scholarly journals Where in the cell is SIRT3? – functional localization of an NAD+-dependent protein deacetylase

2008 ◽  
Vol 411 (2) ◽  
pp. e11-e13 ◽  
Author(s):  
William C. Hallows ◽  
Brittany N. Albaugh ◽  
John M. Denu
Keyword(s):  
Nuclear Localization ◽  
The Elderly ◽  
Active Protein ◽  
Cellular Processes ◽  
Age Related ◽  
Biochemical Journal ◽  
Wide Range ◽  
Functional Localization ◽  
Dependent Protein ◽  
Protein Deacetylase

Sirtuins are NAD+-dependent enzymes that have been implicated in a wide range of cellular processes, including pathways that affect diabetes, cancer, lifespan and Parkinson's disease. To understand their cellular function in these age-related diseases, identification of sirtuin targets and their subcellular localization is paramount. SIRT3 (sirtuin 3), a human homologue of Sir2 (silent information regulator 2), has been genetically linked to lifespan in the elderly. However, the function and localization of this enzyme has been keenly debated. A number of reports have indicated that SIRT3, upon proteolytic cleavage in the mitochondria, is an active protein deacetylase against a number of mitochondrial targets. In stark contrast, some reports have suggested that full-length SIRT3 exhibits nuclear localization and histone deacetylase activity. Recently, a report comparing SIRT3−/− and SIRT+/+ mice have provided compelling evidence that endogenous SIRT3 is mitochondrial and appears to be responsible for the majority of protein deacetylation in this organelle. In this issue of the Biochemical Journal, Cooper et al. present additional results that address the mitochondrial and nuclear localization of SIRT3. Utilizing fluorescence microscopy and cellular fractionation studies, Cooper et al. have shown that SIRT3 localizes to the mitochondria and is absent in the nucleus. Thus this study provides additional evidence to establish SIRT3 as a proteolytically modified, mitochondrial deacetylase.

scholarly journals Age-related Defects in CD4 T Cell Cognate Helper Function Lead to Reductions in Humoral Responses

2004 ◽  
Vol 200 (12) ◽  
pp. 1613-1622 ◽  
Author(s):  
Sheri M. Eaton ◽  
Eve M. Burns ◽  
Kimberly Kusser ◽  
Troy D. Randall ◽  
Laura Haynes
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Donor Cell ◽  
The Elderly ◽  
Transfer Model ◽  
Age Related ◽  
Wide Range ◽  
Helper Function ◽  
Humoral Responses

With increasing age, the ability to produce protective antibodies in response to immunization declines, leading to a reduced efficacy of vaccination in the elderly. To examine the effect of age on the cognate function of CD4 T cells, we have used a novel adoptive transfer model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) donors. Upon transfer of aged donor CD4 T cells to young hosts, there was significantly reduced expansion and germinal center (GC) differentiation of the antigen-specific B cell population after immunization. This reduced cognate helper function was seen at all time points and over a wide range of donor cell numbers. In hosts receiving aged CD4 cells, there were also dramatically lower levels of antigen-specific IgG. These age-related defects were not due to defects in migration of the aged CD4 T cells, but may be attributable to reduced CD154 (CD40L) expression. Furthermore, we found that there was no difference in B cell expansion and differentiation or in IgG production when young CD4 T cells were transferred to young or aged hosts. Our results show that, in this model, age-related reductions in the cognate helper function of CD4 T cells contribute significantly to defects in humoral responses observed in aged individuals.

Signalling functions for sphingolipid long-chain bases in Saccharomyces cerevisiae

2005 ◽  
Vol 33 (5) ◽  
pp. 1170-1173 ◽  
Author(s):  
K. Liu ◽  
X. Zhang ◽  
C. Sumanasekera ◽  
R.L. Lester ◽  
R.C. Dickson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Kinase ◽  
Second Messengers ◽  
Dependent Protein Kinase ◽  
Yeast Saccharomyces Cerevisiae ◽  
Signalling Molecules ◽  
Cellular Processes ◽  
Wide Range ◽  
Dependent Protein ◽  
Long Chain

Over the past several years, studies of sphingolipid functions in the baker's yeast Saccharomyces cerevisiae have revealed that the sphingoid LCBs (long-chain bases), dihydrosphingosine and PHS (phytosphingosine), are important signalling molecules or second messengers under heat stress and during non-stressed conditions. LCBs are now recognized as regulators of AGC-type protein kinase (where AGC stands for protein kinases A, G and C) Pkh1 and Pkh2, which are homologues of mammalian phosphoinositide-dependent protein kinase 1. LCBs were previously shown to activate Pkh1 and Pkh2, which then activate the downstream protein kinase Pkc1. We have recently demonstrated that PHS stimulates Pkh1 to activate additional downstream kinases including Ypk1, Ypk2 and Sch9. We have also found that PHS acts downstream of Pkh1 and partially activates Ypk1, Ypk2 and Sch9. These kinases control a wide range of cellular processes including growth, cell wall integrity, stress resistance, endocytosis and aging. As we learn more about the cellular processes controlled by Ypk1, Ypk2 and Sch9, we will have a far greater appreciation of LCBs as second messengers.

