Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging

Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell–specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca²⁺ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease.     

Hippuric acid: Could became a barometer for frailty and geriatric syndromes?

Aging is a natural biological event that has some downsides such as increased frailty, decline in cognitive and physical functions leading to chronical diseases, and lower quality of life. There is therefore a pressing need of reliable biomarkers to identify populations at risk of developing age-associated syndromes in order to improve their quality of life, promote healthy ageing and a more appropriate clinical management, when needed. Here we discuss the importance of hippuric acid, an endogenous co-metabolite, as a possible hallmark of human aging and age-related diseases, summarizing the scientific literature over the last years. Hippuric acid, the glycine conjugate of benzoic acid, derives from the catabolism by means of intestinal microflora of dietary polyphenols found in plant-based foods (e.g. fruits, vegetables, tea and coffee). In healthy conditions hippuric acid levels in blood and/or urine rise significantly during aging while its excretion drops in conditions related with aging, including cognitive impairments, rheumatic diseases, sarcopenia and hypomobility. This literature highlights the utility of hippuric acid in urine and plasma as a plausible hallmark of frailty, related to low fruit and vegetable intake and changes in gut microflora.     

Matters of size: Roles of hyaluronan in CNS aging and disease

Involvement of extracellular matrix (ECM) components in aging and age-related neurodegeneration is not well understood. The role of hyaluronan (HA), a major extracellular matrix glycosaminoglycan, in malignancy and inflammation is gaining new understanding. In particular, the differential biological effects of high molecular weight (HMW-HA) and low molecular weight hyaluronan (LMW-HA), and the mechanism behind such differences are being uncovered. Tightly regulated in the brain, HA can have diverse effects on cellular development, growth and degeneration. In this review, we summarize the homeostasis and signaling of HA in healthy tissue, discuss its distribution and ontogeny in the central nervous system (CNS), summarize evidence for its involvement in age-related neurodegeneration and Alzheimer Disease (AD), and assess the potential of HA as a therapeutic target in the CNS.     

Inflammaging and Cannabinoids

Aging is a complex phenomenon associated with a wide spectrum of physical and physiological changes affecting every part of all metazoans, if they escape death prior to reaching maturity. Critical to survival, the immune system evolved as the principal component of response to injury and defense against pathogen invasions. Because how significantly immune system affects and is affected by aging, several neologisms now appear to encapsulate these reciprocal relationships, such as Immunosenescence. The central part of Immunosenescence is Inflammaging –a sustained, low-grade, sterile inflammation occurring after reaching reproductive prime. Once initiated, the impact of Inflammaging and its adverse effects determine the direction and magnitudes of further Inflammaging. In this article, we review the nature of this vicious cycle, we will propose that phytocannabinoids as immune regulators may possess the potential as effective adjunctive therapies to slow and, in certain cases, reverse the pathologic senescence to permit a more healthy aging.     

High frequency of extended-spectrum beta-lactamase-producing Enterobacteriaceae carriers at a Japanese long-term care hospital

IntroductionLong-term care hospitals (LTCHs) are at a high risk for the inflow and spread of antimicrobial resistance (AMR) pathogens. However, owing to limited laboratory resources, little is known about the extent to which AMR organisms are endemic.MethodsWe performed active surveillance for carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in newly admitted patients at Marugame Medical Center, a nearly 200-bedded LTCH located in Kagawa, Japan. From August to December 2021, we tested stool samples from patients wearing diapers and confirmed the genetic variants using specific PCR assays. We also collected clinical variables and compared them between AMR carriers and non-carriers.ResultsStool samples were collected from 75 patients, with a median age of 84 years. CRE strain was not detected, but 37 strains of ESBL-E were isolated from 32 patients (42.7%). During the study period, 4.9% of in-hospital patients (37 per 756 patients) were identified to be ESBL-E carriers in the routine microbiological processing, suggesting that active surveillance detected approximately 9-fold more ESBL-E carriers. The bla_CTX-M-9 group was the most common (38.5%), followed by the bla_TEM (26.9%). The clinical backgrounds of the ESBL-E non-carriers and carriers were not significantly different.ConclusionOur active screening demonstrated that nearly half of the patients hospitalized or transferred to a Japanese LTCH were colonized with ESBL-E. We highlight the enforcement of universal basic infection prevention techniques at LTCHs where patients carrying AMR pathogens gather.     

