Salmon A.B.,Geriatric Research |
Salmon A.B.,University of Texas Health Science Center at San Antonio
Antioxidants | Year: 2016
Despite numerous correlative data, a causative role for oxidative stress in mammalian longevity has remained elusive. However, there is strong evidence that increased oxidative stress is associated with exacerbation of many diseases and pathologies that are also strongly related to advanced age. Obesity, or increased fat accumulation, is one of the most common chronic conditions worldwide and is associated with not only metabolic dysfunction but also increased levels of oxidative stress in vivo. Moreover, obesity is also associated with significantly increased risks of cardiovascular disease, neurological decline and cancer among many other diseases as well as a significantly increased risk of mortality. In this review, we investigate the possible interpretation that the increased incidence of these diseases in obesity may be due to chronic oxidative stress mediating segmental acceleration of the aging process. Understanding how obesity can alter cellular physiology beyond that directly related to metabolic function could open new therapeutic areas of approach to extend the period of healthy aging among people of all body composition. © 2016 by the author; licensee MDPI, Basel, Switzerland.
Banks W.A.,Geriatric Research |
Banks W.A.,University of Washington
Advanced Drug Delivery Reviews | Year: 2012
The successful treatment of Alzheimer's disease (AD) will require drugs that can negotiate the blood-brain barrier (BBB). However, the BBB is not simply a physical barrier, but a complex interface that is in intimate communication with the rest of the central nervous system (CNS) and influenced by peripheral tissues. This review examines three aspects of the BBB in AD. First, it considers how the BBB may be contributing to the onset and progression of AD. In this regard, the BBB itself is a therapeutic target in the treatment of AD. Second, it examines how the BBB restricts drugs that might otherwise be useful in the treatment of AD and examines strategies being developed to deliver drugs to the CNS for the treatment of AD. Third, it considers how drug penetration across the AD BBB may differ from the BBB of normal aging. In this case, those differences can complicate the treatment of CNS diseases such as depression, delirium, psychoses, and pain control in the AD population. © 2011.
Leng T.,Morehouse School of Medicine |
Shi Y.,University of Pittsburgh |
Xiong Z.-G.,Morehouse School of Medicine |
Sun D.,University of Pittsburgh |
Sun D.,Geriatric Research
Progress in Neurobiology | Year: 2014
Ischemic brain injury results from complicated cellular mechanisms. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA) and mechanical recanalization. Therefore, a better understanding of ischemic brain injury is needed for the development of more effective therapies. Disruption of ionic homeostasis plays an important role in cell death following cerebral ischemia. Glutamate receptor-mediated ionic imbalance and neurotoxicity have been well established in cerebral ischemia after stroke. However, non-NMDA receptor-dependent mechanisms, involving acid-sensing ion channel 1a (ASIC1a), transient receptor potential melastatin 7 (TRPM7), and Na+/H+ exchanger isoform 1 (NHE1), have recently emerged as important players in the dysregulation of ionic homeostasis in the CNS under ischemic conditions. These H+-sensitive channels and/or exchangers are expressed in the majority of cell types of the neurovascular unit. Sustained activation of these proteins causes excessive influx of cations, such as Ca2+, Na+, and Zn2+, and leads to ischemic reperfusion brain injury. In this review, we summarize recent pre-clinical experimental research findings on how these channels/exchangers are regulated in both in vitro and in vivo models of cerebral ischemia. The blockade or transgenic knockdown of these proteins was shown to be neuroprotective in these ischemia models. Taken together, these non-NMDA receptor-dependent mechanisms may serve as novel therapeutic targets for stroke intervention. © 2014 Elsevier Ltd.
Cole G.M.,University of California at Los Angeles |
Frautschy S.A.,Geriatric Research
Journal of Nutrition | Year: 2010
The risk for dementia, a major contributor to incapacitation and institutionalization, rises rapidly asweage, doubling every 5 y after age 65. Tens of millions ofnewAlzheimer's disease (AD) and other dementia cases are projected as elderly populations increase around the world, creating a projected dementia epidemic for which most nations are not prepared. Thus, there is an urgent need for prevention approaches that are safe, effective, and affordable. This review addresses the potential of one promising candidate, the (n-3) fatty acid docosahexaenoic acid (DHA), which appears to slow pathogenesis of AD and possibly vascular dementia. DHA is pleiotropic, acting at multiple steps to reduce the production of the β-amyloid peptide, widely believed to initiate AD. DHA moderates some of the kinases that hyperphosphorylate the τ-protein, a component of the neurofibrillary tangle. DHA may help suppress insulin/neurotrophic factor signaling deficits, neuroinflammation, and oxidative damage that contribute to synaptic loss and neuronal dysfunction in dementia. Finally, DHA increases brain levels of neuroprotective brain-derived neurotrophic factor and reduces the (n-6) fatty acid arachidonate and its prostaglandin metabolites that have been implicated in promoting AD. Clinical trials suggest thatDHAor fish oil alone can slow early stages of progression, but these effects may be apolipoprotein E genotype specific, and larger trials with very early stages are required to prove efficacy.Weadvocate early intervention in a prodromal period with nutrigenomically defined subjects with an appropriately designed nutritional supplement, including DHA and antioxidants. © 2010 American Society for Nutrition.
