Cellular senescence, aging and age-related disease
Buck Institute for Research on Aging and Lawrence Berkeley National Laboratory
ABSTRACT: Cellular senescence is a complex stress response with two main features: a stable, essentially irreversible arrest of cell proliferation (growth), and a multi-faceted senescence-associated secretory phenotype (SASP). The senescence response is likely antagonistically pleiotropic. That is, it is beneficial early in life, but can be deleterious later in life by driving aging phenotypes and age-related disease. The growth arrest suppresses the development of cancer by halting the growth of cells that have experienced potentially oncogenic stress. The SASP can alter the behavior of neighboring cells within tissues and also the quality of the systemic milieu. On the positive side, the SASP can promote tissue repair. In the skin, this benefit is mediated in part the secretion of a newly identified SASP factor, PDGF-AA, which stimulates the differentiation of dermal fibroblasts into myofibroblasts. On the negative side, the SASP can create a pro-inflammatory tissue environment that can drive the degeneration of the resident tissue. The SASP can also stimulate the growth, migration and invasion of premalignant or weakly malignant cells, and most prominently stimulate the development of cancer metastases. Thus, senescent cells can, ironically, promote the progression of cancer, a major age-related diesease. A critical difference between the positive and negative effects of senescent cells is their resident time in vivo. Short, transient residence times appear to be beneficial, which occurs during wound healing. In contrast, chronic resident times, which occur during aging, appear to be deleterious. Therapies aimed at eliminating senescent cells, or suppressing the deleterious components of the SASP, hold promise for treating a spectrum of diseases associated with aging.
Key words: antagonistic pleiotropy, cancer, tissue repair, tissue degeneration, tumor suppression
Novel conceptual model for complex chronic brain disorders of aging
The Campaign to Prevent Alzheimer’s Disease by 2020 [PAD2020], Potomac, MD, USA
ABSTRACT: The Grand Global Challenge for healthcare systems worldwide is the quandary of how to balance the relative ‘costs’ of investing in research on ‘prevention’ [to delay chronic disabilities] with the scale and price of healthcare services for burgeoning populations with ever-increasing lifespan. The public policy options are limited to: a- either to invest massive funds into research on prevention or, b - develop plans to ration healthcare. The scale of the pending health-economic crisis mandates bold scientific initiative[s] to address this grand global healthcare dilemma. Thus the essential global scientific challenge is to resolve the question of: “How to accelerate the discovery-development of cures for chronic brain diseases – such as dementia/Alzheimer’s disease?” In spite of remarkable recent advances in the neurobiology of neurodegeneration, there is a growing cynicism regarding current paradigms of drug development due to the: a - lack of effective treatments for dementia, b - bleak prospects for a dramatic breakthrough in therapy development anytime soon, and c - inadequate conceptual models of neurodegenerative diseases. Notwithstanding these concerns, many believe the prospect of delaying the onset of disabling symptoms within a decade is an attainable goal, provided we can surmount several scientific, administrative, and financial impediments. Among these obstacles the limitations of current conceptual models about etiologies of the disease is an important factor. A quantum shift in current approaches to therapy development requires the adoption of alternative paradigms; such as a systems failure model of dementia - based on general systems theory. The core premise for such a different approach is to start conceptualizing complex chronic brain disorders [e.g., Alzheimer’s syndrome] in terms of progressive failures in an array of complexly interconnected biological systems and neural networks. The key explanatory concept of this model is that is that the syndrome is not the linear result of a unitary etiologic factor but rather interaction or failures of several components; thus the concept of polygenic etiologies.
Key words: Aging, Alzheimer’s disease, dementia, chronic brain disorders, healthcare, systems biology, systems failure, research policy, treatment, prevention, drug discovery
Vasodegeneration and Neurodegeneration
David A. Greenberg
Buck Institute for Research on Aging, Novato, CA, USA
ABSTRACT: Vasodegenerative disease, like other so-called diseases of aging, begins decades before it becomes clinically apparent. The main underlying pathologies are atherosclerosis, hypertension, and diabetes, which may also contribute to risk and progression of neurodegenerative disease. Early events in atherogenesis include disturbed blood flow leading to endothelial cell (EC) dysfunction and accumulation of oxidized lipids in the arterial wall. To model these processes, we cultured bEnd.3 mouse brain ECs under stationary or flow conditions. Flow induced by orbital rotation altered the expression of key transcription factors and gasotransmitter-synthesizing enzymes, and increased NO production, consistent with an atheroresistant state. Statins and angiotensin receptor blockers reproduced the effect of flow on endothelial nitric oxide synthase. bEnd.3 cells also expressed LOX-1, a scavenger receptor involved in the uptake and toxicity of oxidized low-density lipoprotein (Ox-LDL), but flow did not alter LOX-1 protein expression, Ox-LDL uptake or Ox-LDL toxicity in these cells. Thus, factors in addition to altered flow likely determine the susceptibility of atheroprone vascular sites to lipid accumulation. Because of the putative role of vascular risk factors in neurodegeneration, we also investigated the possible toxicity of LOX-1/Ox-LDL signaling in cultured neural (mouse hippocampal neuron x neuroblastoma; HN33) cells. Like bEnd.3 cells, HN33 cells expressed LOX-1 protein and exhibited Ox-LDL uptake and toxicity. Thus, LOX-1/Ox-LDL signaling may help to mediate effects of cardiovascular risk factors on neurodegenerative disease.
Key words: atherosclerosis, endothelial cell, LOX-1, neurodegeneration, oxidized low-density lipoprotein (Ox-LDL)
The Current Situation and Perspective of Mild Cognitive Impairment and Dementia in China
The Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China
ABSTRACT: BACKGROUND Presently, China has an elderly population, aged 65 years or older, of 130 million, accounting for 9.4% of the total 1.35 billion Chinese population. China is aging and calls for an anti-dementia research. The urgent need is to know the prevalence of MCI and dementia, and how these patients are diagnosed and treated in hospitals. METHODS: For the prevalence of MCI and dementia in China, we performed a population-based cross-sectional survey with a multistage, cluster sampling design, in which residents aged 65 years and older were drawn from 30 urban (n = 6,096) and 45 rural (n = 4,180) communities across China. For the diagnosis and treatment of dementia in the neurology outpatient departments, we randomly selected 36 tier-3 general hospitals across China to collect baseline data. We intervened regarding the drawbacks found and initiated a training program on dementia diagnosis. RESULTS: The prevalences of overall MCI, MCI-A, MCI-CVD, MCI-VRF, and MCI-O were 20.8% (95%CI = 20.0–21.6%), 6.1% (95%CI = 5.7–6.6%), 3.8% (95%CI = 3.4–4.2%), 4.9% (95%CI = 4.5–5.4%), and 5.9% (95%CI = 5.5–6.4%) respectively. The rural population had a higher prevalence of overall MCI (23.4% vs. 16.8%, P < 0.001). The prevalence of dementia, AD, and VaD among individuals aged 65 and older were 5.14% (95%CI = 4.71–5.57%), 3.21% (95%CI = 2.87–3.55%), 1.50% (95%CI = 1.26–1.74%), respectively. The prevalence of dementia was significantly higher in rural than in urban areas (6.05% vs. 4.40%, P < 0.001). The same regional difference was also seen for AD (4.25% vs. 2.44%, P < 0.001) but not for VaD (1.28% vs. 1.61%, P = 0.166). The difference in AD disappeared when the sample was stratified by educational level. Moreover, the risk factors for AD and VaD differed for urban and rural populations. After the intervention in neurology outpatients in 36 general hospitals, the number of dementia doctors increased from 47 to 205, and the number of memory clinics increased from 6 to 36. The detection rate of dementia was augmented significantly from 0.10% (536/553,986) in stage 1 to 0.41% (2482/599, 214). CONCLUSIONS: The prevalence of MCI in elderly Chinese is higher in rural than in urban. Vascular-related MCI (MCI-CVD and MCI-VRF) was most common. A notably higher prevalence of dementia and AD was found in rural than in urban areas, and education might be an important reason for the urban–rural differences.
Many dementia patients may have been overlooked or may not have received proper diagnoses and treatments due to a lack of trained dementia doctors and memory clinics at neurology outpatient departments in general hospitals in China. A new dementia management system needs to be organized by the Chinese health administration to improve the current situation.
1. China needs to have more funding to support MCI and Dementia, since we have 7 million dementia and 30 million MCI patients.
2. China needs to set up new outpatient system to increase memory clinics and dementia doctors in hospitals to meet the increasing patients.
3. China needs national efforts to study familial Alzheimer’s disease (FAD) since it might be a good way to find the crucial pathogenesis and new drug target.
4. China needs to have national AD registry for big data to monitor AD in whole China regarding the diagnosis and treatment even care.
5. China needs to set up some neuropsychological assessment which fit Chinese culture for the diagnosis since we have so many differences in culture from western country.
6. China needs to develop compound from traditional Chinese medicine for anti-dementia, however this needs to be verified by international accepted method to provide evidence.
