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Age-related inflammation or inflammaging is a key mechanism that increases disease burden and may control lifespan. How adipose tissue macrophages (ATMs) control inflammaging is not well understood in part because the molecular identities of niche-specific ATMs are incompletely known. Using intravascular labeling to exclude circulating myeloid cells and subsequent single-cell sequencing with orthogonal validation, we define the diversity and alterations in niche resident ATMs through lifespan. Aging led to depletion of vessel-associated macrophages (VAMs), expansion of lipid-associated macrophages (LAMs), and emergence of a unique subset of CD38+ age-associated macrophages (AAMs) in visceral white adipose tissue (VAT). Interestingly, CD169+CD11c- ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting that they are necessary for preventing catecholamine resistance in VAT. These findings reveal specialized ATMs control adipose homeostasis and link inflammation to tissue dysfunction during aging.

β-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance., Competing Interests: Declaration of interests A provisional patent application has been filed by Stanford University on BHB-amino acids for the treatment of cardiometabolic disease.

Ketone bodies are short-chain fatty acids produced in the liver during periods of limited glucose availability that provide an alternative energy source for the brain, heart, and skeletal muscle. Beyond this metabolic role, β-hydroxybutyrate (BHB), is gaining recognition as a signaling molecule. Lysine β-hydroxybutyrylation (Kbhb) is a newly discovered post-translational modification in which BHB is covalently attached to lysine ε-amino groups. This protein adduct is metabolically sensitive, dependent on BHB concentration, and found on proteins in multiple intracellular compartments. Therefore, Kbhb is hypothesized to be an important component of ketone body-regulated physiology. Kbhb on histones is proposed to be an epigenetic regulator, which links metabolic alterations to gene expression. However, we found that the widely used antibody against β-hydroxybutyrylated lysine 9 on histone H3 (H3K9bhb) also recognizes other modification(s) that likely include acetylation. Therefore, caution must be used when interpreting gene regulation data acquired with the H3K9bhb antibody., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Aging is accompanied by chronic low-grade inflammation, but the mechanisms that allow this to persist are not well understood. Ketone bodies are alternative fuels produced when glucose is limited and improve indicators of healthspan in aging mouse models. Moreover, the most abundant ketone body, β-hydroxybutyrate, inhibits the NLRP3 inflammasome in myeloid cells, a key potentiator of age-related inflammation. Given that myeloid cells express ketogenic machinery, we hypothesized this pathway may serve as a metabolic checkpoint of inflammation. To test this hypothesis, we conditionally ablated ketogenesis by disrupting expression of the terminal enzyme required for ketogenesis, 3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL). By deleting HMGCL in the liver, we validated the functional targeting and establish that the liver is the only organ that can produce the life-sustaining quantities of ketone bodies required for survival during fasting or ketogenic diet feeding. Conditional ablation of HMGCL in neutrophils and macrophages had modest effects on body weight and glucose tolerance in aging but worsened glucose homeostasis in myeloid cell-specific Hmgcl-deficient mice fed a high-fat diet. Our results suggest that during aging, liver-derived circulating ketone bodies might be more important for deactivating the NLRP3 inflammasome and controlling organismal metabolism., Competing Interests: Conflict of interest The authors declare they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cholesterol biosynthetic intermediates, such as lanosterol and desmosterol, are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here, we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ 24 -reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single-cell transcriptomics in isolated CD45 + CD11b + cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon responses and attenuates the expression of antiinflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/retinoid X receptor (RXR) activation and thus macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mitochondrial reactive oxygen species production and NLR family pyrin domain containing 3 (NLRP3)-dependent inflammasome activation. Deficiency of NLRP3 or apoptosis-associated speck-like protein containing a CARD (ASC) rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation by integrating with macrophage cholesterol metabolism and inflammatory activation and protecting from disease progression., Competing Interests: The authors declare no competing interest.

