Lifespan of long-lived growth hormone receptor knockout mice was not normalized by housing at 30°C since weaning

Growth hormone receptor knockout (GHRKO) mice are remarkably long-lived and have improved glucose homeostasis along with altered energy metabolism which manifests through decreased respiratory quotient (RQ) and increased oxygen consumption (VO2 ). Short-term exposure of these animals to increased environmental temperature (eT) at 30°C can normalize their VO2 and RQ. We hypothesized that increased heat loss in the diminutive GHRKO mice housed at 23°C and the consequent metabolic adjustments to meet the increased energy demand for thermogenesis may promote extension of longevity, and preventing these adjustments by chronic exposure to increased eT will reduce or eliminate their longevity advantage. To test these hypotheses, GHRKO mice were housed at increased eT (30°C) since weaning. Here, we report that contrasting with the effects of short-term exposure of adult GHRKO mice to 30°C, transferring juvenile GHRKO mice to chronic housing at 30°C did not normalize the examined parameters of energy metabolism and glucose homeostasis. Moreover, despite decreased expression levels of thermogenic genes in brown adipose tissue (BAT) and elevated core body temperature, the lifespan of male GHRKO mice was not reduced, while the lifespan of female GHRKO mice was increased, along with improved glucose homeostasis. The results indicate that GHRKO mice have intrinsic features that help maintain their delayed, healthy aging, and extended longevity at both 23°C and 30°C

Resistance to Mild Cold Stress is Greater in Both Wild-Type and Long-Lived GHR-KO Female Mice.

Adapting to stress, including cold environmental temperature (eT), is crucial for the survival of mammals, especially small rodents. Long-lived mutant mice have enhanced stress resistance against oxidative and non-oxidative challenges. However, much less is known about the response of those long-lived mice to cold stress. Growth hormone receptor knockout (GHR-KO) mice are long-lived with reduced growth hormone signaling. We wanted to test whether GHR-KO mice have enhanced resistance to cold stress. To examine the response of GHR-KO mice to cold eT, GHR-KO mice were housed at mild cold eT (16 °C) immediately following weaning. Longevity results showed that female GHR-KO and wild-type (WT) mice retained similar lifespan, while both male GHR-KO and WT mice had shortened lifespan compared to the mice housed at 23 °C eT. Female GHR-KO and WT mice housed at 16 °C had upregulated fibroblast growth factor 21 (FGF21), enhanced energy metabolism, reduced plasma triglycerides, and increased mRNA expression of some xenobiotic enzymes compared to females housed at 23 °C and male GHR-KO and WT mice housed under the same condition. In contrast, male GHR-KO and WT mice housed at 16 °C showed deleterious effects in parameters which might be associated with their shortened longevity compared to male GHR-KO and WT mice housed at 23 °C. Together, this study suggests that in response to mild cold stress, sex plays a pivotal role in the regulation of longevity, and female GHR-KO and WT mice are more resistant to this challenge than the males

The dynamics of mature and emerging freshwater conservation programs

Conservation programs range from small, place-based initiatives to large, bureaucracy-heavy systems. The dynamics of these programs vary greatly. New initiatives may experience exponential growth, but participation and spending in mature programs may rise and fall in response to a number of factors. Here, we analyze historical patterns of participation and spending across five freshwater conservation programs in the United States. Our analysis highlights fundamental differences between emerging programs, which may experience exponential or logistic growth, and mature programs with slower growth, in which changes in participation may be driven by a number of internal and exogenous factors. We propose that changes in the number and spatial distribution of conservation projects are associated with four key factors: changes in legislation that open new funding streams; shifting priorities of actors; changes in the policies or management of a program that align it with new funding opportunities; and increases in individuals’ willingness to participate in a program as it grows. These programmatic shifts represent windows of opportunity for strategically reorienting conservation programs to leverage newly-available resources. Given that large, mature conservation programs support biodiversity and ecosystem services worldwide, comparison of their dynamics with those of emerging programs may reveal key opportunities for maximizing the benefits of investments in these programs.SW was supported by a Nancy L. Mergler Dissertation Completion Fellowship at OU. Financial support was provided by the University of Oklahoma Libraries’ Open Access Fund.Ye

Sexual Dimorphic Metabolic and Cognitive Responses of C57BL/6 Mice to Fisetin or Dasatinib and Quercetin Cocktail Oral Treatment.

Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4-13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma, tissue specific markers of senescence-associated secretory phenotype (SASP), and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D + Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Male and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4-13 months of age. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. Females treated with D + Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. No effects were observed in females treated with Fisetin or males treated with D + Q

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer\u27s disease (AD). The APPNL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue and the hippocampus before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL-F/NL-F mice. Thus, 4-month-old male and female APPNL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg dasatinib + 50 mg/kg quercetin, or 100 mg/kg fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + quercetin treatment in female APPNL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-β (Aβ)42 and senescence-associated-β-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APPNL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine

Exploring innovative strategies to improve perinatal mental health in Scotland:co-development of an action research agenda with women, families and practitioners

Perinatal mental health (PNMH) is an ongoing concern for women and families, as well as for health and social care services. It is estimated that 10-20% of women will experience mental health issues and up to 10% of fathers may also experience difficulties with their mental health. This issue was recently highlighted by national media.Our previous stakeholder consultation work identified service gaps for women in the mild-moderate category of PNMH. This project aimed to explore this identified gap further by bringing together a diverse group of partners, including women/families, practitioners and researchers to co-develop a collaborative action-research agenda. Project design and delivery was developed in collaboration with an expert with lived experience to ensure all elements were relevant and relatable.It is crucial to involve all stakeholders, including those with lived experience and practitioners, in discussions regarding successful interventions for perinatal mental health. This approach ensures that families receive better outcomes in a sustainable and scalable manner

Prodromal Glutamatergic Modulation with Riluzole Impacts Glucose Homeostasis and Spatial Cognition in Alzheimer\u27s Disease Mice.

BACKGROUND: Prior research supports a strong link between Alzheimer\u27s disease (AD) and metabolic dysfunction that involves a multi-directional interaction between glucose, glutamatergic homeostasis, and amyloid pathology. Elevated soluble amyloid-β (Aβ) is an early biomarker for AD-associated cognitive decline that contributes to concurrent glutamatergic and metabolic dyshomeostasis in humans and male transgenic AD mice. Yet, it remains unclear how primary time-sensitive targeting of hippocampal glutamatergic activity may impact glucose regulation in an amyloidogenic mouse model. Previous studies have illustrated increased glucose uptake and metabolism using a neuroprotective glutamate modulator (riluzole), supporting the link between glucose and glutamatergic homeostasis. OBJECTIVE: We hypothesized that targeting early glutamatergic hyperexcitation through riluzole treatment could aid in attenuating co-occurring metabolic and amyloidogenic pathologies with the intent of ameliorating cognitive decline. METHODS: We conducted an early intervention study in male and female transgenic (AβPP/PS1) and knock-in (APPNL - F/NL - F) AD mice to assess the on- and off-treatment effects of prodromal glutamatergic modulation (2-6 months of age) on glucose homeostasis and spatial cognition through riluzole treatment. RESULTS: Results indicated a sex- and genotype-specific effect on glucose homeostasis and spatial cognition with riluzole intervention that evolved with disease progression and time since treatment. CONCLUSION: These findings support the interconnected nature of glucose and glutamatergic homeostasis with amyloid pathology and petition for further investigation into the targeting of this relationship to improve cognitive performance

Chronic, Mild Hypothermic Environmental Temperature does not Ameliorate Cognitive Deficits in an Alzheimer\u27s Disease Mouse.

Metabolic dysfunction increases with age and is a contributing factor to Alzheimer\u27s disease (AD) development. We have previously observed impaired insulin sensitivity and glucose homeostasis in the APP/PS1 model of AD. To improve these parameters, we chronically exposed male and female mice to mild hypothermic environmental temperature (eT), which positively modulates metabolism. Although a hypothermic eT normalized insulin sensitivity, glucose tolerance was still impaired in both sexes of AD mice. We observed increased plasma glucagon and BAFF in both sexes, but additional sexually dimorphic mechanisms may explain the impaired glucose homeostasis in AD mice. Hepatic Glut2 was decreased in female while visceral adipose tissue TNFα was increased in male APP/PS1 mice. A mild hypothermic eT did not improve spatial learning and memory in either sex and increased amyloid plaque burden in male APP/PS1 mice. Overall, plasma markers of glucose homeostasis and AD pathology were worse in female compared to male APP/PS1 mice suggesting a faster disease progression. This could affect therapeutic outcome if interventional strategies are administered at the same chronological age to male and female APP/PS1 mice. Furthermore, this data suggests a dichotomy exists between mechanisms to improve metabolic function and cognitive health that may be further impaired in AD

Probabilistic risk assessment of the Space Shuttle. Phase 3: A study of the potential of losing the vehicle during nominal operation. Volume 4: System models and data analysis

In this volume, volume 4 (of five volumes), the discussion is focussed on the system models and related data references and has the following subsections: space shuttle main engine, integrated solid rocket booster, orbiter auxiliary power units/hydraulics, and electrical power system

Probabilistic risk assessment of the Space Shuttle. Phase 3: A study of the potential of losing the vehicle during nominal operation, volume 1

This document is the Executive Summary of a technical report on a probabilistic risk assessment (PRA) of the Space Shuttle vehicle performed under the sponsorship of the Office of Space Flight of the US National Aeronautics and Space Administration. It briefly summarizes the methodology and results of the Shuttle PRA. The primary objective of this project was to support management and engineering decision-making with respect to the Shuttle program by producing (1) a quantitative probabilistic risk model of the Space Shuttle during flight, (2) a quantitative assessment of in-flight safety risk, (3) an identification and prioritization of the design and operations that principally contribute to in-flight safety risk, and (4) a mechanism for risk-based evaluation proposed modifications to the Shuttle System. Secondary objectives were to provide a vehicle for introducing and transferring PRA technology to the NASA community, and to demonstrate the value of PRA by applying it beneficially to a real program of great international importance