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1.  Dysregulated inflammation as a risk factor for pneumonia in the elderly 
Aging and disease  2011;2(6):487-500.
Advances in modern medicine have led to an increase in the median life span and an expansion of the world’s population over the age of 65. With increasing numbers of the population surviving to the extreme of age, those at risk for the development of pneumonia will approach 2 billion by the year 2050. Numerous age-related changes in the lung likely contribute to the enhanced occurrence of pneumonia in the elderly. Inflammation in the elderly has been shown to increase risk prior to infection; age-associated inflammation enhances bacterial ligand expression in the lungs which increases the ability of bacteria to attach and invade host cells. Conversely, the elaboration of the acute inflammatory response during early infection has been found to decrease with age resulting in a delayed immune response and diminished bacterial killing. Finally, the resolution of the inflammatory response during the convalescent stage back to “baseline” is often prolonged in the elderly and associated with negative outcomes, such as adverse cardiac events. The focus of this review will be to discuss our current understanding of the potential mechanisms by which dysregulated inflammation (both prior to and following an infectious insult) enhances susceptibility to and severity of community acquired pneumonia (CAP) in the elderly with an emphasis on pneumococcal pneumonia, the leading cause of CAP.
PMCID: PMC3265328  PMID: 22288022
Aging; Pneumonia; Inflammation; Toll-like Receptors; Statins
2.  Dysregulated Inflammation as a Risk Factor for Pneumonia in the Elderly 
Aging and Disease  2011;2(6):487-500.
Advances in modern medicine have led to an increase in the median life span and an expansion of the world’s population over the age of 65. With increasing numbers of the population surviving to the extreme of age, those at risk for the development of pneumonia will approach 2 billion by the year 2050. Numerous age-related changes in the lung likely contribute to the enhanced occurrence of pneumonia in the elderly. Inflammation in the elderly has been shown to increase risk prior to infection; age-associated inflammation enhances bacterial ligand expression in the lungs which increases the ability of bacteria to attach and invade host cells. Conversely, the elaboration of the acute inflammatory response during early infection has been found to decrease with age resulting in a delayed immune response and diminished bacterial killing. Finally, the resolution of the inflammatory response during the convalescent stage back to “baseline” is often prolonged in the elderly and associated with negative outcomes, such as adverse cardiac events. The focus of this review will be to discuss our current understanding of the potential mechanisms by which dysregulated inflammation (both prior to and following an infectious insult) enhances susceptibility to and severity of community acquired pneumonia (CAP) in the elderly with an emphasis on pneumococcal pneumonia, the leading cause of CAP.
PMCID: PMC3265328  PMID: 22288022
Aging; Pneumonia; Inflammation; Toll-like Receptors; Statins
3.  Aging and Injury: Alterations in Cellular Energetics and Organ Function 
Aging and Disease  2014;5(2):101-108.
Aging is characterized by increased oxidative stress, heightened inflammatory response, accelerated cellular senescence and progressive organ dysfunction. The homeostatic imbalance with aging significantly alters cellular responses to injury. Though it is unclear whether cellular energetic imbalance is a cause or effect of the aging process, preservation of mitochondrial function has been reported to be important in organ function restoration following severe injury. Unintentional injuries are ranked among the top 10 causes of death in adults of both sexes, 65 years and older. Aging associated decline in mitochondrial function has been shown to enhance the vulnerability of heart, lung, liver and kidney to ischemia/reperfusion injury. Studies have identified alterations in the level or activity of factors such as SIRT1, PGC-1α, HIF-1α and c-MYC involved in key regulatory processes in the maintenance of mitochondrial structural integrity, biogenesis and function. Studies using experimental models of hemorrhagic injury and burn have demonstrated significant influence of aging in metabolic regulation and organ function. Understanding the age-associated molecular mechanisms regulating mitochondrial dysfunction following injury is important towards identifying novel targets and therapeutic strategies to improve the outcome after injury in the elderly.
doi:10.14336/AD.2014.0500101
PMCID: PMC3966668
aging; hemorrhage; ischemia; mitochondria; sirt1; hypoxia
4.  Hemodynamic Aging as the Consequence of Structural Changes Associated with Early Vascular Aging (EVA) 
Aging and Disease  2014;5(2):109-113.