Aging impairs the integrated immunometabolic responses, which have evolved to maintain core body temperature in homeotherms to survive cold stress, infections, and dietary restriction. Adipose tissue inflammation regulates the thermogenic stress response, but how adipose tissue-resident cells instigate thermogenic failure in the aged are unknown. Here, we define alterations in the adipose-resident immune system and identify that type 2 innate lymphoid cells (ILC2s) are lost in aging. Restoration of ILC2 numbers in aged mice to levels seen in adults through IL-33 supplementation failed to rescue old mice from metabolic impairment and increased cold-induced lethality. Transcriptomic analyses revealed intrinsic defects in aged ILC2, and adoptive transfer of adult ILC2s are sufficient to protect old mice against cold. Thus, the functional defects in adipose ILC2s during aging drive thermogenic failure., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Respiratory viral infections remain a scourge, with seasonal influenza infecting millions and killing many thousands annually and viral pandemics, such as COVID-19, recurring every decade. Age, cardiovascular disease, and diabetes mellitus are risk factors for severe disease and death from viral infection. Immunometabolic therapies for these populations hold promise to reduce the risks of death and disability. Such interventions have pleiotropic effects that might not only target the virus itself but also enhance supportive care to reduce cardiopulmonary complications, improve cognitive resilience, and facilitate functional recovery. Ketone bodies are endogenous metabolites that maintain cellular energy but also feature drug-like signaling activities that affect immune activity, metabolism, and epigenetics. Here, we provide an overview of ketone body biology relevant to respiratory viral infection, focusing on influenza A and severe acute respiratory syndrome (SARS)-CoV-2, and discuss the opportunities, risks, and research gaps in the study of exogenous ketone bodies as novel immunometabolic interventions in these diseases., Competing Interests: J.C.N. and E.V. are co-founders of and shareholders in BHB Therapeutics, Ltd., which is developing products relating to ketone bodies. B.J.S. is a shareholder of HVMN, Inc., which markets products relating to ketone bodies and of BHB Therapeutics, Ltd. J.C.N., E.V., B.J.S., and A.P.K. are inventors on patents related to the use of ketone bodies. J.C.N. is on the scientific advisory board of Virta Health, Inc. E.V. is an advisor to Keto Fuel, Inc. P.J.T. is on the scientific advisory boards for Kaleido, Pendulum, Seres, and SNIPRbiome. All other authors declare no competing interests., (© 2020 Elsevier Inc.)

Inflammation is a broad term that refers to a collection of carefully balanced programs in the body. These pathways are essential for detecting invading microorganisms, controlling the spread of infection, and instructing appropriate immune responses to eliminate pathogens. During aging there is deterioration of important regulatory mechanisms, giving rise to persistent low-grade inflammation that drives chronic conditions such as metabolic dysregulation, immune senescence, and cognitive decline. Understanding this aspect of the pathobiology of aging is key to uncovering the source(s) and cause(s) of age-related inflammation that underlies disease., Competing Interests: Declaration of competing interest The author declares no conflict of interest.

Ketone bodies are essential alternative fuels that allow humans to survive periods of glucose scarcity induced by starvation and prolonged exercise. A widely used ketogenic diet (KD), which is extremely high in fat with very low carbohydrates, drives the host into using β-hydroxybutyrate for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis affects adipose tissue to control inflammation and energy homeostasis. Here, by using single-cell RNA sequencing of adipose-tissue-resident immune cells, we show that KD expands metabolically protective γδ T cells that restrain inflammation. Notably, long-term ad libitum KD feeding in mice causes obesity, impairs metabolic health and depletes the adipose-resident γδ T cells. In addition, mice lacking γδ T cells have impaired glucose homeostasis. Our results suggest that γδ T cells are mediators of protective immunometabolic responses that link fatty acid-driven fuel use to reduced adipose tissue inflammation.

The collective loss of immune protection during aging leads to poor vaccine responses and an increased severity of infection for the elderly. Here, we review our current understanding of effects of aging on the cellular and molecular dysregulation of innate immune cells as well as the relevant tissue milieu which influences their functions. The innate immune system is composed of multiple cell types which provide distinct and essential roles in tissue surveillance and antigen presentation as well as early responses to infection or injury. Functional defects that arise during aging lead to a reduced dynamic range of responsiveness, altered cytokine dynamics, and impaired tissue repair. Heightened inflammation influences both the dysregulation of innate immune responses as well as surrounding tissue microenvironments which have a critical role in development of a functional immune response. In particular, age-related physical and inflammatory changes in the skin, lung, lymph nodes, and adipose tissue reflect disrupted architecture and spatial organization contributing to diminished immune responsiveness. Underlying mechanisms include altered transcriptional programming and dysregulation of critical innate immune signaling cascades. Further, we identify signaling functions of bioactive lipid mediators which address chronic inflammation and may contribute to the resolution of inflammation to improve innate immunity during aging., (© 2020 S. Karger AG, Basel.)

