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Mycoplasma ovipneumoniae is associated with respiratory disease in wild and domestic Caprinae globally, with wide variation in disease outcomes within and between host species. To gain insight into phylogenetic structure and mechanisms of pathogenicity for this bacterial species, we compared M. ovipneumoniae genomes for 99 samples from 6 countries (Australia, Bosnia and Herzegovina, Brazil, China, France and USA) and 4 host species (domestic sheep, domestic goats, bighorn sheep and caribou). Core genome sequences of M. ovipneumoniae assemblies from domestic sheep and goats fell into two well-supported phylogenetic clades that are divergent enough to be considered different bacterial species, consistent with each of these two clades having an evolutionary origin in separate host species. Genome assemblies from bighorn sheep and caribou also fell within these two clades, indicating multiple spillover events, most commonly from domestic sheep. Pangenome analysis indicated a high percentage (91.4 %) of accessory genes (i.e. genes found only in a subset of assemblies) compared to core genes (i.e. genes found in all assemblies), potentially indicating a propensity for this pathogen to adapt to within-host conditions. In addition, many genes related to carbon metabolism, which is a virulence factor for Mycoplasmas, showed evidence for homologous recombination, a potential signature of adaptation. The presence or absence of annotated genes was very similar between sheep and goat clades, with only two annotated genes significantly clade-associated. However, three M. ovipneumoniae genome assemblies from asymptomatic caribou in Alaska formed a highly divergent subclade within the sheep clade that lacked 23 annotated genes compared to other assemblies, and many of these genes had functions related to carbon metabolism. Overall, our results suggest that adaptation of M. ovipneumoniae has involved evolution of carbon metabolism pathways and virulence mechanisms related to those pathways. The genes involved in these pathways, along with other genes identified as potentially involved in virulence in this study, are potential targets for future investigation into a possible genomic basis for the high variation observed in disease outcomes within and between wild and domestic host species.

Healthy longevity medicine integrates geroscience and other disciplines into clinical settings, aiming to optimize health throughout one's lifespan. Multiple factors have led to increased consumer engagement, with private clinics currently meeting the demand for guidance to improve healthy longevity. The establishment of healthy longevity clinics in publicly funded hospitals is a significant development, making longevity-focused healthcare more accessible. These clinics rely on multidisciplinary teams of physicians and allied health professionals. Diagnostics involve comprehensive evaluations of medical history, physical examinations, and various clinical tests to detect early signs of age-related functional decline. Interventions in healthy longevity medicine encompass lifestyle modifications, supplements, repurposed drugs, and social and environmental interventions. Collaboration with research institutions and industry partners is crucial for advancing healthy longevity medicine and creating standardized protocols. In this article, we review the process of creating healthy longevity clinics in public hospitals to ensure the best possible care for individuals pursuing healthy longevity., (© 2024. The Author(s).)

Objective: Falls in older adults correlate with heightened morbidity and mortality. Assessing fall risk in the emergency department (ED) not only aids in identifying candidates for prevention interventions but may also offer insights into overall mortality risk. We sought to examine the link between fall risk and 30-day mortality in older ED adults., Methods: Observational cohort study of adults aged ≥ 75years who presented to an academic ED and who were assessed for fall risk using the Memorial Emergency Department Fall Risk Assessment Tool (MEDFRAT), a validated, ED-specific screening tool. The fall risk was classified as low (0-2 points), moderate (3-4 points), or high (≥5) risk. The primary outcome was 30-day mortality. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated., Results: A total of 941 patients whose fall risk was assessed in the ED were included in the study. Median age was 83.7 years; 45.6% were male, 75.6% lived in private residences, and 62.7% were admitted. Mortality at 30 days among the high fall risk group was four times that of the low fall risk group (11.8% vs 3.1%; HR 4.00, 95% CI 2.18 to 7.34, p < 0.001). Moderate fall risk individuals had nearly double the mortality rate of the low-risk group (6.0% vs 3.1%), but the difference was not statistically significant (HR 1.98, 95% CI 0.91 to 4.32, p = 0.087)., Conclusion: ED fall risk assessments are linked to 30-day mortality. Screening may facilitate the stratification of older adults at risk for health deterioration., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflict of interest to disclose related to this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Understanding how management influences forage nutritive value and grazer selection within grazing seasons is an ongoing effort for researchers and land managers globally. We used six, 65 ha pastures managed with patch-burn grazing and stocked with either cow-calf pairs (0.45-0.5 ha • AUM -1 ) or gestating ewes (0.4-0.48 ha • AUM-1) to explore how patterns in rangeland forage drive grazer selection in semi-arid rangeland over four summer grazing seasons at monthly intervals. We used near-infrared spectroscopy to determine nutritive value parameters from monthly forage clippings. We evaluated livestock performance as the average daily weight gains of each animal. We used mixed-effect models and ordination to compare patch and grazer types across the time-since-fire gradient and found that time-since-fire was significant for all measured variables. Cattle and sheep consistently preferred recently burned patches throughout grazing seasons. These recently burned patches typically contained available forage with higher crude protein and moisture content, lower biomass, and lower acid detergent fiber, acid detergent lignin, and neutral detergent fiber compared to intermediate time since fire patches and patches burned three years ago. Differences between patch-burn grazing with cattle and sheep were observed as additional patch contrasts for available biomass and crude protein, but grazer type and ecological site were not statistically significant factors for the nutritive value ordination. Our study indicates that patch-burn grazing is capable of imposing and maintaining heterogeneous, grazer selection, forage biomass, and nutritive value patterns desirable for heterogeneity focused land management, regardless of grazer type. These findings are especially relevant to the northern Great Plains where introduced grasses are homogenizing the structural environment of remaining rangelands. With prescribed fire currently an uncommon practice throughout the region, these findings provide a baseline of expectations for practitioners and land managers implementing patch-burn grazing and illustrate how grazing livestock can benefit from the patch contrast in forage nutritive value and biomass., Competing Interests: Declaration of competing interest We have no declared conflicts of interest regarding this manuscript or project., (Published by Elsevier Ltd.)