Session 1: Stem Cells, Aging and Disease
Inducing Neurogenesis in the Adult Central Nervous System after Injury
Wenze Niu, Tong Zang, and Chun-Li Zhang
Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center at Dallas, USA
ABSTRACT: Injury to the central nervous system leads to irreversible neuron loss and the formation of a glial scar. This scar is initially beneficial for restricting secondary damage but ultimately inhibitory for neural regeneration. Strategies remodeling the scar-forming glial cells might enhance regeneration and promote functional recovery after neural damage. We examined the possibility of converting reactive astrocytes, a major cell type forming the glial scar, to neurons in the adult brain. Endogenous reactive astrocytes were specifically targeted by lentivirus-mediated gene expression under the human GFAP promoter. Our in vivo screens showed that the transcription factor SOX2 alone can induce the appearance of neuroblasts (also called neuronal precursors) within the adult or even aged mouse striatum. Fate mapping showed that these induced neuroblasts were generated from the virus-transduced striatal astrocytes but not any other cells. Most interestingly, the induced neuroblasts become functionally mature when additional signaling molecules, such as brain-derived neurotrophic factor (BDNF), BDNF/Noggin, or valproic acid (VPA), were applied. Electrophysiological recordings demonstrate that astrocyte-converted neurons can integrate into the local neuronal network in the adult brain. Importantly, astrocytes can be similarly converted into mature neurons in the adult spinal cord after injury.Together, our results reveal a brand new strategy to regenerate the damaged central nervous system, which is to reprogram the reactive glial cells to functional neurons. This proof-of-concept study may have important implications in regenerative medicine by using a patient’s own cells without the need of transplantation.
Key words: in vivo reprogramming, regeneration, glial scar, SOX2, valproic acid
RESVERATROL THERAPY IN OLD AGE PREVENTS MEMORY DYSFUNCTION VIA PRO-COGNITIVE AND ANTIINFLAMMATORY EFFECTS
Ashok K. Shetty, Maheedhar Kodali, Vipan Parihar, Geetha Shetty. Bharathi Hattiangady, Bing Shuai, Vikas Mishra, and Xiolan Rao
Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas, USA.
Research Service, Olin E. Teague Veterans Affairs Medical Center, Central Texas Veterans Health Care System, Temple, Texas, USA
ABSTRACT: Reduced levels of neurogenesis and microvasculature, and chronic low-level inflammation in the form of astrocyte hypertrophy and activated microglia are among the noticeable changes in the aged hippocampus. Because these alterations can contribute to age-related memory dysfunction, treatment approaches that mitigate these changes may preserve cognitive function in old age. Resveratrol (RESV), a naturally occurring polyphenol having ability for up-regulating SIRT1 (a longevity gene important for cognitive function and synaptic plasticity) and suppressing inflammation, appears to be ideal for easing these age-related changes. Hence, we examined the efficacy of RESV for counteracting age-related memory impairment. We chose four groups of late middle-aged rats having similar learning and memory abilities in a water maze test. The first two groups were treated intraperitoneally with RESV (40 mg/Kg) or vehicle (VEH) for four weeks. Analyses at ~25 months of age uncovered improved learning and memory function in RESV-treated animals but impairments in VEH-treated animals. RESV-treated animals also displayed increased net neurogenesis and microvasculature, and diminished astrocyte hypertrophy and activation of microglia. The next two groups were treated orally with RESV (90 mg/Kg) or VEH for four weeks. Two months later, these rats were tested for learning and memory function through a new water maze test. Aged rats receiving VEH showed memory dysfunction whereas aged rats receiving RESV exhibited normal memory function. To understand mechanisms, we quantified the effects of oral administration of RESV on hippocampus neurogenesis, and the expression of genes related to learning and memory function, anti-inflammatory and microglia activity in the hippocampus. In contrast to rats receiving vehicle (VEH), rats receiving RESV exhibited increased neurogenesis and enhanced expression of genes vital for learning and memory function such as SIRT1, FOXO3 (a substrate of SIRT1 believed to promote cell longevity and healthy aging), CREB1 (a regulator of neuronal survival, learning and consolidation of memory) and PRKACA (cAMP-dependent protein kinase catalytic subunit alpha, important for many cellular functions including memory). RESV treatment also enhanced the expression of genes encoding neurotrophic factors important for neurogenesis and memory (FGF-2, NGF, VEGF and CNTF), a synaptic protein (Synaptotagmin V) and a neuropeptide (Neuropeptide Y). Moreover, RESV treatment reduced the expression of MAPK1 (an Alzheimer disease associated gene that induces hyper-phosphorylation of tau protein) and increased the expression of IL10 (an antiinflammatory cytokine). Analyses with ELISAs further revealed a decreased concentration of pro-inflammatory cytokines IL-1b and TNF-a in the hippocampus of RESV treated animals. Furthermore, RESV treatment enhanced the expression of a gene (MRC1, mannose receptor) linked to alternative activation of microglia (M2 microglia). These results provide novel evidence that RESV treatment in late middle age is efficacious for preventing memory dysfunction in old age. Modulation of the hippocampus plasticity, enhancement of pro-cognitive gene expression and suppression of chronic low-level inflammation appear to underlie the functional benefits mediated by RESV. Supported by grants from the NIH-NCCAM (AT006256 to A.K.S.) and the State of Texas (ET Fund to A.K.S.).
A Brain Stem Cell Niche in Aging and Disease
Joanne C. Conover, Jie Luo, Brett Shook, Jessica Lennington, Rebecca Acabchuk
University of Connecticut, Storrs, CT, USA
ABSTRACT: Along the lateral walls of the lateral ventricles of the adult rodent brain lies a stem cell niche capable of an array of regenerative and reparative functions that persist throughout adulthood. In humans this same region shows robust neurogenesis in neonatal development; however, in contrast to rodents, little to no neurogenesis is detected in adulthood and it is unclear whether stem cells persist and can be prompted to support regenerative repair following injury or disease. I will compare and contrast the molecular and cellular characteristics of the rodent and human subventricular stem cell niche with a particular focus on changes that occur during the process of aging. I will also address the potential to exploit the adult human stem cell niche for therapeutic ends, while acknowledging the obstacles and limitations that currently exist.
Key words: Aging, stem cells, neurogenesis, ventriculomegaly
Cell therapy for Parkinson’s Disease – new hope from reprogramming technologies
Zhiguo Chen 1,2,3,*
1Cell Therapy Center, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China
2Center of Parkinson's Disease, 3 Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China
ABSTRACT: Parkinson’s disease (PD) is a neurodegenerative disease with the major pathology being the progressive loss of dopaminergic (DA) neurons at the substantial nigra in midbrain. As early as in the 1980s, open-label clinical trials employing fetal ventral mesencephalon (fVM) tissues have demonstrated significant efficacy for PD treatment, which led to two NIH-sponsored double-blind placebo-controlled clinical trials. However, both trials showed only mild outcome. Retrospective analysis revealed several possible reasons that include patient selection, heterogeneity of grafts, immune recognition of grafts, lack of standardization of transplantation procedure and uneven distribution of grafts, etc. Recent years have seen advances in reprogramming technologies which may provide solutions to the problems associated with fVM tissues. Induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) hold promise for generating clinical grade DA neural cells that are safe, homogeneous, scalable and standardizable. These new technologies may bring back clinical trials using cell therapy for PD treatment in the future.
Key words: Cell therapy, Parkinson’s disease, Reprogramming, Dopaminergic neurons, Clinical trials
Stem cells as anti-degenerative diseases and anti-aging products
Zhong Chao HAN
Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College
ABSTRACT: Previous studies indicated that aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. Several hallmarks that represent common denominators of aging in different organisms have been discovered, including cellular senescence and stem cell exhaustion. One of anti-aging strategies is the stem cell-based therapy. Here, the current state of stem cell research and development in the field of anti-regenerative diseases and anti-aging was summarized and future research direction of stem cell-based anti-aging therapies was discussed.
Key words: Stem cells, stem cell transplantation, Cell products, anti-aging, regenerative diseases
Session 2: System Aging and Disease
The use of information theory for the study of aging, aging related diseases and healthy longevity
Ilia Stambler1, and David Blokh2
1Department of Science, Technology and Society, Bar Ilan University, Ramat Gan, Israel; 2C.D. Technologies Ltd., Israel
ABSTRACT: The importance of information theory methods for aging research has been recognized for over half a century (Yockey et al. 1958). The information theoretical measures may be more adequate for the study of aging and disease processes than statistical measures, as the former take into consideration the non-linear relations in the biological systems. Yet relatively few works have appeared on the subject. In our study, we apply information theory methodology, using measures of entropy and mutual information, to estimate the relation between aging and disease, with specific reference to diagnostic parameters of major age related diseases, such as diabetes, heart disease and cancer. We show that aging and disease are characterized by a decrease of entropy (loss of heterogeneity) in the parameters and samples under consideration. Furthermore, we show that age is a powerful “metamarker” of disease, whose combined consideration with other diagnostic parameters can dramatically improve diagnostic results. Finally, we show that the thresholds for the parameters association with disease are strongly related to age, in the parameters and samples studied. Further use of information theoretical measures in the study of aging, aging related diseases and longevity, using a wide array of clinical parameters and large samples, may provide a useful comprehensive measure to determine physiological age and to estimate the influence of potential anti-aging interventions.
Key words: information theory, system entropy, normalized mutual information, aging, aging related diseases, physiological age, in silico analysis of anti-aging interventions
Lifespan extension by Korean red ginseng and ginseng berry extract
Shin-Hae Lee, Hae-Yeon Lee, Kyung-Jin Min
Department of Biological Sciences, Inha University, Korea
ABSTRACT: Ginseng is well known for its beneficial effects for many aspects of health. So far, the root of ginseng has been extensively studied, but recent studies indicate that the fruit of ginseng, ginseng berry is also useful and contains more amounts of some ginsenosides like Re, Rb2 and Rd. Although ginseng has been claimed to have anti-aging effects, there has been no solid experimental data with model organisms on the effects of ginseng on lifespan. Therefore, we evaluated the impact of ginseng (root and fruit) on lifespan in flies and worms. We report that both root and fruit extract extended the lifespan of D. melanogaster and C. elegans at least 10%. The working concentration was lower and magnitude of lifespan extension was greater in flies fed ginseng berry extract than flies fed root extract. The active component of lifespan extension by ginseng berry seems to be syringaresinol. Syringaresinol treatment increased the lifespan of flies and worms. The effect of lifespan extension by syringaresinol was not additive to the effect of dietary restriction indicating that the pathway of syringaresinol is overlapping with that of dietary restriction. The positive effects of ginseng in two different species demonstrate a potential broad applicability of ginseng as anti-aging treatment.
