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ISSN 2152-5250
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2015 impact factor: 3.697
5 year impact factor: 3.602
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Stop Aging Disease! ICAD 2014
Stambler Ilia
Aging and Disease    2015, 6 (2): 76-94.   DOI: 10.14336/AD.2015.0115
Abstract   HTML   PDF (653KB)

On November 1–2, 2014, there took place in Beijing, China, the first International Conference on Aging and Disease (ICAD 2014) of the International Society on Aging and Disease (ISOAD). The conference participants presented a wide and exciting front of work dedicated to amelioration of aging-related conditions, ranging from regenerative medicine through developing geroprotective substances, elucidating a wide range of mechanisms of aging and aging-related diseases, from energy metabolism through genetics and immunomodulation to systems biology. The conference further emphasized the need to intensify and support research on aging and aging-related diseases to provide solutions for the urgent health challenges of the aging society.

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Dizziness and Imbalance in the Elderly: Age-related Decline in the Vestibular System
Shinichi Iwasaki,Tatsuya Yamasoba
Aging and Disease    2015, 6 (1): 38-47.   DOI: 10.14336/AD.2014.0128
Abstract   HTML   PDF (457KB)

Dizziness and imbalance are amongst the most common complaints in older people, and are a growing public health concern since they put older people at a significantly higher risk of falling. Although the causes of dizziness in older people are multifactorial, peripheral vestibular dysfunction is one of the most frequent causes. Benign paroxysmal positional vertigo is the most frequent form of vestibular dysfunction in the elderly, followed by Meniere’s disease. Every factor associated with the maintenance of postural stability deteriorates during aging. Age-related deterioration of peripheral vestibular function has been demonstrated through quantitative measurements of the vestibulo-ocular reflex with rotational testing and of the vestibulo-collic reflex with testing of vestibular evoked myogenic potentials. Age-related decline of vestibular function has been shown to correlate with the age-related decrease in the number of vestibular hair cells and neurons. The mechanism of age-related cellular loss in the vestibular endorgan is unclear, but it is thought that genetic predisposition and cumulative effect of oxidative stress may both play an important role. Since the causes of dizziness in older people are multi-factorial, management of this disease should be customized according to the etiologies of each individual. Vestibular rehabilitation is found to be effective in treating both unilateral and bilateral vestibular dysfunction. Various prosthetic devices have also been developed to improve postural balance in older people. Although there have been no medical treatments improving age-related vestibular dysfunction, new medical treatments such as mitochondrial antioxidants or caloric restriction, which have been effective in preventing age-related hearing loss, should be ienvestigated in the future.

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Raised Serum Proinflammatory Cytokines in Alzheimer’s Disease with Depression
Vineet Kumar Khemka,Anirban Ganguly,Debajit Bagchi,Arindam Ghosh,Aritri Bir,Atanu Biswas,Sita Chattopadhyay,Sasanka Chakrabarti
Aging and Disease    2014, 5 (3): 170-176.   DOI: 10.14336/AD.2014.0500170
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The purpose of the present study was to identify the changes in the levels of proinflammatory cytokines like IL-1β, IL-6 and TNF-α in peripheral circulation in Alzheimer’s disease (AD) subjects and to correlate these with associated depression and cognitive deficit. Fifty five AD subjects and thirty seven age and sex matched controls were included in the study. The AD patients were grouped as AD with depression (n= 31) and AD without depression (n= 24). The serum levels of IL-1β, IL-6 and TNF-α were determined by immunoassay by commercially available kits. The serum levels of IL-6 and TNF-α were elevated in AD patients with depression compared to control (p<0.001) or AD without depression (p<0.001). The serum level of IL-1β was higher in AD patients with or without depression as compared to controls. Furthermore, a strong inverse correlation was observed between the MMSE scores and serum levels of IL-6 or TNF-α in AD subjects with depression. The study highlights the important role of peripheral IL-6 and TNF-α in AD associated depression and cognitive deficits.

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Poor Aerobic Fitness May Contribute to Cognitive Decline in HIV-infected Older Adults
Mark Mapstone, Tiffany N. Hilton, Hongmei Yang, Joseph J. Guido, Amneris E. Luque, William J. Hall, Stephen Dewhurst, Krupa Shah
Aging and Disease    2013, 4 (6): 311-319.   DOI: 10.14336/AD.2013.0400311
Abstract   HTML   PDF (738KB)

The HIV-infected older adult (HOA) community is particularly vulnerable to cognitive impairment. Previous studies in the general older adult population have reported that lower scores on tests of cognitive function often correlate negatively with aerobic fitness [5–7]. HIV-infected individuals have significantly reduced aerobic fitness and physical function compared to HIV-uninfected individuals. Determining important correlates of cognitive ability may be beneficial in not only detecting precursors to future cognitive impairments, but also target areas for interventions. The purpose of this study was to investigate the relationship between cognitive ability and aerobic fitness in HIV-infected older adults. We conducted a cross-sectional study of HOA on antiretroviral therapy (ART) >50 years of age. Domain specific cognitive function was assessed by means of a neuropsychological battery. Aerobic fitness (VO2peak) was assessed using a graded, progressive treadmill test. Thirty-seven HOA on ART (mean±SD: age 59±6 years, BMI 28±5, CD4 663±337 cells/ml, duration since HIV diagnosis 17±7 years; 81% males) completed the cognitive tests. Several domains of cognition were significantly associated with VO2peak by Spearman correlation analysis (p<0.05). By step-wise adjusted regression VO2peak was most frequently and significantly related to many cognitive domains such as verbal and visual memory, visual perception, and language (p<0.05). We found that participants with higher Vo2peak were less likely to have more severe forms of HIV-associated neurocognitive disorders (HAND) such as mild neurocognitive disorder (OR=0.65; p=0.01) and HIV-associated dementia (OR=0.64; p=0.0006). In HOA and in conclusion, aerobic fitness is related to cognitive performance on various tasks. The likelihood of cognitive impairment increased with lower fitness levels. Therefore, increased fitness may serve an important factor in maintenance of cognition and neural integrity for aging HIV-infected individuals. Future prospective and large scale studies are needed to evaluate the effect of fitness and vascular stiffness and function on cognition and brain structure among HOA.