An increase in peripheral vascular resistance at rest is not routinely observed in healthy older persons, but often associated with increased stiffness of central elastic arteries, as hallmarks of aging effects on the vasculature, referred to as early vascular aging (EVA). In clinical practice, the increased arterial stiffness translates into increased brachial and central systolic blood pressure and corresponding pulse pressure in subjects above 50 years of age, as well as increased carotid-femoral pulse wave velocity (c-f PWV), a marker of arterial stiffness. A c-f PWV value ≥ 10 m/s is currently defined as a threshold for increased cardiovascular risk, based on consensus statement from 2012. Prevention and treatment strategies include a healthy lifestyle and the control of risk factors via appropriate drug therapy to achieve vascular protection related to EVA. New drugs are under development for vascular protection, for example the selective Angiotensin II (AT2) receptor agonist called compound 21. One target group for early intervention could be members of risk families including subjects with early onset cardiovascular disease.
doi:10.14336/AD.2014.0500109
PMCID: PMC3966669
aging; arterial stiffness; cardiac; blood pressure; haemodynamic; vasculature
5.  Vascular Hyperpermeability and Aging 
Aging and Disease  2014;5(2):114-125.
Vascular hyperpermeability, the excessive leakage of fluid and proteins from blood vessels to the interstitial space, commonly occurs in traumatic and ischemic injuries. This hyperpermeability causes tissue vasogenic edema, which often leads to multiple organ failure resulting in patient death. Vascular hyperpermeability occurs most readily in small blood vessels as their more delicate physical constitution makes them an easy target for barrier dysfunction. A single layer of endothelial cells, linked to one another by cell adhesion molecules, covers the interior surface of each blood vessel. The cell adhesion molecules play a key role in maintaining barrier functions like the regulation of permeability. Aging is a major risk factor for microvascular dysfunction and hyperpermeability. Apart from age-related remodeling of the vascular wall, endothelial barrier integrity and function declines with the advancement of age. Studies that address the physiological and molecular basis of vascular permeability regulation in aging are currently very limited. There have been many cellular and molecular mechanisms proposed to explain aging-related endothelial dysfunction but their true relationship to barrier dysfunction and hyperpermeability is not clearly known. Among the several mechanisms that promote vascular dysfunction and hyperpermeability, the following are considered major contributors: oxidative stress, inflammation, and the activation of apoptotic signaling pathways. In this review we highlighted (a) the physiological, cellular and molecular changes that occur in the vascular system as a product of aging; (b) the potential mechanisms by which aging leads to barrier dysfunction and vascular hyperpermeability in the peripheral and the blood-brain barrier; (c) the mechanisms by which the age-related increases in oxidative stress, inflammatory markers and apoptotic signaling etc. cause endothelial dysfunction and their relationship to hyperpermeability; and (d) the relationship between aging, vascular permeability and traumatic injuries.
doi:10.14336/AD.2014.0500114
PMCID: PMC3966670
aging; vascular hyperpermeability; vascular endothelium; permeability regulation
6.  Sepsis in Old Age: Review of Human and Animal Studies 
Aging and Disease  2014;5(2):126-136.
Sepsis is a serious problem among the geriatric population as its incidence and mortality rates dramatically increase with advanced age. Despite a large number of ongoing clinical and basic research studies, there is currently no effective therapeutic strategy that rescues elderly patients with severe sepsis. Recognition of this problem is relatively low as compared to other age-associated diseases. The disparity between clinical and basic studies is a problem, and this is likely due, in part, to the fact that most laboratory animals used for sepsis research are not old while the majority of sepsis cases occur in the geriatric population. The objective of this article is to review recent epidemiological studies and clinical observations, and compare these with findings from basic laboratory studies which have used aged animals in experimental sepsis.
doi:10.14336/AD.2014.0500126
PMCID: PMC3966671
aging; animal models; coagulation; elderly; inflammation; sepsis
7.  Sepsis-induced Cardiac Mitochondrial Damage and Potential Therapeutic Interventions in the Elderly 
Aging and Disease  2014;5(2):137-149.
