Microphysiological systems for human aging research.

Recent advances in microphysiological systems (MPS), also known as organs-on-a-chip (OoC), enable the recapitulation of more complex organ and tissue functions on a smaller scale in vitro. MPS therefore provide the potential to better understand human diseases and physiology. To date, numerous MPS platforms have been developed for various tissues and organs, including the heart, liver, kidney, blood vessels, muscle, and adipose tissue. However, only a few studies have explored using MPS platforms to unravel the effects of aging on human physiology and the pathogenesis of age-related diseases. Age is one of the risk factors for many diseases, and enormous interest has been devoted to aging research. As such, a human MPS aging model could provide a more predictive tool to understand the molecular and cellular mechanisms underlying human aging and age-related diseases. These models can also be used to evaluate preclinical drugs for age-related diseases and translate them into clinical settings. Here, we provide a review on the application of MPS in aging research. First, we offer an overview of the molecular, cellular, and physiological changes with age in several tissues or organs. Next, we discuss previous aging models and the current state of MPS for studying human aging and age-related conditions. Lastly, we address the limitations of current MPS and present future directions on the potential of MPS platforms for human aging research.

Soluble TNFR1 has greater reproducibility than IL-6 for the assessment of chronic inflammation in older adults: the case for a new inflammatory marker in aging.

Chronic inflammatory pathway activation, commonly referred to as "Inflammaging" or chronic inflammation (CI), is associated with frailty, cognitive and functional decline, and other causes of health span decline in older adults. We investigated the variability of candidate serum measures of CI among community-dwelling older adults selected for mild low-grade inflammation. We focused on serum cytokines known to be highly predictive of adverse health outcomes in older adults (sTNFR1, IL-6) during a short-term (weeks) and medium-term (months) follow-up, as well as immune markers that are less studied in aging but reflect other potentially relevant domains such as adaptive immune activation (sCD25), innate immune activation (sCD14 and sCD163), and the inflammation-metabolism interface (adiponectin/Acrp30) during short-term (weeks) follow up. We found that sTNFR1 was more reproducible than IL-6 over a period of weeks and months short-term and medium-term. The intra-class correlation coefficient (ICC) for sTNFR1 was 0.95 on repeated measures over 6 weeks, and 0.79 on repeated measures with mean interval of 14 weeks, while the ICC for IL-6 was 0.52 over corresponding short-term and 0.67 over corresponding medium-term follow-up. This suggests that sTNFR1 is a more reliable marker of CI than IL-6. This study provides new insights into the reproducibility of serum markers of CI in older adults. The findings suggest that sTNFR1 may be a better marker of CI than IL-6 in this population. Further studies are needed to confirm these findings and to investigate the clinical utility of sTNFR1 in older adults.

Interseason waning of vaccine-induced hemagglutination inhibition antibody titers and contributing factors to pre-existing humoral immunity against influenza in community-dwelling older adults 75 years and older.

BACKGROUND: Seasonal influenza causes significant morbidity and mortality with a disproportionately high disease burden in older adults. Strain-specific hemagglutination-inhibition (HAI) antibody titer is a well-established measure of humoral immunity against influenza and pre-vaccination HAI titer is a valuable indicator of pre-existing humoral immunity at the beginning of each influenza season in highly vaccinated older adults. While vaccine-induced HAI antibody titers are known to wane over time, accurate assessment of their interseason waning has been challenging. This is because pre-vaccination HAI titers are routinely measured using current season vaccine strain antigens instead of the prior season vaccines with which individuals were immunized; as such, they do not accurately represent residual antibody titers from prior season vaccination. This study took advantage of available pre-vaccination HAI titers measured using both current and prior season vaccine strain antigens in a longitudinal influenza immunization study with participants enrolled for multiple consecutive influenza seasons from 2014 through 2017. Influenza A virus (IAV) H3N2 and influenza B virus (IBV) strains in the vaccine formula changed in 2015 and again in 2016 season. IAV H1N1 vaccine strain remained the same from 2014 through 2016 seasons, but changed in 2017. We also investigated factors contributing to pre-existing humoral immunity. RESULTS: Interseason waning of HAI titers was evident, but rates of waning varied among vaccine strains and study seasons, from 18% (p = .43) to 61% (p < .01). Rates of waning were noticeably greater when pre-vaccination HAI titers were measured by the routine approach, i.e., using current season vaccine strain antigens, from 33% (p = .12) to 83% (p < .01), adjusting for age at prior study season, sex, race, and education. This was largely because the routinely measured pre-vaccination HAI titers underrepresented residual HAI titers from prior season vaccinations. Moreover, interseason antibody waning and prior season post-vaccination HAI titers had significant and independent associations with pre-vaccination HAI titers. CONCLUSIONS: The routinely measured pre-vaccination HAI titer overestimates interseason HAI antibody waning as it underestimates residual antibody titers from prior season vaccination when virus strains in the vaccine formula change. Moreover, interseason antibody waning and prior season post-vaccination HAI titers independently contribute to pre-existing humoral immunity in this highly vaccinated, community-dwelling older adult population.

Risk Factors for Nonresilient Outcomes in Older Adults After Total Knee Replacement.

