Decline In Organ Function Research Articles

Taurine/chenodeoxycholic acid ratio as a potential serum biomarker for low vitamin B12 levels in humans.

Deficiency of vitamin B12 (B12 or cobalamin), an essential water-soluble vitamin, leads to neurological damage, which can be irreversible and anaemia, and is sometimes associated with chronic disorders such as osteoporosis and cardiovascular diseases. Clinical tests to detect B12 deficiency lack specificity and sensitivity. Delays in detecting B12 deficiency pose a major threat because the progressive decline in organ functions may go unnoticed until the damage is advanced or irreversible. Here, using targeted unbiased metabolomic profiling in the sera of subjects with low B12 levels v control individuals, we set out to identify biomarker(s) of B12 insufficiency. Metabolomic profiling identified seventy-seven metabolites, and partial least squares discriminant analysis and hierarchical clustering analysis showed a differential abundance of taurine, xanthine, hypoxanthine, chenodeoxycholic acid, neopterin and glycocholic acid in subjects with low B12 levels. Random forest multivariate analysis identified a taurine/chenodeoxycholic acid ratio, with an AUC score of 1, to be the best biomarker to predict low B12 levels. Mechanistic studies using a mouse model of B12 deficiency showed that B12 deficiency reshaped the transcriptomic and metabolomic landscape of the cell, identifying a downregulation of methionine, taurine, urea cycle and nucleotide metabolism and an upregulation of Krebs cycle. Thus, we propose taurine/chenodeoxycholic acid ratio in serum as a potential biomarker of low B12 levels in humans and elucidate using a mouse model of cellular metabolic pathways regulated by B12 deficiency.

The implications of frailty in older adults with epilepsy.

Older adults constitute a large proportion of people with epilepsy (PWE) due to the changing demographics worldwide and epilepsy's natural history. Aging-related pathophysiological changes lower the tolerance and increase our vulnerability to stressors, which manifests as frailty. Frailty is closely associated with adverse health outcomes. This narrative review examines the interplay between frailty and epilepsy, especially in older adults, emphasizing its clinical implications, including its role in managing PWE. Mechanistically, frailty develops through complex interactions among molecular and cellular damage, including genomic instability, mitochondrial dysfunction, and hormonal changes. These contribute to systemic muscle mass, bone density, and organ function decline. The concept of frailty has evolved from a primarily physical syndrome to include social, psychological, and cognitive dimensions. The "phenotypic frailty" model, which focuses on physical performance, and the "deficit accumulation" model, which quantifies health deficits, provide frameworks for understanding and assessing frailty. PWE are potentially more prone to developing frailty due to a higher prevalence of risk factors predisposing to frailty. These include, but are not limited to, polypharmacy, higher comorbidity, low exercise level, social isolation, low vitamin D, and osteoporosis. We lack commercial biomarkers to measure frailty but can diagnose it using self- or healthcare provider-administered frailty scales. Recent attempts to develop a PWE-specific frailty scale are promising. Unlike chronological age, frailty is reversible, so its management using multidisciplinary care teams should be strongly considered. Frailty can affect antiseizure medication (ASM) tolerance secondary to its impact on pharmacokinetics and pharmacodynamics. While frailty's effect on seizure control efficacy of ASM is poorly understood, its undoubted association with overall poor outcomes, including epilepsy surgery, behooves us to consider its presence and implication while treating older PWE. Incorporation of frailty measures in future research is essential to improve our understanding of frailty's role in PWE health. PLAIN LANGUAGE SUMMARY: Frailty is the declining state of the human body. People with epilepsy are more prone to it. It should be factored into their management.

