Decline In Organ Function Research Articles

A Healthy Heart and a Healthy Brain: Looking at Mitophagy.

Mitochondrial dysfunction is a hallmark of aging and is a major contributor to neurodegenerative diseases and various cardiovascular disorders. Mitophagy, a specialized autophagic pathway to remove damaged mitochondria, provides a critical mechanism to maintain mitochondrial quality. This function has been implicated in a tissue’s ability to appropriately respond to metabolic and to bioenergetic stress, as well as to recover from mitochondrial damage. A global decline in mitophagic flux has been postulated to be linked to pathological alterations that occur in the heart and the brain as well as a general age-dependent decline in organ function. Cellular observation suggests multiple mechanistically distinct pathways converge upon and activate mitophagy. Over the past decade, additional molecular components within mitophagy have been discovered, including several disease-associated genes that are functionally implicated in mitophagy. However, the pathophysiological role of mitophagy, and how it is regulated within normal physiology or various disease states, is less well established. Here, we will review the evidence that a decline in mitophagy contributes to impaired mitochondrial homeostasis and may be particularly detrimental to postmitotic neurons and cardiomyocytes. We will discuss mitophagy’s pathological significance in both neurodegenerative diseases and cardiovascular disorders. Additionally, signaling pathways regulating mitophagy are reviewed, with emphasis placed on how these pathways might contribute to disease progression. Understanding mitophagy’s role in the mechanisms of disease pathogenesis should allow for the development of more efficient strategies to battle pathological conditions associated with mitochondrial dysfunction.

Refining the unilateral ureteral obstruction mouse model: No sham, no shame.

Fibrosis, as a common final pathway in many renal diseases, contributes significantly to the decline of organ function and to progression to end-stage renal disease. To establish therapeutic interventions that target fibrosis, animal models are essential. The most widely used model of renal fibrosis is the unilateral ureteral obstruction (UUO) model. Typically, the control for this model is a sham-operated animal. Sham surgery causes pain and distress to these control animals, and here we aim to show that there is no difference in the main read-outs of this model between sham-operated animals and non-operated C57BL/6J mice. In five experiments, quantification of Picro Sirius Red stained collagen in the renal cortex did not show any difference between 15 sham and 25 non-operated individuals. A comparison of the regulation of genes involved with fibrosis did not show any difference between sham and non-operated groups at 21 days post surgery either. We conclude that there are no significant differences between non-operated controls and sham animals with respect to collagen deposition and fibrosis pathways in the UUO mouse model.

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

Not So Fast: Geriatric Syndromes Can Be Identified and Intervened upon Prior to Allogeneic Stem Cell Transplantation

<h3>Introduction</h3> The use of alternative donor sources has led to increased access to allogeneic stem cell transplantation (allo-SCT) for older adults (OA) who are less likely to have healthy siblings able to serve as donors. Reduced intensity conditioning has also increased access to allo-SCT for OA but has not definitively mitigated risk of non-relapse mortality (NRM). Age-related decline in organ function and increasing prevalence of co-morbidities in OA support the need for a comprehensive pre-transplant geriatric assessment (GA) for older adults. GA is prognostic but may also serve to guide pre-transplant optimization efforts. <h3>Objectives</h3> To describe the prevalence of geriatric syndromes in OA under consideration for allo-SCT and their association with proceeding to allo-SCT. <h3>Methods</h3> Retrospective study of OA under consideration for allo-SCT evaluated in Cancer and Aging Resiliency (CARE) clinic at Ohio State University from 2016-2018. GA is performed at CARE clinic visit (CCV) and includes physical therapy and audiometric assessments, medication review, and screening for cognitive impairment and psychosocial concerns. Statistical analyses performed include univariable proportional hazard ratio (HR) of proceeding to allo-SCT and Kaplan-Meier survival analyses of overall survival (OS) from CCV and time to allo-SCT from CCV with death treated as competing risk. <h3>Results</h3> Thirty-four patients were included in analyses, 18 went on to allo-SCT. Median age at CCV was 69.4 years (range: 61.4-76.5). All were non-Hispanic, Caucasian and the majority were male (79%). The most prevalent primary diagnoses were acute leukemia or myelodysplastic syndrome (82%) and 32% had more than one cancer diagnosis. See Table 1 for prevalence of frailty and geriatric syndromes. The median time from primary diagnosis to CCV was 5.2 months (range: 0-93.4). Cumulative incidence of allo-SCT was 30% at 3 months (95% CI: 15-46%) and 48% at 6 months (95% CI: 30-64%) after CCV (figure 1). HR for proceeding to allo-SCT by age, gender, disease, and CARE clinic-identified deficits are presented in Table 2. OS from CCV was 97% at 6 months (95% CI: 80-100%) and 75% at 1 year (95% CI: 46-90%). Median OS has not been reached with median follow-up of 8 months (range: 2.2-15.6). The risk of death in patients who went on to allo-SCT was lower than in those who did not though it did not reach statistical significance (HR: 0.185, 95% CI: 0.019-1.787, p = 0.1447). <h3>Conclusions</h3> The most commonly encountered geriatric syndromes among older adults under consideration for allo-SCT are reversible. There was a linear increase in incidence of allo-SCT over the first 6 months after CCV indicating that there is a window in which patient deficits can be optimized prior to allo-SCT. Early referral for GA is important to allow time for optimization. Future study is needed to determine the effect of GA-directed intervention on NRM.