The study of the change & function of DNA polymerase δ in ageing
Medical Laboratory Department, Xuanwu Hospital, Capital Medical University, Beijing,P.R.china
ABSTRACT: Free Radical(FR) and Reactive Oxygen Species(ROS) accumulate in ageing, which leads to oxidative damage of DNA and proteins, speeding up of telomere-shortening rate, accumulation of advanced glycation end products(AGEs),over-expression of senescence-associated genes,etc. DNA polymerase δ(DNA polδ), which is responsible for the replication of DNA & DNA damage repair, could play a key role in ageing.
DNA pol δ consists of 4 subunit, including δ1(catalytic subunit), δ2(binding subunit), δ3 and δ4. To investigate the change of DNA pol δ in ageing, we observed the expression of δ1 in the different population doublings(PDs) of human fetal lung diploid fibroblasts(2BS),and human lymphocytes at different age stages. To clarify the function of DNA polδ, we examined the effects of DNA pol δ1 on the growth & proliferation, cell cycle, Brdu, and DNA damage & repair ability in 2BS cells. We find that the expression of DNA pol δ1 both in mRNA and protein decreased substantially with replicative senescence, which was demonstrated by the results in human lymphocytes at different age stages. The constructed recombinant plasmids pcDNA3.0-polδ1, shPol δ1, the control pcDNA3.0 and shControl were transfected into HEK293 cells. The expression of DNA pol δ1 was markedly increased in the pcDNA3.0- polδ1 group but was inhibited in the shPol δ1 group as seen by quantitative real-time PCR and western blot. Silencing of polδ1 suppressed HEK293 cell proliferation, cell cycle and DNA synthesis, but there were no obvious effects on the cells in the pcDNA3.0-POLD1 group. Finally, comet assay for oxidative DNA damage induced by H2O2 analysis suggested that silencing of polδ1 obviously increased the extent of DNA damage, while over-expression of polδ1 mildly protected against oxidative DNA damage, but there was no statistical significance.
In conclusion, DNA polδ1 may be a potential biomarker, and plays a very important role in replicative senescence and aging.
Key words: DNA polymerase δ, 2BS, lymphocyte, replicative senescence, ageing
Acute Inflammatory Diseases in Old Age
Department of Surgery and Physiology, University of Kentucky, USA
ABSTRACT: Aging is characterized by reduced tolerance to physiological stressors including infection and inflammation. Incidence and mortality rate of acute inflammatory diseases, such as sepsis and acute pancreatitis, increase progressively with advancing age. Our past studies on these acute inflammatory diseases using aged mice have revealed that dysregulated/prolonged inflammation, increased thrombosis, and increased oxidative damage, are all partly responsible for the elevated mortality (PMC3966671, PMC3784256). The increased thrombosis and oxidative damage is caused by a suppressed anti-coagulation pathway and anti-oxidant mechanism, respectively (PMC2890181, PMC3340560). During acute systemic inflammation, adipose tissues produce a large amount of various inflammatory cytokines and pro-thrombotic factors, and these productions are further increased in advanced age (PMC2844135, PMC3633415). Expression of these factors were examined after cell separation experiments, showing that age-dependent induction of these factors occurs more strongly in stromal cells compared to adipocytes. Both mortality rate and inflammatory response after induction of acute inflammatory stresses are significantly reduced by dietary restriction on aged mice. Our in vitro organ culture experiments revealed that adipose tissues from aged mice, as compared to young mice, showed increased inflammatory gene expression. In vitro studies also demonstrated that adipose tissues from dietary restricted aged mice, as compared to freely fed control mice, showed significantly reduced inflammatory gene expression. These results indicate that age-associated increase in inflammatory gene expression is due, not only to increased fat mass, but to changes in the nature of the fat by both aging and diet.
Session 3: Age-Related Neurodegenerative Disease
Neural Progenitors by Direct Reprogramming: Strategies for the Treatment of Alzheimer's Diseases
Jialin C. Zheng and Changhai Tian
Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA
ABSTRACT: Age-related neurodegenerative diseases, such as Alzheimer′s (AD) disease, are seriously threatening the health of an increasing aging society. Although there is no cure for AD, a variety of medications can provide relief from some of the symptoms. Recently, the development of direct reprogramming technologies has shed light on promising strategies for stem cell-based therapies for AD. The direct conversion of somatic cells from one cell type to another has been achieved by ectopic expression of specifically defined transcription factors. Using gene expression profiling and parental cells from E/Nestin:EGFP transgenic mice as a monitor system, we identified nine candidates with the ability to directly convert fibroblasts into NPCs. We found that five of the nine factors can directly convert adult dermal fibroblasts into NPC-like cells, named iNPCs, and these resulting iNPCs possessed the same properties as primary NPCs including proliferation, self-renewal and differentiation. Importantly, we have been working on the direct reprogramming of somatic cells into region-specific iNPCs as well as subtype-specific iNPCs by overexpression of defined transcription factors. The further development of this technology will undoubtedly provide promising strategies for the effective treatment of AD.
Keywords: Neural progenitor cells, direct conversion, iNPCs, neurodegenerative disease
TOR in Brain Aging and Age-Associated Neurological Disease
Veronica Galvan, PhD1,2, Ai-Ling Lin, PhD3, Stacy Hussong, PhD1,2, Jordan Jahrling, PhD1,2, Nick DeRosa, MS1,2, Reto Asmis, PhD4, Matthew J, Hart5, Steven Austad, PhD 6 and Kathleen Fischer, PhD6
1Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
2The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
3College of Medicine, University of Kentucky, Lexington, KY, USA
4Department of Clinical Lab Sciences and Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
5 Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
6Department of Biology, University of Alabama at Birmingham, AL, USA
Abstract: We recently showed that chronic treatment with the target-of-rapamycin (TOR) inhibitor rapamycin, a drug that extends lifespan and delays aging in mice, halted and even reversed Alzheimer’s (AD)-like memory deficits and reduced Aβ accumulation in brains of hAPP(J20) mice modeling the disease. We showed that attenuating TOR activity restored cerebral blood flow (CBF) and vascular density (VD) via eNOS activation in brain vascular endothelium, reduced CAA and microhemorrhages, and reestablished blood-brain barrier integrity in brains of hAPP(J20) mice. Reducing TOR activity also restored cognitive function, CBF and VD in mice modeling atherosclerosis, as well as in aged rats, in which reduced TOR activity was associated with complete recovery of cortical network activation and functional hyperemia evoked by somatosensory stimulation. Thus, the mechanisms by which TOR attenuation restores CBF may be common to different models of age-associated neurological disease and to brain aging. To distinguish between effects of TOR attenuation in cerebrovasculature and in brain parenchyma we used genetic tools to reduce mTORC1 complex formation in neurons by 30% and 60%. Reducing mTORC1 complex formation in neurons by 30% but not by 60% enhanced memory and increased brain glucose metabolism. We propose that TOR attenuation blocks age-associated brain dysfunction or disease by (a) preserving cerebrovascular function during aging through the restoration of endothelium-dependent, NO-mediated vasodilation, and by (b) enhancing brain metabolism. TOR inhibitors already used in the clinic may have promise as therapies for age-associated cognitive decline as well as for neurological diseases associated with aging.
New insight into the therapeutic role of serotonergic system in Parkinson’s disease
Laboratory of Pharmacology, Osaka University of Pharmacological Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, JAPAN
ABSTRACT: Parkinson’s disease (PD) is the most common neurological disorder in the elderly. Patients with PD suffer from progressive extrapyramidal motor dysfunctions including resting tremors, muscle rigidity, hypolocomotion (bradykinesia and akinesia) and postural instability. Various non-motor features are also observed in PD patients such as cognitive impairments (deficits in learning and memory) and mood disorders (depression and anxiety). While the serotonergic nervous system plays crucial roles in regulating psycho-emotional, cognitive, sensori-motor and autonomic functions, it is now known that multiple serotonin (5-HT) receptors regulate extrapyramidal motor functions. Specifically, stimulation of 5-HT1A receptors and blockade of 5-HT2A/2C, 5-HT3, or 5-HT6 receptors improve abnormalities of extrapyramidal motor functions. Among them, 5-HT1A receptors seem to serve as a novel therapeutic target for the treatment of PD since recent research revealed that 5-HT1A receptors play important roles in the treatment of PD. These include the modulation of parkinsonian motor symptoms, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, cognitive impairments and emesis. Thus, 5-HT1A agonists improve the various motor disorders associated with dopaminergic deficits, dyskinesia induced by chronic L-DOPA treatment, mood disturbances (anxiety and depression) and dopamine agonist-induced emesis. In addition, partial 5-HT1A agonists are expected to improve cognitive impairment in Parkinson’s patients. These findings encourage research into new 5-HT1A receptor ligands, which will improve efficacy and/or ameliorate adverse reactions in the treatment of PD.