Frailty management in older patients: a best practice implementation project

ABSTRACT Introduction: Frailty in older adults can lead to a gradual decline in organ function. Without timely diagnosis and intervention, this condition can progress rapidly, increasing the risk of disability and mortality. Objectives: The aim of this project was to implement evidence-based practices for managing frailty in the medical ward to prevent disability in older patients. Methods: This project was conceptually informed by the JBI Evidence Implementation Framework. This framework uses an audit and feedback approach and a pre- and post-test design to measure baseline compliance, develop implementation strategies responsive to gaps in compliance, and conduct a final evaluation to measure changes in compliance. JBI PACES and JBI GRiP situational analysis software were used to support data collection and implementation planning. Ten audit criteria were used with a sample of 30 patients in a regional teaching hospital in southern Taiwan. Results: The baseline audit showed poor compliance, with rates below 30% for all ten audit criteria. Through strategies such as professional training and education, the implementation of evidence-based care guidelines, and interdisciplinary consensus-building, the follow-up audit revealed an increase in compliance to over 90% for each audit criterion. Conclusions: Frailty management strategies based on evidence-based audit criteria were implemented and routinely measured. The most effective strategies for improving compliance included the development of a training course, a digitized assessment tool, team meetings, interdisciplinary collaboration, communication, and consensus-building. Spanish abstract: http://links.lww.com/IJEBH/A225

Single-drug Chemotherapy Plus Immunotherapy as First-line Treatment for Stage Ⅳ Non-small Cell Lung Cancer Elderly Patients: A Phase II Clinical Trial UNICORN Study

IntroductionLung cancer remains the most common malignancy and the leading cancer-related death among the elderly in China, which deserves more research attention. Immunotherapy combined with platinum-based doublet chemotherapy has been approved as the standard treatment for advanced non-small cell lung cancer (NSCLC) patients who are devoid of specific gene mutations or fusions. Given that patients with NSCLC over the age of 65 typically exhibit declining organ function and physical condition, they often showed reduced tolerance for this rigorous treatment regimen. However, the KEYNOTE-042 study illuminated a promising pathway: in patients testing positive for programmed death-ligand 1 (PD-L1), immunotherapy alone has demonstrated a superior overall survival (OS) compared to platinum-based doublet chemotherapy. This suggests that moderating the intensity of chemotherapy and prioritizing immunotherapy may be a gentler alternative in elderly demographic. Patients and MethodsThis multicenter phase II clinical trial named UNICORN aimed to enroll 49 patients aged 65 and older, utilizing paclitaxel or nab-paclitaxel for those with squamous NSCLC, and pemetrexed for those diagnosed with lung adenocarcinoma. The treatment protocol entails 4 cycles of serplulimab plus chemotherapy followed by an extended regimen of serplulimab maintenance, spanning a total of 35 cycles. Primary endpoints of this study are progression-free survival (PFS), disease control rate (DCR) and the secondary endpoints are OS, objective control rate (ORR) and safety metrics. ConclusionThis is the first study to evaluate the efficacy and safety of serplulimab combined with either paclitaxel or pemetrexed in elderly treatment-naïve patients with stage IV NSCLC whose PD-L1 are positive.

#2372 Investigating the effects of low-level and transient DNA damage on kidney health in a novel mouse model of aging

Abstract Background and Aims Increasing life expectancy worldwide underscores the importance of addressing the effects of aging on organ and cell function. Aging is characterized by a gradual decline in organ function that varies among individuals and is influenced by lifestyle choices and various external factors that induce DNA stress. This mismatch between kidney aging and an individual's lifespan contributes to the increase in end-stage renal disease. Among the kidney's constituent cells, the proximal tubules are frequently damaged by external factors such as ischemia and drugs. Our research has focused on DNA damage and its repair mechanisms (DDR) caused by these injuries, and we have previously shown that extensive DNA damage beyond the capacity of DDR or abnormalities in DDR cause cellular senescence in proximal tubules, resulting in incomplete renal repair after injury (Kishi et al. Sci Transl Med 2019, J Clin Invest 2019). In this study, we extend these studies and test whether acquired and mild DNA stress induces renal senescence using a novel mouse model of aging, the Inducible Changes to the Epigenome (ICE) mouse (Hayano et al. Cell. 2023). Method ICE mice were generated by mating I-PpoI STOP/+ mice with CreERT2/+ mice. I-PpoI, an endonuclease, cleaves DNA only upon administration of tamoxifen and the resulting DNA damage is subsequently repaired by the DDR. To induce transient DNA damage, 4- to 6-month-old mice were fed a tamoxifen-containing diet for 3 weeks and then housed until they reached 14 months of age. A comprehensive renal analysis was then performed, which included renal tissue evaluation, single-nucleus RNA sequencing, q-PCR, and Western blot analysis for phenotypic analysis of mouse kidneys. Results No significant histological changes were observed in the kidney tissues between the ICE mice and the control group, and the levels of interstitial fibrosis were comparable. To ensure unbiased evaluation, we performed single-nucleus RNA-seq. In ICE mice, there was an increased presence of proximal tubules with incomplete repair expressing KIM-1 and VCAM-1. In addition, ICE mice showed increased gene expression of DNA repair-related enzymes (Mgmt) in proximal tubules and evidence of cellular senescence. No differences in mitochondrial number or biosynthetic capacity were observed. Conclusion The consequences of short-term and transient DNA damage were found to have lasting effects on the kidney. In particular, significant changes were observed in the proximal tubules, where DNA instability and accelerated cellular senescence were evident, suggesting an impaired repair phenotype within the proximal tubules. This may be related to increased susceptibility to various external stimuli. For further detailed analysis, studies using proximal tubule-specific ICE mice are currently performed.