The incidence of sepsis and its attendant mortality risk are significantly increased with aging. Thus, severe sepsis in the elderly is likely to become an emerging concern in critical care units. Cardiac dysfunction is an important component of multi-organ failure after sepsis. In our laboratory, utilizing a pneumonia-related sepsis animal model, our research has been focused on the mechanisms underlying sepsis-induced cardiac failure. In this review, based on findings from others and ours, we discussed age-dependent decay in mitochondria and the role of mitochondrial reactive oxygen species (mtROS) in sepsis-induced cardiac inflammation and autophagy. Our recent discovery of a potential signal transduction pathway that triggers myocardial mitochondrial damage is also discussed. Because of the significance of mitochondria damage in the aging process and in sepsis pathogenesis, we hypothesize that specific enhancing mitochondrial antioxidant defense by mitochondria-targeted antioxidants (MTAs) may provide important therapeutic potential in treating elder sepsis patients. In this review, we summarized the categories of currently published MTA molecules and the results of preclinical evaluation of MTAs in sepsis and aging models.
doi:10.14336/AD.2014.0500137
PMCID: PMC3966672
mitochondria; sepsis; cardiac function; inflammation; autophagy; mitochondria-targeted antioxidants
8.  NAD+ Metabolism in Age-Related Hearing Loss 
Aging and Disease  2014;5(2):150-159.
Age-related hearing loss (ARHL), a degenerative disorder characterized by age-dependent progressive increase in the threshold of auditory sensitivity, affects 40% of people over the age of 65, and it has emerged as an important social and public health problem. Various factors, including genetic and environmental components, are known to affect both the onset and severity of ARHL. In particular, age-dependent changes in cellular oxidative stress and inflammatory responses accompanied by altered cellular signaling and gene expression progressively affect the function of the auditory system and eventually lead to hearing impairment. Recent findings suggest that a disturbance of intracellular NAD+ levels is clinically related to the progression of age-associated disorders. Therefore, maintenance of optimal intracellular NAD+ levels may be a critical factor for cellular senescence, and thus, understanding its molecular signaling pathways would provide critical insights into the prevention and treatment of ARHL as well as other age-related diseases. In this review, we describe the role of NAD+ metabolism in aging and age-related diseases, including ARHL, and discuss a potential strategy for prevention or treatment of ARHL with a particular interest in NAD+-dependent cellular pathways.
doi:10.14336/AD.2014.0500150
PMCID: PMC3966673
Age-related hearing loss; NAD+; degenerative disorder; metabolism
9.  Gender Differences, Aging and Hormonal Status in Mucosal Injury and Repair 
Aging and Disease  2014;5(2):160-169.
As the “baby boomers” age, the percentage of the population over sixty-five years of age is increasing rapidly. Chronic disease management is an important component in the care of the elderly. The effects of aging on different organ systems are also pertinent; such as the weakening homeostatic response to injury in the older individuals. Mucosal surfaces have the largest combined surface area in the body and are the site of important host microbe interactions, especially in the gut which is prone to injury, both from local and systemic insult. This susceptibility has been known to increase with age. Therefore it is important to understand the interplay between aging, injury and recovery at the mucosal surface. Sex hormones play an important role in the maintenance of the mucosal barrier function as well as the mucosa associated immune function in both genders. Menopause in women is a defined time period in which major hormonal changes occur such as a decline in systemic estradiol levels. The differential levels of sex hormones contribute to the sexual dimorphism seen in response to injury at the mucosal surface, prior to and following menopause. Thus the effect of sex hormone and aging on mucosal mechanisms in response to injury is an important area of investigation.
doi:10.14336/AD.2014.0500160
PMCID: PMC3966674
aging; mucosal injury; gut mucosa; epithelial barrier function; microbial translocation; estradiol; hormones; menopause
10.  Susceptibility to Focal and Global Brain Ischemia of Alzheimer Mice Displaying Aβ Deposits: Effect of Immunoglobulin 
Aging and Disease  2014;5(2):76-87.