Keywords: Parkinson’s disease, Serotonergic system, 5-HT receptors, 5-HT1A receptors, Extrapyramidal motor disorders, Cognitive impairment, Mood disorders
NAD+ Metabolism in Age-Related Hearing Loss
Hyung-Jin Kim1, Gi-Su Oh1, Ai Hwa Shen1,2, Su-Bin Lee1,2, Arpana Pandit1, Dipendra Khadka1,2 and Hong-Seob So1,2
1Center for Metabolic Function Regulation & Department of Microbiology, School of Medicine, 2BK21plus Program & Department of Smart Life-Care Convergence, Wonkwang University Graduate School, 460 Iksan-Daero, Iksan, Jeonbuk, 570-749, Korea
ABSTRACT: 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 study, 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.
Influence of physical exercise on age-related neurodegeneration: studies with models of dopamine deficiency
Michael J Zigmond1 and Richard J. Smeyne2
1University of Pittsburgh and 2St. Jude Children’s Research Hospital, Pittsburgh, USA
ABSTRACT: The motor deficits associated with Parkinson’s disease (PD) appear due in large part to the loss of dopamine (DA)-containing neurons projecting from substantia nigra (SN) to striatum. The motor impairments normally associate with aging also appear to involve a dopaminergic deficit. Pharmacological treatments exist that reduce the symptoms of PD. However, they have a limited period of efficacy, often produce side effects, and fail to significantly attenuate the neurodegenerative process. Despite the absence of neuroprotective pharmacological interventions, several labs have shown that physical exercise can reduce the vulnerability of DA neurons to neurotoxins in laboratory animals, suggesting that exercise would be useful in slowing the progression of PD and might be useful for age-related motor dysfunction a well. Furthermore, the impact of exercise seems to be associated with an increase in the concentration of neurotrophic factors (NTFs). We have studied these phenomena in animals and in several in vitro models. Among our conclusions are that several NTFs are likely to work synergistically to produce their neuroprotective actions and that this involves the activation of the phosphokinases, ERK and Akt, among other intracellular events that retard apoptosis.
Key words: Akt, BDNF, ERK, GDNF, rodent models,
Circadian rhythm, molecular clock and Parkinson's disease
Department of Neurobiology, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China
ABSTRACT: Parkinson's disease (PD), the second most common neurodegenerative disorder in the elderly, is characterized by the degeneration of melanized dopamine containing neurons in the substantia nigra, which results in a deﬁciency of dopamine in the striatum. Although the movement-related symptoms are still regarded as the main problem, extensive evidence supports the contention that circadian alterations are tightly associated with PD. Because circadian disruptions may result in sleep problems, oxidative stress and an altered inflammatory response, it has been speculated that circadian disruptions could contribute to PD pathogenesis. In the last few years, we demonstrated that a peripheral molecular clock, as reﬂected in the dampened expression of the clock genes BMAL1 in total leukocytes, is altered in PD patients. In addition, the relative BMAL1 levels correlate positively with PD severity, which could provide a molecular basis to help monitor disease progression and response to investigational drugs. Moreover, our study also demonstrates a significant association between clock genes tagSNP and sporadic PD in a Chinese population, suggesting that targeting circadian disruption and the molecular components of the clock may have therapeutic potential in PD.
Key words：circadian rhythm; clock gene; Parkinson's disease; gene expression; SNP
Session 4: Aging and Cardiovascular Diseases
Understanding aging and injury using a focused microarray
Departments of Laboratory Science, Surgery, and Biochemistry and Molecular Biology Georgia Regents University, Augusta, GA 30912
ABSTRACT: Aging increases predisposition to critical illness and old age is an independent risk factor for mortality in critically ill patients. Mitochondrial function is important in cellular homeostasis in aging and injury. Mitochondria play a critical role in the energy demand of cardiac muscles, and thereby on the function of the heart. Recent studies using our custom-made mitochondrial gene chip, RoMitochip, identified alteration of a number of genes related to cellular energetics, following trauma-hemorrhage (T-H) in 6 and 22 month old rats. There was a decline in the number and amplitude of expression of mitochondria-related genes in aged rats as compared to the younger rats, following T-H. Further, the study identified SIRT1 as a potential molecular target in T-H. Activators of SIRT1 improve mitochondrial function and Sirt1 activity is known to increase with caloric restriction. Resveratrol (RSV) has been shown to significantly increase Sirt1 activity through an allosteric interaction, resulting in the increase of Sirt1 affinity for both NAD+ and the acetylated substrate. We observed a significant improvement in left ventricular function (p<0.05, n=4-5) following RSV treatment, in rats subjected to T-H procedure. RSV treatment restored the expression of SIRT1 (p<0.05), Pgc-1 (p<0.05), and c-Myc (p<0.05), and tissue ATP content following T-H. We also observed significantly declined cytosolic cytochrome c and plasma TNF- levels in the RSV treated group as compared to vehicle treated group subjected to T-H. We conclude that modulation of mitochondrial function by SIRT1 activation may have beneficial effect in reducing cardiovascular functional decline following hemorrhagic injury. Support: NIH R01 GM101927.
Keywords: aging, cardiac function, mitochondria, trauma, hemorrhage
mHealth technology: a efficient way to manage chronic diseases
The Institute of Geriatric, the Chinese PLA General Hospital, Beijing, 100853, China
ABSTRACT: Our country has entered the aging society, with a large population of patients of chronic diseases ( hypertension, diabetes mellitus cardiovascular and cerebral vascular disease), which have raised a huge burden of medical care and also consumed huge medical resources in our country. Development of wearable medical equipment and network based on mHealth provides a new way to manage this kind of diseases.By using mobile wearable device, we can remotely monitor the patient's ECG, blood pressure, blood glucose and sleep. mHealth provides an efficient management mode for chronic disease, greatly improving affordability access and treatment of high quality medical resources. However, it should be mentioned that the application of wearable devices must be closely combined with the clinical team of experts, based on a new medical care runing mode. Wearable medical devices without medical guidance from senior medical personnel will just be fashionable toys of short duration.
Neuroplasticity and Motor Memory Retention for Reduction of Idiopathic Falls among Community-Dwelling Older Adults
Yi-Chung (Clive) Pai1,2,3, Tanvi Bhatt1 , and Feng Yang3
1Department of Physical Therapy, 2Department of Biomedical Engineering and 3Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA
ABSTRACT: The cumulative effect of falls on older adults and on our healthcare system is enormous: the results are debilitating injuries, loss of independence, and transfer to an institution or even death. Nearly 60% of outdoor falls among community-living adults aged 70 or older come from slips or trips during walking, resulting from their inability to control stability, often coupled with inadequate limb support against gravity during the recovery. Conventional programs rely on improving a person’s volitional skills requiring weeks or months of training. Recently emerged perturbation-based motor (implicit) learning involves of destabilization process to improve both volitional and reactive skills. This trial-and-error (learning-from-falling) practice stimulates the central nervous system (CNS) to make adaptive. This study was to determine whether older adults could retain fall-resisting skills acquired from a single perturbation-training session for up to 12 months. Seventy-three community-dwelling older adults (72.7+5.4 years) received single-session treatment consisted of 24 slips through unannounced unlocking of a low-friction, moveable section of the walkway. A single retest scheduled based on a 3-stage sequential, pre-post-retest design. The training boosted their resilience to falls by 43.1%. Falls remained low in 6-month (0%), 9-month (8.7%) and 12-month retest (12%); all attributable to the retention of their significantly improved control of stability, proactive and reactive, acquired from the initial training session. The findings reveal promising functional plasticity of the CNS and outstanding motor memory of such adaptive control of stability, in spite of commonly known age-related sensory motor decay.
Session 5: Aging and Stroke
Attenuating Brain Metabolic Dysfunction Improves Stroke Outcome: Is Ethanol A Solution?
Department of Neurological Surgery, Wayne State University School of Medicine, USA
ABSTRACT: Stroke is the 3rd-leading cause of death and leading cause of serious, long-term disability worldwide. Cellular oxidative stress, which is associated with excessive production of reactive oxygen species (ROS), is the foundation of brain damage and loss of function after stroke. Energy failure and mitochondrial dysfunction resulting from the impaired delivery of glucose and oxygen to brain tissue have been extensively studied as mechanisms of detrimental oxidative stress. Thus far, however, research has failed to develop targeted therapies to normalize neural catabolic metabolism and mitochondrial function, and confer neuroprotection in ischemic stroke. Ethanol (ETOH) is an old drug that decreases brain metabolism, thus raising the possibility that ETOH serves as a clinical neuro-protectant in stroke by ameliorating metabolic dysfunction. In addition, ETOH has been proven safe in the clinic as an antidote to toxic alcohol (e.g., methanol) ingestion. Therefore, we seek to investigate the contribution of impaired neural catabolism and mitochondrial function to poor outcome in stroke, and to establish the clinical potential of ETOH as a new neuroprotective strategy for attenuating metabolic disorder after stroke, leading to improved recovery.
Therapeutic Mechanism of Endothelial Progenitor Cell Transplantation for Ischemic Stroke
Med-X Research Institute and School of Biomedical Engineering,
Shanghai Jiao Tong University, Shanghai, China
ABSTRACT: Circulating endothelial progenitor cells (EPCs) has been linked to the risk factor and prognosis of cerebrovascular or cardiovascular diseases. However, the role of EPC transplantation for ischemic stroke therapy is unknown. It was reported that astrocytic-high mobility group box1 (HMGB1) promoted endogenous EPC-mediated neurovascular remodeling during stroke recovery. It is unclear whether HMGB1 involves in exogenous EPC-mediated stroke recovery. In the current study, we explore whether microglial HMGB1 contributes to EPCs-mediated neurovascular remodeling by modulating the paracrine function of exogenous EPCs.