Gambaran Status Tekanan Darah Penderita Hipertensi di Desa Karanganyar Kecamatan Kalianget Kabupaten Sumenep

ABSTRACT&#x0D; Hypertension is a health problem in the world, especially in developing countries. Hypertension is often called a silent killer (silent killer) because it is included in a deadly disease without accompanied by symptoms first as a warning for victims. The problem of high hypertension, especially in the elderly with concomitant decline in organ function.&#x0D; This type of research is quantitative descriptive using non-analytic cross sectional design. The sampling technique used was total sampling with a sample size of 32 people. The instrument used in the form of a tensimeter and blood pressure observation sheet.&#x0D; The results showed that the majority of respondents aged 55-60 years were 10 people (31.25%), the majority of respondents were male as many as 18 people (56.25%). Blood pressure status in patients with hypertension in Karanganyar village is systolic blood pressure 140-159 mmHg, diastolic blood pressure 90-99 mmHg as many as 18 people (56.25%)&#x0D; It can be concluded that the majority of blood pressure status of hypertension sufferers in Gadung Hamlet, Karanganyar Village, Kalianget Subdistrict are in the category of Hypertension.&#x0D; &#x0D; Keywords: Blood Pressure, Hypertension

An Overview on Stem Cells in Tissue Regeneration

Deteriorations in tissues and decline in organ functions, due to chronic diseases or with advancing age or sometimes due to infections or injuries, can severely compromise the quality of life of an individual. Regenerative medicine, a field of medical research focuses on replacing non-functional or dead cells or repairing or regenerating tissues and organs to restore normal functions of an impaired organ. Approaches used in regenerative therapy for achieving the objective employ a number of means which include soluble biomolecules, stem cell transplants, tissue engineering, gene therapy and reprogramming of cells according to target tissue types. Stem cells transplant and tissue regeneration methods for treating various diseases have rapidly grown in usage over the past decades or so. There are different types of stem cells such as mesenchymal, hematopoietic, embryonic, mammary, intestinal, endothelial, neural, olfactory, neural crest, testicular and induced pluripotent stem cells. This review covers the recent advances in tissue regeneration and highlights the application of stem cell transplants in treating many life-threatening diseases or in improving quality of life. Remarkable progress in stem cell research has established that the cell-based therapy could be an option for treating diseases which could not be cured by conventional medical means till recent. Stem cells play major roles in regenerative medicine with its exceptional characteristics of self-renewal capacity and potential to differentiate into almost all types of cells of a body. Vast number of reports on preclinical and clinical application of stem cells revealed its vital role in disease management and many pharmacological industries around the globe working to achieve effective stem cell based products.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Treating Non-Hodgkin Lymphoma.

Non-Hodgkin lymphoma (NHL) includes a variety of closely related malignancies that originate from lymphoid precursors. The majority of NHLs are of B-cell lineage, for which traditional therapy involves chemotherapy in combination with the anti-CD20 monoclonal antibody rituximab. Ongoing research into the pathogenesis of NHL subtypes has given rise to the use of novel agents that target specific molecular pathways. While the incidence of NHL extends over a range of ages from pediatric to elderly settings, the majority of diagnoses occur over age 60years. Increasing the use of concomitant medication coupled with declining organ function among this group of patients creates pharmacokinetic (PK) challenges in administering a number of agents involved in the treatment of NHL. In addition, since many of the new agents are administered orally, there are a number of added PK factors that must be taken into consideration with their prescribing and administration. This article will review the available literature on the PK and pharmacodynamic properties of agents commonly used in the treatment of NHL, and intends to provide information that can assist with properly using these drugs in this setting.

Exosomal long noncoding RNAs in aging and age-related diseases.