Cerebral ischemia is a risk factor for Alzheimer’s disease (AD). Moreover, recent evidence indicates that it is a two-way street as the incidence rate of stroke is significantly higher in AD patients than those without the disease. Here we investigated the interaction of ischemic brain insults and AD in 9-month-old ApdE9 mice, which show full-blown accumulation of Aβ deposits and microgliosis in the brain. Permanent occlusion of the middle cerebral artery (pMCAo) resulted in 36% larger infarct in ApdE9 mice compared to their wild-type (wt) controls. This was not due to differences in endothelium-dependent vascular reactivity. Treatment with human intravenous immunoglobulin (IVIG) reduced the infarct volumes and abolished the increased vulnerability of ApdE9 mice to pMCAo induced brain ischemia. When the mice were exposed to global brain ischemia (GI), an insult of hippocampal cells, ApdE9 mice showed increased neuronal loss in CA2 and CA3 subregions compared to their wt controls. GI was associated with increased microgliosis, astrogliosis, infiltration of blood-derived monocytic cells, and neurogenesis without clear differences between the genotypes. IVIG treatment prevented the GI-induced neuron loss in hippocampal CA1 and CA3 regions in ApdE9 mice. IVIG treatment increased microgliosis in wt but not in ApdE9 mice. Finally, GI induced 60% reduction in the hippocampal Aβ burden in ApdE9 mice, which was not affected by IVIG treatment. The results indicate that the AD pathology with Aβ deposits and microgliosis increases ischemic vulnerability in various brain areas. Moreover, IVIG treatment may be beneficial especially in patients suffering from both acute ischemic insult and AD.
doi:10.14336/AD.2014.050076
PMCID: PMC3966675
Alzheimer’s disease; ApdE9 mice; global ischemia; hippocampus; IVIG treatment
11.  Resveratrol Suppresses Expression of VEGF by Human Retinal Pigment Epithelial Cells: Potential Nutraceutical for Age-related Macular Degeneration 
Aging and Disease  2014;5(2):88-100.
Age-related macular degeneration (AMD) is a sight threating retinal eye disease that affects millions of aging individuals world-wide. Choroid-retinal pigment epithelium (RPE)-neuroretina axis in the posterior compartment of the eye is the primary site of AMD pathology. There are compelling evidence to indicate association of vascular endothelial growth factors (VEGF) to AMD. Here, we report the inhibitory actions of resveratrol (RSV) on inflammatory cytokine, TGF-β and hypoxia induced VEGF secretion by human retinal pigment epithelial cells (HRPE). HRPE cultures prepared from aged human donor eyes were used for the studies in this report. HRPE secreted both VEGF-A and VEGF-C in small quantities constitutively. Stimulation with a mixture of inflammatory cytokines (IFN-γ, TNF-α, IL-1β), significantly increased the secretion of both VEGF-A and VEGF-C. RSV, in a dose dependent (10–50 uM) manner, suppressed VEGF-A and VEGF-C secretion induced by inflammatory cytokines significantly. RT-PCR analysis indicated that effects of RSV on VEGF secretion were possibly due to decreased mRNA levels. TGF-β and cobalt chloride (hypoxia mimic) also upregulated HRPE cell production of VEGF-A, and this was inhibited by RSV. In contrast, RSV had no effect on anti-angiogenic molecules, endostatin and pigment epithelial derived factor secretion. Studies using an in vitro scratch assay revealed that wound closure was also inhibited by RSV. These results demonstrate that RSV can suppress VEGF secretion induced by inflammatory cytokines, TGF-β and hypoxia. Under pathological conditions, over expression of VEGF is known to worsen AMD. Therefore, RSV may be useful as nutraceutical in controlling pathological choroidal neovascularization processes in AMD.
doi:10.14366/AD.2014.050088
PMCID: PMC3966676
Resveratrol; VEGF; SIRT1; Cytokines; Retina; Retinal pigment epithelium; Age-related macular degeneration
12.  Impact of Maternal Prenatal Stress on Growth of the Offspring 
Aging and Disease  2013;5(1):1-16.
Unperturbed fetal development is essential for future health of an individual. Previous studies have linked diseases of aging to harmful alterations that happen during fetal development. Given the significant long-term impact that intrauterine environment has on an individual’s life, it was hypothesized that maternal stress during pregnancy will have negative effects on the offspring’s prenatal and postnatal growth. To test this, twenty-eight female and seven male Wistar rats (Rattus norvegicus) were purchased and bred to produce 176 offspring. During pregnancy, dams were randomly divided into four groups (n=7, per group) and immobilization stress induced as follows; Group 1 (GW1): immobilization stress on days 1–7 of pregnancy, Group 2 (GW2): on days 8–14, Group 3 (GW3): on days 15–21, Group 4 (Controls): left undisturbed. Maternal cortisol hormone, food intake, and weight gain were monitored during pregnancy. Pups were raised under normal laboratory conditions and sacrificed at ages: 4, 8, 12, and 16 weeks to determine the effect of prenatal stress. At necropsy, the tibia was removed and processed for histology. Differences among groups were determined by T-test or analysis of variance (ANOVA). Linear regression analysis was performed to establish the relationship between stress in utero and indicators of bone development in offspring. P values ≤ 0.05 were considered significant. Cortisol hormone levels in controls were lower than those of stressed animals. Stressed dams consumed 12.5% less food per day compared to controls. Animals in GW1 and GW2 gained less weight during pregnancy but had larger litters than did GW3 or the control group. Offspring born to GW3 were heavier compared to all other groups. GW3 offspring had a higher rate of bone formation. In conclusion, stress during pregnancy resulted in increased cortisol and reduced food intake in mothers, but faster growth and higher weight gain in offspring compared to controls.