A mixture of butorphanol, azaperone, and medetomidine (BAM) is frequently used for immobilization of North American hoofstock. Common adverse effects include respiratory depression, hypoxemia, and bradycardia. In this nonblinded crossover study the efficacy of two a-2 adrenergic antagonists, tolazoline and vatinoxan, were evaluated in alleviating adverse effects of BAM in Rocky Mountain elk ( Cervus canadensis ). Early administration of these antagonists was hypothesized to cause an increase in heart rate, respiratory rate, partial pressure of oxygen (PaO 2 ) and hemoglobin oxygen saturation (SpO 2 ), as well as reduction in mean arterial blood pressure without affecting sedation levels. Eight captive adult female elk were immobilized on three separate occasions at least 14 d apart with 0.15 mg/kg butorphanol, 0.05 mg/kg azaperone, and 0.06 mg/kg medetomidine. Tolazoline (2 mg/kg IM), vatinoxan (3 mg/mg medetomidine IV) or sterile saline (2 ml IM) were administered 20 min postinduction. The BAM caused hypoxemia, bradycardia, and moderate hypertension, and because of the severe hypoxemia observed, all animals received intratracheal oxygen throughout immobilization. Heart rate, respiratory rate, rectal temperature, SpO 2 , PaO 2 , and systolic, diastolic, and mean arterial blood pressure were monitored every 5 min throughout the immobilization. Intramuscular tolazoline caused a brief but significant drop in mean arterial pressure compared with controls and a brief but nonsignificant increase in heart rate. Vatinoxan caused a significant drop in blood pressure and a brief significant increase in heart rate. Changes in respiratory rates and PaO 2 were not observed with either antagonist; however, all animals received oxygen, which may have influenced this result. The depth of sedation was unchanged after administration of either drug.

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76-0.82) than the covariates alone (0.70, CI: 0.67-0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death., (© 2023 Mayo Clinic. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Giardia and Cryptosporidium are zoonotic protozoan parasites that can infect humans and other taxa, including wildlife, often causing gastrointestinal illness. Both have been identified as One Health priorities in the Arctic, where climate change is expected to influence the distribution of many wildlife and zoonotic diseases, but little is known about their prevalence in local wildlife. To help fill information gaps, we collected fecal samples from four wildlife species that occur seasonally on the northern Alaska coastline or in nearshore marine waters-Arctic fox ( Vulpes lagopus ), polar bear ( Ursus maritimus ), Pacific walrus ( Odobenus rosmarus divergens ), and caribou ( Rangifer tarandus )-and used immunofluorescence assays to screen for Giardia cysts and Cryptosporidium oocysts. We detected Giardia cysts in 18.3% and Cryptosporidium oocysts in 16.5% of Arctic foxes ( n  = 109), suggesting that foxes may be potentially important hosts in this region. We also detected Giardia cysts in a single polar bear (12.5%; n  = 8), which to our knowledge represents the first such report for this species. Neither parasite was detected in walruses or caribou., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Paralytic shellfish poisoning is a global issue that would benefit from additional screening methods and rapid testing capacities. In this study, we applied 1 H NMR spectroscopy-based metabolomics to identify biomarkers of Paralytic Shellfish Toxin (PST) exposure. We characterized the metabolic phenotypes of field-collected Alaskan mussels Mytilus trossulus across a wide range of bioaccumulated PST levels, from 0 to 1590 μg/100 g. A between-level grouping emerged for high (740-1590 μg/100 g) compared to low/non-detect (0-3.91 μg/100 g) PST levels. High levels of PST contamination in mussels were consistent with alterations to energy and amino acid metabolism, and disturbances in osmoregulation. This research demonstrates the effectiveness of 1 H NMR-based metabolomics in elucidating the biological effects of paralytic shellfish toxin on the health of wild mussel populations, spatial variation, and identifies a metabolic signature indicative of PST contamination in Mytilus trossulus for potential use in a PSP biomarker panel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cellular senescence is a cell fate involving cell cycle arrest, resistance against apoptosis, and the development of a secretome that can be pro-inflammatory. In aging and obesity, senescent cells accumulate in many tissues, including adipose tissue, brain, kidney, pancreas, and liver. These senescent cells and their downstream effects appear to perpetuate inflammation and have been implicated in the pathogenesis of metabolic dysfunction. Senescent cells are cleared in part by the immune system, a process that is diminished in obesity and aging, likely due in part to senescence of immune cells themselves. Targeting senescent cells or their products improves metabolic function in both aging and in animal models of obesity. Novel therapeutics to target senescent cells are on the horizon and are currently being investigated in clinical trials in humans for multiple diseases. Early evidence suggests that senolytic drugs, which transiently disarm the anti-apoptotic defenses of pro-inflammatory senescent cells, are effective in causing depletion of senescent cells in humans. Senescence-targeting therapeutics, including senolytic drugs and strategies to increase immune clearance of senescent cells, hold significant promise for treating metabolic dysfunction in multiple tissues and disease states., Competing Interests: Conflict of interest AKP, TT, and JLK have a financial interest related to this research. Patents on senolytic drugs are held by Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Similar to the several pinniped and a few terrestrial carnivore species, the Steller sea lion has a seasonal synchronized mating scheme enabled by a female reproductive cycle that includes embryonic diapause, delayed implantation, and pseudopregnancy (a state in which the corpus luteum produces progesterone for approximately as long as in pregnant females). Due to this, circulating systemic progesterone concentrations cannot be used to differentiate pregnant and nonpregnant females during early gestation. With the use of advanced measurement technologies such as liquid chromatography tandem mass spectrometry (LC-MS/MS) additional steroid hormones are measurable which can provide additional information on the endocrine pathways throughout gestation. Our objectives were to further characterize endocrine patterns in female Steller sea lion pregnancy by 1) quantifying longitudinal profiles of hormone metabolites in pregnant and non-pregnant female sera, and 2) evaluating hormone profiles to identify pregnant animals within the early stage of gestation. Three gestation stages were delineated based on what is believed to be the period of implantation (September-October): EARLY (August- November), MID (December-February), and LATE (March to May). Five steroids, Progesterone (P 4 ), 5α-dihydroprogesterone (DHP), 17αOH-progesterone (17OHP), 20αOH-progesterone (20OHP), and androstenedione (A 4 ), were detected in both pregnant and non-pregnant animals. A significant difference in P 4 concentrations was measured between EARLY and MID gestation (p ≤ 0.01) in both pregnant and non-pregnant animals. During MID gestation there was a significant difference (p ≤ 0.05) between pregnant and non-pregnant animals in all pregnanes measured. Significant patterns of correlation between P 4 and 17OHP and between P 4 and DHP were detected during EARLY and MID gestation in non-pregnant animals. While those significant correlations also exist in EARLY pregnant animals, this pattern was lost by MID gestation. This loss of correlation suggests a potential shift in progesterone metabolism from ovarian to alternative tissue (e.g. fetal gonads or adrenal glands) by MID gestation in Steller sea lions. We were unable to identifying a steroid hormone biomarker capable of differentiating pseudopregnancy from pregnant animals and conclude that such a biomarker likely falls outside of the traditional progesterone metabolic pathway., (Published by Elsevier Inc.)

Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues - adipose, muscle, and liver - as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.

Background: α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans., Methods: We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q)., Findings: We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence., Interpretation: Senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials., Funding: This work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network., Competing Interests: Declaration of interests Y.Z., T.T., N.G., T.P., A.K.P., and J.L.K. have a financial interest related to this research. Patents on senolytic drugs are held by Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. No conflicts of interest, financial or otherwise, are declared by the other authors., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Therapeutics that target cellular senescence, including novel "senolytic" compounds, hold significant promise for treating or preventing obesity-induced metabolic dysfunction, type 2 diabetes, and the multiple complications of diabetes and obesity. Senolytics selectively clear senescent cells, which accumulate with aging and obesity and represent a fundamental mechanism of aging that contributes to metabolic dysfunction and diabetes pathogenesis. In addition to improving metabolic function, targeting senescent cells holds promise as a preventive strategy to reduce the incidence and severity of diabetes complications. The intermittent administration schedule used for senolytic therapy may confer benefits in terms of improving adherence and limiting adverse effects. It is necessary to design effective clinical trials that will safely translate discoveries from preclinical models into human studies that may pave the way for a novel therapeutic class for treating obesity, diabetes, and their complications. In this review, we outline what is known regarding the role of cellular senescence in the pathogenesis of type 2 diabetes and its complications, present evidence from preclinical models that targeting cellular senescence is beneficial, review senolytic drugs, and outline the features of clinical trials investigating the role of targeting senescent cells for diabetes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Safety isolation protocols in response to the COVID-19 (coronavirus disease 2019) pandemic have had the unintended consequence of social isolation for adolescents, youth who have a developmental need for autonomy and peer connection. Social isolation alone can lead to various psychological effects such as anxiety, stress, low mood, fear, frustration, and boredom. School nurses serve a vital role in addressing stress among adolescents by initiating early interventions, ensuring positive school experiences for students, and providing support surrounding the development of mental health disorders. Through implementation of NASN's Framework for 21st Century School Nursing Practice, school nurses address stress among high school students during the COVID-19 pandemic. Innovative interventions can include recognizing signs and symptoms of stress on physical and emotional health, advocating for mental health literacy curriculums, social prescribing, incorporating anticipatory guidance related to health promotion lifestyle practices into each school health encounter, and creating a virtual school health office to reach students while COVID-19 safety isolation continues.