scholarly journals Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling

1998 ◽  
Vol 333 (3) ◽  
pp. 471-490 ◽  
Author(s):  
Peter R. SHEPHERD ◽  
Dominic J. WITHERS ◽  
Kenneth SIDDLE
Keyword(s):  
Protein Kinase ◽  
Insulin Signalling ◽  
Protein Substrates ◽  
Cellular Processes ◽  
Glucose And Lipid Metabolism ◽  
Wide Range ◽  
Dependent Protein ◽  
Switch Mechanism ◽  
Phosphoinositide 3 Kinase ◽  
Allosteric Regulators

Insulin plays a key role in regulating a wide range of cellular processes. However, until recently little was known about the signalling pathways that are involved in linking the insulin receptor with downstream responses. It is now apparent that the activation of class 1a phosphoinositide 3-kinase (PI 3-kinase) is necessary and in some cases sufficient to elicit many of insulin's effects on glucose and lipid metabolism. The lipid products of PI 3-kinase act as both membrane anchors and allosteric regulators, serving to localize and activate downstream enzymes and their protein substrates. One of the major ways these lipid products of PI 3-kinase act in insulin signalling is by binding to pleckstrin homology (PH) domains of phosphoinositide-dependent protein kinase (PDK) and protein kinase B (PKB) and in the process regulating the phosphorylation of PKB by PDK. Using mechanisms such as this, PI 3-kinase is able to act as a molecular switch to regulate the activity of serine/threonine-specific kinase cascades important in mediating insulin's effects on endpoint responses.

Resveratrol Promotes Recovery of Hearing following Intense Noise Exposure by Enhancing Cochlear SIRT1 Activity

2017 ◽  
Vol 22 (4-5) ◽  
pp. 303-310 ◽  
Author(s):  
Hao Xiong ◽  
Yongkang Ou ◽  
Yaodong Xu ◽  
Qiuhong Huang ◽  
Jiaqi Pang ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Noise Exposure ◽  
Therapeutic Potential ◽  
High Dose ◽  
Protective Effects ◽  
Wide Range ◽  
Dependent Protein ◽  
Intense Noise ◽  
Protein Deacetylase

The sirtuin SIRT1 is a highly conserved nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase known to have protective effects against a wide range of neurological disorders. In the present study, we discovered that C57BL/6 mice fed a long-term diet supplemented with high-dose resveratrol exhibited increased cochlear SIRT1 activity and presented a better recovery of hearing and less loss of hair cells after intense noise exposure compared with those fed a standard chew. Moreover, resveratrol attenuated cochlear SIRT1 decrease and reduced oxidative stress in the cochlea after noise exposure. These results suggest a considerable therapeutic potential of resveratrol for the treatment of noise-induced hearing loss.

scholarly journals Comparative characteristics of patients with gastroesophageal reflux disease in the age aspect

2017 ◽  
Vol 89 (4) ◽  
pp. 53-56
Author(s):  
O A Denisova ◽  
M A Livzan ◽  
A P Denisov
Keyword(s):  
Gastroesophageal Reflux Disease ◽  
Gastroesophageal Reflux ◽  
Elderly Patients ◽  
Reflux Disease ◽  
Clinical Signs ◽  
The Elderly ◽  
Control Group ◽  
Age Related ◽  
Wide Range ◽  
Ph Metry

Aim. To compare the characteristics of patients with gastroesophageal reflux disease (GERD) by age groups, a wide range of clinical signs, including life-of-quality (QOL) indicators, and instrumental findings. Subjects and methods. A total of 110 patients aged 18 to 86 years with GERD were examined in accordance with the standard protocol. Two groups with equal numbers of patents were formed. A study group included elderly and senile patients and a control group consisted of young and adult ones. Results. The elderly patients with GERD were observed to have a number of age-related clinical features and age-unrelated symptoms. The scores in the scales characterizing the physical health component and those in the general health and vital activity scales were markedly decreased in patients older than 60 years of age. No age-related statistically significant differences were found in the esophageal, gastric, and duodenal mucosae. Daily pH-metry in the elderly showed indirect evidence for esophageal hypomotor dyskinesia in the predominance of alkaline refluxes. Conclusion. The cohort of elderly patients with GERD was ascertained to have statistically significant clinical characteristics, and QOL and pH-metry indicators, which will be able to improve methods for diagnosis and early prevention in this age group.