Co-culture with LPS-activated BV2 cells up-regulated IL-8, VEGF, IGF-1, HGF and FGF expression in EPCs (p<0.05). Suppressing HMGB1 using glycyrrhizin inhibited IL-8 up-regulation in EPCs (p<0.05). Conditional medium from EPC co-cultured with activated BV2 cells promoted proliferation and tube formation for HUVECs (p<0.05). Suppression of HMGB1 in BV2 cells or IL-8 knockdown in EPCs by siRNA reversed the effect of EPC conditional medium on HUVECs (p<0.05). In vivo study showed EPC transplantation led to increased vessel density in perifocal region, reduced atrophy volume and improvement in neurobehavioral functions following 14 days of focal cerebral ischemia in mice (p<0.05). Administration of glycyrrhizin (10 mg/kg/d) blocked the beneficial effect of EPC transplantation (p<0.05). Further investigation showed GFP+ exogenous endothelial progenitor cells accumulated in perifocal region following 14 days of ischemia in mice, but integration of exogenous EPCs with CD31+ microvessels was not detected.
Patient-specific peripheral blood-derived endothelial progenitor cells are an ideal source of stem cell for the ischemic stroke treatment. The therapeutic mechanism of exogenous EPCs is associated with paracrine function of EPCs. Ischemia-induced microglial HMGB1 hyperexpression is an important factor for the trigger the repairing and remodeling during post-ischemia.
Significance and Mechanisms of Ischemic Postconditioning against Stroke
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5327, USA
ABSTRACT: Stroke remains one of the leading causes of human death and disability worldwide, yet treatments are very limited. Therefore, it is necessary to explore novel neuroprotectants for stroke therapy. One of novel concepts is ischemic postconditioning (IPostC), which is defined in contrast with ischemic preconditioning (IPreC). While IPreC refers to a sub-lethal, brief ischemia before stroke onset, IPostC refers to a mechanical interruption of reperfusion, as if IPostC is conducted when the stimulus of IPreC is removed before stroke onset to after reperfusion. Both IPreC and IPostC protect against brain injury. Nevertheless, as the occurrence of most strokes cannot be predicted, IPostC is more clinically relevant. Now, the concept of IPostC has been expanded from reperfusion interruption to a broad range of intervention, including hypoxic postconditioning, remote postconditioning, and pharmacological postconditioning. The aim of this presentation is to review the progress of IPostC in stroke research. I will summarize the IPostC models, therapeutic time windows, and the underlying protective mechanisms. Both rapid and delayed IPostC will be discussed; the protective mechanisms of IPostC include the involvement of reactive oxygen species (ROS), apoptosis, inflammation, and neuronal survival signaling pathways, such as the Akt/mTOR pathways. These protective mechanisms will be compared with those of IPreC. Lastly, future research directions of IPostC will be discussed.
Key words: ischemic postconditioning, stroke, Akt, mTOR
EFFECTS OF LIPOCALIN-2 IN THE REGULATION OF GLIAL ACTIVATION AND ANGIOGENESIS
Changhong Xing, Limin Wu, Wendy Leung, Josephine Lok, & Eng H. Lo
Departments of Radiology, Neurology and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129
Abstract: Inflammation is a key part of central nervous system pathophysiology. Recently, it is thought that inflammatory factors may have both beneficial and deleterious actions. Here, we examine the hypothesis that lipocalin-2, an inflammatory molecule that can be upregulated in the distressed central nervous system, may regulate glial activation and enhance angiogenesis in brain cells. Methods – In vitro, microglia, astrocytes, or brain endothelial cells were exposed to lipocalin-2 and various markers and assays of glial activation and angiogenesis including tube formation and migration were quantified. Results - In primary glial cell cultures, exposing microglia and astrocytes to lipocalin-2 resulted in glial activation. In microglia, lipocalin-2 converted resting ramified shapes into a long-rod morphology with reduced branching, increased interleukin-10 release, and enhanced phagocytosis. In astrocytes, lipocalin-2 upregulated GFAP, BDNF and thrombospondin-1. Adding lipocalin-2 (0.5-2.0μg/ml) to RBE.4 rat brain endothelial cells significantly increased matrigel tube formation and scratch migration, and also elevated levels of iron and reactive oxygen species (ROS). Co-treatment with a radical scavenger (UE83836E), a Nox inhibitor (apocynin) and an iron chelating agent (deferiprone) significantly dampened the ability of lipocalin-2 to enhance tube formation and scratch migration in brain endothelial cells. Conclusions - These findings provide in vitro proof-of-concept that lipocalin-2 may contribute to gliovascular recovery aspects of inflammation by activating microglia and astrocytes into potentially pro-recovery phenotypes and promoting angiogenesis via iron and ROS-related pathways.
Session 6: Aging, Metabolism, hormone and Diseases
Caloric Restriction, Brain Aging, and Neurodegenerative Disease
Michael J. Forster
University of North Texas Health Science Center, Fort Worth, TX. 76107, USA
ABSTRACT: The observation that a reduction in food intake, or caloric restriction (CR), delays the decline in physiological fitness and extends the life span of organisms of diverse phylogenetic groups, has for some time been considered the primary evidence for a public mechanism of aging and disease. Because CR is presumed to retard such a universal aging process, it has been considered as a valuable tool for elucidating mechanisms of vulnerability in neurodegenerative disease. Emerging evidence has disputed some of the primary tenets of this conception, suggesting that the CR-related increase in longevity is not shared among different strains of the same species, and that the beneficial effects of CR accrue in proportion to the propensity, under non-restricted feeding, for different genotypes or diets to promote energy imbalance leading to weight gain across the life span. Among common laboratory mouse backgrounds used in studies of aging and neurodegenerative disease, the ability of CR to extend longevity and ameliorate age associated declines in cognitive and psychomotor function was most evident in B6D2F1 and B6C3F1 mice, less evident in C57BL/6, and nearly absent in DBA/2 mice. The long-term beneficial effects of CR occurred in direct proportion to the cumulative adult body weight gain associated with each genotype under conditions of non-restricted feeding. When present, the beneficial effects of CR were partially or fully reversible, albeit in an age-dependent manner, following experimentally imposed positive or negative shifts energy intake. A survey of rat genotypes used in studies of aging and neurodegenerative disease revealed a similar relationship between weight gain in control groups and the beneficial effects of CR. Existing evidence supports the view that CR increases the life span and delays brain aging and vulnerability to disease, only in those particular genotypes that develop energy imbalance due to non-restricted feeding. It is further suggested that use of non-restricted controls to study the interaction of aging and disease should be reconsidered.
Key Words: energy balance, obesity, animal models, memory, motor function
Sirt1 Sits at the Crossroad of Cancer, Metabolism and Aging
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Health (NIH), Bethesda, MD, USA
ABSTRACT: Mammalian Sirt1, the closest homolog of yeast sir2, is a NAD+ dependent protein deacetylase. Liver specific deletion of Sirt1 abolished AKT activation upon insulin stimulation; leads to hepatic hyperglycemia, fatty liver and eventually type 2 diabetes. Pancreatic deletion of Sirt1 impaired beta-cell formation; results in hyperglycemia as well. In combination with p53, whole body Sirt1 haplo-efficiency displayed carcinoma in mammary gland, endothelial compartment and lymphoma. At last, loss of SIRT1 disrupts circadian clock, and leads to premature aging phenotype. With above evidence, we predict utilization of Sirt1 angonists might generate clinical benefits.
Keywords: SIRT1, Aging, Type2 diabetes, Breast cancer
Growth hormone, methionine metabolism and aging
Holly M. Brown-Borg
University of North Dakota School of Medicine and Health Sciences, North Dakota, USA
ABSTRACT: Endocrine hormones impact aging and age-related disease. Growth hormone (GH) affects not only somatic growth but also drives aspects of metabolism and stress resistance. We have shown that GH modulates methionine metabolism and longevity in GH mutant mice. Our studies focus on delineating the relationships between dietary methionine, metabolism and plasma GH levels as they relate to DNA methylation and potential epigenetic stability. Long living Ames dwarf, GH receptor knock out and short-living GH transgenic mice were subjected to different levels of dietary methionine in short-term (8 weeks) and long-term (lifetime) studies. Methionine metabolism, plasma IGF1, body weights, food consumption, end of life pathology and lifespan were examined in respective studies. In addition, DNA methylation differences between Ames dwarf and wild type mice were evaluated. Methionine conserving and catabolizing enzymes were differentially affected by dietary methionine level. Underlying GH status also influenced the metabolic responses to alterations of this amino acid. We observed that long-living GH signaling deficient (Ames, GHRKO) mice were not able to discriminate differences in dietary methionine in terms of lifespan. GH transgenic mice and the wild type mice from each line lived longer when fed methionine-restricted but not methionine-supplemented diets. Evaluation of the DNA methylation data set, thus far, suggests that the Ames mice maintain their epigenome better (from young to old) than wild type mice supporting the hypothesis that epigenetic stability contributes to longevity. These studies indicate that GH status affects the ability to respond to dietary methionine, and downstream aspects of metabolism including DNA methylation, health and lifespan.