doi:10.14336/AD.2014.05001
PMCID: PMC3901609  PMID: 24490112
prenatal stress; elevated cortisol; offspring development
13.  Up-Regulating Telomerase and Tumor Suppressors: Focusing on Anti-Aging Interventions at the Population Level 
Aging and Disease  2013;5(1):17-26.
Most human populations are undergoing a demographic transition regarding their age structure. This transition is reflected in chronic non-communicable diseases featuring among the main contributors to burden of disease. Considering that the aging process is a major risk factor for such conditions, understanding the mechanisms underlying aging and age-related diseases is critical to develop strategies to impact human health at population and/or individual-levels. Two different aspects of aging process (namely, telomere shortening and DNA damage accumulation) were shown to interact in positively impacting mice median survival. However, strategies aimed at translating such knowledge into actual human health benefits have not yet been discussed. In this manuscript, we present potential exposures that are suited for population-level interventions, and contextualize the roles of population (based on behavioral exposures) and individual-level (based on small-molecule administration) anti-aging interventions in different levels of disease prevention. We suggest that exposures such as moderate wine consumption, reducing calorie intake and active lifestyle are potentially useful for primordial and primary prevention, while small-molecules that activate telomerase and/or tumor suppression responses are more suited for secondary and tertiary prevention (although important for primary prevention in specific population subgroups). We also indicate the need of studying the impacts, on aging and age-related diseases, of different combinations of these exposures in well-conducted randomized controlled trials, and propose Mendelian randomization as a valuable alternative to gather information in human populations regarding the effects of potential anti-aging interventions.
doi:10.14336/AD.2014.050017
PMCID: PMC3901610  PMID: 24490113
Aging; Telomerase; Tumor suppression; Population-level interventions; Levels of disease prevention
14.  Emerging Candidate Biomarkers for Parkinson’s Disease: a Review 
Aging and Disease  2013;5(1):27-34.
Parkinson’s disease is a chronic neurodegenerative disorder leading to progressive motor impairment affecting more than 1% of the over-65 population. In spite of considerable progress in identifying the genetic and biochemical basis of PD, to date the diagnosis remains clinical and disease-modifying therapies continue to be elusive. A cornerstone in recent PD research is the investigation of biological markers that could help in identifying at-risk population or to track disease progression and response to therapies. Although none of these parameters has been validated for routine clinical practice yet, however some biochemical candidates hold great promise for application in PD patients, especially in the early stages of disease, and it is likely that in the future the diagnosis of PD will require a combination of genetic, imaging and laboratory data. In this review we discuss the most interesting biochemical markers for PD (including the “-omics” techniques), focusing on the methodological challenges in using ex vivo blood/CSF/tissue-based biomarkers and suggesting alternative strategies to overcome the difficulties that still prevent their actual use.
doi:10.14366/AD.2014.050027
PMCID: PMC3901611  PMID: 24490114
biomarkers; Parkinson’s disease; premotor; α-synuclein; DJ-1; proteomic
15.  Is Emotional Working Memory Training a New Avenue of AD Treatment? A review 
Aging and Disease  2013;5(1):35-40.
Emotional working memory training is a new area of research. In this study, we review a series of recent works describing a range of emotional working memory interventions that go from training single affective working memory function to teaching emotion regulation strategies. Generally speaking, research to date has established that emotional working memory may be preserved in Alzheimer’s disease. However, much work remains to be done in clarifying what aspects of affective domain is preserved, and testing short- and long-term effects of the trainings as well as their generalization to everyday affective functioning. We conclude by offering suggestions about the development of emotional working memory training for Alzheimer’s patients.
doi:10.14336/AD.2014.050035
PMCID: PMC3901612  PMID: 24490115
AD; emotion; working memory; training
16.  Quality and Innovations for Caring Hospitalized Older Persons in the Unites States 
Aging and Disease  2013;5(1):41-51.