MDM2 accelerated renal senescence via ubiquitination and degradation of HDAC1.

Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-β-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

Pengaruh Pendidikan Kesehatan dengan Media Video terhadap Kepatuhan Diit Hipertensi pada Lansia di Puskesmas Purwokerto Timur 2

Elderly is the final phase of the human journey where there will be changes and decline in organ function due to the aging process. The incidence of hypertension in the elderly is seen to increase from 2013 to 2018 reaching 25.8% and increasing to 34.1% in 2018. Hypertension diet is one of the non-pharmacological therapies to control and maintain normal blood pressure values. Health education is an activity to convey health messages to individuals, groups or communities that aims to improve health using video media. The purpose of this study was to analyze the effect of health education with video media on adherence to hypertension diet in the elderly at Pukesmas Purwokerto Timur 2. This study was a quantitative study with a pre-experimental design one group pre and post test using accidental sampling technique with a total sample of 30 elderly respondents. and using a questionnaire instrument Formular Food Frequency Questionnaire. Analysis using univariate test, bivariate and Wilcoxon test. The results of the Wilcoxon statistical test show that there is an influence between health education and video media on hypertension diet compliance with a p-value of 0.000, so that there is a decrease in the number of daily calories by 141.1 Kcal (5.71%), after being given a video, the average number of calories in the elderly before being given a video was 2470.07 kkl, after being given a video the average was 2328,97 kkl.

Abstract 2963: Dihydromyricetin is a senomorphic agent to promote therapeutic outcome of age-related conditions including cancer and Alzheimer's disease

Abstract Aging is characterized by a progressive decline of organ function and gradual rise of susceptibility to multiple chronic disorders, with cancer being a primary cause of human morbidity and mortality worldwide. Cellular senescence represents a state of permanent cell cycle arrest and contributes to chronological aging and age-related diseases including Alzheimer's disease (AD), mainly through development of a distinct secretome termed the senescence-associated secretory phenotype (SASP). By screening a natural medicinal agent library, we noticed Rattan tea extract (RTE) has a prominent antiaging potential, wherein dihydromyricetin (DMY), the most abundant natural flavonoid in RTE, played a central role in suppressing the SASP expression of senescent cells. DMY enhanced total antioxidant capacity (T-AOC), increased catalase (CAT) and glutathione peroxidase (GSH-Px) activity, upregulated the expression of HO-1, NQO1, nuclear Nrf2 and phospho-ERK (p-ERK), but decreased malondialdehyde (MDA) level in senescent cells. Furthermore, DMY regulates PI3K/Akt/mTOR signaling pathway, NLRP3 inflammasome formation, the NF-κB complex activity and ER stress-response, each responsible for a full spectrum SASP development. Transcriptomic profiling suggested that DMY can dampen the genome-wide upregulation of pro-inflammatory factors produced by senescent cells, resulting in abrogated progression of cancer malignancy including elevated proliferation, migration, invasion and chemoresistance. Importantly, combination of DMY with classic chemotherapy significantly enhanced therapeutic efficacy, causing remarkable tumor regression and extending posttreatment survival. Alzheimer's disease (AD) is marked by the presence of amyloid plaques, neurofibrillary tangles, damaged neuronal macromolecules and redox sensitive ions. We found that DMY restrains inflammatory injury in microglial cells, reduces their apoptosis and inflammation, and inhibits TLR4 and MD2 expression. Results of small molecule-protein docking and pull-down assays indicated that DMY binds MD2 to suppress the formation of TLR4 complex. In AD mice, DMY improved the cognitive disorder of animals, suppressed inflammatory injury in brain and reduced TLR4 expression. Together, DMY represents a valid natural candidate that has senomorphic activity and can be applied for treatment of malignancies or neurodegenerative disorders such as AD, pathologies that frequently arise in late life of humans. Citation Format: Qixia Xu, Zi Li, Zhirui Jiang, Judith Campisi, Yu Sun. Dihydromyricetin is a senomorphic agent to promote therapeutic outcome of age-related conditions including cancer and Alzheimer's disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2963.