During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Influenza A virus (IAV) infection-associated morbidity and mortality are a key global health care concern, necessitating the identification of new therapies capable of reducing the severity of IAV infections. In this study, we show that the consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. KD feeding resulted in an expansion of γδ T cells in the lung that improved barrier functions, thereby enhancing antiviral resistance. Expansion of these protective γδ T cells required metabolic adaptation to a ketogenic diet because neither feeding mice a high-fat, high-carbohydrate diet nor providing chemical ketone body substrate that bypasses hepatic ketogenesis protected against infection. Therefore, KD-mediated immune-metabolic integration represents a viable avenue toward preventing or alleviating influenza disease., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

An integrated immunometabolic response during negative energy balance is required for host survival. Three new papers by Jordan et al. (2019), Nagai et al. (2019), and Collins et al. (2019) report that monocytes, naive B cells, and memory CD8 T cells use bone marrow as a haven to tide off periods of metabolic adversity to maintain immune-responsiveness., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Key Points: Oestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies. Insulin sensitivity is greater in premenopausal women compared with age-matched men, and metabolism-related cardiovascular diseases and type 2 diabetes are less frequent in these same women. Both female and male mice treated with oestradiol are protected against obesity-induced insulin resistance. The protection against obesity-induced insulin resistance is associated with reduced ectopic lipid content in liver and skeletal muscle. These results were associated with increased insulin-stimulated suppression of white adipose tissue lipolysis and reduced inflammation., Abstract: Oestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies. Overall, females are protected against obesity-induced insulin resistance; yet, the mechanisms responsible for this protection are not well understood. Therefore, the aim of the present work was to evaluate the underlying mechanism(s) by which female mice are protected against obesity-induced insulin resistance compared with male mice. We studied male and female mice in age-matched or body weight-matched conditions. They were fed a high-fat diet (HFD) or regular chow for 4 weeks. We also studied HFD male mice treated with oestradiol or vehicle. Both HFD female and HFD male mice treated with oestradiol displayed increased whole-body insulin sensitivity, associated with reduction in ectopic hepatic and muscle lipid content compared to HFD male mice. Reductions in ectopic lipid content in these mice were associated with increased insulin-stimulated suppression of white adipose tissue (WAT) lipolysis. Both HFD female and HFD male mice treated with oestradiol also displayed striking reductions in WAT inflammation, represented by reductions in plasma and adipose tissue tumour necrosis factor α and interleukin 6 concentrations. Taken together these data support the hypothesis that HFD female mice are protected from obesity-induced insulin resistance due to oestradiol-mediated reductions in WAT inflammation, leading to improved insulin-mediated suppression of WAT lipolysis and reduced ectopic lipid content in liver and skeletal muscle., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides, declines with age. The defect in the mobilization of free fatty acids in the elderly is accompanied by increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. Although catecholamine signalling in adipocytes is normal in the elderly, how lipolysis is impaired in ageing remains unknown. Here we show that adipose tissue macrophages regulate the age-related reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased whole-transcriptome analyses of adipose macrophages revealed that ageing upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in ageing restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3) and monoamine oxidase A (MAOA) that is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1. Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-immunometabolic signalling between the sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Fatty acid oxidation in macrophages is thought to regulate inflammatory status and insulin-sensitivity. An important unanswered question in this field is whether carnitine acetyl-transferase (CrAT) that regulates fatty acid oxidation and mitochondrial acetyl-CoA balance is required to integrate nutrient stress sensing to inflammatory response in macrophages., Methods: Mice with myeloid lineage-specific Crat deletion were subjected to several metabolic stressors, including high-fat diet-induced obesity, fasting, and LPS-induced endotoxemia. Their metabolic homeostasis was compared to that of Crat-sufficient littermate controls. Inflammatory potential of Crat-deficient and Crat-sufficient macrophages were measured both in vitro and in vivo ., Results: Our studies revealed that ablation of CrAT in myeloid lineage cells did not impact glucose homeostasis, insulin-action, adipose tissue leukocytosis, and inflammation when animals were confronted with a variety of metabolic stressors, including high-fat diet, fasting, or LPS-induced acute endotoxemia., Conclusions: These findings demonstrate that unlike muscle cells, substrate switch mechanisms that control macrophage energy metabolism and mitochondrial short-chain acyl-CoA pools during nutrient stress are controlled by pathways that are not solely reliant on CrAT.