Older persons are occasionally acutely ill and their hospitalizations frequently end up with complications and adverse outcomes. Medicare from U.S. federal government’s payment resource for older persons is facing financial strain. Medicare highlights both cost-saving and high quality of care while older persons are hospitalized. Several health policy changes were initiated to achieve Medicare’s goals. In response to Medicare’s health policy changes, U.S. hospital environments have been changed and these resulted in hospital quality measurements’ improvement. American seniors are facing the challenges during and around their hospital care. Several innovative measures are suggested to overcome these challenges.
doi:10.14366/AD.2014.050041
PMCID: PMC3901613  PMID: 24490116
Elderly; Health policy; Health services; Health care quality; Hospitalization
17.  New Nucleophilic Mechanisms of Ros-Dependent Epigenetic Modifications: Comparison of Aging and Cancer 
Aging and Disease  2013;5(1):52-62.
It has been shown that ROS (reactive oxygen species, superoxide and hydrogen peroxide) regulate major epigenetic processes, DNA methylation and histone acetylation, although the mechanism of ROS action (ROS signaling) is still unknown. Both DNA methylation and histone acetylation are nucleophilic processes and therefore ROS signaling through typical free radical processes, for example hydrogen atom abstraction is impossible. However, being “super-nucleophile” superoxide can participate in these reactions. Now we propose new nucleophilic mechanisms of DNA methylation and histone modification. During DNA methylation superoxide can deprotonate the cytosine molecule at C-5 position and by this accelerate the reaction of DNA with the positive-charged intermediate S-adenosyl-L-methionine (SAM). Superoxide can also deprotonate histone N-terminal tail lysines and accelerate the formation of their complexes with acetyl-coenzyme A (AcCoA), the supplier of acetyl groups. In cancer cells ROS enhance DNA methylation causing the silencing of tumor suppressor and antioxidant genes and enhancing the proliferation of cancer cells under condition of oxidative stress. ROS signaling in senescent cells probably causes DNA hypomethylation although there are insufficient data for such proposal.
doi:10.14336/AD.2014.050052
PMCID: PMC3901614  PMID: 24490117
ROS; DNA Methylation; Histone Modification; Nucleophilic Mechanisms
18.  Evidence for Gender Differences in Cognition, Emotion and Quality of Life in Parkinson’s Disease? 
Aging and Disease  2013;5(1):63-75.
A number of gender differences have been documented in the incidence and symptomatology of the second most common age-related neurodegenerative disorder, idiopathic Parkinson’s disease (PD). Overall, previous reports suggest a less frequent incidence and a more benign phenotype in women mainly in Western populations, which is thought to be mediated by estrogens in particular in early stages of the disease. Not only motor symptoms seem to underlie gender effects, but also non-motor symptoms such as psychiatric and cognitive impairments, which can often precede motor manifestation. However, reliable results for gender differences in PD in particular of cognitive function and emotion processing, having a major impact on quality of life, are lacking. Moreover, studies investigating gender effects in PD in these areas have revealed highly heterogeneous results. The present review summarizes findings of currently available studies on gender effects on neuropsychological tests covering major cognitive domains, emotion processing as well as quality of life in patients with PD. Overall, the occurrence of cognitive impairment in PD seems to be associated with male gender, though inconsistent results were shown in cognitive screening tests. Regarding emotion recognition, men with PD were found to be less accurate than women with PD at identifying fearful expressions, whereas vice versa results appeared in healthy subjects. Lower quality of life and greater disability were reported by women compared to men with PD, which corresponds with the results in healthy subjects. Several disease-specific mediators as well as the question of a general gender and age-related effect as observed in healthy individuals are discussed. Increased knowledge on possible gender effects in PD would provide an enhanced insight in underlying pathological mechanisms, and has potential implications for the diagnosis and treatment of PD.
doi:10.14366/AD.2014.050063
PMCID: PMC3901615  PMID: 24490118
Parkinson’s disease; gender; estrogen; emotion; cognition; quality of life
19.  Poor Aerobic Fitness May Contribute to Cognitive Decline in HIV-infected Older Adults 
Aging and Disease  2013;4(6):311-319.