Distraction Guided Imagery Technique to Reduce Anxiety Levels in Elderly with Hypertension

Elderly is an aging process with increasing individual age characterized by a decrease in the function of organs such as the brain, heart, liver and kidneys and increased loss of active body tissue in the form of body muscles. The decline in organ function in the elderly is due to a decrease in the number and ability of body cells, so that the ability of body tissues to maintain normal function disappears, so they cannot defend against infection and repair damage suffered (Fatmah, 2010). The purpose of this study was to identify the Guidance Imagery Distraction Technique on Reducing Anxiety Levels in Elderly People with Hypertension in Rt 010 / Rw 005 Lenteng Agung South Jakarta Year 2023.This type of research uses a quantitative type research design with a research design using pre-experiment. The population in the study was elderly with hypertension as many as 39 people in RT 010 / RW 05 Lenteng Agung The sample technique used was putposive sampling and data analysis using paired sample t-test. The results of this study indicate that after being given guided imagery techniques, the majority experienced a decrease in anxiety levels, namely mild anxiety as many as 11 elderly people (73.3%) and respondents who experienced moderate anxiety as many as 4 elderly people (46.7%). anxiety in elderly people with hypertension in RT 010 In RT 010 /RW 05 Lenteng Agung before being given the Guided Imagery distraction technique, the majority experienced severe anxiety. Anxiety in the elderly with hypertension in RT 010 / RW 05 Lenteng Agung before being given the Guided Imagery distraction technique, the majority experienced mild anxiety. There is an effect of Guidance Imagery distraction techniques on reducing anxiety levels in the elderly with hypertension in RT 010 / Rw 005 Lenteng Agung, South Jakarta in 2023.

Aging Gut Microbiome in Healthy and Unhealthy Aging.

The characteristics of human aging manifest in tissue and organ function decline, heightening susceptibility to age-related ailments, thereby presenting novel challenges to fostering and sustaining healthy longevity. In recent years, an abundance of research on human aging has surfaced. Intriguingly, evidence suggests a pervasive correlation among gut microbiota, bodily functions, and chronic diseases. From infancy to later stages of adulthood, healthy individuals witness dynamic shifts in gut microbiota composition. This microbial community is associated with tissue and organ function deterioration (e.g., brain, bones, muscles, immune system, vascular system) and heightened risk of age-related diseases. Thus, we present a narrative review of the aging gut microbiome in both healthy and unhealthy aging contexts. Additionally, we explore the potential for adjustments to physical health based on gut microbiome analysis and how targeting the gut microbiome can potentially slow down the aging process.