Molecules secreted by cells into the internal environment during aging, including those secreted in exosomes, have long been a matter of concern. Those cells that absorb exosomes, also known as recipient cells, exhibit certain phenotypic changes because of the regulatory role of functional molecules (including proteins and nucleic acids) released in exosomes. Involvement of noncoding RNAs (ncRNAs) in the regulation of aging has received increasing attention, and long ncRNAs (lncRNAs) have become one of the research hotspots in recent years. LncRNAs carried by exosomes play a role in intercellular communication between adjacent and distant cells. Moreover, exosomal lncRNAs promote the decline of organ functions and the development of age-related diseases, including atherosclerosis, Type 2 diabetes, osteoporosis, osteoarthritis, rheumatoid arthritis, Parkinson's disease, multiple sclerosis, and cancer. Here, we review the regulatory roles of exosomal lncRNAs in aging and age-related diseases.

Antiepileptic drug therapy in the elderly: a clinical pharmacological review.

Seizure disorder is the third most common neurological disorder in the elderly after stroke and dementia. With the increasing geriatric population, the situation of clinicians seeing more and more elderly epilepsy patients is very likely. Not only is the diagnosis of epilepsy tedious in the elderly, its management raises many challenging issues for the treating physicians. Altered physiology, age-related decline in organ function, and plasma protein binding and altered pharmacodynamics make the elderly patients with seizure disorder a difficult group to treat. This is further complicated by the presence of comorbidities and polypharmacy which increase the chances of drug interactions. The adverse effects that might be tolerated well in younger populations may be disastrous for the aged. Although the newer antiepileptic drugs are found to have a favorable safety profile, there is relative scarcity of randomized-controlled trials involving older and newer antiepileptics in the geriatric population. This review tries to compile the available literature on management of epilepsy in the elderly population including evidence of safety and efficacy of newer and older antiepileptics with special reference to the 'geriatric giants'. It also deals with the interactions between antiepileptic medications and other commonly prescribed drugs in the elderly such as anti-hypertensives and antiischemic agents. The recommended guidelines of various international bodies are also analyzed from the perspective of elderly with seizure disorder.

PENGARUH KOMUNIKASI TERAPEUTIK TERHADAP HARGA DIRI KLIEN DENGAN GAGAL GINJAL KRONIS

Introduction: Chronic renal failure is clinical syndrome caused by declining renal function, lasting progressively and irreversible. Physical change due to organ function decline will affect client psychologicaly and socially. These changes cause self esteem disorder where client tend to use maladaptive coping with manifestation of frequent irritating, angry, anxiety, and depression. Therapeutic communication between nurse and client that lead to client healing process which planned in conscious, purposive manner and this activity is centered on client. Method: This research used quasi experimental. Total sample in this research was 12 clients with chronic renal failure that meet inclusion criteria grouped in two groups: treatment group and control group. Independent variable was therapeutic communication while dependent variable was self esteem. In this research data analysis used was Wilcoxon Sign Rank Test with significance α ≤ 0,05 and Mann Whitney Test with significance α ≤0,05. Result: Result obtained after therapeutic communication intervention provided was p = 0,002 where there is significant difference on client self esteem before and after therapeutic communication intervention given. Result showed that there is significant difference between treatment group and comparative group with p = 0.026. Discussion: It is concluded that therapeutic communication has effect on improving self esteem in client with chronic renal failure. Therapeutic communication helps client to express his/her feeling and problems clients self esteem were improved.

The dynamic nature of senescence in cancer.

Cellular senescence is implicated in physiological and pathological processes spanning development, wound healing, age-related decline in organ functions and cancer. Here, we discuss cell-autonomous and non-cell-autonomous properties of senescence in the context of tumour formation and anticancer therapy, and characterize these properties, such as reprogramming into stemness, tissue remodelling and immune crosstalk, as far more dynamic than suggested by the common view of senescence as an irreversible, static condition.

Epigenetic Clock: Just a Convenient Marker or an Active Driver of Aging?

A global DNA hypomethylation and local changes in the methylation levels of specific DNA loci occur during aging in mammals. Global hypomethylation mainly affects highly methylated repeat sequences, such as transposable elements; it is an essentially stochastic process usually referred to as "epigenetic drift." Specific changes in DNA methylation affect various genome sequences and could be either hypomethylation or hypermethylation, but the prevailing tendencies are hypermethylation of promoter sequences associated with CpG islands and hypomethylation of CpG poor genes. Methylation levels of multiple CpG sites display a strong correlation to age common between individuals of the same species. Collectively, methylation of such CpG sites could be used as "epigenetic clocks" to predict biological age. Furthermore, the discrepancy between epigenetic and chronological ages could be predictive of all-cause mortality and multiple age-associated diseases. Random changes in DNA methylation (epigenetic drift) could also affect the aging phenotype, causing accidental changes in gene expression and increasing the transcriptional noise between cells of the same tissue. Both effects could become detrimental to tissue functioning and cause a gradual decline in organ function during aging. Strong evidence shows that epigenetic systems contribute to lifespan control in various organisms. Similar to other cell systems, the epigenome is prone to gradual degradation due to the genome damage, stressful agents and other aging factors. However, unlike mutations and many other hallmarks of aging, age-related epigenetic changes could be fully or partially reversed to a "young" state.