Key words: growth hormone, aging, methionine, DNA methylation, dwarf mice
Estrogens are Potent Neuroprotectants
James W. Simpkins
Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 2608 USA
ABSTRACT: Estrogens have been shown to protect brain tissue in a number of acute neuronal compromising conditions as well as in chronic neurodegenerative diseases. The mechanism(s) of estrogen neuroprotection are many, suggesting that these hormone are pleotropic and therefore may be useful multiple-targeted therapies in a single molecule. Our research has assessed estrogens in experimental models for stroke, traumatic brain injury and Alzheimer’s disease, and in each model, low doses of estrogens were neuroprotective. Additionally, we have assess a number of mechanism of estrogen neuroprotection. We have shown that estrogens undergo redox cycling and thereby can repeatedly neutralize reactive oxygen species. Additionally, estrogens activate a number of antiapoptotic signaling pathways. Further, estrogens enhance mitochondrial function and thereby ameliorate the toxic effects of oligomeric Aβ. Finally, we have shown that estrogens stimulate then rapidly terminate ERK signaling, providing a signal for neuroprotection. Inasmuch as chronic estrogen therapy, as would be required for the prevention and/or treatment of neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease, is associated with a hyper-coagulatory state and adverse events, we conducted a drug discovery program to enhance the neuroprotective of estrogens while eliminating their adverse effects. We discovered that the phenolic A ring of estrogen is essential for neuroprotection, but that other modification of the molecule can occur that eliminate interaction with estrogen receptors while maintaining neuroprotection. Collectively, these studies indicate that estrogens can be built that are safe, effective and useful in a number of acute neuronal compromising conditions, as well as in neurodegenerative disease. (Supported by the following grants for the NIH: P01 AG022550; P01 AG027956; P20 GM109098; and U54GM104942.)
Energy Metabolism as a Target for Neuroprotection and Glioblastoma
Shaohua Yang, MD., PhD.
Department of Pharmacology and Neuroscience, University of North Texas health Science Center at Fort Worth, TX. 76107, USA; Department of Neurosurgery, Beijing Tiantan Hospital, Beijing Neurosurgical Institute, Capital Medical University, Beijing. 100050, China.
ABSTRACT: Brain has an exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Although the overall oxygen and glucose consumption does not change in the whole brain, the energy demand and supply is tightly coupled in different brain area through neurovascular and neurometabolic coupling. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer, Parkinson and other neurodegenerative diseases, providing a clear link between neurodegenerative disease and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) might provide macromolecule for biosynthesis and proliferation. We found that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates to cytochrome C, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Parkinson and ischemic stroke. In glioblastoma, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation and inhibiting lactate production. Methylene blue arrests glioma cell cycle at s-phase and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP-activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin-dependent kinases. In summary, our studies have provided a proof of concept that enhancement of mitochondrial oxidative phosphorylation offer protective action against neurodegenerative diseases and inhibit glioblastoma proliferation.
Session 7: Genetics, Aging and Disease
Variation in the autophagic beclin-1 (BECN1) has a potential to modify onset of
Machado–Joseph disease (MJD/SCA3): a study of the BECN1 gene promoter and the evolutionarily conserved domain (ECD).
Nadiya Kazachkova1,2, Mafalda Raposo1,2, Rafael Montiel3, Amanda Ramos1,2 & Manuela Lima1,2
1Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal. 2Center of Research in Natural Resources (CIRN), University of the Azores, Ponta Delgada, Portugal 3Laboratorio Nacional de Genómica para la Biodiversidad (LANGEBIO), Unidad de Genómica Avanzada, CINVESTAV-IPN, Irapuato, Mexico
ABSTRACT: Autophagy, as a process of lysosomal-dependent intracellular components degradation, is especially important in disorders where accumulation of the mutant protein is a hallmark, such as Machado-Joseph disease (MJD/SCA3; OMIM 109150), a late onset progressive polyglutamine ataxia, considered the worldwide most common autosomal dominant polyQ SCA caused by a CAG tract expansion in the ATXN3 gene (OMIM 607047). Beclin 1 is one of the autophagy-related proteins, defects in which were found to be correlated with neurodegenerative diseases. The increase of Beclin 1 at the site of injury may represent enhanced autophagy as a mechanism to discard injured cells and reduce damage to cells by disposing of injured components. We studied the variation in the evolutionarily conserved domain (ECD) and promoter of the BECN1 gene, whose overexpression has been reported to exert neuroprotective effects in MJD. The relation between BECN1 promoter variation and expression levels was studied, as well as its impact on disease onset. The BECN1 promoter and ECD were sequenced in 95 MJD patients and 120 controls. In silico analysis (PROMO) were performed to detect differences in putative transcription factor binding sites (TFBS). BECN1 expression level was quantified by real-time PCR in 29 MJD patients and 27 controls, for which cDNA from peripheral blood was available. No variations were found in ECD; in the BECN1 promoter four previously described variants (rs60221525, rs116943570, rs34882610 and rs34037822) and one novel - c.-933delG were found in MJD patients and in controls. Because a novel SNP was detected only in 2 controls and 1 MJD case, and SNPS rs34882610 and rs34037822 – only in 1 control and 1 MJD case, respectively, only two SNPs (rs60221525 and rs116943570) were selected for further analysis. In silico analysis predicted the existence of less putative TFBS for rs60221525 and of more TFBS for rs116943570. BECN1 expression levels were in agreement with the in silico predictions, showing decreased and increased expression for rs60221525 and rs116943570, respectively. CAG number explained 60.5% of the variance in onset; when rs60221525 and rs116943570 were added to the multiple regression model, there was a tendency for the increase in the explanation. Variation found in the BECN1 promoter modulates expression and has a potential to modify onset of MJD. The analysis of more patients should increase the power of the study and confirm the role of BECN1 as a modifier of MJD.
Keywords: autophagy, neurodegeneration, Machado–Joseph disease, ataxia, promoter, evolutionarily conserved domain (ECD), gene expression
The physics behind the Gompertz law, aging, and negligible senescence
I. Molodtsov, A. Tarkhov, V. Kogan, L. Menshikov, R. Shmookler J. Reis and P. Fedichev
Quantum Pharmaceuticals, Moscow, Russia
ABSTRACT: The biology of aging has more than its share of conundrums -- why do we become less fit as we age; why does resistance to a host of stresses decline with age; why does mortality rise exponentially with age, as described by “Gompertz’ law”; and how do some species evade senescence, such as the Naked Mole Rat that lives >28 years with no increase in mortality or decline in reproduction? We begin with an analysis of network stability, and the assumption that most biological organisms inhabit a precarious domain between instability and stability, and strive to maintain that critical balance in the face of environmental perturbations (stresses). From these premises, we derive an equation with both stable and unstable solutions, reflecting negligibly senescent and normally senescing species respectively. Our model predicts that all controlled parameters of the organism (transcript levels, epigenetic states, metabolites, etc.) will be maintained close to initial values in stable systems, but will progressively drift away from young levels in species with unstable networks. The model’s predictions are remarkably consistent with observations from the transcriptome of aging fruitflies (whether calorically restricted or not), the observed progressive decline in stress resistance with age in senescing species only, and the ability of even unstable (aging) animals to recover from most perturbations with no reduction in longevity. Most importantly, the model clarifies the nature and lets rationally design the kinds of interventions that could stabilize networks, and extend lifespan of model animals and, hopefully, humans.
Iron dysregulation and oxidative stress interact to cause increased amyloid beta production in aged rat brain: implications in the pathogenesis of sporadic Alzheimer's disease.
Sasanka Chakrabarti, Priyanjalee Banerjee, Shruti Anand, Arghyadip Sahoo and Aritri Bir
Department of Biochemistry, Institute of Post-graduate Medical Education and Research, Kolkata, India
ABSTRACT: The pathogenesis of sporadic Alzheimer's disease (AD) is intimately related to brain aging. Thus, the aged brain especially when metabolically manipulated can be employed as a useful tool to study AD pathogenesis. In the present study we have attempted to explore how iron dysregulation is involved in enhanced amyloid precursor protein (APP) and amyloid beta peptide (Aβ42) synthesis and accumulation in the aged brain. We observed that iron accumulated in aged (22 - 24 months) rat brain compared to that in the brain of young (4 - 6 months) animals presumably as a result of overexpression of transferrin receptor and ferritin. Concomitant with these changes, an accumulation of APP and Aβ42 along with increased β secretase activity and decreased activity of neprilysin was noticed in the aged rat brain. When rats were given the iron-chelator, deferasirox, regularly with the diet in a dose of 25 mg/kg of body weight from 18 months onwards till they were sacrificed between 22 - 24 months, most of the age-dependent changes in iron and amyloid beta metabolism in the brain were reversed implying the critical role of iron in these phenomena. Further, we are exploring whether the oxidative stress has any role in the upregulation of transferrin receptor and ferritin with consequent increased iron accumulation in the aged brain by analyzing these parameters in the brain of aged rats (22 - 24 months) who were given daily dietary supplementation with a cocktail of antioxidants comprising of α-tocopherol, α-lipoic acid and N-acetylcysteine from 18 months onwards. The upregulation of several redox-sensitive transcription factors in the brain of aged rats with or without antioxidant supplementation is currently under investigation in this context. The results of our study have clear implications in the pathogenesis of AD.
Keywords: Brain aging, Amyloid beta peptide, Amyloid precursor protein, Transferrin, Ferritin, Iron, Alzheimer's disease
Maf1 regulation of mitochondrial function mediates TOR signaling for longevity
Ying Cai and Yuehua Wei
No.3 People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
ABSTRACT: Calorie restriction (CR) can extend lifespan of various species, ranging from single organisms such as budding yeast to human. The target of rapamycin complex 1 (TORC1) has recently been shown to be a critical modulator of CR-induced lifespan extension. However, the underlying mechanisms remain poorly understood. We have previously shown that Maf1, a protein involved in tRNA synthesis, is phosphorylated by TORC1 kinase. Here we show that Maf1 is required for CR and mTOR complex 1 (mTORC1) inhibition to extend lifespan. mTORC1 inhibition induces mitochondrial hyper-fusion, up-regulation of mitochondrial antioxidant enzymes and enhanced respiration, all of which are dependent on Maf1. Further analysis suggests that tRNAs may play a key role in mediating Maf1’s life-prolonging effect. Together, we propose that in response to CR, Maf1 acts as a key activator of mitochondrial stress response to promote longevity.