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Mechanisms of Muscle Denervation in Aging: Insights from a Mouse Model of Amyotrophic Lateral Sclerosis
Kevin H.J. Park
Aging and Disease    2015, 6 (5): 380-389.   DOI: 10.14336/AD.2015.0506
Abstract   HTML   PDF (609KB)

Muscle denervation at the neuromuscular junction (NMJ) is thought to be a contributing factor in age-related muscle weakness. Therefore, understanding the mechanisms that modulate NMJ innervation is a key to developing therapies to combat age-related muscle weakness affecting the elderly. Two mouse models, one lacking the Cu/Zn superoxide dismutase (SOD1) gene and another harboring the transgenic mutant human SOD1 gene, display progressive changes at the NMJ, including muscle endplate fragmentation, nerve terminal sprouting, and denervation. These changes at the NMJ share many of the common features observed in the NMJs of aged mice. In this review, research findings demonstrating the effects of PGC-1α, IGF-1, GDNF, MyoD, myogenin, and miR-206 on NMJ innervation patterns in the G93A SOD1 mice will be highlighted in the context of age-related muscle denervation.

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Aging is Associated with Impaired Renal Function, INF-gamma Induced Inflammation and with Alterations in Iron Regulatory Proteins Gene Expression
Costa Elísio,Fernandes João,Ribeiro Sandra,Sereno José,Garrido Patrícia,Rocha-Pereira Petronila,Coimbra Susana,Catarino Cristina,Belo Luís,Bronze-da-Rocha Elsa,Vala Helena,Alves Rui,Reis Flávio,Santos-Silva Alice
Aging and Disease    2014, 5 (6): 356-365.   DOI: 10.14366/AD.2014.0500356
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Our aim was to contribute to a better understanding of the pathophysiology of anemia in elderly, by studying how aging affects renal function, iron metabolism, erythropoiesis and the inflammatory response, using an experimental animal model. The study was performed in male Wistar, a group of young rats with 2 months age and an old one with 18 months age. Old rats presented a significant higher urea, creatinine, interferon (INF)-gamma, ferritin and soluble transferrin receptor serum levels, as well as increased counts of reticulocytes and RDW. In addition, these rats showed significant lower erythropoietin (EPO) and iron serum levels. Concerning gene expression of iron regulatory proteins, old rats presented significantly higher mRNA levels of hepcidin (Hamp), transferrin (TF), transferrin receptor 2 (TfR2) and hemojuvelin (HJV); divalent metal transporter 1 (DMT1) mRNA levels were significantly higher in duodenal tissue; EPO gene expression was significantly higher in liver and lower in kidney, and the expression of the EPOR was significantly higher in both liver and kidney. Our results showed that aging is associated with impaired renal function, which could be in turn related with the inflammatory process and with a decline in EPO renal production. Moreover, we also propose that aging may be associated with INF-gamma-induced inflammation and with alterations upon iron regulatory proteins gene expression.

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SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?
Juliana B. Hoppe,Christianne G. Salbego,Helena Cimarosti
Aging and Disease    2015, 6 (5): 322-330.   DOI: 10.14336/AD.2014.1205
Abstract   HTML   PDF (711KB)

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized in the brain by the formation of amyloid-beta (Aβ)-containing plaques and neurofibrillary tangles containing the microtubule-associated protein tau. Neuroin?ammation is another feature of AD and astrocytes are receiving increasing attention as key contributors. Although some progress has been made, the molecular mechanisms underlying the pathophysiology of AD remain unclear. Interestingly, some of the main proteins involved in AD, including amyloid precursor protein (APP) and tau, have recently been shown to be SUMOylated. The post-translational modification by SUMO (small ubiquitin-like modifier) has been shown to regulate APP and tau and may modulate other proteins implicated in AD. Here we present an overview of recent studies suggesting that protein SUMOylation might be involved in the underlying pathogenic mechanisms of AD and discuss how this could be exploited for therapeutic intervention.

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Potential Therapeutical Contributions of the Endocannabinoid System towards Aging and Alzheimer’s Disease
Amandine E. Bonnet,Yannick Marchalant
Aging and Disease    2015, 6 (5): 400-405.   DOI: 10.14336/AD.2015.0617
Abstract   HTML   PDF (636KB)

Aging can lead to decline in cognition, notably due to neurodegenerative processes overwhelming the brain over time. As people live longer, numerous concerns are rightfully raised toward long-term slowly incapacitating diseases with no cure, such as Alzheimer’s disease. Since the early 2000’s, the role of neuroinflammation has been scrutinized for its potential role in the development of diverse neurodegenerative diseases notably because of its slow onset and chronic nature in aging. Despite the lack of success yet, treatment of chronic neuroinflammation could help alleviate process implicated in neurodegenerative disease. A growing number of studies including our own have aimed at the endocannabinoid system and unfolded unique effects of this system on neuroinflammation, neurogenesis and hallmarks of Alzheimer’s disease and made it a reasonable target in the context of normal and pathological brain aging.

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Dopamine Receptors and Neurodegeneration
Claudia Rangel-Barajas,Israel Coronel,Benjamín Florán
Aging and Disease    2015, 6 (5): 349-368.   DOI: 10.14336/AD.2015.0330
Abstract   HTML   PDF (1415KB)

Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson’s disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases.

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Relationship between CYP17A1 Genetic Polymorphism and Essential Hypertension in a Chinese Population
Chuan-Fang Dai, Xiang Xie, Yi-Tong Ma, Yi-Ning Yang, Xiao-Mei Li, Zhen-Yan Fu, Fen Liu, Bang-Dang Chen, Min-Tao Gai
Aging and Disease    2015, 6 (6): 486-498.   DOI: 10.14336/AD.2015.0505
Abstract   HTML   PDF (1188KB)

The relationship between CYP17A1 genetic polymorphisms and essential hypertension (EH) remains unclear. The aim of this study was to investigate the association of CYP17A1 genetic polymorphisms with EH in Han and Uighur populations in China. A Han population including 558 people (270 EH patients and 288 controls) and a Uighur population including 473 people (181 EH patients and 292 controls) were selected. Five single-nucleotide polymorphisms (SNPs) (rs4919686, rs1004467, rs4919687, rs10786712, and rs2486758) were genotyped using real-time PCR (TaqMan). In the Uighur population, for the total and the men, rs4919686, rs4919687 and rs10786712 were found to be associated with EH (rs4919686: P≤0.02, rs4919687: P≤0.002, rs10786712: P≤0.004, respectively). The difference remained statistically significant after the multivariate adjustment (all P<0.05). The overall distributions of the haplotypes established by SNP1-SNP3, SNP1-SNP4, SNP1-SNP3-SNP5 and SNP1-SNP4-SNP5 were significantly different between the EH patients and the control subjects (for the total: P=0.013, P=0.008, P=0.032, P=0.010, for men: P<0.001, P=0.001, P=0.010, P=0.00). In the Han population, for men, rs2486758 was found to be associated with EH in a recessive model (P=0.007); the significant difference was not retained after the adjustment for the covariates (date not shown). The A allele of rs4919686 could be a susceptible genetic marker, and the T allele of rs10786712 could be a protective genetic marker of EH. The AC genotype of rs4919686, the AG genotype of rs4919687 and the TT genotype of rs10786712 could be protective genetic markers of EH.

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Oxidation of K+ Channels in Aging and Neurodegeneration
Federico Sesti
Aging and Disease    2016, 7 (2): 130-135.   DOI: 10.14336/AD.2015.0901
Abstract   HTML   PDF (582KB)

Reversible regulation of proteins by reactive oxygen species (ROS) is an important mechanism of neuronal plasticity. In particular, ROS have been shown to act as modulatory molecules of ion channels—which are key to neuronal excitability—in several physiological processes. However ROS are also fundamental contributors to aging vulnerability. When the level of excess ROS increases in the cell during aging, DNA is damaged, proteins are oxidized, lipids are degraded and more ROS are produced, all culminating in significant cell injury. From this arose the idea that oxidation of ion channels by ROS is one of the culprits for neuronal aging. Aging-dependent oxidative modification of voltage-gated potassium (K+) channels was initially demonstrated in the nematode Caenorhabditis elegans and more recently in the mammalian brain. Specifically, oxidation of the delayed rectifier KCNB1 (Kv2.1) and of Ca2+- and voltage sensitive K+ channels have been established suggesting that their redox sensitivity contributes to altered excitability, progression of healthy aging and of neurodegenerative disease. Here I discuss the implications that oxidation of K+ channels by ROS may have for normal aging, as well as for neurodegenerative disease.

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Possible Benefit of Dietary Carnosine towards Depressive Disorders
Alan R. Hipkiss*
Aging and Disease    2015, 6 (5): 300-303.   DOI: 10.14336/AD.2014.1211
Abstract   HTML   PDF (489KB)

Many stress-related and depressive disorders have been shown to be associated with one or more of the following; shortened telomeres, raised cortisol levels and increased susceptibility to age-related dysfunction. It is suggested here that insufficient availability of the neurological peptide, carnosine, may provide a biochemical link between stress- and depression-associated phenomena: there is evidence that carnosine can enhance cortisol metabolism, suppress telomere shortening and exert anti-aging activity in model systems. Dietary supplementation with carnosine has been shown to suppress stress in animals, and improve behaviour, cognition and well-being in human subjects. It is therefore proposed that the therapeutic potential of carnosine dietary supplementation towards stress-related and depressive disorders should be examined.