Frailty and anesthesia - risks during and post-surgery.

Frailty is a state of decreased physiologic reserve and resistance to stressors. Its prevalence increases with age and is estimated to be 26% in those aged above 85 years. As the population ages, frailty will be increasingly seen in surgical patients receiving anesthesia. Here, we evaluate the instruments which have been developed and validated for measuring frailty in surgical patients and summarize frailty tools used in 110 studies linking frailty status with adverse outcomes post-surgery. Frail older people are vulnerable to geriatric syndromes, and complications such as postoperative cognitive dysfunction and delirium are explored. This review also considers how frailty, with its decline of organ function, affects the metabolism of anesthetic agents and may influence the choice of anesthetic technique in an older person. Optimal perioperative care includes the identification of frailty, a multisystem and multidisciplinary evaluation preoperatively, and discussion of treatment goals and expectations. We conclude with an overview of the emerging evidence that Comprehensive Geriatric Assessment can improve postoperative outcomes and a discussion of the models of care that have been developed to improve preoperative assessment and enhance the postoperative recovery of older surgical patients.

The application of dexmedetomidine in clinical anesthesia of elderly patients

Background Due to the decline of organ function, the elderly patients have decreased tolerance to stress response such as surgery and anesthesia. Also, their sensitivity to drug may be increased. Therefore, the perioperative medication regimen and dosage should be carefully considered. Objective To review the application of dexmedetomidine (Dex) in clinical anesthesia on elderly patients. Content Dex has the function of sedation, analgesic, anti-anxiety and inhibiting sympathetic nerve without respiratory inhibition effect. It can be safely and effectively used in the clinical anesthesia on elderly patients. But the dose of using should be reduced when it was applied to elderly patient. Strict monitoring and following the principle of individualized medication are needed. Trend Dex has promising prospects for clinical anesthesia in elderly patients. But the dosage and methods of drug administration need to be further investigated. Key words: Dexmedetomidine; Aged; Anesthesia; Sedation; Analgesia; Delirium

Advances in geriatric oncology: a multidisciplinary perspective.

A growing majority of people with cancer is composed of older patients. For many such patients, independence and quality of life are as important as prolongation of survival, emphasizing the need for treatments that are not only effective but also well-tolerated. Given age-related decline in organ function and the prevalence of comorbidities and polypharmacy, optimum management is complex and requires collaboration between oncologists and geriatricians. Advances in surgery now include preoperative assessment and, when indicated, prehabilitation of the patient, as well as the enhanced recovery after surgery approach. Medical treatment is benefiting from the advent of highly effective novel immunomodulatory agents that join the tumor-targeted small molecule tyrosine kinase inhibitors and monoclonal antibodies in modifying the tolerability of therapy. Improved tolerability is evident with radiotherapy (RT). The adoption of stereotactic body RT in community oncology practice is increasing the proportion of elderly patients with comorbidities who can receive curative treatment. A further aspect of precision medicine as it relates to the older cancer patient is the tailoring of intervention to the robustness or frailty and life expectancy of the individual. Quantitative and validated tools for comprehensive geriatric assessment are playing an important role in this process.

Reducing neglect and improving social support for older people following a self-help group in the poor urban community of Jakarta, Indonesia

Increasing age has an impact on the decline of organ function and results in increasing dependence on others, including family. Efforts must be made to increase older adult's' independence to help them overcome naturally occurring changes and health problems. This research aims to determine the effects of the self-help groups as nursing interventions using guidelines of selfhealth monitoring and management on the incidence of neglecting and the social support of older people. A quasi-experimental design was used on a total sample of 208 people, consisting of 103 in the intervention group and 105 in the control group. An independent t-test was conducted before and after the intervention model to analyze the social support variable, and chi-square test was applied to analysis the neglect variable. The results showed the effects on the incidence of neglect of older people, and there were significant differences between and within the intervention and control groups (p < 0.05) in terms of social support. The intervention model demonstrated reduction of the incidence of neglect and an increase in social support. The results indicate that this program can be used as a guideline for health care center nurses in fostering self-help groups for older people in the community.