The hallmarks of age-related immune senescence are chronic inflammation, aberrant expansion of effector memory, and loss of naive T lymphocytes due in part to systemic activation of innate immune sensor NLRP3 inflammasome in myeloid lineage cells. The endogenous mechanisms that regulate inflammasome activation during aging are unknown. Here, we present evidence that growth hormone receptor (GH-R)-dependent downregulation of NLRP3 inflammasome in macrophages is linked to pro-longevity effects that maintain immune system homeostasis in aging. Deletion of GH-R prevented the macrophage-driven age-related activation of inflammasome in response to NLRP3 ligands and also increased the preservation of naive T cells, even in advanced age and with higher IFNγ secretion from effector cells. The mechanism of inflammasome inhibition is linked to autocrine somatotropic axis as ablation of IGF1R in macrophages lowered the NLRP3 inflammasome activation. Together, our findings show that functional somatotropic axis in macrophages controls inflammation, thus linking NLRP3-mediated innate immune signaling to health span and longevity., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Aging is the greatest risk factor for the development of chronic diseases such as arthritis, type 2 diabetes, cardiovascular disease, kidney disease, Alzheimer's disease, macular degeneration, frailty, and certain forms of cancers. It is widely regarded that chronic inflammation may be a common link in all these age-related diseases. This raises the question, can one alter the course of aging and potentially slow the development of all chronic diseases by manipulating the mechanisms that cause age-related inflammation? Emerging evidence suggests that pro-inflammatory cytokines interleukin-1 (IL-1) and IL-18 show an age-dependent regulation implicating inflammasome-mediated caspase-1 activation in the aging process. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome controls the caspase-1 activation in myeloid-lineage cells in several organs during aging. The NLRP3 inflammasome is especially relevant to aging as it can get activated in response to structurally diverse damage-associated molecular patterns (DAMPs) such as extracellular ATP, excess glucose, ceramides, amyloids, urate, and cholesterol crystals, all of which increase with age. Interestingly, reduction in NLRP3-mediated inflammation prevents age-related insulin resistance, bone loss, cognitive decline, and frailty. NLRP3 is a major driver of age-related inflammation and therefore dietary or pharmacological approaches to lower aberrant inflammasome activation holds promise in reducing multiple chronic diseases of age and may enhance healthspan., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.

Aging of the world population and a concomitant increase in age-related diseases and disabilities mandates the search for strategies to increase healthspan, the length of time an individual lives healthy and productively. Due to the age-related decline of the immune system, infectious diseases remain among the top 5-10 causes of mortality and morbidity in the elderly, and improving immune function during aging remains an important aspect of healthspan extension. Calorie restriction (CR) and more recently rapamycin (rapa) feeding have both been used to extend lifespan in mice. Preciously few studies have actually investigated the impact of each of these interventions upon in vivo immune defense against relevant microbial challenge in old organisms. We tested how rapa and CR each impacted the immune system in adult and old mice. We report that each intervention differentially altered T-cell development in the thymus, peripheral T-cell maintenance, T-cell function and host survival after West Nile virus infection, inducing distinct but deleterious consequences to the aging immune system. We conclude that neither rapa feeding nor CR, in the current form/administration regimen, may be optimal strategies for extending healthy immune function and, with it, lifespan., (© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Direct mammalian target of rapamycin (Rapa) complex 1 inhibition by short-term low-dose Rapa treatment has recently been shown to improve CD8 T cell immunological memory. Whereas these studies focused on memory development, the impact of low-dose Rapa on the primary immune response, particularly as it relates to functional effector immunity, is far less clear. In this study, we investigated the impact of acute Rapa treatment on immune effector cell function during the primary immune response to several acute infections. We found that functional CD8 T cell and macrophage responses to both viral and intracellular bacterial pathogens were depressed in mice in vivo and in humans to phorbol ester and calcium ionophore stimulation in vitro in the face of low-dose Rapa treatment. Mechanistically, the CD8 defect was linked to impaired glycolytic switch in stimulated naive cells and the reduced formation of short-lived effector cells. Therefore, more than one cell type required for a protective effector immune response is impaired by Rapa in both mice and humans, at the dose shown to improve immune memory and extend lifespan. This urges caution with regard to the relative therapeutic costs and benefits of Rapa treatment as means to improve immune memory., (Copyright © 2014 by The American Association of Immunologists, Inc.)