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Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity
Xiaoting Luo,Jinzi Wu,Siqun Jing,Liang-Jun Yan
Aging and Disease    2016, 7 (1): 90-110.   DOI: 10.14336/AD.2015.0702
Abstract   HTML   PDF (1213KB)

Diabetes and its complications are caused by chronic glucotoxicity driven by persistent hyperglycemia. In this article, we review the mechanisms of diabetic glucotoxicity by focusing mainly on hyperglycemic stress and carbon stress. Mechanisms of hyperglycemic stress include reductive stress or pseudohypoxic stress caused by redox imbalance between NADH and NAD+ driven by activation of both the polyol pathway and poly ADP ribose polymerase; the hexosamine pathway; the advanced glycation end products pathway; the protein kinase C activation pathway; and the enediol formation pathway. Mechanisms of carbon stress include excess production of acetyl-CoA that can over-acetylate a proteome and excess production of fumarate that can over-succinate a proteome; both of which can increase glucotoxicity in diabetes. For hyperglycemia stress, we also discuss the possible role of mitochondrial complex I in diabetes as this complex, in charge of NAD+ regeneration, can make more reactive oxygen species (ROS) in the presence of excess NADH. For carbon stress, we also discuss the role of sirtuins in diabetes as they are deacetylases that can reverse protein acetylation thereby attenuating diabetic glucotoxicity and improving glucose metabolism. It is our belief that targeting some of the stress pathways discussed in this article may provide new therapeutic strategies for treatment of diabetes and its complications.

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Association between Apolipoprotein C-III Gene Polymorphisms and Coronary Heart Disease: A Meta-analysis
Jing-Zhan Zhang,Xiang Xie,Yi-Tong Ma,Ying-Ying Zheng,Yi-Ning Yang,Xiao-Mei Li,Zhen-Yan Fu,Chuan-Fang Dai,Ming-Ming Zhang,Guo-Ting Yin,Fen Liu,Bang-Dang Chen,Min-Tao Gai
Aging and Disease    2016, 7 (1): 36-44.   DOI: 10.14336/AD.2015.0709
Abstract   HTML   PDF (503KB)

Polymorphisms in the apolipoprotein C-III (APOC3) gene have been reported to be associated with coronary heart disease (CHD), but the data so far have been conflicting. To derive a more precise estimation of these associations, we performed a meta-analysis to investigate the three main polymorphisms (SstI, T-455C, C-482T) of APOC3 in all published studies. Databases including PubMed, Web of Science, Wanfang, SinoMed and CNKI were systematically searched. The association was assessed using odds ratios (ORs) with 95% confidence intervals (CIs). The statistical analysis was performed using Review Manager 5.3.3 and Stata 12.0. A total of 31 studies have been identified. The pooled odds ratio (OR) for the association between the APOC3 gene polymorphisms and CHD and its corresponding 95% confidence interval (95% CI) were evaluated by random or fixed effect models. A statistical association between APOC3 SstI polymorphism and CHD susceptibility was observed under an allelic contrast model (P= 0.003, OR = 1.14, 95% CI = 1.05-1.24), dominant genetic model (P= 0.01, OR = 1.14, 95% CI = 1.03-1.26), and recessive genetic model (P= 0.02, OR = 1.35, 95% CI = 1.06-1.71), respectively. A significant association between the APOC3 T-455C polymorphism and CHD was also detected under an allelic contrast (P < 0.0001, OR = 1.19, 95% CI = 1.10-1.29), dominant genetic model (P= 0.0003, OR = 1.24, 95% CI = 1.11-1.39) and recessive genetic model (P= 0.04, OR = 1.30, 95% CI = 1.01-1.67). No significant association between the APOC3 C-482T polymorphism and CHD was found under an allelic model (P= 0.94, OR = 1.00, 95% CI = 0.93-1.08), dominant genetic model (P= 0.20, OR = 1.07, 95% CI = 0.97-1.18) or recessive genetic model (P= 0.13, OR = 0.90, 95% CI = 0.79-1.03). This meta-analysis revealed that the APOC3 SstI and T-455C polymorphisms significantly increase CHD susceptibility. No significant association was observed between the APOC3 C-482T polymorphism and CHD susceptibility.

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Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment
Sasanka Chakrabarti,Vineet Kumar Khemka,Anindita Banerjee,Gargi Chatterjee,Anirban Ganguly,Atanu Biswas
Aging and Disease    2015, 6 (4): 282-299.   DOI: 10.14336/AD.2014.002
Abstract   HTML   PDF (1071KB)

Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.

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Carnosine and Related Peptides: Therapeutic Potential in Age-Related Disorders
Jos, H. Cararo, Emilio L. Streck, Patricia F. Schuck, Gustavo da C. Ferreira
Aging and Disease    2015, 6 (5): 369-379.   DOI: 10.14336/AD.2015.0616
Abstract   HTML   PDF (879KB)

Imidazole dipeptides (ID), such as carnosine (β-alanyl-L-histidine), are compounds widely distributed in excitable tissues of vertebrates. ID are also endowed of several biochemical properties in biological tissues, including antioxidant, bivalent metal ion chelating, proton buffering, and carbonyl scavenger activities. Furthermore, remarkable biological effects have been assigned to such compounds in age-related human disorders and in patients whose activity of serum carnosinase is deficient or undetectable. Nevertheless, the precise biological role of ID is still to be unraveled. In the present review we shall discuss some evidences from clinical and basic studies for the utilization of ID as a drug therapy for age-related human disorders.