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.
doi:10.14336/AD.2013.0400311
PMCID: PMC3843648  PMID: 24307964
HIV; older adults; aerobic fitness; cognition
20.  Autonomic Cardiovascular Damage during Post-menopause: the Role of Physical Training 
Aging and Disease  2013;4(6):320-328.
Menopause is part of the aging process and is characterized by the natural cessation of menstruation; during this time, the production of ovarian hormones, especially estrogen, is sharply reduced. This reduction can cause symptoms and disorders that affect most women and can interfere with their quality of life. Women are also more susceptible to cardiovascular diseases during this period, considering that these ovarian hormones would be associated with a protective effect on the cardiovascular system, by acting at various levels, contributing to the body homeostasis. Among several effects on the cardiovascular system, the ovarian hormones seem to play an important role in the autonomic control of heart rate and blood pressure. A reduction in ovarian hormones causes an autonomic imbalance and increases the risk of cardiovascular diseases. In fact, this increased risk is justified by the key role the autonomic nervous system plays in all cardiac regulatory mechanisms, exerting a tonic and reflexive influence on the main variables of the cardiovascular system. The autonomic system controls various cardiovascular parameters, such as the modulation of heart rate and blood pressure, myocardial contractility and venous capacitance, directly participating in the regulation of cardiac output. Over the years, the standard treatment for menopause symptoms and disorders has been hormone replacement therapy (HRT). However, many studies have indicated the risks of HRT, which justify the need for new non-pharmacological therapies. To this end, physical training, mainly aerobic, has been applied with excellent results on the cardiovascular autonomic nervous system, as it reduces the risk of cardiac diseases and improves the survival rate with direct beneficial effects on the quality of life of these women during the aging process.
doi:10.14336/AD.2013.0400320
PMCID: PMC3843649  PMID: 24307965
Menopause; Aging; Physical Training; Cardiovascular Autonomic Control
21.  Depression Treatment Non-adherence and its Psychosocial Predictors: Differences between Young and Older Adults? 
Aging and Disease  2013;4(6):329-336.
Depression is a common disease among young and older adults. Although it can be treated, non-adherence is very common among individuals of different ages. The aim of the present paper is to review and summarize research findings regarding depression among young and older adults, with a special focus on the phenomenon of treatment non-adherence among young and older adults with depression. The first section of the review focuses on describing the characteristics of depression in young and older adults. The second section focuses on treatment non-adherence of young and older adults, the prevalence of this phenomenon, and its consequences. The third section focuses on several factors (illness beliefs, treatment beliefs, self-stigma, and self-esteem) that were identified as having a significant association with treatment non-adherence of individuals with depression, with special attention focused on age differences. Results of the review of the literature reveal that research in the area of depression treatment non-adherence and its predictors among young and older adults has received, to date, very minor and limited attention. Thus, there is a need to expand the current body of knowledge and promote future interventions geared towards the unique characteristics of depression among young and older adults, in order to increase their treatment adherence.
doi:10.14336/AD.2013.0400329
PMCID: PMC3843650  PMID: 24307966
depression; treatment adherence; age differences
22.  Mitochondrial DNA Damage Patterns and Aging: Revising the Evidences for Humans and Mice 
Aging and Disease  2013;4(6):337-350.
A significant body of work, accumulated over the years, strongly suggests that damage in mitochondrial DNA (mtDNA) contributes to aging in humans. Contradictory results, however, are reported in the literature, with some studies failing to provide support to this hypothesis. With the purpose of further understanding the aging process, several models, among which mouse models, have been frequently used. Although important affinities are recognized between humans and mice, differences on what concerns physiological properties, disease pathogenesis as well as life-history exist between the two; the extent to which such differences limit the translation, from mice to humans, of insights on the association between mtDNA damage and aging remains to be established. In this paper we revise the studies that analyze the association between patterns of mtDNA damage and aging, investigating putative alterations in mtDNA copy number as well as accumulation of deletions and of point mutations. Reports from the literature do not allow the establishment of a clear association between mtDNA copy number and age, either in humans or in mice. Further analysis, using a wide spectrum of tissues and a high number of individuals would be necessary to elucidate this pattern. Likewise humans, mice demonstrated a clear pattern of age-dependent and tissue-specific accumulation of mtDNA deletions. Deletions increase with age, and the highest amount of deletions has been observed in brain tissues both in humans and mice. On the other hand, mtDNA point mutations accumulation has been clearly associated with age in humans, but not in mice. Although further studies, using the same methodologies and targeting a larger number of samples would be mandatory to draw definitive conclusions, the revision of the available data raises concerns on the ability of mouse models to mimic the mtDNA damage patterns of humans, a fact with implications not only for the study of the aging process, but also for investigations of other processes in which mtDNA dysfunction is a hallmark, such as neurodegeneration.
doi:10.14336/AD.2013.0400337
PMCID: PMC3843651  PMID: 24307967
aging; mtDNA; damage patterns; deletion; copy number; point mutation
23.  Aging, Functional Capacity and Eccentric Exercise Training 
Aging and Disease  2013;4(6):351-363.