Key words: Calorie restriction (CR), Target of rapamycin (TOR), Maf1, tRNA, mitochondria
Aberrant expression of microRNA according to aging is participating in hepatocarcinogenesis
Y-h. Taguchi1, Yoshiki Murakami2, Saori Itami2, Masahiko Kuroda3, Hidenori Toyoda4 and Takashi Kumada4
1Department of Physics, Chuo University, Tokyo, Japan
2Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
3Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
4Department of Gastroenterology, Ogaki Municipal, Gifu, Japan
ABSTRACT: A large cohort study was carried out to determine that the aging was strong risk factor on hepatocarcinogenesis in spite of the stage of liver fibrosis. Several miRNAs have emerged as potentially coordinating multiple pathways during aging. We compared hepatic miRNA and mRNA expression profile in between chronic hepatitis C (CHC) and hepatocellular carcinoma (HCC) in order to elucidate the difference in the carcinogenetic mechanism according to age. miRNA expression pattern in 110 HCC from surgical resection and 105 CHC from fine needle biopsy, and mRNA expression profile was 24 HCC and 24 CHC were analyzed by microarray, respectively. The HCC-CHC pair was created from all samples and expression of miRNA and mRNA was also compared, respectively.13 miRNA in which p-value (HCC>CHC: miRNA) and p-value (HCC>CHC: mRNA) have negative correlation has identified. Bottom of p-value of these miRNAs and top of p-value of their target genes showed at 60 years old. To clarify the contribution ofhepatocarcinogenesis by miRNA, we investigate hypothetical pathways by the DIANA-miRPath pathway in these 13 miRNAs. miRNAs had significant change by the case where of the same age compared CHC and HCC, and the peak of p-value was about 60 years old.
515-3p as a miRNA and Cyclin-dependent kinase inhibitor 1A (CDKN1A) as its target genes which is participating in hepatocarcinogenesis from this information were obtained. Because the expression level of miR-515-3p varied regards to aging, aberrant expression of these miRNAs were able to participate hepatocarcinogenesis in different way.
Session 8: Aging, DNA damage, Telomeres, Protein oxidation and Disease
Small Heat-Shock Proteins in Lens Aging and Cataract
K. Krishna Sharma
Departments of Ophthalmology and Biochemistry, School of Medicine, University of Missouri, Columbia, MO, USA, 65212
ABSTRACT: The eye lens is a transparent tissue with primary function of focusing the light on the retina. Alpha-crystallin, belonging to the small heat shock protein family is the major protein in the lens. Its chaperone activity is responsible for maintaining lens transparency. Loss of a-crystallin chaperone activity has been implicated in age-related cataract, affecting over 90 million people world-wide. Using mass spectrometric imaging methods we and others have reported that in aging lenses there is a breakdown of a-crystallin. The concentrations of crystallin-derived peptides increase with age. The cataract lenses as well as opaque regions of otherwise clear lenses show accumulation of crystallin fragments. We hypothesized that a-crystallin-derived peptides interact with lens crystallins (native and modified by age-related reactions) and the resulting complexes clump together to form light scattering aggregates, the hall mark of cataract lenses. Analysis cataract lenses showed that specific peptides (aA66-80 peptide and its truncated forms) associate with water-insoluble proteins fraction, pro-apoptotic and generate H2O2 in presence of metal ions. Guinea pig lens tissue subjected to hyperbaric oxygen (HBO), a model for age-related cataract formation in humans also shows the accumulation of these peptides. Additionally, αA66-80 peptide interaction with a-crystallin diminishes the chaperone activity of the latter. Time-lapse recordings shows that preformed complexes of a-crystallin and aA66-80 attract additional crystallin molecules to form light scattering aggregates. These results demonstrate that the molecular mechanism of peptide–mediated cataract development in aged human lens can be replicated in HBO-induced lens opacity in guinea pig model of age-related cataract.
Key words: Crystallin, Cataract, Aging, Chaperone, Peptides.
Endogenous formaldehyde and age-related cognitive impairment
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
ABSTRACT: Formaldehyde, one of the most toxic organic compounds, is produced and processed in human cells. The level of human endogenous formaldehyde is maintained at a low concentration (0.01−0.08 mM in blood) under physiological conditions, but the concentration gradually increases during ageing (over 65 years old). Clinical trials have shown that urine formaldehyde concentrations are significantly different between elderly Alzheimer’s patients and normal elderly volunteers. Abnormally high levels of intrinsic formaldehyde lead to cognitive impairment for instance learning decline. Excess extracellular and intracellular formaldehyde could induce metabolic response and abnormal modifications of cellular proteins such as hyperphosphorylation of Tau protein in particular of nucleus Tau. Senescence Accelerated Mouse P8 (SAMP8) over three months old has also imbalance of brain formaldehyde metabolism with a distinctly learning impairment. Epidemiological investigation showed that the intrinsic formaldehyde level of aging people (over age of 65, n=606) is closely related with their education grades, namely the illiterate persons have high concentrations of intrinsic formaldehyde, but those with high education (more than 12 years) have relatively low concentration of formaldehyde. It appears that formaldehyde plays a role in learning. Chronic impairments of the brain resulted from formaldehyde stress could be one of the risk factors for age-related cognitive impairment.
Key words: formaldehyde, age-related cognitive impairment, Alzheimer’s disease, metabolic imbalance.
Session 9: Aging, immune and translation
Targeting Inflammatory Cytokine Dysregulation in Neurodegenerative Disorders
Linda J. Van Eldik
University of Kentucky, Lexington, KY, USA
ABSTRACT: Evidence from clinical studies and preclinical animal models suggests that proinflammatory cytokine overproduction from activated glia is a potential driving force for pathology progression in neurodegenerative conditions such as traumatic brain injury and Alzheimer’s disease. In addition, a prior head injury can increase the risk for later development of dementia, and excessive proinflammatory responses in the brain could be a key link between these two events. This raises the possibility that selective targeting of the dysregulated cytokine response, a component of the neuroinflammation that contributes to neuronal dysfunction, may be a useful therapeutic approach. We are developing CNS-active, small molecule experimental therapeutics that selectively restore injury- or disease-induced overproduction of proinflammatory cytokines back towards homeostasis. We have used both molecular target-based and function-based drug discovery approaches to develop compounds that act on different signaling pathways. One class of compounds are highly selective inhibitors of p38α MAPK, a key protein kinase involved in the pathological up-regulation of proinflammatory cytokines and other neuroinflammatory responses in activated glia, as well as in stress-related axonal and synaptic dysfunction in neurons. The other class of compounds are not p38 inhibitors, but act through other signal transduction pathways to selectively suppress stressor-induced glial activation and overproduction of proinflammatory cytokines that contribute to pathology. Both classes of compounds attenuate excessive glial activation, cytokine production and downstream neurologic sequelae in CNS disease models. Our data continue to add to the growing body of evidence that has identified dysregulated glial activation and proinflammatory cytokine overproduction as a common early pathophysiologic mechanism and potential therapeutic target in diverse neurodegenerative disorders.
Keywords: microglia, kinase, cytokines, traumatic brain injury, Alzheimer’s disease, drug discovery
Greater Glucocorticoid Receptor Activation in Hippocampus of Aged Rats Sensitizes Microglia
Ruth M. Barrientos1, Vanessa M. Thompson1, Meagan M. Kitt1, Jose Amat1, Matthew W. Hale2,3, Matthew G. Frank1, Nicole Y. Crysdale1, Christopher E. Stamper2, Patrick A. Hennessey2, Linda R. Watkins1, Robert L. Spencer1, Christopher A. Lowry2, Steven F. Maier1
1Dept. of Psychology and Neuroscience, 2Dept. of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA, 3School of Psychological Science, La Trobe University, Melbourne Campus, Victoria, 3086, Australia
ABSTRACT: Healthy aging individuals are more likely to suffer profound memory impairments following an immune challenge than are younger adults. These challenges produce a brain inflammatory response that is exaggerated with age. Sensitized microglia found in the normal aging brain are responsible for this amplified response, which in turn interferes with processes involved in memory formation. Because glucocorticoids, under certain circumstances, have been shown to be immunoenhancing rather than immunosuppressive, the role of corticosterone (CORT) in microglial sensitization was examined in aged rats. Aged rats exhibited higher CORT levels in the hippocampus, but not in plasma, throughout the daytime (diurnal inactive phase). These age-related daytime elevated hippocampal CORT levels are associated with increased hippocampal 11β-HSD1 protein expression, the enzyme that catalyzes glucocorticoid formation, and greater hippocampal glucocorticoid receptor (GR) activation at this time of day. A low dose of mifepristone, a GR antagonist, administered intracisternally in the daytime was found to be effective at reducing immune-activated proinflammatory responses, specifically from hippocampal microglia, and at preventing E. coli-induced memory impairments in aged rats. Voluntary exercise as a therapeutic intervention did not alter hippocampal CORT levels, but did significantly reduce total hippocampal GR expression. These findings strongly suggest that increased GR activation in the aged hippocampus plays a critical role in sensitizing microglia, as reduction of this activation either pharmacologically or through voluntary exercise reduced neuroinflammatory responses, and prevented long-lasting memory deficits following an immune challenge.