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Limb Ischemic Perconditioning Attenuates Blood-Brain Barrier Disruption by Inhibiting Activity of MMP-9 and Occludin Degradation after Focal Cerebral Ischemia
Changhong Ren,Ning Li,Brian Wang,Yong Yang,Jinhuan Gao,Sijie Li,Yuchuan Ding,Kunlin Jin,Xunming Ji
Aging and Disease    2015, 6 (6): 406-417.   DOI: 10.14336/AD.2015.0812
Abstract   HTML   PDF (1434KB)

Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke.

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Hip Fractures in a Geriatric Population - Rehabilitation Based on Patients Needs
Natasa Radosavljevic,Dejan Nikolic,Milica Lazovic,Aleksandar Jeremic
Aging and Disease    2014, 5 (3): 177-182.   DOI: 10.14336/AD.2014.0500177
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With an increased life expectancy in humans and thus an increase in the number of the elderly population, the frequency of hip fractures will rise as well. Aside from a higher incidence, hip fractures in a geriatric population is a significant problem due to the possible onset of severe and in some cases dramatic complications and consequences. The primary purpose of treatment and rehabilitation in the elderly after a hip fracture is to improve an individual’s quality of life. It is important to underline that principles and methods of functional restoration after hip fracture should consider careful planning of a rehabilitation program individually for every patient and its implementation with respect to decisions made by the rehabilitation team.

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Strength and Endurance Training Prescription in Healthy and Frail Elderly
Eduardo Lusa Cadore,Ronei Silveira Pinto,Martim Bottaro,Mikel Izquierdo
Aging and Disease    2014, 5 (3): 183-195.   DOI: 10.14336/AD.2014.0500183
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Aging is associated with declines in the neuromuscular and cardiovascular systems, resulting in an impaired capacity to perform daily activities. Frailty is an age-associated biological syndrome characterized by decreases in the biological functional reserve and resistance to stressors due to changes in several physiological systems, which puts older individuals at special risk of disability. To counteract the neuromuscular and cardiovascular declines associated with aging, as well as to prevent and treat the frailty syndrome, the strength and endurance training seems to be an effective strategy to improve muscle hypertrophy, strength and power output, as well as endurance performance. The first purpose of this review was discuss the neuromuscular adaptations to strength training, as well as the cardiovascular adaptations to endurance training in healthy and frail elderly subjects. In addition, the second purpose of this study was investigate the concurrent training adaptations in the elderly. Based on the results found, the combination of strength and endurance training (i.e., concurrent training) performed at moderate volume and moderate to high intensity in elderly populations is the most effective way to improve both neuromuscular and cardiorespiratory functions. Moreover, exercise interventions that include muscle power training should be prescribed to frail elderly in order to improve the overall physical status of this population and prevent disability.

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Aging Is Not a Disease: Implications for Intervention
Suresh I. S. Rattan
Aging and Disease    2014, 5 (3): 196-202.   DOI: 10.14336/AD.2014.0500196
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Aging of biological systems occurs in spite of numerous complex pathways of maintenance, repair and defense. There are no gerontogenes which have the specific evolutionary function to cause aging. Although aging is the common cause of all age-related diseases, aging in itself cannot be considered a disease. This understanding of aging as a process should transform our approach towards interventions from developing illusory anti-aging treatments to developing realistic and practical methods for maintaining health throughout the lifespan. The concept of homeodynamic space can be a useful one in order to identify a set of measurable, evidence-based and demonstratable parameters of health, robustness and resilience. Age-induced health problems, for which there are no other clear-cut causative agents, may be better tackled by focusing on health mechanisms and their maintenance, rather than only disease management and treatment. Continuing the disease-oriented research and treatment approaches, as opposed to health-oriented and preventive strategies, are economically, socially and psychologically unsustainable.

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Link between PI3K/AKT/PTEN Pathway and NOX Proteinin Diseases
Atsuko Nakanishi,Yoko Wada,Yasuko Kitagishi,Satoru Matsuda
Aging and Disease    2014, 5 (3): 203-211.   DOI: 10.14336/AD.2014.0500203
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Accumulating evidence has revealed that thePI3K/AKT/PTENpathway acts as a pivotal determinant of cell fate regarding senescence and apoptosis, which is mediated by intracellular reactive oxygen species (ROS) generation. NADPH oxidase (NOX) family of enzymes generates the ROS. The regulation of NOX enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. Cells are continuously exposed to the ROS, which represent mutagens and are thought to be a major contributor to several diseases including cancer and aging process. Therefore, cellular ROS sensing and metabolism are firmly regulated by a variety of proteins involved in the redox mechanism. In this review, the roles of oxidative stress in PI3K/AKT/PTEN signaling are summarized with a focus on the links between the pathways and NOX protein in several diseases including cancer and aging.

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The Neuroprotective Properties of the Amyloid Precursor Protein Following Traumatic Brain Injury
Stephanie Plummer,Corinna Van den Heuvel,Emma Thornton,Frances Corrigan,Roberto Cappai
Aging and Disease    2016, 7 (2): 163-179.   DOI: 10.14336/AD.2015.0907
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Despite the significant health and economic burden that traumatic brain injury (TBI) places on society, the development of successful therapeutic agents have to date not translated into efficacious therapies in human clinical trials. Injury to the brain is ongoing after TBI, through a complex cascade of primary and secondary injury events, providing a valuable window of opportunity to help limit and prevent some of the severe consequences with a timely treatment. Of note, it has been suggested that novel treatments for TBI should be multifactorial in nature, mimicking the body’s own endogenous repair response. Whilst research has historically focused on the role of the amyloid precursor protein (APP) in the pathogenesis of Alzheimer’s disease, recent advances in trauma research have demonstrated that APP offers considerable neuroprotective properties following TBI, suggesting that APP is an ideal therapeutic candidate. Its acute upregulation following TBI has been shown to serve a beneficial role following trauma and has lead to significant advances in understanding the neuroprotective and neurotrophic functions of APP and its metabolites. Research has focused predominantly on the APP derivative sAPPα, which has consistently demonstrated neuroprotective and neurotrophic functions both in vitro and in vivo following various traumatic insults. Its neuroprotective activity has been narrowed down to a 15 amino acid sequence, and this region is linked to both heparan binding and growth-factor-like properties. It has been proposed that APP binds to heparan sulfate proteoglycans to exert its neuroprotective action. APP presents us with a novel therapeutic compound that could overcome many of the challenges that have stalled development of efficacious TBI treatments previously.

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Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity
Heng Hu,Danielle N. Doll,Jiahong Sun,Sara E. Lewis,Jeffrey H. Wimsatt,Matthew J. Kessler,James W. Simpkins,Xuefang Ren
Aging and Disease    2016, 7 (1): 14-27.   DOI: 10.14336/AD.2015.0906
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Stroke is the second leading cause of death worldwide. The prognostic influence of body temperature on acute stroke in patients has been recently reported; however, hypothermia has confounded experimental results in animal stroke models. This work aimed to investigate how body temperature could prognose stroke severity as well as reveal a possible mitochondrial mechanism in the association of body temperature and stroke severity. Lipopolysaccharide (LPS) compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells (CVECs) and worsens murine experimental stroke. In this study, we report that LPS (0.1 mg/kg) exacerbates stroke infarction and neurological deficits, in the mean time LPS causes temporary hypothermia in the hyperacute stage during 6 hours post-stroke. Lower body temperature is associated with worse infarction and higher neurological deficit score in the LPS-stroke study. However, warming of the LPS-stroke mice compromises animal survival. Furthermore, a high dose of LPS (2 mg/kg) worsens neurological deficits, but causes persistent severe hypothermia that conceals the LPS exacerbation of stroke infarction. Mitochondrial respiratory chain complex I inhibitor, rotenone, replicates the data profile of the LPS-stroke study. Moreover, we have confirmed that rotenone compromises mitochondrial oxidative phosphorylation in CVECs. Lastly, the pooled data analyses of a large sample size (n=353) demonstrate that stroke mice have lower body temperature compared to sham mice within 6 hours post-surgery; the body temperature is significantly correlated with stroke outcomes; linear regression shows that lower body temperature is significantly associated with higher neurological scores and larger infarct volume. We conclude that post-stroke body temperature predicts stroke severity and mitochondrial impairment in CVECs plays a pivotal role in this hypothermic response. These novel findings suggest that body temperature is prognostic for stroke severity in experimental stroke animal models and may have translational significance for clinical stroke patients - targeting endothelial mitochondria may be a clinically useful approach for stroke therapy.

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Reduced Apoptosis by Ethanol and Its Association with PKC-δ and Akt Signaling in Ischemic Stroke
Hafeez Adam,Elmadhoun Omar,Peng Changya,Y. Ding Jamie,Geng Xiaokun,Guthikonda Murali,Ding Yuchuan
Aging and Disease    2014, 5 (6): 366-372.   DOI: 10.14336/AD.2014.0500366
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Along with thrombolytic therapy, which has a number of limitations, stroke outcome may be improved with neuroprotective therapies that disrupt ischemic cell death. Recent research has shown a neuroprotective role of ethanol administration during ischemic stroke, such as its ability to reduce infarct volume and neurologic deficit. In order to investigate this further, we assessed the hypothesis that ethanol’s neuroprotective effect is through reduction of apoptosis and the modulation of the important apoptotic PKC-δ and Akt signaling pathway. Ethanol (1.5 g/kg) was given by intraperitoneal injections to 54 Sprague-Dawley rats after 2 hours of middle cerebral artery (MCA) occlusion, followed by 3 or 24 hours of reperfusion. We measured apoptotic cell death, PKC-δ, and Akt mRNA and protein expressions in each of ischemic groups with or without ethanol treatment using ELISA, real-time PCR and Western blot analysis. Our results showed that cell death was significantly increased in rats following 2 hour MCA occlusion and 24 hour reperfusion. Subsequently, cell death was significantly reduced by an administration of ethanol. We further found that ethanol administration, prior to either 3 or 24 hours of reperfusion, significantly decreased the expression of PKC-δ while simultaneously increasing the expression Akt at both mRNA and protein levels at the two points. In conclusion, our study suggests that ethanol administration following ischemic stroke modulates the gene and protein profile in such a way that it increased expression of anti-apoptotic Akt and decreased the pro-apoptotic PKC-δ. This ultimately results in a decrease in neuronal apoptosis, thus conferring neuroprotection.