Aging is a multi-factorial process that ultimately induces a decline in our physiological functioning, causing a decreased health-span, quality of life and independence for older adults. Exercise participation is seen as a way to reduce the impact of aging through maintenance of physiological parameters. Eccentric exercise is a model that can be employed with older adults, due to the muscle’s ability to combine high muscle force production with a low energy cost. There may however be a risk of muscle damage before the muscle is able to adapt. The first part of this review describes the process of aging and how it reduces aerobic capacity, muscle strength and therefore functional mobility. The second part highlights eccentric exercise and the associated muscle damage, in addition to the repeated bout effect. The final section reviews eccentric exercise interventions that have been completed by older adults with a focus on the changes in functional mobility. In conclusion, eccentric endurance exercise is a potential training modality that can be applied to older adults for improving muscle strength, aerobic capacity and functional ability. However, further research is needed to assess the effects on aerobic capacity and the ideal prescription for eccentric endurance exercise.
doi:10.14336/AD.2013.0400351
PMCID: PMC3843652  PMID: 24307968
Eccentric exercise; functional ability; muscle strength; aerobic capacity; muscle damage
24.  mtDNA Mutations and Their Role in Aging, Diseases and Forensic Sciences 
Aging and Disease  2013;4(6):364-380.
Mitochondria are independent organelles with their own DNA. As a primary function, mitochondria produce the energy for the cell through Oxidative Phosphorylation (OXPHOS) in the Electron Transport Chain (ETC). One of the toxic products of this process is Reactive Oxygen Species (ROS), which can induce oxidative damage in macromolecules like lipids, proteins and DNA. Mitochondrial DNA (mtDNA) is less protected and has fewer reparation mechanisms than nuclear DNA (nDNA), and as such is more exposed to oxidative, mutation-inducing damage. This review analyzes the causes and consequences of mtDNA mutations and their relationship with the aging process. Neurodegenerative diseases, related with the aging, are consequences of mtDNA mutations resulting in a decrease in mitochondrial function. Also described are “mitochondrial diseases”, pathologies produced by mtDNA mutations and whose symptoms are related with mitochondrial dysfunction. Finally, mtDNA haplogroups are defined in this review; these groups are important for determination of geographical origin of an individual. Additionally, different haplogroups exhibit variably longevity and risk of certain diseases. mtDNA mutations in aging and haplogroups are of special interest to forensic science research. Therefore this review will help to clarify the key role of mtDNA mutations in these processes and support further research in this area.
doi:10.14336/AD.2013.0400364
PMCID: PMC3843653  PMID: 24307969
Mitochondrial DNA (mtDNA); Electron Transport Chain (ETC); Reactive Oxygen Species (ROS); Aging; Diseases; Forensic Sciences
25.  Is Bilateral Orchiectomy for Metastatic Prostate Cancer Treatment Associated with High Cardiovascular Risk? 
Aging and Disease  2013;4(6):381-384.
Cardiovascular disease is one of the most common causes of death worldwide and the most usual in the western populations. Although it affects both sexes, it is more frequent in males in whom it shortens the average life expectancy. This difference has been attributed to the negative effects of testosterone; however, recent research showed that this hormone may have protective effects on the cardiovascular system. In confirmation to the above current evidence suggests that the low levels of testosterone could be associated with an increased CVD risk and with an augmentation of morbidity and mortality in males. In the present article, we present 2 cases of men with CVD and metastatic prostate cancer treated with bilateral orchiectomy who died of acute stroke during the perioperational period. The possible association of androgen deprivation with cardiovascular disease progression and the consequent risk of stroke are briefly discussed.
doi:10.14336/AD.2013.0400381
PMCID: PMC3843654  PMID: 24307970
Orchiectomy; Metastatic Prostate Cancer; Cardiovascular Risk

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