GDF15 (p = 0.05), and the interaction of D + Q and CR dramatically reduced glycosylated hemoglobin A1c (p = 0.03). This work indicates that 6 months of intermittent D + Q exposure is safe and may combat inflammaging via immune benefits and improved intestinal barrier function. We also saw renal benefits, and with CR, improved metabolic health. These data are intended to provide direction for the design of larger controlled intervention trials in older patients.

Viability of internal comparisons for epidemiological research in the US astronaut corps.

This study aims to determine whether astronauts who have not flown in space can provide an unbiased comparison to astronauts who have flown in space when analyzing long-term health outcomes such as incidence of chronic disease and mortality. Various propensity score methods failed to achieve good balance between groups, demonstrating that even with sophisticated rebalancing methods the group of non-flight astronauts cannot be demonstrated to be an unbiased comparison group for examining the effect of the hazards of spaceflight on incidence and mortality from chronic diseases.

Contrapositive logic suggests space radiation not having a strong impact on mortality of US astronauts and Soviet and Russian cosmonauts.

Space travelers are exposed to unique forms of ionizing radiation that pose potentially serious health hazards. Prior analyses have attempted to quantify excess mortality risk for astronauts exposed to space radiation, but low statistical power has frustrated inferences. If exposure to deep space radiation were causally linked to deaths due to two particular causes, e.g., cancer and cardiovascular disease, then those cause-specific deaths would not be statistically independent. In this case, a Kaplan-Meier survival curve for a specific cause that treats deaths due to competing causes as uninformative censored events would result in biased estimates of survival probabilities. Here we look for evidence of a deleterious effect of historical exposure to space radiation by assessing whether or not there is evidence for such bias in Kaplan-Meier estimates of survival probabilities for cardiovascular disease and cancer. Evidence of such bias may implicate space radiation as a common causal link to these two disease processes. An absence of such evidence would be evidence that no such common causal link to radiation exposure during space travel exists. We found that survival estimates from the Kaplan-Meier curves were largely congruent with those of competing risk methods, suggesting that if ionizing radiation is impacting the risk of death due to cancer and cardiovascular disease, the effect is not dramatic.

Mortality Among International Astronauts.

INTRODUCTION: Research on the mortality of space explorers has focused exclusively on U.S. astronauts and Soviet and Russian cosmonauts. However, other nations have organized space programs over the last 40 yr and the European Space Agency, the Canadian Space Agency, the China National Space Administration, and the Japan Aerospace Exploration Agency all offer an opportunity for further study of the mortality of space explorers.METHODS: We used biographical and vital data abstracted from public sources for European, Canadian, Chinese, and Japanese astronauts. Using general population mortality rates from the Human Mortality Database and mortality rates derived from the cohort of U.S. astronauts, we computed standardized mortality ratios.RESULTS: The groups displayed different preferences in selection of astronauts. As there were no deaths in any of the four groups, the point estimates for standardized mortality ratios were all 0. However, the European cohort experienced a statistically significant reduction in all-cause mortality risk in comparison to the European general population as well as in comparison to U.S. astronauts.DISCUSSION: The healthy worker effect predicts that all study cohorts should have lower all-cause mortality risk in comparison to their general populations. The general population of Japan has mortality rates low enough that any reduction in mortality risk may remain undetectable in the Japanese cohort. Continued surveillance of these populations in the coming decades will make them a useful addition to the evidence base for astronaut mortality.Reynolds RJ, Day SM. Mortality among international astronauts. Aerosp Med Hum Perform. 2019; 90(7):647-651.

Mortality of US astronauts: comparisons with professional athletes.