64 - Progressive loss of dual oxidase 1 (DUOX1) contributes to impaired airway epithelial wound responses in the aging lung

Age-related chronic diseases, including chronic respiratory diseases such as COPD, are associated with organ function decline, impaired regenerative capacity, and immuno-senescence. Our recent studies indicate that such reparative processes in the lung are mediated by innate epithelial injury responses and production of reactive oxygen species (ROS) by the NADPH oxidase dual oxidase 1 (DUOX1), which were found to be associated with oxidation and activation of epithelial tyrosine kinases, such as epidermal growth factor receptor (EGFR) and the non-receptor tyrosine kinase Src, and also with epithelial secretion of alarmins such as IL-33, which promote epithelial regeneration by activating type 2 immune responses. Contrasting the common belief that aging is associated with increased ROS production, we observed that DUOX1 expression in mouse lungs markedly decreases with age. Moreover, we noticed that DUOX1-deficient mice display accelerated age-related decline in lung function and features of emphysema, as shown by airspace enlargement and increased lung compliance. We hypothesized that loss of DUOX1 may contribute to other features of lung aging, but aged-related lung changes such as increased parenchymal collagen deposition, molecular indices of senescence, or tissue levels of pro-inflammatory cytokines, were all largely unaltered in DUOX1-deficient mice. However, we observed that aged mice display markedly attenuated innate airway responses to inhaled allergens, as illustrated by diminished secretion of IL-33 and other related cytokines. Similar findings were observed in vitro using cultured mouse tracheal epithelial cells (MTEC), in which MTECs from older mice showed dramatically reduced innate responses to injury, which was associated with reduced oxidation and activation of Src and EGFR. Consistent with a potential age-related suppression of DUOX1 by epigenetic mechanisms such as promoter hypermethylation, allergen-induced IL-33 secretion in MTECs from aged mice could be rescued by treatment with the DNA methyltransferase inhibitor AzdC. Overall, these results underline the importance of DUOX1 in airway host defense and regenerative capacity, and indicate that age-related loss of DUOX1 contributes to accelerated impairment of epithelial regenerative capacity and air-space enlargement.

Protective effect of resveratrol against inflammation, oxidative stress and apoptosis in pancreas of aged SAMP8 mice

Aging is a physiological state in which a progressive decline in organ functions is accompanied by the development of age-related diseases. Resveratrol supplementation has been shown to exert anti-inflammatory and antioxidant effects in various mammalian models of aging. Senescence-accelerated mice (SAM) are commonly used as animal models to investigate the aging process. In the present study, the effects of inflammation, oxidative stress and apoptosis in pancreas of two different types of SAM (SAMR1 or resistant to aging, and SAMP8 or prone to aging) have been analysed, as well as the effect of resveratrol administration (5mg/kg/day) on these parameters in the SAMP8 strain. mRNA expressions of sirtuin 1 and FoxO factors were found to be decreased with aging in SAMP8 mice. An increase in inflammatory status and nuclear-factor kappa B (NFκB) protein expression was also observed in old mice, together with a decrease of anti-apoptotic markers and antioxidant-enzyme activity. Resveratrol administration was able to increase sirtuin 1 mRNA expression, as well as decreasing NFκB expression and reducing the proinflammatory and prooxidant status associated with age. In conclusion, resveratrol was able to modulate the inflammatory, oxidative and apoptotic status related to aging, thereby exerting a protective effect on pancreas age-induced damage.

Guidance on opioids prescribing for the management of persistent non-cancer pain in older adults.

Many older adults suffer from persistent pain but prevalence studies consistently showed high levels of untreated or under-treated pain in old population. Both persistent pain and pain under-treatment adversely affect independence and quality of life in geriatric patients. Pain management is challenging in this age-group because of the declining organ function, the presence of concurrent diseases and polypharmacy. For all the above reasons, persistent pain in the elderly should be considered a geriatric syndrome per se and effective approaches are warranted. Current guidelines and consensus statements recommend opioid therapy for older adults with moderate-to-severe persistent pain or functional impairment and diminished quality of life due to pain. However clinicians and patients themselves have some concerns about opioids use. Age-related decline in organs functions and warnings about risk of addiction and drug misuse/abuse also in geriatric patients need particular attention for safe prescribing. On the basis of clinical evidence, these practical recommendations will help to improve the competence on opioid role in persistent pain management and the likelihood of a successful analgesic trial in older patients.

Peptidylarginine deiminase 4 promotes age-related organ fibrosis.

Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4-/- mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4-/- mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4-/- myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction.