Longitudinal Functional Study of Murine Aging: A Resource for Future Study Designs.

Aging is characterized by systemic declines in tissue and organ functions. Interventions that slow these declines represent promising therapeutics to protect against age-related disease and improve the quality of life. In this study, several interventions associated with lifespan extension in invertebrates or improvement of age-related disease were tested in mouse models to determine if they were effective in slowing tissue aging in a broad spectrum of functional assays. Benzoxazole, which extends the lifespan of Caenorhabditis elegans, slowed age-related femoral bone loss in mice. Rates of change were established for clinically significant parameters in untreated mice, including kyphosis, blood glucose, body composition, activity, metabolic measures, and detailed parameters of skeletal aging in bone. These findings have implications for the study of preclinical physiological aging and therapies targeting aging. Finally, an online application was created that includes the calculated rates of change and that enables power and variance to be calculated for many clinically important metrics of aging with an emphasis on bone. This resource will help in future study designs employing novel interventions in aging mice. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Automated lifespan determination across Caenorhabditis strains and species reveals assay-specific effects of chemical interventions.

The goal of the Caenorhabditis Intervention Testing Program is to identify robust and reproducible pro-longevity interventions that are efficacious across genetically diverse cohorts in the Caenorhabditis genus. The project design features multiple experimental replicates collected by three different laboratories. Our initial effort employed fully manual survival assays. With an interest in increasing throughput, we explored automation with flatbed scanner-based Automated Lifespan Machines (ALMs). We used ALMs to measure survivorship of 22 Caenorhabditis strains spanning three species. Additionally, we tested five chemicals that we previously found extended lifespan in manual assays. Overall, we found similar sources of variation among trials for the ALM and our previous manual assays, verifying reproducibility of outcome. Survival assessment was generally consistent between the manual and the ALM assays, although we did observe radically contrasting results for certain compound interventions. We found that particular lifespan outcome differences could be attributed to protocol elements such as enhanced light exposure of specific compounds in the ALM, underscoring that differences in technical details can influence outcomes and therefore interpretation. Overall, we demonstrate that the ALMs effectively reproduce a large, conventionally scored dataset from a diverse test set, independently validating ALMs as a robust and reproducible approach toward aging-intervention screening.

Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects.

Limiting the debilitating consequences of ageing is a major medical challenge of our time. Robust pharmacological interventions that promote healthy ageing across diverse genetic backgrounds may engage conserved longevity pathways. Here we report results from the Caenorhabditis Intervention Testing Program in assessing longevity variation across 22 Caenorhabditis strains spanning 3 species, using multiple replicates collected across three independent laboratories. Reproducibility between test sites is high, whereas individual trial reproducibility is relatively low. Of ten pro-longevity chemicals tested, six significantly extend lifespan in at least one strain. Three reported dietary restriction mimetics are mainly effective across C. elegans strains, indicating species and strain-specific responses. In contrast, the amyloid dye ThioflavinT is both potent and robust across the strains. Our results highlight promising pharmacological leads and demonstrate the importance of assessing lifespans of discrete cohorts across repeat studies to capture biological variation in the search for reproducible ageing interventions.

Late-life rapamycin treatment reverses age-related heart dysfunction.

Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity-enhancing paradigm in mammalian tissues. We treated 24-month-old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late-life cardiovascular function with a reversal or attenuation of age-related changes in the heart. RNA-seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late-life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age-related inflammation.

Acute oral potassium overdose: the role of hemodialysis.

INTRODUCTION: Hyperkalemia is a common condition, particularly in the setting of renal dysfunction. Hyperkalemia due to intentional oral potassium overdose is not commonly reported. CASE REPORT: We present a case of acute intentional potassium overdose in a patient with normal renal function resulting in significant hyperkalemia, with a maximum serum potassium concentration of 11 mEq/L. Despite an initial course complicated by various unstable cardiac rhythms, including ventricular tachycardia, ventricular fibrillation, and pulseless electrical activity, the patient was discharged from the hospital neurologically intact. Treatment for hyperkalemia included hemodialysis. DISCUSSION: The role of dialysis in potassium overdose is poorly defined. CONCLUSION: Based on this case and a review of the medical literature, we recommend hemodialysis for cases of potassium overdose with hemodynamic instability and significantly elevated serum potassium concentrations that do not respond promptly to medical therapy. Hemodialysis should also be considered in cases with underlying renal dysfunction.

Percutaneous transtracheal ventilation: resuscitation bags do not provide adequate ventilation.

INTRODUCTION: Percutaneous, transtracheal jet ventilation (PTJV) is an effective way to ventilate both adults and children. However, some authors suggest that a resuscitation bag can be utilized to ventilate through a cannula placed into the trachea. HYPOTHESIS: Percutaneous transtracheal ventilation (PTV) through a 14-gauge catheter is ineffective when attempted using a resuscitation bag. METHODS: Eight insufflation methods were studied. A 14-gauge intravenous catheter was attached to an adult resuscitation bag, a pediatric resuscitation bag, wall-source (wall) oxygen, portable-tank oxygen with a regulator, and a jet ventilator (JV) at two flow rates. The resuscitation bags were connected to the 14-gauge catheter using a 7 mm adult endotracheal tube adaptor connected to a 3 cc syringe barrel. The wall and tank oxygen were connected to the 14-gauge catheter using a three-way stopcock. The wall oxygen was tested with the regulator set at 15 liters per minute (LPM) and with the regulator wide open. The tank was tested with the regulator set at 15 and 25 LPM. The JV was connected directly to the 14-gauge catheter using JV tubing supplied by the manufacturer. Flow was measured using an Ohmeda 5420 Volume Monitor. A total of 30 measurements were taken, each during four seconds of insufflation, and the results averaged (milliliters (ml) per second (sec)) for each device. RESULTS: Flow rates obtained using both resuscitation bags, tank oxygen, and regulated wall oxygen were extremely low (adult 215 +/- 20 ml/sec; pediatric 195 +/- 19 ml/sec; tank 358 +/- 13 ml/sec; wall at 15 l/min 346 +/- 20 ml/sec). Flow rates of 1,394 +/- 13 ml were obtained using wall oxygen with the regulator wide open. Using the JV with the regulator set at 50 pounds per square inch (psi), a flow rate of 1,759 +/- 40 was obtained. These were the only two methods that produced flow rates high enough to provide an adequate tidal volume to an adult. CONCLUSIONS: Resuscitation bags should not be used to ventilate adult patients through a 14-gauge, transtracheal catheter. Jet ventilation is needed when percutaneous transtracheal ventilation is attempted. If jet ventilation is attempted using oxygen supply tubing, it must be connected to an unregulated oxygen source of at least 50 psi.