Late-onset stress symptomatology (LOSS) scale – short form: development and validation

Objectives: Late-onset stress symptomatology (LOSS) is a phenomenon observed in older combat veterans who experience increased combat-related thoughts, feelings, and reminiscences corresponding with the changes and challenges of aging. Previously, we developed the LOSS Scale to assess LOSS. This paper describes the development and validation of a LOSS Scale short form (LOSS-SF) to screen veterans in various settings who may be actively re-examining their past wartime experiences.

Method: Three studies examined the reliability and validity of the LOSS-SF in separate samples of male combat veterans age 55 and older (total N = 346). Veterans were administered measures via telephone and mail survey. Correlation and regression analyses examined the reliability and validity of the LOSS-SF.

Results: The LOSS-SF exhibited strong internal consistency (alpha = .93), test-retest reliability (2 week interval on average; r = .88), and good concurrent validity with the LOSS Scale (r = .81). Convergent and divergent validity were supported by the pattern of correlations between the LOSS-SF and other construct measures.

Conclusion: The LOSS-SF is a reliable and valid measure to quickly assess thoughts, feelings, and reminiscences about past combat experiences in older veterans and identify those veterans in distress who may benefit from psychological interventions..     

Mitochondria in the signaling pathways that control longevity and health span

Genetic and pharmacological intervention studies have identified evolutionarily conserved and functionally interconnected networks of cellular energy homeostasis, nutrient-sensing, and genome damage response signaling pathways, as prominent regulators of longevity and health span in various species. Mitochondria are the primary sites of ATP production and are key players in several other important cellular processes. Mitochondrial dysfunction diminishes tissue and organ functional performance and is a commonly considered feature of the aging process. Here we review the evidence that through reciprocal and multilevel functional interactions, mitochondria are implicated in the lifespan modulation function of these pathways, which altogether constitute a highly dynamic and complex system that controls the aging process. An important characteristic of these pathways is their extensive crosstalk and apparent malleability to modification by non-invasive pharmacological, dietary, and lifestyle interventions, with promising effects on lifespan and health span in animal models and potentially also in humans.     

Chronic inflammation and risk of lung cancer in older adults in the health,aging and body composition cohort study

Objectives

We examined the association between three inflammatory markers (Interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) and incident lung cancer using baseline, updated, and averaged inflammatory measures in older adults.

Association between sarcopenia and diabetes in community dwelling elderly in the Amazon region – Viver Mais Project

BackgroundStudies indicate the intrinsic relationship between sarcopenia and diabetes mellitus (DM) pathophysiological mechanisms. Changes in insulin and muscular metabolism are features of diabetic patients and can interact as sarcopenic accelerators. Conversely, sarcopenic patients feature lower glucose tolerance and higher serum insulin levels, predisposing them to DM.ObjectiveTo study the association between sarcopenia and DM in a community-dwelling elderly population of the Amazon region.MethodsCross-sectional study, performed in Belém, Brazil, with 1078 patients aged above 60 years old from the Viver Mais Project (VMP). The definition of sarcopenia was based in the European Working Group on Sarcopenia in Older People (EWGSOP). Calf circumference >31 cm was considered normal, muscle strength was discriminated by BMI and measured with the hand grip test, and gait speed <0.8 m/s configured low performance. DM was diagnosed when reported by the patient or medical form, use of hypoglycemic medications/insulin and in the presence of fasting glucose >126 mg/dl or glycated hemoglobin (HbA1c) >6.5% on two occasions. Other medical and socio-demographic data were extracted from medical forms.ResultsThe frequency of sarcopenia was 9.4%, while DM was present in 36.87% of the patients, and had an increased occurrence in the sarcopenic group. Female sex, advanced age, DM, coronary insufficiency, osteoporosis, body mass index, waist circumference, triglycerides and functionality were associated with sarcopenia. In multivariate analysis, sarcopenia remained strongly associated with DM (OR: 3.208, 95%CI: 1.784–5.769).ConclusionThis study describes strong and independent association between sarcopenia and DM. To further clarify these findings, broader prospective cohorts are necessary.