Background/Objectives Polypharmacy is receiving increased attention as a potential problem for older persons, who frequently have multiple chronic conditions. The purpose of this study was to summarize evidence regarding the health outcomes associated with polypharmacy, defined as number of prescribed medications,among older community-dwelling persons. Design Systematic review of MEDLINE (OvidSP 1946 to May Week 3 2014). Setting Community Participants Observational studies examining health outcomes according to the number of prescription medications taken. Measurements Association of number of medications with health outcomes. Because of the importance of comorbidity as a potential confounder of the relationship between polypharmacy and health outcomes, articles were assessed regarding the quality of their adjustment for confounding. Results Of the total of 50 studies identified, the majority studies that were rated as “good” in terms of their adjustment for comorbidity demonstrated relationships between polypharmacy and a range of outcomes, including falls/fall outcomes/fall risk factors; adverse drug events, hospitalization, mortality, and measures of function and cognition. However, a number of these studies failed to demonstrate associations, as did a substantial proportion of those studies rated as “fair” or “poor.” Conclusions Data are mixed regarding the relationship between polypharmacy, considered in terms of number of medications, and adverse outcomes among community-dwelling older persons. Because of the challenge of confounding, randomized controlled trials of medication discontinuation may provide more definitive evidence regarding this relationship.

Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.

Scholars argue about whether age stereotypes (beliefs about old people) are becoming more negative or positive over time. No previous study has systematically tested the trend of age stereotypes over more than 20 years, due to lack of suitable data. Our aim was to fill this gap by investigating whether age stereotypes have changed over the last two centuries and, if so, what may be associated with this change. We hypothesized that age stereotypes have increased in negativity due, in part, to the increasing medicalization of aging. This study applied computational linguistics to the recently compiled Corpus of Historical American English (COHA), a database of 400 million words that includes a range of printed sources from 1810 to 2009. After generating a comprehensive list of synonyms for the term elderly for these years from two historical thesauri, we identified 100 collocates (words that co-occurred most frequently with these synonyms) for each of the 20 decades. Inclusion criteria for the collocates were: (1) appeared within four words of the elderly synonym, (2) referred to an old person, and (3) had a stronger association with the elderly synonym than other words appearing in the database for that decade. This yielded 13,100 collocates that were rated for negativity and medicalization. We found that age stereotypes have become more negative in a linear way over 200 years. In 1880, age stereotypes switched from being positive to being negative. In addition, support was found for two potential explanations. Medicalization of aging and the growing proportion of the population over the age of 65 were both significantly associated with the increase in negative age stereotypes. The upward trajectory of age-stereotype negativity makes a case for remedial action on a societal level.

Analysis of immune cell states is paramount to our understanding of the pathogenesis of a broad range of human diseases. Immunologists rely on fluorescence cytometry for cellular analysis, and while detection of 8 markers is now well established, the overlap of fluorescent signals limits efficiency. Mass cytometry or CyTOF (Cytometry by Time-Of-Flight) is a new technology for multiparameter single cell analysis that overcomes many limitations of fluorescence-based flow cytometry and can routinely detect as many as 40 markers per sample. This technology provides tremendous detail for cellular analysis of multiple cell populations simultaneously and is a powerful technique for translational investigations. Here we present reproducible detection of immune cell subsets starting with as few as 10,000 cells. Our study provides methods to employ CyTOF for small samples, which is especially relevant for investigation of limited patient biopsies in translational and clinical research.

To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age ≥65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty. PBMCs obtained prior to vaccination (Day 0) and at day 2 or 4, day 7 and day 28 post-vaccine were subjected to gene expression microarray analysis. We defined a response signature and also detected induction of a type I interferon response at day 2 and a plasma cell signature at day 7 post-vaccine in young responders. The response signature was dysregulated in older adults, with the plasma cell signature induced at day 2, and was never induced in frail subjects (who were all non-responders). We also identified a mitochondrial signature in young vaccine responders containing genes mediating mitochondrial biogenesis and oxidative phosphorylation that was consistent in two different vaccine seasons and verified by analyses of mitochondrial content and protein expression. These results represent the first genome-wide transcriptional profiling analysis of age-associated dynamics following influenza vaccination, and implicate changes in mitochondrial biogenesis and function as a critical factor in human vaccine responsiveness.

-Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed. Although an important mediator of sepsis is thought to be mitochondrial dysfunction, the underlying molecular mechanism is unclear. Modulation of mitochondrial processes may be an effective therapeutic strategy in sepsis. Here, we investigated the role of the kinase MKK3 in regulation of mitochondrial function in sepsis. Using clinically relevant animal models, we examined mitochondrial function in primary mouse lung endothelial cells exposed to LPS. MKK3 deficiency reduces lethality of sepsis in mice and by lowering levels of lung and mitochondrial injury as well as reactive oxygen species. Furthermore, MKK3 deficiency appeared to simultaneously increase mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This led to a more robust mitochondrial network, which we propose provides protection against sepsis. We also detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls. Our findings demonstrate a critical role for mitochondria in the pathogenesis of sepsis that involves a previously unrecognized function of MKK3 in mitochondrial quality control. This mitochondrial pathway may help reveal new diagnostic markers and therapeutic targets against sepsis. sepsis; lung injury; mitogen-activated protein kinases; mitochondria; mitophagy; biogenesis SEPSIS, A SYSTEMIC INFLAMMATORY reaction to infection, is the leading cause of death globally. The incidence of sepsis worldwide is 18 million every year with 30% mortality. The economic impact of sepsis is substantial with costs of up to $50,000/patient and $17 billion annually in United States alone (30, 43). Death from sepsis occurs due to multiorgan failure, and biological therapies do not exist. Prevailing theories attribute multiple organ failure in sepsis to an uncontrolled inflammatory response, apoptosis, or disorders in the coagulation (38). Unfortunately, therapies against these responses, such as anti-inflammatory agents and activated protein C, have been unsuccessful. Since current medical care remains purely supportive, there is an urgent need to develop targeted therapies.Mitochondria are mediators of inflammatory responses (19, 54) and become dysfunctional in sepsis and lung injury (4, 6), suggesting they are involved in the observed pathology. Mitochondria are essential hubs of innate immune signaling and inflammation in sepsis (48, 49) and are also major sites of reactive oxygen species (ROS) production in the cells. Mitochondria are constantly exposed to ROS, and hence ongoing biogenesis and turnover are needed to maintain a functional network. Dysfunctional mitochondria are removed through selective degradation via autophagy by the lysosomal mach...

The pathogenesis of chronic obstructive pulmonary disease (COPD) remains poorly understood. Cellular senescence and apoptosis contribute to the development of COPD; however, crucial regulators of these underlying mechanisms remain unknown. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that antagonizes both apoptosis and premature senescence and may be important in the pathogenesis of COPD. This study examines the role of MIF in the pathogenesis of COPD. Mice deficient in MIF (Mif(-/-)) or the MIF receptor CD74 (Cd74(-/-)) and wild-type (WT) controls were aged for 6 mo. Both Mif(-/-) and Cd74(-/-) mice developed spontaneous emphysema by 6 mo of age compared with WT mice as measured by lung volume and chord length. This was associated with activation of the senescent pathway markers p53/21 and p16. Following exposure to cigarette smoke, Mif(-/-) mice were more susceptible to the development of COPD and apoptosis compared with WT mice. MIF plasma concentrations were measured in a cohort of 224 human participants. Within a subgroup of older current and former smokers (n = 72), MIF concentrations were significantly lower in those with COPD [8.8, 95%CI (6.7-11.0)] compared with those who did not exhibit COPD [12.7 ng/ml, 95%CI (10.6-14.8)]. Our results suggest that both MIF and the MIF receptor CD74 are required for maintenance of normal alveolar structure in mice and that decreases in MIF are associated with COPD in human subjects.

We evaluated in vivo innate immune responses in monocyte populations from 67 young (aged 21-30 years) and older (aged ≥65 years) adults before and after influenza vaccination. CD14(+)CD16(+) inflammatory monocytes were induced after vaccination in both young and older adults. In classical CD14(+)CD16(-) and inflammatory monocytes, production of tumor necrosis factor α and interleukin 6, as measured by intracellular staining, was strongly induced after vaccination. Cytokine production was strongly associated with influenza vaccine antibody response; the highest levels were found as late as day 28 after vaccination in young subjects and were substantially diminished in older subjects. Notably, levels of the anti-inflammatory cytokine interleukin 10 (IL-10) were markedly elevated in monocytes from older subjects before and after vaccination. In purified monocytes, we found age-associated elevation in phosphorylated signal transducer and activator of transcription-3, and decreased serine 359 phosphorylation of the negative IL-10 regulator dual-specificity phosphatase 1. These findings for the first time implicate dysregulated IL-10 production in impaired vaccine responses in older adults.