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Use of Anthropometry for the Prediction of Regional Body Tissue Distribution in Adults: Benefits and Limitations in Clinical Practice
Scafoglieri Aldo,Pieter Clarys Jan,Cattrysse Erik,Bautmans Ivan
Aging and Disease    2014, 5 (6): 374-393.   DOI: 10.14366/AD.2014.05003743
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Regional body composition changes with aging. Some of the changes in composition are considered major risk factors for developing obesity related chronic diseases which in turn may lead to increased mortality in adults. The role of anthropometry is well recognized in the screening, diagnosis and follow-up of adults for risk classification, regardless of age. Regional body composition is influenced by a number of intrinsic and extrinsic factors. Therapeutic measures recommended to lower cardiovascular disease risk include lifestyle changes. The aim of this review is to systematically summarize studies that assessed the relationships between anthropometry and regional body composition. The potential benefits and limitations of anthropometry for use in clinical practice are presented and suggestions for future research given.

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Age-dependent Muscle Adaptation after Chronic Stretch-shortening Contractions in Rats
Erik P. Rader,Kayla N. Layner,Alyssa M. Triscuit,Robert D. Chetlin,James Ensey,Brent A. Baker
Aging and Disease    2016, 7 (1): 1-13.   DOI: 10.14336/AD.2015.0920
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Age-related differences in contraction-induced adaptation have been well characterized especially for young and old rodent models but much less so at intermediate ages. Therefore, additional research is warranted to determine to what extent alterations in adaptation are due to maturation versus aging per se. The purpose of our study was to evaluate muscles of Fisher 344XBrown Norway rats of various ages following one month of exposure to stretch-shortening contractions (SSCs). With exposure, muscles mass increased by ~10% for 27 and 30 month old rats vs. ~20% for 3 and 6 month old rats (P < 0.05). For 3 month old rats, maximum isometric force and dynamic peak force increased by 22 ± 8% and 27 ± 10%, respectively (P < 0.05). For 6 month old rats, these forces were unaltered by exposure and positive work capacity diminished by 27 ± 2% (P = 0.006). By 30 months of age, age-related deficits in maximum isometric force, peak force, negative work, and positive work were apparent and SSC exposure was ineffective at counteracting such deficits. Recovery from fatigue was also tested and exposure-induced improvements in fatigue recovery were indicated for 6 month old rats and to a lesser extent for 3 month old rats whereas no such effect was observed for older rats. Alterations in fatigue recovery were accompanied by evidence of substantial type IIb to IIx fiber type shifting. These results highlight the exceptional adaptive capacity for strength at a young age, the inclination for adaptation in fatigue recovery at early adulthood, and diminished adaptation for muscle performance in general beginning at late adulthood. Such findings motivate careful investigation to determine appropriate SSC exposures at all stages of life.

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Aortic Complex Plaque Predicts the Risk of Cryptogenic Ischemic Cerebrovascular Disease Recurrence
Jing Dong,Xin Ma,Jingyuan Qie,Xunming Ji
Aging and Disease    2016, 7 (2): 114-120.   DOI: 10.14336/AD.2015.0923
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To evaluate the correlations between aortic complex plaque (ACP) and the recurrence of cryptogenic ischemic cerebrovascular disease (CICVD), and to investigate the clinical significance of ACP in CICVD. Methods CICVD patients (aged 17 to 84 years) admitted into the Department of Neurology, Xuanwu Hospital, from July 2011 to December 2013, were consecutively recruited, and divided into ACP and non-ACP groups according to head and neck computerized tomographic (CT) angiography. Recurrences of cerebral ischemic events (CIEs) were compared between these groups after follow-up. Results A total of 117 patients were enrolled (ACP group: 69, non-ACP group: 48) and followed up for a mean of 9.86 months (range: 3-33). The average age of the ACP group was 62.88 years, with 59.4% older than 60 years; the average age of the non-ACP group was 50.29 years, with 37.5% older than 60 years. At the 6-month follow-up, the recurrence rate of CIEs in the ACP group was significantly higher than that of the non-ACP group (17.0% [7/47] and 0% [0/36], respectively; χ2 = 4.283, P = 0.046). The cumulative recurrence risk for CIEs of the ACP group was significantly higher than for the non-ACP group (P = 0.004). Multivariate Cox survival analysis showed that ACP presence was an independent risk factor for CIE recurrence for CICVD patients (relative risk [RR] = 7.803, 95% confidence interval [CI], 1.827~33.319, P = 0.006). Conclusions ACP increased the recurrence risk of CIE in CICVD, and elderly CICVD patients should receive greater attention regarding the significance of ACP in recurrent CICVD.