OBJECTIVE: Studies of mortality among US astronauts are complicated by the healthy worker effect, which predicts lower mortality for astronauts than the general population based solely on the ability to become and remain an astronaut. We attempt to evaluate astronaut mortality risk while accounting for the healthy worker effect. METHODS: We compare mortality rates of male US astronauts with those of professional athletes from Major League Baseball and the National Basketball Association between January 1, 1960 and May 31, 2018. RESULTS: Both athlete cohorts and astronauts had significantly lower-than-expected mortality in comparison with the general population. For the overall study period, there were no significant differences in all-cause mortality rates between astronauts and athletes. Astronauts were at greater risk of death from external causes (SMR=583; 95% CI 377 to 860) and reduced risk of death from cardiovascular disease (SMR=39; 95% CI 18 to 73) and all natural causes (SMR=67; 95% CI 47 to 93). CONCLUSIONS: The data presented here do not support increased mortality for astronauts due to unique exposures received in space. The mortality experience of astronauts as compared with professional baseball and basketball players should be re-examined periodically as part of the ongoing surveillance of astronaut mortality in years to come.

The effect of competing risks on astronaut and cosmonaut mortality.

Astronauts and cosmonauts have been reported to be at substantially lower age-specific risk of death from chronic disease (primarily heart disease and cancers) in comparison to the general populations of the United States and Russia, respectively. Yet, both groups have been at greater age-specific risk of death from external causes, mainly due to plane crashes and spacecraft accidents. In this study we tested the hypothesis that the reported reductions in mortality from natural causes result, to some degree, from survival bias created by early deaths from external causes. Statistical comparisons of baseline characteristics between cause-of-death groups showed no significant differences. Cause-specific survival curves showed no difference in long-term mortality from external causes among either astronauts or cosmonauts compared to Kaplan-Meier curves with censoring for competing causes. Cause-specific survival curves for natural causes suggested a possible upward bias in mortality estimates published thus far for both groups of space explorers. Differences in survival between Kaplan-Meier curves and the cause-specific survival curves were 7% and 5% for astronauts and cosmonauts respectively after 55 years. The data do not support the hypothesis that observed reductions in mortality from natural causes are due in whole or in part to bias created by deaths from external causes at young ages. The data imply that reports of cause-specific mortality for astronauts and cosmonauts may in fact systematically overestimate mortality rates, though these findings should be interpreted with caution as the data are thin at the extremes of follow-up time.

Mortality Rates and Excess Death Rates for the Seriously Mentally Ill.

OBJECTIVES: -To compute mortality rates and excess death rates for patients with serious mental illness, specific to categories of gender, age and race/ethnicity. BACKGROUND: -People with serious mental illness are known to be at greatly increased risk of mortality across the lifespan. However, the measures of mortality reported for this high-risk population are typically only summary measures, which do not provide either the mortality rates or excess death rates needed to construct life tables for individuals with serious mental illness. METHODS: -Mortality rates were computed by dividing the number of deaths by the amount of life-years lived in strata specific to gender, age and race/ethnicity. Age-specific excess death rates were determined as the difference between the study population rate and the corresponding general population rate in each stratum. To compute excess death rates beyond observed ages in the cohort, a method with documented reliability and validity for chronic medical conditions was used. RESULTS: -For the cohort with mental illness, mortality rates for Black and White females were mostly equal, and consistently greater than those for Hispanic females; excess death rates for females displayed a similar pattern. Among males, mortality rates were highest for Whites, with Hispanics and Blacks close in magnitude at all ages. Excess death rates for males showed more divergence between the categories of race/ethnicity across the age range. CONCLUSIONS: -Mortality rates specific to categories of gender, age and race/ethnicity show sufficient differences as to make them the preferred way to construct life tables. This is especially true in contrast to broader summary measures such as risk ratios, standardized incidence rates, or life expectancy.

Mortality Due to Cardiovascular Disease Among Apollo Lunar Astronauts.