15-Pgdh Inhibition Alternatively Activates Macrophages to Promote Hematopoietic Function during Aging

Aging results in the progressive decline of organ function and integrity across species. In the hematopoietic system aging is associated with diminished stem cell regenerative capacity and contributes to compromised tissue homeostasis and heightened vulnerability to age-related diseases including anemia, myelodysplastic syndromes, and hematological malignancies. Macrophages, integral components of the innate immune system, demonstrate remarkable functional plasticity and play diverse roles in tissue homeostasis, inflammation, and immunity. The balance between pro-inflammatory M1 and anti-inflammatory M2 macrophages significantly influences immune and inflammatory responses, and thus the progression of hematopoietic aging. We have previously demonstrated that the prostaglandin degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell (HSC) activity, that 15-PGDH inhibition (PGDHi) following transplantation results in a markedly accelerated recovery of neutrophils, platelets, and HSCs, and that 15-PGDH knockout animals display enhanced HSC function with age. Here we expand on our previous work and demonstrate in aged mice that (1) 15-PGDH expression and activity remains conserved (2) that PGDHi induces a gene expression signature consistent with alternatively activated M2 macrophages, (3) that prolonged PGDHi results in a significant increase in phenotypic HSCs in both the bone marrow and spleen and induces a gene signature consistent with enhanced HSC function, and (4) that PGDHi treated bone marrow (BM) displays a advantage during primary competitive repopulation studies and prevents age-associated myeloid bias during secondary transplants. Taken together we propose PGDHi represents an in vivo switch to alternatively activate macrophages, which has significant implications to not only prevent age-associated hematopoietic decline, but also as a novel strategy to treat age-associated hematologic disease.

Failure to repair endogenous DNA damage in β-cells causes adult-onset diabetes in mice.

Age is the greatest risk factor for the development of type 2 diabetes mellitus (T2DM). Age-related decline in organ function is attributed to the accumulation of stochastic damage, including damage to the nuclear genome. Islets of T2DM patients display increased levels of DNA damage. However, whether this is a cause or consequence of the disease has not been elucidated. Here, we asked if spontaneous, endogenous DNA damage in β-cells can drive β-cell dysfunction and diabetes, via deletion of Ercc1, a key DNA repair gene, in β-cells. Mice harboring Ercc1-deficient β-cells developed adult-onset diabetes as demonstrated by increased random and fasted blood glucose levels, impaired glucose tolerance, and reduced insulin secretion. The inability to repair endogenous DNA damage led to an increase in oxidative DNA damage and apoptosis in β-cells and a significant loss of β-cell mass. Using electron microscopy, we identified β-cells in clear distress that showed an increased cell size, enlarged nuclear size, reduced number of mature insulin granules, and decreased number of mitochondria. Some β-cells were more affected than others consistent with the stochastic nature of spontaneous DNA damage. Ercc1-deficiency in β-cells also resulted in loss of β-cell function as glucose-stimulated insulin secretion and mitochondrial function were impaired in islets isolated from mice harboring Ercc1-deficient β-cells. These data reveal that unrepaired endogenous DNA damage is sufficient to drive β-cell dysfunction and provide a mechanism by which age increases the risk of T2DM.

Health education for elderly with hypertension in RW 17 Mojosongo Jebres Surakarta

Hypertension in the elderly has a high prevalence, which is due to the decline in organ function in the elderly. Based on the previous research, it was found that blood pressure was originally high, but after being given the intervention of slow deep breathing, stretching, and brisk walking exercise, it obtained relevant depreciation. With this counseling, it is hoped that all people, especially the elderly who have a history of high blood pressure, can increase their knowledge about exercises that can be done to reduce high blood pressure. This program included counseling about hypertension and exercises that could be done by the elderly to reduce high blood pressure. The evaluation result shows that there is an increase in the knowledge of the elderly about a healthy lifestyle by 8% for a good level of knowledge.

Occupational Therapy to Improve Productivity of the Elderly by Creating Photo Frames at Panti Werdha Batam

Aging is accompanied by physiological changes and an increased prevalence of acute and chronic diseases, leading to a decline in organ function and a reduced ability to adapt to environmental factors. Occupational therapy, encompassing activities related to personal care, recreation, and productivity, holds significance for individuals. This study aimed to identify the needs and analyze the situation of elderly residents at the Budi Sosial Foundation's Elderly Home. The four-stage methodology involved situational analysis, health assessments, and physical activity education sessions. The implementation phase included simulation and assistance, where participants were engaged in arranging popsicle sticks into frame shapes. Monitoring and evaluation were conducted to assess the effectiveness of the health assessments and physical activity education, with all 17 (100%) active elderly participants observed. The results demonstrate the potential benefits of occupational therapy in promoting physical activity and overall health among elderly individuals. These findings imply the importance of integrating occupational therapy interventions to enhance the well-being and functional abilities of the elderly population.
 Highlights:
 
 Occupational therapy: A beneficial intervention for elderly individuals' well-being and functional abilities.
 Physical activity promotion: Enhancing the overall health and adaptability of the aging population.
 Health assessment: Evaluating the effectiveness of occupational therapy interventions in elderly care.
 