Modern pinnipeds (true and eared seals) employ two radically different swimming styles, with true seals (phocids) propelling themselves primarily with their hindlimbs, whereas eared seals (otariids) rely on their wing-like foreflippers. 1 , 2 Current explanations of this functional dichotomy invoke either pinniped diphyly 3-5 or independent colonizations of the ocean by related but still largely terrestrial ancestors. 6-8 Here, we show that pinniped swimming styles form an anatomical, functional, and behavioral continuum, within which adaptations for forelimb swimming can arise directly from a hindlimb-propelled bauplan. Within phocids, southern seals (monachines) show a convergent trend toward wing-like, hydrodynamically efficient forelimbs used for propulsion during slow swimming, turning, bursts of speed, or when initiating movement. This condition is most evident in leopard seals, which have well-integrated foreflippers with little digit mobility, reduced claws, and hydrodynamic characteristics comparable to those of forelimb-propelled otariids. Using monachines as a model, we suggest that the last common ancestor of modern seals may have been hindlimb-propelled and aquatically adapted, thus resolving the apparent contradiction at the root of pinniped evolution., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Modes of mammalian reproduction are diverse and not always conserved among related species. Progesterone is universally required to supports pregnancy but sites of synthesis and metabolic pathways vary widely. The steroid metabolome of mid-to late gestation was characterized, focusing on 5α-reduced pregnanes in species representing the Perissodactyla, Cetartiodactyla and Carnivora using mass spectrometry. Metabolomes and steroidogenic enzyme ortholog sequences were used in heirarchial analyses. Steroid metabolite profiles were similar within orders, whales within cetartiodactyls for instance, but with notable exceptions such as rhinoceros clustering with goats, and tapirs with pigs. Steroidogenic enzyme sequence clustering reflected expected evolutionary relationships but once again with exceptions. Human sequences (expected outgroups) clustered with perissodactyl CYP11A1, CYP17A1 and SRD5A1 gene orthologues, forming outgroups only for HSD17B1 and SRD5A2. Spotted hyena CYP19A1 clustered within the Perissodactyla, between rhinoceros and equid orthologues, whereas CYP17A1 clustered within the Carnivora. This variability highlights the random adoption of divergent physiological strategies as pregnancy evolved among genetically similar species., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of the most conserved biological pathways that regulates aging across species. 17α-Estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin sensitivity and extend longevity exclusively in male mice. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic insulin-like growth factor 1 (IGF1) production in male mice without inducing any changes in pulsatile growth hormone (GH) secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on IGF1 production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17α-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17α-E2 treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The elderly population is increasing faster than other segments of the population throughout the world. Age is the leading predictor for most chronic diseases and disorders, multimorbidity, geriatric syndromes, and impaired ability to recover from accidents or illnesses. Enhancing the duration of health and independence, termed healthspan, would be more desirable than extending lifespan merely by prolonging the period of morbidity toward the end of life. The geroscience hypothesis posits that healthspan can be extended by targeting fundamental aging mechanisms, rather than attempting to address each age-related disease one at a time, only so the afflicted individual survives disabled and dies shortly afterward of another age-related disease. These fundamental aging mechanisms include, among others, chronic inflammation, fibrosis, stem cell/ progenitor dysfunction, DNA damage, epigenetic changes, metabolic shifts, destructive metabolite generation, mitochondrial dysfunction, misfolded or aggregated protein accumulation, and cellular senescence. These processes appear to be tightly interlinked, as targeting any one appears to affect many of the rest, underlying our Unitary Theory of Fundamental Aging Mechanisms. Interventions targeting many fundamental aging processes are being developed, including dietary manipulations, metformin, mTOR (mechanistic target of rapamycin) inhibitors, and senolytics, which are in early human trials. These interventions could lead to greater healthspan benefits than treating age-related diseases one at a time. To illustrate these points, we focus on cellular senescence and therapies in development to target senescent cells. Combining interventions targeting aging mechanisms with disease-specific drugs could result in more than additive benefits for currently difficult-to-treat or intractable diseases. More research attention needs to be devoted to targeting fundamental aging processes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Large stocks of soil organic carbon (SOC) have accumulated in the Northern Hemisphere permafrost region, but their current amounts and future fate remain uncertain. By analyzing dataset combining >2700 soil profiles with environmental variables in a geospatial framework, we generated spatially explicit estimates of permafrost-region SOC stocks, quantified spatial heterogeneity, and identified key environmental predictors. We estimated that Pg C are stored in the top 3 m of permafrost region soils. The greatest uncertainties occurred in circumpolar toe-slope positions and in flat areas of the Tibetan region. We found that soil wetness index and elevation are the dominant topographic controllers and surface air temperature (circumpolar region) and precipitation (Tibetan region) are significant climatic controllers of SOC stocks. Our results provide first high-resolution geospatial assessment of permafrost region SOC stocks and their relationships with environmental factors, which are crucial for modeling the response of permafrost affected soils to changing climate., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The Arctic is entering a new ecological state, with alarming consequences for humanity. Animal-borne sensors offer a window into these changes. Although substantial animal tracking data from the Arctic and subarctic exist, most are difficult to discover and access. Here, we present the new Arctic Animal Movement Archive (AAMA), a growing collection of more than 200 standardized terrestrial and marine animal tracking studies from 1991 to the present. The AAMA supports public data discovery, preserves fundamental baseline data for the future, and facilitates efficient, collaborative data analysis. With AAMA-based case studies, we document climatic influences on the migration phenology of eagles, geographic differences in the adaptive response of caribou reproductive phenology to climate change, and species-specific changes in terrestrial mammal movement rates in response to increasing temperature., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Temperatures in arctic-boreal regions are increasing rapidly and pose significant challenges to moose ( Alces alces ), a heat-sensitive large-bodied mammal. Moose act as ecosystem engineers, by regulating forest carbon and structure, below ground nitrogen cycling processes, and predator-prey dynamics. Previous studies showed that during hotter periods, moose displayed stronger selection for wetland habitats, taller and denser forest canopies, and minimized exposure to solar radiation. However, previous studies regarding moose behavioral thermoregulation occurred in Europe or southern moose range in North America. Understanding whether ambient temperature elicits a behavioral response in high-northern latitude moose populations in North America may be increasingly important as these arctic-boreal systems have been warming at a rate two to three times the global mean., Methods: We assessed how Alaska moose habitat selection changed as a function of ambient temperature using a step-selection function approach to identify habitat features important for behavioral thermoregulation in summer (June-August). We used Global Positioning System telemetry locations from four populations of Alaska moose ( n  = 169) from 2008 to 2016. We assessed model fit using the quasi-likelihood under independence criterion and conduction a leave-one-out cross validation., Results: Both male and female moose in all populations increasingly, and nonlinearly, selected for denser canopy cover as ambient temperature increased during summer, where initial increases in the conditional probability of selection were initially sharper then leveled out as canopy density increased above ~ 50%. However, the magnitude of selection response varied by population and sex. In two of the three populations containing both sexes, females demonstrated a stronger selection response for denser canopy at higher temperatures than males. We also observed a stronger selection response in the most southerly and northerly populations compared to populations in the west and central Alaska., Conclusions: The impacts of climate change in arctic-boreal regions increase landscape heterogeneity through processes such as increased wildfire intensity and annual area burned, which may significantly alter the thermal environment available to an animal. Understanding habitat selection related to behavioral thermoregulation is a first step toward identifying areas capable of providing thermal relief for moose and other species impacted by climate change in arctic-boreal regions., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: The burden of surgical disease in refugee and internally displaced person (IDP) populations has not been well defined. Populations fleeing conflict are mobile, limiting the effectiveness of traditional sampling methods. We employed novel sampling and survey techniques to conduct a population-based surgical needs assessment amongst IDPs in Kerenik, West Darfur, Sudan, over 4 weeks in 2008., Methods: Satellite imagery was used to identify man-made structures. Ground teams were guided by GPS to randomly selected households. A newly created surgical needs survey was administered by surgeons to household members. One randomly selected individual answered demographic and medical history questions pertaining to themselves and first-degree blood relatives. All household members were offered a physical examination looking for surgical disease., Findings: There were 780 study participants; 82% were IDPs. A history since displacement of surgical and potentially surgical conditions was reported in 38% of respondents and by 73% of respondents in first-degree blood relatives. Surgical histories included trauma (gunshots, stabbings, assaults) (5% respondents; 27% relatives), burns (6% respondents; 14% relatives), and obstetrical problems (5% female respondents; 11% relatives). 1485 individuals agreed to physical examinations. Untreated surgical and potentially surgical disease was identified in 25% of participants., Interpretation: We identified and characterized a high burden of surgical and potentially surgical disease in an IDP population in West Darfur. Our study is unique in its direct assessment of a traumatized, mobile, vulnerable population. Health officials and agencies charged with the care of IDP and refugee populations should be aware of the high prevalence of surgical and potentially surgical conditions in these communities. This study adds to the growing body of evidence that investment in surgical resources may address a significant portion of the overall burden of disease in marginalized populations.