INTRODUCTION: Recent research has postulated increased cardiovascular mortality for astronauts who participated in the Apollo lunar missions. The conclusions, however, are based on small numbers of astronauts, are derived from methods with known weaknesses, and are not consistent with prior research. METHODS: Records for NASA astronauts and U.S. Air Force astronauts were analyzed to produce standardized mortality ratios. Lunar astronauts were compared to astronauts who have never flown in space (nonflight astronauts), those who have only flown missions in low Earth orbit (LEO astronauts), and the U.S. general population. RESULTS: Lunar astronauts were significantly older at cohort entry than other astronaut group and lunar astronauts alive as of the end of 2015 were significantly older than nonflight astronauts and LEO astronauts. No significant differences in cardiovascular disease (CVD) mortality rates between astronaut groups was observed, though lunar astronauts were noted to be at significantly lower risk of death by CVD than are members of the U.S. general population (SMR = 13, 95% CI = 3-39). DISCUSSION: The differences in age structure between lunar and nonlunar astronauts and the deaths of LEO astronauts from external causes at young ages lead to confounding in proportional mortality studies of astronauts. When age and follow-up time are properly taken into account using cohort-based methods, no significant difference in CVD mortality rates is observed. Care should be taken to select the correct study design, outcome definition, exposure classification, and analysis when answering questions involving rare occupational exposures.Reynolds RJ, Day SM. Mortality due to cardiovascular disease among Apollo lunar astronauts. Aerosp Med Hum Perform. 2017; 88(5):492-496.

The relationship of life expectancy to the development and valuation of life care plans.

BACKGROUND: A life care plan often analyzes needs up to a person's life expectancy. Expected present value of necessary funding for such a plan is likewise based on the fixed survival time. If a client should live beyond or die before the life expectancy, a shortfall or excess of funding may seem inevitable. The life table, of which life expectancy is a summary measure, clarifies these issues. OBJECTIVES: We explain life expectancy and how it is used in tort litigation, economic calculations, and life care planning. We examine the life table, of which life expectancy is one output. We illustrate how a life table provides age-specific probabilities of death and survival, life expectancies, and median survival times, and other information and that every life expectancy must be associated with a life table. We consider the implications for life care planners, forensic economists, and others. CONCLUSIONS: Life expectancy is a summary of more detailed information provided in a life table. The full life table provides better information for planning purposes. Whether life expectancy or a full life table should be used in developing and valuing a life care plan is not well understood. A multi-disciplinary approach may help clarify these issues.

Extrapolating published survival curves to obtain evidence-based estimates of life expectancy in cerebral palsy.

Studies reporting long-term survival probabilities for cohorts of persons with cerebral palsy provide evidence-based information on the life expectancy of those cohorts. Some studies have provided estimates of life expectancy based on extrapolation of such evidence, whereas many others have opted not to do so. Here we review the basic methods of life table analysis necessary for performing such extrapolations, and apply these methods to obtain evidence-based estimates of life expectancy from several studies that do not report such estimates themselves.

Comparative Mortality and Risk Factors for Death among US Supreme Court Justices (1789-2013).

Objectives .- To compare the mortality experience of 112 justices of the US Supreme Court with that expected in the general population. To identify variables associated with mortality within this cohort. Background .- Supreme Court justices are a select occupational cohort. High socio-economic status, advanced education, lifetime appointment, and the healthy worker effect suggest lower mortality. Sedentary work, stress, and a tendency to work beyond typical retirement age may attenuate this. Methods .- Standardized mortality ratios compare the observed mortality rates of justices with those expected in age- and sex-matched contemporary general populations. Poisson regression analyzes variables associated with mortality within the cohort. Results .- From 1789 to 2013, 112 justices (108 male) contributed 2,355 person-years of exposure. Mean age (standard deviation) at appointment was 53.1 years (6.7); at retirement 69.7 years (9.9); at death (n = 100) 74.4 years (10.3); and at end of the study for those alive (n = 12) 72.1 years (11.8). Standardized mortality ratios (95% ci) were: overall 0.87 (0.70-1.05); prior to 1950 0.92 (0.61-1.33); and from 1950 to 2013 0.66 (0.42-0.99). Variables in the final Poisson model and their associated mortality rate ratios (95% ci) were: age 1.06 (1.03-1.09); calendar year 0.99 (0.99-1.00); active status 0.41 (0.25-0.68); career length 1.04 (1.01-1.07); and chief justice 1.08 (0.59-1.84). Conclusions .- Supreme Court mortality was lower than that of the general population in the period from 1950 to the present, but was on par prior to 1950. Increasing age and career length were associated with greater mortality, while active status and later calendar year with lower. These results may add to a body of knowledge that may help to develop or refine models of mortality risk in increasingly aged working populations.