 Keywords: aging, occupational therapy, physical activity, health assessment, elderly population

Kapasitas Total Antioksidan dan Uji Toksisitas Ekstrak Bunga Kecombrang (Etlingera elatior (Jack) R.M.Sm)

Oxidative stress is imbalance between antioxidant production and the formation of free radicals, which are involved in the development of degenerative diseases. Declining organ function is a symptom of degenerative diseases. The antioxidant helps protect the body from free radicals and prevent oxidative stress. Antioksidan classified into exogenous and endogenous. (Etlingera elatior (Jack) R.M.Sm) flower is known for its antioxidants. This study aimed to establish the toxicity and antioxidant features of kecombrang flower. Total antioxidant capacity test by Blois 1,1 Diphenyl-2Picryhydrazyl (DPPH) method, toxicity test by Brine Shrimp Lethality Test (BSLT) method. After acquiring simplicia by grinding and aerating the flowers, the extract was obtained by the maceration process using methanol as the solvent and evaporation. The extract was then analyzed. The total antioxidant capacity test showed an IC50 of 931.53 g/mL, indicating that kecombrang flower has a low total antioxidant capacity. Based on the results of the toxicology tests, the LC50 value for the kecombrang flower extract was 612.66 g/mL, indicating that it possessed toxic properties. This study concluded that kecombrang flower extract was shown to have low antioxidant levels and potential antimitotic activity.

Narrative Review of Multidisciplinary Management of Central Nervous Involvement in Patients with HER2-Positive Metastatic Breast Cancer: Focus on Elderly Patients.

The tumor biology of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) promotes the development of central nervous system (CNS) metastases, with 25% of patients with HER2-positive BC developing CNS metastases. Furthermore, the incidence of HER2-positive BC brain metastases has increased in the last decades, likely because of the improved survival with targeted therapies and better detection methods. Brain metastases are detrimental to quality of life and survival and represent a challenging clinical problem, particularly in elderly women, who comprise a substantial proportion of patients diagnosed with BC and often have comorbidities or an age-related decline in organ function. Treatment options for patients with BC brain metastases include surgical resection, whole-brain radiation therapy, stereotactic radiosurgery, chemotherapy, and targeted agents. Ideally, local and systemic treatment decisions should be made by a multidisciplinary team, with input from several specialties, based on an individualized prognostic classification. In elderly patients with BC, additional age-associated conditions, such as geriatric syndromes or comorbidities, and the physiologic changes associated with aging, may impact their ability to tolerate cancer therapy and should be considered in the treatment decision-making process. This review describes the treatment options for elderly patients with HER2-positive BC and brain metastases, focusing on the importance of multidisciplinary management, the different points of view from the distinct disciplines, and the role of oncogeriatric and palliative care in this vulnerable patient group.

Chronological Age and DNA Damage Accumulation in Blood Mononuclear Cells: A Linear Association in Healthy Humans after 50 Years of Age.

Aging is characterized by the progressive deregulation of homeostatic mechanisms causing the accumulation of macromolecular damage, including DNA damage, progressive decline in organ function and chronic diseases. Since several features of the aging phenotype are closely related to defects in the DNA damage response (DDR) network, we have herein investigated the relationship between chronological age and DDR signals in peripheral blood mononuclear cells (PBMCs) from healthy individuals. DDR-associated parameters, including endogenous DNA damage (single-strand breaks and double-strand breaks (DSBs) measured by the alkaline comet assay (Olive Tail Moment (OTM); DSBs-only by γH2AX immunofluorescence staining), DSBs repair capacity, oxidative stress, and apurinic/apyrimidinic sites were evaluated in PBMCs of 243 individuals aged 18-75 years, free of any major comorbidity. While OTM values showed marginal correlation with age until 50 years (rs = 0.41, p = 0.11), a linear relationship was observed after 50 years (r = 0.95, p < 0.001). Moreover, individuals older than 50 years showed increased endogenous DSBs levels (γH2Ax), higher oxidative stress, augmented apurinic/apyrimidinic sites and decreased DSBs repair capacity than those with age lower than 50 years (all p < 0.001). Results were reproduced when we examined men and women separately. Prospective studies confirming the value of DNA damage accumulation as a biomarker of aging, as well as the presence of a relevant agethreshold, are warranted.

Sarcoidosis: Epidemiology and clinical insights.

Sarcoidosis is characterized by noncaseating granulomas which form in almost any part of the body, primarily in the lungs and/or thoracic lymph nodes. Environmental exposures in genetically susceptible individuals are believed to cause sarcoidosis. There is variation in incidence and prevalence by region and race. Males and females are almost equally affected, although disease peaks at a later age in females than in males. The heterogeneity of presentation and disease course can make diagnosis and treatment challenging. Diagnosis is suggestive in a patient if one or more of the following is present: radiologic signs of sarcoidosis, evidence of systemic involvement, histologically confirmed noncaseating granulomas, sarcoidosis signs in bronchoalveolar lavage fluid (BALF), and low probability or exclusion of other causes of granulomatous inflammation. No sensitive or specific biomarkers for diagnosis and prognosis exist, but there are several that can be used to support clinical decisions, such as serum angiotensin-converting enzyme levels, human leukocyte antigen types, and CD4 Vα2.3+ T cells in BALF. Corticosteroids remain the mainstay of treatment for symptomatic patients with severely affected or declining organ function. Sarcoidosis is associated with a range of adverse long-term outcomes and complications, and with great variation in prognosis between populations. New data and technologies have moved sarcoidosis research forward, increasing our understanding of the disease. However, there is still much left to be discovered. The pervading challenge is how to account for patient variability. Future studies should focus on how to optimize current tools and develop new approaches so that treatment and follow-up can be targeted to individuals with more precision.

3D reconstruction shows mouse skeletal muscle may decline in function across aging due to the MICOS complex

Mitochondria are active organelles, undergoing harmonized cycles of fission and fusion, driven by ‘mitochondrial dynamics,’ to retain their morphology, distribution, and size. Mitochondrial dynamics has emerged as a critical process in maintaining cellular homeostasis. Interestingly, it has been long respected that a decrease in mitochondrial function escorts aging in specific tissues. For example, skeletal muscle gradually loses mass, strength, endurance, and oxidative capacity during aging. This decrease might, in turn, contribute to the observed age-dependent decline in organ function by mutations or alterations in mitochondrial fusion and fission proteins associated with several diseases. However, new players in regulating mitochondrial shape and cristae shape have been recently studied, such as the mitochondrial contact site and cristae organizing system (MICOS) complex. The MICOS complex is a multi-protein interaction hub that helps define cristate and mitochondria architecture. However, the MICOS complex has not been implicated in regulating organelle structure changes during aging. Thus, we hypothesized that loss of the MICOS complex during aging may increase mitochondrial fragmentation, decrease nanotunnels, and alter cristae morphology. To do this, we examined the three-dimensional morphology of mitochondria networks in young (3-month) and aged (2-year) murine gastrocnemius muscle via serial block face-scanning electron microscopy and the Amira program for segmentation, analysis, and quantification. We found differences in mitochondrial network configuration, nanotunneling, size, shape, number, contact sites, MICOS dynamics, and gene expression in skeletal muscle during aging. We also found an association between OPA-1 and the MICOS complex in the gastrocnemius with mitochondrial aging. Furthermore, the loss of the MICOS complex was linked with decreased oxidative capacity and altered mitochondrial metabolism. Potentially, this suggests a novel relationship between the MICOS complex and aging in skeletal muscle.

Health Equity in Sickle Cell Research and Access to Therapy

Health Equity in Sickle Cell Research and Access to Therapy