scholarly journals Connective tissue diseases, multimorbidity and the ageing lung

2016 ◽  
Vol 47 (5) ◽  
pp. 1535-1558 ◽  
Author(s):  
Paolo Spagnolo ◽  
Jean-François Cordier ◽  
Vincent Cottin
Keyword(s):  
Interstitial Lung Disease ◽  
Connective Tissue ◽  
Lung Disease ◽  
Connective Tissue Diseases ◽  
The Elderly ◽  
Morbidity And Mortality ◽  
Immune Functions ◽  
Loss Of Function ◽  
Age Related ◽  
Wide Range

Connective tissue diseases encompass a wide range of heterogeneous disorders characterised by immune-mediated chronic inflammation often leading to tissue damage, collagen deposition and possible loss of function of the target organ. Lung involvement is a common complication of connective tissue diseases. Depending on the underlying disease, various thoracic compartments can be involved but interstitial lung disease is a major contributor to morbidity and mortality. Interstitial lung disease, pulmonary hypertension or both are found most commonly in systemic sclerosis. In the elderly, the prevalence of connective tissue diseases continues to rise due to both longer life expectancy and more effective and better-tolerated treatments. In the geriatric population, connective tissue diseases are almost invariably accompanied by age-related comorbidities, and disease- and treatment-related complications, which contribute to the significant morbidity and mortality associated with these conditions, and complicate treatment decision-making. Connective tissue diseases in the elderly represent a growing concern for healthcare providers and an increasing burden of global health resources worldwide. A better understanding of the mechanisms involved in the regulation of the immune functions in the elderly and evidence-based guidelines specifically designed for this patient population are instrumental to improving the management of connective tissue diseases in elderly patients.

scholarly journals Advances and challenges in geroscience research: An update

2018 ◽  
Vol 105 (4) ◽  
pp. 298-308 ◽  
Author(s):  
A Yabluchanskiy ◽  
Z Ungvari ◽  
A Csiszar ◽  
S Tarantini
Keyword(s):  
Risk Factor ◽  
Chronic Diseases ◽  
Interdisciplinary Approach ◽  
The Elderly ◽  
Vascular Cognitive Impairment ◽  
Developed Countries ◽  
The United States ◽  
Chronic Obstructive ◽  
Age Related ◽  
Wide Range

Aging remains the most pervasive risk factor for a wide range of chronic diseases that afflict modern societies. In the United States alone, incidence of age-related diseases (e.g., cardiovascular disease, stroke, Alzheimer’s disease, vascular cognitive impairment and dementia, cancer, hypertension, type-2 diabetes, chronic obstructive pulmonary disease, and osteoarthritis) is on the rise, posing an unsustainable socioeconomic burden even for the most developed countries. Tackling each and every age-related disease alone is proving to be costly and ineffective. The emerging field of geroscience has posed itself as an interdisciplinary approach that aims to understand the relationship between the biology of aging and the pathophysiology of chronic age-related diseases. According to the geroscience concept, aging is the single major risk factor that underlies several age-related chronic diseases, and manipulation of cellular and systemic aging processes can delay the manifestation and/or severity of these age-related chronic pathologies. The goal of this endeavor is to achieve health improvements by preventing/delaying the pathogenesis of several age-related diseases simultaneously in the elderly population by targeting key cellular and molecular processes of aging instead of managing diseases of aging as they arise individually. In this review, we discuss recent advances in the field of geroscience, highlighting their implications for potential future therapeutic targets and the associated scientific challenges and opportunities that lay ahead.

scholarly journals Lifetime of actin-dependent protein nanoclusters

2022 ◽  
Author(s):  
Sumantra Sarkar ◽  
Debanjan Goswami
Keyword(s):  
Spatial Organization ◽  
Lipid Membrane ◽  
Simple Extension ◽  
Ligand Interaction ◽  
Cellular Processes ◽  
Wide Range ◽  
Dependent Protein ◽  
Protein Ligand Interaction ◽  
Kinetics Of