The ecosystems supporting Pacific salmon (Oncorhynchus spp.) are changing rapidly as a result of climate change and habitat alteration. Understanding how-and how consistently-salmon populations respond to changes at regional and watershed scales has major implications for fisheries management and habitat conservation. Chinook salmon (O. tshawytscha) populations across Alaska have declined over the past decade, resulting in fisheries closures and prolonged impacts to local communities. These declines are associated with large-scale climate drivers, but uncertainty remains about the role of local conditions (e.g., precipitation, streamflow, and stream temperature) that vary among the watersheds where salmon spawn and rear. We estimated the effects of these and other environmental indicators on the productivity of 15 Chinook salmon populations in the Cook Inlet basin, southcentral Alaska, using a hierarchical Bayesian stock-recruitment model. Salmon spawning during 2003-2007 produced 57% fewer recruits than the previous long-term average, leading to declines in adult returns beginning in 2008. These declines were explained in part by density dependence, with reduced population productivity following years of high spawning abundance. Across all populations, productivity declined with increased precipitation during the fall spawning and early incubation period and increased with above-average precipitation during juvenile rearing. Above-average stream temperatures during spawning and rearing had variable effects, with negative relationships in many warmer streams and positive relationships in some colder streams. Productivity was also associated with regional indices of streamflow and ocean conditions, with high variability among populations. The cumulative effects of adverse conditions in freshwater, including high spawning abundance, heavy fall rains, and hot, dry summers may have contributed to the recent population declines across the region. Identifying both coherent and differential responses to environmental change underscores the importance of targeted, watershed-specific monitoring and conservation efforts for maintaining resilient salmon runs in a warming world., (© 2020 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Rock ptarmigan (Lagopus muta) and willow ptarmigan (L. lagopus) are Arctic birds with a circumpolar distribution but there is limited knowledge about their status and trends across their circumpolar distribution. Here, we compiled information from 90 ptarmigan study sites from 7 Arctic countries, where almost half of the sites are still monitored. Rock ptarmigan showed an overall negative trend on Iceland and Greenland, while Svalbard and Newfoundland had positive trends, and no significant trends in Alaska. For willow ptarmigan, there was a negative trend in mid-Sweden and eastern Russia, while northern Fennoscandia, North America and Newfoundland had no significant trends. Both species displayed some periods with population cycles (short 3-6 years and long 9-12 years), but cyclicity changed through time for both species. We propose that simple, cost-efficient systematic surveys that capture the main feature of ptarmigan population dynamics can form the basis for citizen science efforts in order to fill knowledge gaps for the many regions that lack systematic ptarmigan monitoring programs.