The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metformin-mediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological processes for potential adverse effects that may compromise health span.

Microbial infection during various stages of human development produces widely different clinical outcomes, yet the links between age-related changes in the immune compartment and functional immunity remain unclear. The ability of the immune system to respond to specific antigens and mediate protection in early life is closely correlated with the level of diversification of lymphocyte antigen receptors. We have previously shown that the neonatal primary CD8+ T cell response to replication competent virus is significantly constricted compared to the adult response. In the present study, we have analyzed the subsequent formation of neonatal memory CD8+ T cells and their response to secondary infectious challenge. In particular, we asked whether the less diverse CD8+ T cell clonotypes that are elicited by neonatal vaccination with replication competent virus are 'locked-in' to the adult memory T cell, and thus may compromise the strength of adult immunity. Here we report that neonatal memory CD8+ T cells mediate poor recall responses compared to adults and are comprised of a repertoire of lower avidity T cells. During a later infectious challenge the neonatal memory CD8+ T cells compete poorly with the fully diverse repertoire of naïve adult CD8+ T cells and are outgrown by the adult primary response. This has important implications for the timing of vaccination in early life.

Objective: To identify predictors of self-reported discontinuation of overactive bladder (OAB) medication using a three-phase survey., Patients and Methods: In January 2005, a phase 1 survey was sent to 260 000 households in the USA to assess the prevalence of OAB symptom bother, treatment patterns and healthcare consulting behaviour. In July 2005, a detailed phase 2 follow-up survey was sent to 6577 phase 1 respondents who had used one or more OAB medications within the 12 months before phase 1; the phase 2 survey included questions about respondents' sociodemographic characteristics, general health status, OAB symptom bother, healthcare consulting behaviour, beliefs about OAB and treatment options, and medication usage. Six months later, a phase 3 survey was sent to 3387 phase-2 respondents who were persistent with OAB medication or had discontinued within <18 months of phase 2; the phase 3 survey measured the same variables as phase 2. Only phase 3 respondents who were persistent with OAB medication at phase 2 were included in the analyses reported here. Assessed were the proportions of respondents who were still persistent with OAB medication at phase 3 and who discontinued OAB medication between phases 2 and 3. The variables measured during the phase 2 survey were screened as potential predictors of discontinuation at phase 3 using univariate analysis and then assessed using multivariate logistic regression., Results: Among 2838 respondents at phase 3 (84% response rate), 1194 had recently discontinued and 1644 were persistent with medication at phase 2. Among phase-3 respondents who were persistent at phase 2, 1040 (66%) continued to be persistent at phase 3, 280 (18%) had discontinued between phases 2 and 3, and 261 (17%) had switched medication between phases 2 and 3; 63 respondents had missing prescription information at phase 3. Predictors of discontinuing at phase 3 included smoking (odds ratio 1.80; 95% confidence interval 1.15-2.83; P = 0.010), not knowing whether treating bladder problems requires multiple daily doses of medication (1.71, 1.10-2.67; P = 0.018), believing (2.11, 1.34-3.33; P = 0.001) or not knowing (1.76, 1.23-2.52; P = 0.002) whether adverse effects of OAB medications are often severe, and being bothered 'quite a bit or more' by a sudden urge to urinate (1.54, 1.05-2.26; P = 0.028). Respondents taking two or more medications were less likely to discontinue (odds ratio 0.45-0.58; P < 0.05)., Conclusion: Persistence with OAB medications might be improved by addressing predictors of discontinuation in the management of OAB, by proactively informing patients about the severity of antimuscarinic adverse effects, and dosing regimens. Bother associated with the key OAB symptom, urgency, is a predictor of discontinuation of treatment.

The full benefit of biologic therapies isn't reached and quality of life is compromised if patients don't adhere to their medication regimen. Are adherence interventions in order?

Objective: Describe challenges to improving management of overactive bladder (OAB) outcomes and summarize research findings on critical success factors for supporting OAB treatment., Study Design: A multidisciplinary team collected primary and secondary data, including an OAB-specific survey; a literature review; and an expert panel discussion., Methods: A US survey of patients who were prescribed antimuscarinics included topics related to OAB, such as reasons for medication discontinuation. The PubMed database was searched for articles published in the past 10 years on OAB treatment and adherence, and additional publications were reviewed related to health behavior change models. An expert panel reviewed findings and provided perspective., Results: The survey (n = 5392) showed that, among patients discontinuing OAB medications, 45.4% reported unmet treatment expectations as the reason for discontinuation. Literature review findings supported intervention at the beginning of OAB treatment, specific messages to increase treatment adherence, and involving the healthcare stakeholders most trusted by patients. Implications of OAB patient support were drawn from reviews of the Transtheoretical Model, the Health Belief Model, and social learning theory. The expert panel highlighted desirable attributes of OAB patient education delivered in the medical care setting., Conclusion: Challenges to improving OAB symptom burden and outcomes include underdiagnosis, undertreatment, and patient nonadherence with medications. Patient support of medication adherence may be enhanced by simultaneously supporting the use of nonpharmaceutical lifestyle modifications and behavioral interventions. Healthcare providers acknowledge the need for patient education but lack the time and resources to deliver interventions or monitor patients' progress outside the medical office. Patient support may be achieved through external programs that complement patient-physician interactions.

Thermodynamic parameters of coaxial stacking at complementary helix-helix interfaces GX*pYG/CZVC (X,Y=A,C,T,G;*-nick) created by contiguous oligonucleotide hybridization were determined. The data obtained were compared to the thermodynamic parameters of coaxial stacking at the interfaces CX*pYC/GZVG. Multiple linear regression analysis has revealed that the free-energy increments of interaction for the contacts GX*pYG/CZVC and CX*pYC/GZVG can be described by a set of uniform Delta G degrees(X*pY/ZV) values. The difference in the observed free-energy of the coaxial stacking between the two sets is defined by the contribution from the factors reflecting structural differences between compared DNA duplexes.

The expected duration and magnitude of elevations in depressive symptomatology following bereavement have not been fully characterized. This study describes the natural history of changes in depressive symptomatology after widowhood, using the Center for Epidemiologic Studies Depression Scale. We studied 1144 elderly married women who completed a baseline interview; 136 women who were subsequently widowed, and a subset of 409 still-married women, selected as controls, were reinterviewed at 1, 6, 12, 18, and 24 months after bereavement. Widows were more depressed than their married controls at every interview, including baseline. About 10% of married women had high scores (> 15) at each interview. One month after bereavement, the proportion of widows with high scores rose to 58%; this proportion declined but remained elevated at 6 months. By 12 months, the proportion with high scores was comparable with prebereavement levels. Only about 40% of the elevation in widows' scores at 12 months is potentially attributable to bereavement.

Few studies have examined whether risk factors for depressive symptomatology differ in bereaved and nonbereaved individuals or whether risk factors differ in bereaved individuals over time. Between 1979 and 1983 in Washington County, Maryland, the associations between various health and social network variables and depressive symptomatology were evaluated prior to bereavement and at 1 and 12 months after bereavement in 136 widows and 409 married controls. Prior Center for Epidemiologic Studies Depression Scale scores were generally a good predictor of subsequent scores; however, shortly after bereavement prior scores proved relatively uninformative as most widows experienced a marked increase in depressive symptomatology. Poor health and limitations in physical activity at baseline were consistently associated with higher levels of symptomatology. Although having more friends was also consistently associated with lower levels of symptomatology, the effect of family size appeared to be time and circumstance specific. These results suggest that women at risk of prolonged depression after the death of their husbands can be identified prior to or at the time of bereavement and that widows have risk factors similar to those of women at risk of depression in the general community.