Protein nanoclusters (PNCs) are dynamic collections of a few proteins that spatially organize in nanometer length clusters. PNCs are one of the principal forms of spatial organization of membrane proteins and they have been shown or hypothesized to be important in various cellular processes, including cell signaling. PNCs show remarkable diversity in size, shape, and lifetime. In particular, the lifetime of PNCs can vary over a wide range of timescales. The diversity in size and shape can be explained by the interaction of the clustering proteins with the actin cytoskeleton or the lipid membrane, but very little is known about the processes that determine the lifetime of the nanoclusters. In this paper, using mathematical modelling of the cluster dynamics, we model the biophysical processes that determine the lifetime of actin-dependent PNCs. In particular, we investigated the role of actin aster fragmentation, which had been suggested to be a key determinant of the PNC lifetime, and found that it is important only for a small class of PNCs. A simple extension of our model allowed us to investigate the kinetics of protein-ligand interaction near PNCs. We found an anomalous increase in the lifetime of ligands near PNCs, which agrees remarkably well with experimental data on RAS-RAF kinetics. In particular, analysis of the RAS-RAF data through our model provides falsifiable predictions and novel hypotheses that will not only shed light on the role of RAS-RAF kinetics in various cancers, but also will be useful in studying membrane protein clustering in general.

scholarly journals Proposed Tandem Effect of Physical Activity and Sirtuin 1 and 3 Activation in Regulating Glucose Homeostasis

2019 ◽  
Vol 20 (19) ◽  
pp. 4748 ◽  
Author(s):  
Francesca Pacifici ◽  
Davide Di Cola ◽  
Donatella Pastore ◽  
Pasquale Abete ◽  
Fiorella Guadagni ◽  
...  
Keyword(s):  
Physical Activity ◽  
Diabetes Mellitus ◽  
Glucose Homeostasis ◽  
Cell Function ◽  
The Elderly ◽  
Sirtuin 1 ◽  
Β Cell ◽  
Cellular Processes ◽  
Age Related ◽  
Β Cell Function

Sirtuins (SIRTs) are seven nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases enzymes (SIRT1–7) that play an important role in maintaining cellular homeostasis. Among those, the most studied are SIRT1 and SIRT3, a nuclear SIRT and a mitochondrial SIRT, respectively, which significantly impact with an increase in mammals’ lifespan by modulating metabolic cellular processes. Particularly, when activated, both SIRT1 and 3 enhance pancreatic β-cells’ insulin release and reduce inflammation and oxidative stress pancreatic damage, maintaining then glucose homeostasis. Therefore, SIRT1 and 3 activators have been proposed to prevent and counteract metabolic age-related diseases, such as type 2 diabetes mellitus (T2DM). Physical activity (PA) has a well-established beneficial effect on phenotypes of aging like β-cell dysfunction and diabetes mellitus. Recent experimental and clinical evidence reports that PA increases the expression levels of both SIRT1 and 3, suggesting that PA may exert its healthy contribute even by activating SIRTs. Therefore, in the present article, we discuss the role of SIRT1, SIRT3, and PA on β-cell function and on diabetes. We also discuss the possible interaction between PA and activation of SIRTs as a possible therapeutic strategy to maintain glucose hemostasis and to prevent T2DM and its complications, especially in the elderly population.

DSM-5 alcohol use disorder features among treatment-seeking older adults

2018 ◽  
Vol 64 (4) ◽  
pp. 185-196 ◽  
Author(s):  
Silke Behrendt ◽  
Barbara Braun ◽  
Randi Bilberg ◽  
Gerhard Bühringer ◽  
Michael Bogenschutz ◽  
...  
Keyword(s):  
Older Adults ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
The Elderly ◽  
Treatment Seeking ◽  
Controlled Clinical Trial ◽  
Dsm 5 ◽  
Wide Range ◽  
And Gender ◽  
International Multicenter

Abstract. Background: The number of older adults with alcohol use disorder (AUD) is expected to rise. Adapted treatments for this group are lacking and information on AUD features in treatment seeking older adults is scarce. The international multicenter randomized-controlled clinical trial “ELDERLY-Study” with few exclusion criteria was conducted to investigate two outpatient AUD-treatments for adults aged 60+ with DSM-5 AUD. Aims: To add to 1) basic methodological information on the ELDERLY-Study by providing information on AUD features in ELDERLY-participants taking into account country and gender, and 2) knowledge on AUD features in older adults seeking outpatient treatment. Methods: baseline data from the German and Danish ELDERLY-sites (n=544) were used. AUD diagnoses were obtained with the Mini International Neuropsychiatric Interview, alcohol use information with Form 90. Results: Lost control, desired control, mental/physical problem, and craving were the most prevalent (> 70 %) AUD-symptoms. 54.9 % reported severe DSM-5 AUD (moderate: 28.2 %, mild: 16.9 %). Mean daily alcohol use was 6.3 drinks at 12 grams ethanol each. 93.9 % reported binging. More intense alcohol use was associated with greater AUD-severity and male gender. Country effects showed for alcohol use and AUD-severity. Conclusion: European ELDERLY-participants presented typical dependence symptoms, a wide range of severity, and intense alcohol use. This may underline the clinical significance of AUD in treatment-seeking seniors.

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