BACKGROUND: Total knee replacement (TKR) is a common procedure in older adults. Physical resilience may be a useful construct to explain variable outcomes. We sought to define a simple measure of physical resilience and identify risk factors for nonresilient patient outcomes. METHODS: Secondary analysis of Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR) cohort study, a prospective registry of total joint replacement. The analysis included 7 239 adults aged 60 or older who underwent TKR between 2011 and 2015. Measures included sociodemographic and health factors. Outcomes were categorized as physically resilient versus nonresilient based on the change from baseline to 1-year follow-up for 3 patient-reported outcomes: the physical component summary (PCS), bodily pain (BP), and vitality (VT) from the Short Form-36 subcomponent scores, at preop and 1-year postprocedure. Associations were expressed as relative risk (RR) of physically nonresilient outcomes using generalized linear regression models, with Poisson distribution and log link. RESULTS: Age, body mass index, and Charlson Comorbidity Index (CCI) were associated with increased risk of physically nonresilient outcomes across PCS, BP, and VT: age, per 5 years for PCS (RR = 1.18 [1.12-1.23]), BP (RR = 1.06 [1.01-1.11), and VT (RR = 1.09 [1.06-1.12]); body mass index, per 5 kg/m2, for PCS (RR = 1.13 [1.07-1.19]), BP (RR = 1.06 [1.00-1.11]), and VT (RR = 1.08 [1.04-1.11]); and CCI for PCS CCI = 1 (RR = 1.38 [1.20-1.59]), CCI = 2-5 (RR = 1.59 [1.35-1.88]), CCI ≥6 (RR = 1.55 [1.31-1.83]. Household income >$45 000 associated with lower risk for PCS (RR = 0.81 [0.70-0.93]), BP (RR = 0.80 [0.69-0.91]), and VT (RR = 0.86 [0.78-0.93]). CONCLUSIONS: We operationalized physical resilience and identified factors predicting resilience after TKR. This approach may aid clinical risk stratification, guide further investigation of causes, and ultimately aid patients through the design of interventions to enhance physical resilience.

Narrative Interventions in the Palliative Care Setting: A Scoping Review.

CONTEXT: This scoping review maps the existing literature on narrative interventions within a palliative care and end-of-life context. OBJECTIVES: A scoping review was performed to address the following research question: What observational or randomized controlled trials have been performed to evaluate narrative interventions in the palliative care setting? METHODS: A search across multiple electronic databases was performed. The search results were screened. Relevant articles were reviewed for the identification of common themes and challenges. RESULTS: After reviewing 495 citations from electronic searches, and 44 articles from author archives or from manual review of article reference lists, we identified 34 articles for inclusion. Narrative interventions have focused on reflection or communication, and have been studied among providers, students, patients, and caregivers. Only patient/caregiver studies used randomized controlled design. Most studies were small and at the level of evaluating feasibility. Challenges include a high degree of heterogeneity among interventions and heterogeneity among parameters for evaluating those interventions. CONCLUSION: Narrative interventions are actively being evaluated with the intention of improving communication and well-being among all parties within the palliative care and end-of-life experience. The field would benefit from selecting a subset of outcomes that are comparable across studies, and a common framework for describing narrative interventions. Scant literature exists regarding narrative interventions to assist providers in communication.

Latent Expression of the Epstein-Barr Virus (EBV)-Encoded Major Histocompatibility Complex Class I TAP Inhibitor, BNLF2a, in EBV-Positive Gastric Carcinomas.

The Epstein-Barr virus (EBV) BNLF2a gene product provides immune evasion properties to infected cells through inhibition of transporter associated with antigen processing (TAP)-mediated transport of antigen peptides. Although BNLF2a is considered to be a lytic gene, we demonstrate that it is expressed in nearly half of the EBV-associated gastric carcinomas analyzed. Further, we show that BNLF2a expression is dissociated from lytic gene expression. BNLF2a is therefore expressed in this latency setting, potentially helping protect the infected tumor cells from immunosurveillance.

Cell-mediated autophagy promotes cancer cell survival.

Immune effector cells integrate signals that define the nature and magnitude of the subsequent response. Experimental measures for immune cell-mediated lysis of tumors or virally infected targets rely on average responses of permeability or apoptotic changes within a population of targets. Here, we examined individual target cells following interaction with lymphoid effectors. We found that human peripheral blood lymphocytes not only provide lytic signals but also promote autophagy in the remaining cells. At high effector-to-target ratios, autophagy was induced in several human tumors, as assessed by induction of LC3 puncta and diminished p62. Natural killer cells are a primary mediator of this process. In addition, target cell autophagy was enhanced by provision of interleukin (IL)-2, whereas IL-10 attenuated this effect, and cell-to-cell contact strongly enhanced lymphocyte-mediated autophagy. Although IFN-γ can induce autophagy in target cells, IFN-α acted directly on the targets or in concert with lymphocytes to diminish target autophagy in some cell types. Importantly, cell-mediated autophagy promoted resistance from treatment modalities designed to eradicate tumor cells. Our findings therefore show that the lymphocyte-induced cell-mediated autophagy promotes cancer cell survival and may represent an important target for development of novel therapies.

Zinc in innate and adaptive tumor immunity.

Zinc is important. It is the second most abundant trace metal with 2-4 grams in humans. It is an essential trace element, critical for cell growth, development and differentiation, DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency has adverse consequences during embryogenesis and early childhood development, particularly on immune functioning. It is essential in members of all enzyme classes, including over 300 signaling molecules and transcription factors. Free zinc in immune and tumor cells is regulated by 14 distinct zinc importers (ZIP) and transporters (ZNT1-8). Zinc depletion induces cell death via apoptosis (or necrosis if apoptotic pathways are blocked) while sufficient zinc levels allows maintenance of autophagy. Cancer cells have upregulated zinc importers, and frequently increased zinc levels, which allow them to survive. Based on this novel synthesis, approaches which locally regulate zinc levels to promote survival of immune cells and/or induce tumor apoptosis are in order.