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Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases
Salminen Antero,Kaarniranta Kai,Kauppinen Anu
Aging and Disease    2016, 7 (2): 180-200.   DOI: 10.14336/AD.2015.0929
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Hypoxia is an environmental stress at high altitude and underground conditions but it is also present in many chronic age-related diseases, where blood flow into tissues is impaired. The oxygen-sensing system stimulates gene expression protecting tissues against hypoxic insults. Hypoxia stabilizes the expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls the expression of hundreds of survival genes related to e.g. enhanced energy metabolism and autophagy. Moreover, many stress-related signaling mechanisms, such as oxidative stress and energy metabolic disturbances, as well as the signaling cascades via ceramide, mTOR, NF-κB, and TGF-β pathways, can also induce the expression of HIF-1α protein to facilitate cell survival in normoxia. Hypoxia is linked to prominent epigenetic changes in chromatin landscape. Screening studies have indicated that the stabilization of HIF-1α increases the expression of distinct histone lysine demethylases (KDM). HIF-1α stimulates the expression of KDM3A, KDM4B, KDM4C, and KDM6B, which enhance gene transcription by demethylating H3K9 and H3K27 sites (repressive epigenetic marks). In addition, HIF-1α induces the expression of KDM2B and KDM5B, which repress transcription by demethylating H3K4me2,3 sites (activating marks). Hypoxia-inducible KDMs support locally the gene transcription induced by HIF-1α, although they can also control genome-wide chromatin landscape, especially KDMs which demethylate H3K9 and H3K27 sites. These epigenetic marks have important role in the control of heterochromatin segments and 3D folding of chromosomes, as well as the genetic loci regulating cell type commitment, proliferation, and cellular senescence, e.g. the INK4 box. A chronic stimulation of HIF-1α can provoke tissue fibrosis and cellular senescence, which both are increasingly present with aging and age-related diseases. We will review the regulation of HIF-1α-dependent induction of KDMs and clarify their role in pathological processes emphasizing that long-term stress-related insults can impair the maintenance of chromatin landscape and provoke cellular senescence and tissue fibrosis associated with aging and age-related diseases.

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Successful Aging among Elders Living in the Mani Continental Region vs. Insular Areas of the Mediterranean: the MEDIS Study
Anargiros Mariolis,Alexandra Foscolou,Stefanos Tyrovolas,Suzanne Piscopo,Giuseppe Valacchi,Nikos Tsakountakis,Akis Zeimbekis,Vassiliki Bountziouka,Efthimios Gotsis,George Metallinos,Dimitra Tyrovola,Josep-Antoni Tur,Antonia-Leda Matalas,Christos Lionis,Evangelos Polychronopoulos,Demosthenes Panagiotakos,for the MEDIS study group
Aging and Disease    2016, 7 (3): 285-294.   DOI: 10.14336/AD.2015.1002
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To evaluate the role of geography i.e., continental vs. insular Mediterranean, on successful aging among older inhabitants. During 2005-2014, 2693 elderly (aged 65 to 100 years) individuals from 21 Mediterranean islands in Greece, Italy and Spain as well as Cyprus, Malta, and the rural region of Mani (southeast continental region of Greece keeping old-time traditions), were voluntarily recruited. Successful aging was evaluated using a validated index composed of 10 health-related socio-lifestyle and clinical characteristics. After accounting for age, sex, body mass index (BMI), physical activity, smoking habits, MedDietScore and access to health care services, the older inhabitants of islands were found to have a higher level of the successful aging index when compared to their counterparts in Mani (Beta=0.174, p<0.001); moreover, islanders exhibited slightly more years of “good” health (68.7 vs 68.4 years for Mani residents (p=0.99)). However, compared to the residents of Mani, islanders had 1.64 times higher odds (95%CI, 1.08-2.48) for having hypertension, 2.4-times higher odds (95%CI, 1.34-4.21) for having diabetes and 1.52 times higher odds (95%CI, 0.97-2.38) for having hypercholesterolemia. Engaging in physical activities and healthy dietary habits were the major determinants of healthy aging, among islanders as compared to their counterparts of continental Mani region. Elder residents of the continental Mani area enjoyed a better health status, whereas elder islanders had a higher level of successful aging; a finding which could be attributed to differences in lifestyle among elders.

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Linear and Curvilinear Trajectories of Cortical Loss with Advancing Age and Disease Duration in Parkinson’s Disease
Daniel O. Claassen,David G. Dobolyi,David A. Isaacs,Olivia C. Roman,Joshua Herb,Scott A. Wylie,Joseph S. Neimat,Manus J. Donahue,Peter Hedera,David H. Zald,Bennett A. Landman,Aaron B. Bowman,Benoit M. Dawant,Swati Rane
Aging and Disease    2016, 7 (3): 220-229.   DOI: 10.14336/AD.2015.1110
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Advancing age and disease duration both contribute to cortical thinning in Parkinson’s disease (PD), but the pathological interactions between them are poorly described. This study aims to distinguish patterns of cortical decline determined by advancing age and disease duration in PD. A convenience cohort of 177 consecutive PD patients, identified at the Vanderbilt University Movement Disorders Clinic as part of a clinical evaluation for Deep Brain Stimulation (age: M= 62.0, SD 9.3), completed a standardized clinical assessment, along with structural brain Magnetic Resonance Imaging scan. Age and gender matched controls (n=53) were obtained from the Alzheimer Disease Neuroimaging Initiative and Progressive Parkinson’s Marker Initiative (age: M= 63.4, SD 12.2). Estimated changes in cortical thickness were modeled with advancing age, disease duration, and their interaction. The best-fitting model, linear or curvilinear (2nd, or 3rd order natural spline), was defined using the minimum Akaike Information Criterion, and illustrated on a 3-dimensional brain. Three curvilinear patterns of cortical thinning were identified: early decline, late decline, and early-stable-late. In contrast to healthy controls, the best-fit model for age related changes in PD is curvilinear (early decline), particularly in frontal and precuneus regions. With advancing disease duration, a curvilinear model depicts accelerating decline in the occipital cortex. A significant interaction between advancing age and disease duration is evident in frontal, motor, and posterior parietal areas. Study results support the hypothesis that advancing age and disease duration differentially affect regional cortical thickness and display regional dependent linear and curvilinear patterns of thinning.

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