Objective: Activin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD., Research Design and Methods: In two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin., Results: Plasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (r s =-0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (r s =0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased., Conclusions: Circulating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ageing and diabetes lead to similar organ dysfunction that is driven by parallel molecular mechanisms, one of which is cellular senescence. The abundance of senescent cells in various tissues increases with age, obesity and diabetes. Senescent cells have been directly implicated in the generation of insulin resistance. Recently, drugs that preferentially target senescent cells, known as senolytics, have been described and recently entered clinical trials. In this review, we explore the biological links between ageing and diabetes, specifically focusing on cellular senescence. We summarise the current data on cellular senescence in key target tissues associated with the development and clinical phenotypes of type 2 diabetes and discuss the therapeutic potential of targeting cellular senescence in diabetes.

Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16 Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Because of their agricultural value, there is a great body of research dedicated to understanding the microorganisms responsible for rumen carbon degradation. However, we lack a holistic view of the microbial food web responsible for carbon processing in this ecosystem. Here, we sampled rumen-fistulated moose, allowing access to rumen microbial communities actively degrading woody plant biomass in real time. We resolved 1,193 viral contigs and 77 unique, near-complete microbial metagenome-assembled genomes, many of which lacked previous metabolic insights. Plant-derived metabolites were measured with NMR and carbohydrate microarrays to quantify the carbon nutrient landscape. Network analyses directly linked measured metabolites to expressed proteins from these unique metagenome-assembled genomes, revealing a genome-resolved three-tiered carbohydrate-fuelled trophic system. This provided a glimpse into microbial specialization into functional guilds defined by specific metabolites. To validate our proteomic inferences, the catalytic activity of a polysaccharide utilization locus from a highly connected metabolic hub genome was confirmed using heterologous gene expression. Viral detected proteins and linkages to microbial hosts demonstrated that phage are active controllers of rumen ecosystem function. Our findings elucidate the microbial and viral members, as well as their metabolic interdependencies, that support in situ carbon degradation in the rumen ecosystem.

Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.

Soil nutrient stoichiometry and its environmental controllers play vital roles in understanding soil-plant interaction and nutrient cycling under a changing environment, while they remain poorly understood in alpine grassland due to lack of systematic field investigations. We examined the patterns and controls of soil nutrients stoichiometry for the top 10cm soils across the Tibetan ecosystems. Soil nutrient stoichiometry varied substantially among vegetation types. Alpine swamp meadow had larger topsoil C:N, C:P, N:P, and C:K ratios compared to the alpine meadow, alpine steppe, and alpine desert. In addition, the presence or absence of permafrost did not significantly impact soil nutrient stoichiometry in Tibetan grassland. Moreover, clay and silt contents explained approximately 32.5% of the total variation in soil C:N ratio. Climate, topography, soil properties, and vegetation combined to explain 10.3-13.2% for the stoichiometry of soil C:P, N:P, and C:K. Furthermore, soil C and N were weakly related to P and K in alpine grassland. These results indicated that the nutrient limitation in alpine ecosystem might shifts from N-limited to P-limited or K-limited due to the increase of N deposition and decrease of soil P and K contents under the changing climate conditions and weathering stages. Finally, we suggested that soil moisture and mud content could be good predictors of topsoil nutrient stoichiometry in Tibetan grassland., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Built and social environments, including one's perception of their environment, are important determinants of health. The intersection of gender and HIV status may complicate the role of neighborhood cohesion in safety, personal well-being, and health outcomes for populations impacted by social and structural inequities. Among women in particular, social cohesion within the neighborhood they reside in may have a greater influence on health outcomes compared to their male counterparts. We sought to examine perception of neighborhood cohesion (validated scale with a range 0-100, with higher scores indicating higher perceived neighborhood cohesion) among women living with HIV, impacted by social-structural inequities, receiving combination antiretroviral therapy, and enrolled in the Longitudinal Investigations into Supportive Ancillary health services (LISA) study in British Columbia, Canada. Cross-sectional data on neighborhood cohesion and socio-demographic data were collected in an interviewer-administered survey. Of the 1,000 LISA participants interviewed, 908 (including 249 women and 659 men) had complete data for the variables of interest. At the bivariate level, women had worse perceived neighborhood cohesion scores compared to men (median: 56 [95% CI: 44-66] vs. 60 [95% CI: 47-71]). Multivariable model results indicated that for women living with HIV in our sample, greater neighborhood cohesion scores were positively associated with stable housing (β coefficient = 7.85; 95% CI: 3.61, 12.10, p < 0.001), and negatively associated with greater perceived HIV stigma (β coefficient = -1.19; 95% CI: -2.24 to-0.15; p = 0.025). The results illustrate the gendered nature of experiencing built and social environments, and highlight the need for women-centred interventions to address the social determinants of HIV burden associated with negative perceptions of neighborhood cohesion.