Blood pressure levels as recorded in a community-wide screening programme were compared with findings in an earlier mental health study for persons who participated in both programmes. Blood pressure was not related to previously ascertained psychosocial characteristics among persons who were not under treatment for hypertension, suggesting that depression, hostility, psychosomatic reactions to stress, or the felt need for help with emotional problems were not important in the pathogenesis of hypertension. Treatment for hypertension, however, was associated with an excess of psychosomatic symptoms, a factor which needs to be taken into account in assessing the benefits of treatment.

The Drug Abuse Administration of the State of Maryland in 1972 established an emergency holding facility in Baltimore. Its purpose was to attract into programs those addicts who had been treated by a private physician in Washington, D.C., until his office had been abruptly closed by the Federal Government for lack of compliance with Federal regulations controlling the use of narcotics. A comprehensive data collection system for the holding program was immediately instituted to produce the information needed for programmatic decision making and to provide quantification and characterization of the population under treatment so that appropriate referral and long-range planning could be rationally undertaken. With data collected through this system, those 408 patients in the holding program from February to May 26, 1972, who reported they had participated in the Washington physician's program were compared with (a) the 925 other persons in the holding program during the same period and (b) the 5,578 other persons who were reported to the Maryland Narcotics Addict Register during fiscal year 1972. In both comparisons, larger percentages of the clients of the unauthorized program than of the other group were white and older. More of the clients of the unauthorized program than the other patients in the holding program were married or had been, had a high school education or more, had received occupational training, and were employed. These differences are similar to those generally found between the clientele of private physicians and the clientele of public clinics. The persons who had traveled to Washington, D.C., to seek care from a private physician seemed to resemble the persons who seek private medical care; the other clients in the holding program seemed more like those who use hospital clinics.

The objective was to provide additional background information for a refinement of life events methodolgy. Data about life events for a one year period were gathered from a representative sample of the population in Kansas City, Missouri, and Washington County, Maryland, between 1971-1974. Using binary variable multiple regression, the relationships between individual events, overall scores and demographic variables were examined for 2780 subjects. Age, education, marital status, location and race were shown to be significantly related to scores of one or more on the life events scale. Individual items were also related to these and other demographic variables. Fifteen individual events were shown to be moderately related to one another, so that when one event occurred the other was likely to occur also. Because different subgroups of the population experience different frequencies of total life events and of particular individual events, life events scores can vary considerably from group to group, depending on demographic composition and the appropriateness of the life events list for each demographic subgroup. Such relationships, if not adjusted for, could lead to coincidental associations between life events and health-related outcomes.

Because gallstones and breast cancer were reported to have several of the same risk factors, a study was conducted in Washington County, Maryland to determine if women with breast cancer have an increased risk of prior gallbladder disease. Living white female breast cancer cases (n = 133), who were diagnosed from 1973 to 1983, were identified from the county's cancer registry and interviewed along with an equal number of sex-, race-, and age-matched controls about a history of gallbladder disease and other risk factors. Medical records were used to verify a history of gallbladder disease in interviewed cases and controls and to search for a diagnosis of gallbladder disease in 52 white female breast cancer cases who were diagnosed and died between 1974 and 1983, and 52 matched controls. No difference was found in gallbladder disease frequency among living or deceased cases and their matched controls. The results confirm the known association of several risk factors with breast cancer and with gallbladder disease, but most of the risk factors hypothesized to be the same for the two diseases were not the same. However, an unexpectedly strong association was found between gallbladder disease and history of myocardial infarction; this result deserves further study.

As part of the Community Mental Health Epidemiology Program 489 18--24-year-olds in Washington County, Md., and Kansas City, Mo., were studied to learn which factors are related to thoughts of suicide in young adults. Depressive symptomatology, poor physical health, and minor psychiatric symptoms were present in this population, as they are in adults of all ages who have suicide ideation. Overt aggression and separation from the mother before 16 years of age were also present. These factors have been previously shown to be characteristic of suicide attempters and completers, so early identification of people at high risk for suicide by use of these factors may be feasible.