Donskey C.J.,Geriatric Research |
Donskey C.J.,Case Western Reserve University
American Journal of Infection Control | Year: 2013
Contaminated environmental surfaces provide an important potential source for transmission of health care-associated pathogens. In recent years, a variety of interventions have been shown to be effective in improving cleaning and disinfection of surfaces. This review examines the evidence that improving environmental disinfection can reduce health care-associated infections.
Taylor W.D.,Geriatric Research |
Taylor W.D.,Vanderbilt University
New England Journal of Medicine | Year: 2014
A 74-year-old woman with hypertension that is well controlled with hydrochlorothiazide is brought by her daughter for an evaluation. The daughter states that her mother is withdrawn, often tearful, and at times appears to have memory problems but has no history of psychiatric illness. The patient is a retired teacher who is widowed and has lived independently for several years. During the last few months, she has stopped going to church and visiting friends. The patient's symptoms include irritability, anhedonia, fatigue, a 4.5-kg (10-lb) weight loss over a period of 3 months, and difficulty sleeping. She feels like a burden to her family. How should she be treated? Copyright © 2014 Massachusetts Medical Society.
Azhar S.,Geriatric Research
Future Cardiology | Year: 2010
Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARα/β and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPAR (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones. © 2010 Future Medicine Ltd.
Atri A.,Geriatric Research
The American journal of managed care | Year: 2011
Alzheimer's dementia represents organ failure of the brain. It denotes a clinical milestone that is the result of a pathological process, Alzheimer's disease (AD), which over 1 or more decades has wrought insidious destruction, and finally overwhelmed the brain's capacities to compensate. It is incurable, progressive, and follows an individual pace and course. AD is particularly demanding and devastating to family and caregivers, and patients, all of whom suffer psychologically and emotionally. The cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine and the N-methyl- D-aspartate receptor antagonist memantine are approved by the US Food and Drug Administration for AD; they are often used in combination once the disease reaches moderate stages. The relatively good safety profile of these medications, along with their efficacy in alleviating symptoms, is supported by several level-I evidence-grade, short-term, randomized, placebo-controlled trials (RCTs). However, these studies are of limited value in assessing the real-world clinical and economic impact of AD therapies. Long-term, observational studies can provide complementary information to results from short-term clinical trials and more accurately assess practical long-term benefits, risks, costs, and effects on clinically meaningful end points. There is now accumulating and convergent evidence from short- and long-term RCTs, longer-term open-label extensions of RCTs, and long-term observational studies that ChEIs and memantine reduce decline in cognition and daily function, and delay nursing home placement. Optimal care in AD is multifactorial; it includes early diagnosis and multidisciplinary care with educational and nonpharmacological interventions, while ensuring safety, treating comorbidities, caring for caregivers, and appropriate initiation and maintenance of combination therapy.
Morley J.E.,Saint Louis University |
Morley J.E.,Geriatric Research
Family Practice | Year: 2012
Undernutrition in older persons usually presents as weight loss and is predominantly due to protein energy wasting. The presentation of undernutrition is often subtle in older persons and there is a need to utilize screening tools and increasing physician awareness. There are multiple treatable causes of undernutrition in older persons. The major causes are anorexia, cachexia, sarcopenia, dehydration, malabsorption and hypermetabolism. This article also provides an overview of the use of nutritional supplements and an approach to managing protein energy wasting. © The Author 2012. Published by Oxford University Press. All rights reserved.
Tennen R.I.,Stanford University |
Chua K.F.,Stanford University |
Chua K.F.,Geriatric Research
Trends in Biochemical Sciences | Year: 2011
Saccharomyces cerevisiae Sir2 is an NAD+-dependent histone deacetylase that links chromatin silencing to genomic stability, cellular metabolism and lifespan regulation. In mice, deficiency for the Sir2 family member SIRT6 leads to genomic instability, metabolic defects and degenerative pathologies associated with aging. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear. However, new mechanistic insights have come from the discovery that SIRT6 is a highly substrate-specific histone deacetylase that promotes proper chromatin function in several physiologic contexts, including telomere and genome stabilization, gene expression and DNA repair. By maintaining both the integrity and the expression of the mammalian genome, SIRT6 thus serves several roles that parallel Sir2 function. In this article, we review recent advances in understanding the mechanisms of SIRT6 action and their implications for human biology and disease. © 2010.