Introduction: Use of the intramedullary Conventus DRS Cage and fragment-specific screw fixation of distal radial fractures minimizes soft-tissue trauma, leading to earlier and improved wrist and finger motion while reducing traditional complications seen with internal fixation of distal radial fractures., Step 1 Reduce the Fracture: Reduce the fracture with closed or, if necessary, open methods to achieve anatomic restoration of articular congruity, radial inclination, radial length, volar tilt, and coronal shift., Step 2 Provisionally Stabilize the Fracture: Provisionally stabilize the reduced fracture for insertion of the cage and fragment-specific screws with either longitudinal finger-trap traction or longitudinal Kirschner wires., Step 3 Prepare for Cage Fixation: Prepare the distal part of the radius for cavity preparation and insertion of the Conventus DRS Cage., Step 4 Insert the Conventus Drs Cage: Insert the previously chosen small or large Conventus DRS Cage., Step 5 Fix the Fracture Fragments: Anatomically fix the fracture fragments to the cage and radial shaft., Step 6 Confirm Fracture Stability: Move the wrist through a full range of motion while assessing fluoroscopically whether the fracture has been stabilized with the cage-and-screw construct., Step 7 Close the Wound: Close the skin incision and cutdown wounds and apply dressings., Results: The Conventus DRS Cage has been used for treatment of distal radial fractures in the U.S. for >3 years.

The muscles of herbivores commonly harbor sarcocysts of parasites belonging to species in the genus Sarcocystis, but such muscle parasites are rare in carnivores. Here, we report Sarcocystis arctica-like sarcocysts in muscles of Arctic foxes (Vulpes lagopus) from Alaska, USA, for the first time. The tongues of 56 foxes were examined for Sarcocystis infection using several methods. Sarcocystis bradyzoites were detected in pepsin digests of 13 (23.2%), and sarcocysts were found in histological sections stained with hematoxylin and eosin (HE) of 9 (16.0%). By light microscopy, sarcocysts were up to 4 mm long and up to 245 μm wide. In HE-stained sections, the sarcocyst wall appeared smooth and up to 1.5 μm thick without visible protrusions. By transmission electron microscopy, the sarcocyst wall had a wavy parasitophorous vacuolar membrane (pvm) folded as pleomorphic villar protrusions (vp), sometimes with anastomoses of villar tips. The vp and the ground substance (gs) layer were smooth and without microtubules. The gs was up to 2.0 μm thick. The total width of the wall including vp and the gs was up to 4.0 μm. The vp were up to 3.0 μm long and most closely resembled "type 9c." All sarcocysts were mature and contained numerous 8.1 × 2.1 μm sized bradyzoites. Molecular characterization (at 18S rDNA, 28S rDNA, ITS-1, and cox1) showed the highest affinity for S. arctica of the Arctic fox (V. lagopus) from Norway. In the present investigation, we provide evidence that sarcocysts are common in tongues of Alaskan Arctic foxes suggesting that these carnivores are serving as intermediate hosts, and we also provide ultrastructure of S. arctica from the Arctic fox for the first time.

Ruminants have co-evolved with their gastrointestinal microbial communities that digest plant materials to provide energy for the host. Some arctic and boreal ruminants have already shown to be vulnerable to dietary shifts caused by changing climate, yet we know little about the metabolic capacity of the ruminant microbiome in these animals. Here, we use meta-omics approaches to sample rumen fluid microbial communities from Alaskan moose foraging along a seasonal lignocellulose gradient. Winter diets with increased hemicellulose and lignin strongly enriched for BS11, a Bacteroidetes family lacking cultivated or genomically sampled representatives. We show that BS11 are cosmopolitan host-associated bacteria prevalent in gastrointestinal tracts of ruminants and other mammals. Metagenomic reconstruction yielded the first four BS11 genomes; phylogenetically resolving two genera within this previously taxonomically undefined family. Genome-enabled metabolic analyses uncovered multiple pathways for fermenting hemicellulose monomeric sugars to short-chain fatty acids (SCFA), metabolites vital for ruminant energy. Active hemicellulosic sugar fermentation and SCFA production was validated by shotgun proteomics and rumen metabolites, illuminating the role BS11 have in carbon transformations within the rumen. Our results also highlight the currently unknown metabolic potential residing in the rumen that may be vital for sustaining host energy in response to a changing vegetative environment.