All newly diagnosed cases of Hirschsprung's Disease among children born in Baltimore City and County, Maryland and diagnosed within the Baltimore Standard Metropolitan Area during 1969 through 1977 were identified. Using hospital records and death certificates, 33 cases were ascertained. An overall incidence rate of 18.6 per 100 000 livebirths was found, similar to that reported by others. A high male to female ratio (4.32:1) was found; the ratio for non-whites to whites was 1.67:1. Non-white males had the highest rate, 37.6 per 100 000 livebirths. These findings plus the fact that 9% of these children were also diagnosed as having Down's Syndrome, were evidence that the aetiology of Hirschsprung's Disease may be partially genetic. Among environmental factors studied, there was no time trend and no relationship with socioeconomic status found. Among whites, there was a larger percentage of children who were the first births of mothers aged 30 and above, a result previously reported for children with neural tube defects. Very little is known about micro-environmental factors in relation to Hirschsprung's Disease and this would seem to be the area for future emphasis in research.

In 1979, 1,144 married women between the ages of 65 and 75 were interviewed about their health and social support networks. During the next two-and-a-half years, 150 of them were widowed; 128 were interviewed six months after bereavement. Among the 115 women who had denied needing help for an emotional problem at the initial interview, 25 admitted the need for such help after the deaths of their husbands. Predictive factors for needing emotional counseling six months after bereavement were recent disability, having few friends, and not feeling close to one's children.

A total of 1,144 white married women aged 65-75 years living in Washington County, Maryland were interviewed during February-August 1979 as part of a larger study. This cross-sectional analysis was undertaken to investigate the question of whether or not selected demographic, social network, and social support characteristics of these women were related to their level of depressive symptoms. Women at the low end of the socioeconomic scale were found more likely to have a high level of depressive symptoms than were women at the high end. Two structural characteristics, size and homogeneity of the social network, were also found to be related to symptoms of depression, although only homogeneity of the social network reached statistical significance. There was a larger percentage of women with a high level of depressive symptoms among those with small networks and among those with heterogeneous networks. Those women with good quality networks, which offer the opportunity for social support, were much less likely to have a high level of depressive symptoms than others. Cross-sectionally, social network factors were related to level of depressive symptoms; this relationship now needs to be demonstrated prospectively.

The objective was to examine for relationships between stress, as measured by life events, and hospitalization or death during the following 6 to 12 months, using a case-control design. As part of the Community Mental Epidemiology Program, life events data for the preceding year were gathered on a random sample of the population at two sites, and health data for the interval between interviews were collected at follow-up. A case is defined as anyone becoming ill and being hospitalized or dying during the interval between interviews. Each case was individually matched by several variables to a control who had neither been sick nor hospitalized. There were no significant demographic differences between cases and control in either site or between sites. When life events were examined by various scoring methods, there were no differences between cases and controls. This finding is important since most longitudinal studies that have shown a positive relationship between life events and subsequent illness have had methodologic limitations or have been based on healthy, young, male populations who generally did not become seriously ill during the study period. The results of this study plus the lack of generalizability of previous findings and their somewhat conflicting results raise serious questions about the etiologic relationship of life events to subsequent illness.

This study presents male and female responses of 193 university students to questions about sexual experiences and fantasies. There are few significant gender differences in experiences, but many in fantasies. Males fantasized about sex more and exhibited greater interest in partner variation and in the spectrum from domination to sadism. While male sexuality is often described as aggressive/sadistic and female sexuality as passive/masochistic, most men and women in our population do not report fantasies supporting such stereotypes.

Deaths associated with strokes from 1963 to 1975 among 36,860 adult residents of Washington County, Maryland, were studied in relation to the hardness of drinking water at home, assessed on the basis of 1,569 water samples taken during this period. There was no satisfactory evidence that water hardness was related to stroke mortality. Age was a strongly related factor. There was little or no association with sex, marital status, socio-economic status as reflected by education or housing, smoking history, or frequency of church attendance.