Aging is associated with visceral adiposity, metabolic disorders, and chronic low-grade inflammation. 17α-estradiol (17α-E2), a naturally occurring enantiomer of 17β-estradiol (17β-E2), extends life span in male mice through unresolved mechanisms. We tested whether 17α-E2 could alleviate age-related metabolic dysfunction and inflammation. 17α-E2 reduced body mass, visceral adiposity, and ectopic lipid deposition without decreasing lean mass. These declines were associated with reductions in energy intake due to the activation of hypothalamic anorexigenic pathways and direct effects of 17α-E2 on nutrient-sensing pathways in visceral adipose tissue. 17α-E2 did not alter energy expenditure or excretion. Fasting glucose, insulin, and glycosylated hemoglobin were also reduced by 17α-E2, and hyperinsulinemic-euglycemic clamps revealed improvements in peripheral glucose disposal and hepatic glucose production. Inflammatory mediators in visceral adipose tissue and the circulation were reduced by 17α-E2. 17α-E2 increased AMPKα and reduced mTOR complex 1 activity in visceral adipose tissue but not in liver or quadriceps muscle, which is in contrast to the generalized systemic effects of caloric restriction. These beneficial phenotypic changes occurred in the absence of feminization or cardiac dysfunction, two commonly observed deleterious effects of exogenous estrogen administration. Thus, 17α-E2 holds potential as a novel therapeutic for alleviating age-related metabolic dysfunction through tissue-specific effects., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Adipose tissue dysfunction occurs with aging and has systemic effects, including peripheral insulin resistance, ectopic lipid deposition, and inflammation. Fundamental aging mechanisms, including cellular senescence and progenitor cell dysfunction, occur in adipose tissue with aging and may serve as potential therapeutic targets in age-related disease. In this review, we examine the role of adipose tissue in healthy individuals and explore how aging leads to adipose tissue dysfunction, redistribution, and changes in gene regulation. Adipose tissue plays a central role in longevity, and interventions restricted to adipose tissue may impact lifespan. Conversely, obesity may represent a state of accelerated aging. We discuss the potential therapeutic potential of targeting basic aging mechanisms, including cellular senescence, in adipose tissue, using type II diabetes and regenerative medicine as examples. We make the case that aging should not be neglected in the study of adipose-derived stem cells for regenerative medicine strategies, as elderly patients make up a large portion of individuals in need of such therapies., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long-term senolytic treatment is unknown. To determine whether long-term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF(+) cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK-ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT-PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Projections related to future climate warming indicate the potential for an increase in the distribution and prevalence of blood parasites in northern regions. However, baseline data are lacking for resident avian host species in Alaska. Grouse and ptarmigan occupy a diverse range of habitat types throughout the northern hemisphere and are among the most well-known and important native game birds in North America. Information regarding the prevalence and diversity of haemosporidian parasites in tetraonid species is limited, with few recent studies and an almost complete lack of genetic data. To better understand the genetic diversity of haemosporidian parasites in Alaskan tetraonids and to determine current patterns of geographic range and host specificity, we used molecular methods to screen 459 tissue samples collected from grouse and ptarmigan species across multiple regions of Alaska for infection by Leucocytozoon, Haemoproteus, and Plasmodium blood parasites. Infections were detected in 342 individuals, with overall apparent prevalence of 53% for Leucocytozoon, 21% for Haemoproteus, and 9% for Plasmodium. Parasite prevalence varied by region, with different patterns observed between species groups (grouse versus ptarmigan). Leucocytozoon was more common in ptarmigan, whereas Haemoproteus was more common in grouse. We detected Plasmodium infections in grouse only. Analysis of haemosporidian mitochondrial DNA cytochrome b sequences revealed 23 unique parasite haplotypes, several of which were identical to lineages previously detected in other avian hosts. Phylogenetic analysis showed close relationships between haplotypes from our study and those identified in Alaskan waterfowl for Haemoproteus and Plasmodium parasites. In contrast, Leucocytozoon lineages were structured strongly by host family. Our results provide some of the first genetic data for haemosporidians in grouse and ptarmigan species, and provide an initial baseline on the prevalence and diversity of blood parasites in a group of northern host species.

Alaska has one of the most rapidly changing climates on earth and is experiencing an accelerated rate of human disturbance, including resource extraction and transportation infrastructure development. Combined, these factors increase the state's vulnerability to biological invasion, which can have acute negative impacts on ecological integrity and subsistence practices. Of growing concern is the spread of Alaska's first documented freshwater aquatic invasive plant Elodea spp. (elodea). In this study, we modeled the suitable habitat of elodea using global and state-specific species occurrence records and environmental variables, in concert with an ensemble of model algorithms. Furthermore, we sought to incorporate local subsistence concerns by using Native Alaskan knowledge and available statewide subsistence harvest data to assess the potential threat posed by elodea to Chinook salmon (Oncorhynchus tshawytscha) and whitefish (Coregonus nelsonii) subsistence. State models were applied to future climate (2040-2059) using five general circulation models best suited for Alaska. Model evaluations indicated that our results had moderate to strong predictability, with area under the receiver-operating characteristic curve values above 0.80 and classification accuracies ranging from 66 to 89 %. State models provided a more robust assessment of elodea habitat suitability. These ensembles revealed different levels of management concern statewide, based on the interaction of fish subsistence patterns, known spawning and rearing sites, and elodea habitat suitability, thus highlighting regions with additional need for targeted monitoring. Our results suggest that this approach can hold great utility for invasion risk assessments and better facilitate the inclusion of local stakeholder concerns in conservation planning and management.

Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast-food diet (FFD). Using transgenic mice that express EGFP in response to activation of the senescence-associated p16(INK4a) promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associated β-galactosidase, and the senescence-associated secretory phenotype (SASP) specifically in visceral adipose tissue. We show that exercise prevents the accumulation of senescent cells and the expression of the SASP while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated after long-term FFD feeding reduces senescent phenotype markers in visceral adipose tissue while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforces the effect of modifiable lifestyle choices on health span., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Senescent cells accumulate in fat with aging. We previously found genetic clearance of senescent cells from progeroid INK-ATTAC mice prevents lipodystrophy. Here we show that primary human senescent fat progenitors secrete activin A and directly inhibit adipogenesis in non-senescent progenitors. Blocking activin A partially restored lipid accumulation and expression of key adipogenic markers in differentiating progenitors exposed to senescent cells. Mouse fat tissue activin A increased with aging. Clearing senescent cells from 18-month-old naturally-aged INK-ATTAC mice reduced circulating activin A, blunted fat loss, and enhanced adipogenic transcription factor expression within 3 weeks. JAK inhibitor suppressed senescent cell activin A production and blunted senescent cell-mediated inhibition of adipogenesis. Eight weeks-treatment with ruxolitinib, an FDA-approved JAK1/2 inhibitor, reduced circulating activin A, preserved fat mass, reduced lipotoxicity, and increased insulin sensitivity in 22-month-old mice. Our study indicates targeting senescent cells or their products may alleviate age-related dysfunction of progenitors, adipose tissue, and metabolism., Competing Interests: AKP, TP, NG, TT and JLK: This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. The other author declares that no competing interests exist.