Keywords: neuroinflammation, hippocampus, cognition, aging, microglia sensitization, glucocorticoid receptor, mifepristone, voluntary exercise
Phosphatase Wip1 is essential for the maturation and homeostasis of medullary thymic epithelial cells in mice
Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beichen Westen Road 1-5, Chaoyang District, Beijing, China
ABSTRACT: Thymic epithelial cells (TECs) are a key cell type in thymic microenvironment essential for T cell development. However, intrinsic molecular mechanisms controlling TEC differentiation and activities are poorly defined. Herein we found that deficiency of p53-induced phosphatase 1 (Wip1) in mice selectively caused severe medullary TEC (mTEC) maturation defect in an intrinsic manner. Wip1 knockout (KO) mice had decreased mature EpCAM+UEA-1+ mTECs, including UEA-1+MHCIIhigh, UEA-1+CD80+, UEA-1+CD40+ and UEA-1+Aire+ cells but not numbers of cortical EpCAM+BP-1+TECs (cTECs) in postnatal but not in fetal stage. Wip1-deficient mTECs express less tissue-restricted antigens and UEA-1+involucrin+ terminal differentiated cells. Animal models including grafting fetal Wip1-deficient thymic tissue into T cell-deficient nude mice and reconstitution of lethally irradiated Wip1KO mouse recipients with wild-type bone marrow cells also showed the impaired mTEC components in Wip1KO thymi, indicating the intrinsic regulatory role of Wip1 in mTEC maturation. Furthermore, the thymus regeneration was significantly less efficient in adult Wip1KO mice than in wild-type mice after cyclophosphamide-treatment. Wip1 deficiency resulted in an elevated p38 MAPK activity in mTECs. Activated p38 MAPK has the ability to suppress CD40 expression on mTECs. Wip1-deficient thymi displayed poor response to CD40L in fetal thymus organ culture system. Thus, Wip1 positively controls mTEC maturation, homeostasis and regeneration through limiting p38 MAPK pathway.
Self-reactive T cells participate in inflamm-aging due to compromised thymic negative selection, but not defects in regulatory T cell generation
Brandon Coder1, Linhui Ruan2, and Dong-Ming Su1,2*
1.Department of Molecular Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX, 76107, USA. 2.First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, P. R. China.
ABSTRACT: Age-related chronic persistent low-grade pro-inflammatory state, termed inflamm-aging, is attributed to senescence-associated secretory phenotype (SASP) and persistent activation of immune cells. The persistent activation of immune cells was reported to be mainly attributed to long-term viral infections, such as cytomegalovirus (CMV), etc. However, we found that non-viral infection mice also possess a persistent activation of immune T cells, which raises a new question regarding to whether self-reactive T cells released from the aged atrophied thymus involve a process of inflamm-aging. If so, what is a mechanism responsible for the self-reactive T cell emigration and whether can immune tolerance another arm—regulatory T cells (Tregs) be effectively generated? With multiple genetically engineered mouse models we demonstrated that self-reactive T cells indeed involved inflamm-aging, since they displayed an activated state shortly after exiting the atrophied thymus. The release of the self-reactive T cells resulted from intrinsic defects in thymocyte negative selection, rather than defects in the Treg generation in the atrophied thymus, confirmed by a combination of mOVA/OT-I/OT-II transgenic and Foxn1 conditional gene knockout mouse systems. Previously reported accumulation of Tregs in the aged peripheral lymph system could be rejuvenated in young microenvironment, suggesting an extrinsic defect, whereas aged thymus-released self-reactive T cells could not be eliminated by the same young microenvironment, exhibiting that they sufficiently induced inflammatory cell infiltration in young mice. In conclusion, increased self-reactive T cells, emigrated from the aged atrophied thymus, are due to intrinsic defects in thymocyte negative selection, but not in Treg generation. These self-reactive T cells profoundly participate in the process of inflamm-aging. This insight enriches inflamm-aging mechanism, which will be used for prevention and treatment of age-related diseases.
Unraveling the Physiologic Construct of Successful Aging; Integral Connectivity Between Immune, Physical, and Cognitive Domains of Function
Abbe N. de Vallejo
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
ABSTRACT: Older adults (defined as ³75 years) are highly heterogeneous, ranging from the frail, chronically ill residents of long-term care facilities to elders who are living in the community and remain functionally independent. Indeed, cross sectional and longitudinal studies of clinically defined community dwelling elderly populations have led to the recognition of successful or exceptional agers who remain physically and cognitive functional up to and beyond the 10th decade of life despite a long history of disease, poor lifestyle choices, and/or concurrent medical conditions. Genetic elements of long-term survivorship are accumulating. More significantly, emerging data from biological studies indicate physiologic adaptations or remodeling or plasticity of brain and muscle that contribute to maintenance of function in old age. Because immunity is a determinant of individual fitness, we sought to examine two cohorts of community dwellers to evaluate the hypothesis that connectivity of the immune system with physical and cognitive domains of function in determining the trajectory of successful aging. In this presentation, data from these cohorts will be presented showing the predictable age-related declines of classical immune function. But more importantly, data will be presented about the unique repertoire of NK-like T cells, along with objective measures of physical and cognitive function, comprise a signature of successful aging. Experimental data will be presented to show the novel immune effector function of these unusual T cells, many of them have senescent features, and how they may communicate with muscle and brain. This presentation will demonstrate the need on research paradigm shift from the usual young-vs-old comparison, to the analyses of clinically defined populations. It will also demonstrate that while old people perhaps perform less robustly compared to young people, aging is not synonymous with ill health, nor are elders mere defective versions of young people. Older adults are simply different.
Session 10: HIV/AIDS and aging
HIV-1 Infection and Neurogenesis: Roles of Tat protein
Yan Fan and Johnny J. He
Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107
ABSTRACT: HIV-1 infection of the central nervous system (CNS) often leads to neurological disorders ranging from minor cognitive-motor disorder to HIV-associated dementia. The common hallmarks of HIV-associated neuropathologies include increased blood-brain barrier permeability, microglia activation, astrocytosis, comprised neuronal integrity, and neuronal inflammation. While the combination antiretroviral therapy has increased the life span of HIV-infected individuals, it has failed to provide any protection or relief from HIV-associated neuropathologies. Thus, it is imperative to gain a better understanding of the cellular and molecular mechanisms of HIV-associated neurological disorders. HIV-1 Tat protein is one of the viral soluble factors and plays important roles in HIV-associated neuropathogenesis. Tat protein is secreted from HIV-infected cells and taken up by uninfected cells. Accumulating evidence suggests that Tat adversely affects neurons in both direct and indirect manners. Direct exposure of Tat to neurons causes neurotoxicity. Tat also has cytokine/chemokine-like activity, which contributes to infiltration of immune cells into the CNS and their subsequent activation and infection. Moreover, Tat elicits intrinsic signaling cascades and indirectly affects CNS. HIV-1 infection has been recently linked to decreased neural progenitor cells (NPC) proliferation, increased astrogliogenesis and decreased neurogenesis. Recent studies including ours have shown that HIV-1 Tat alone is sufficient to decrease NPC proliferation and neurogenesis but increase astrogliogenesis. In addition, we have shown that majority of Tat-binding proteins share common EGF-like motifs, which are present in the extracellular domain of all the Notch isoforms and their respective ligands, and directly involved in Notch/ligand interaction. In agreement with this finding, we have demonstrated that Tat expression leads to activation of Hes1, a critical molecule downstream of Notch signaling, and that mutation in the Tat cysteine-rich domain abrogates Tat-induced Hes1 transactivation. Taken together, these results suggest that HIV-1 Tat protein may likely contribute to altered neurogenesis in HIV-infected individuals through Tat interaction with Notch signaling pathways.
Impact of HIV and Aging on the Central Nervous System
Scott Letendre, M.D.
University of California, San Diego, CA, USA
ABSTRACT: Antiretroviral therapy (ART) has improved survival among HIV+ adults and, as a result, HIV disease has become a chronic illness in many. UNAIDS recently estimated that more than 4.2 million people living with HIV are older than 50. More than half of HIV+ adults in the U.S. will be older than 50 by 2015. Enthusiasm over this success has been dampened by the observation that several other medical conditions seem to be more common in older HIV+ adults than in the general population. These conditions include cardiovascular disease, kidney disease, bone loss, and neurocognitive impairment. With regard to neurocognitive impairment, several large studies have now confirmed that HIV-associated neurocognitive disorder, or HAND, occurs in a substantial proportion of people living with HIV and have linked the condition to advancing age in addition to worse immune suppression prior to ART and the central nervous system (CNS) conditions that can affect this population (e.g., psychiatric and substance use disorders). The challenges in determining the impact of unsuccesful aging on people with HIV include determining if age-linked complications truly occur more frequently in people with HIV than in the general population (i.e., the effects of HIV and age are additive or synergistic) and if these complications occur at a younger age in people with HIV than in others (i.e., premature aging). Using assessments such as neurocognitive testing and neuroimaging, the relationship between HIV, age, and CNS disease does appear to be at least additive. The possible risk factors for this include immune senescence, persistent inflammation, co-infections (e.g., CMV), metabolic and vascular disorders, and polypharmacy and drug toxicity. Improving understanding of the pathogenesis of premature aging in HIV+ adults should further improve disease outcomes in HIV+ adults and could identify interventions that will improve successful aging in the general population.
Key words: HIV, Aging, Brain, Cognition
Astrocyte elevated gene 1 (AEG-1) in HAND and Aging
Neha Vartak-Sharma1, Benjamin B Gelman2 and Anuja Ghorpade1
1Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
2Departments of Pathology and Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, TX, 77555, USA
ABSTRACT: The progressive loss of cognitive function is a debilitating complication in individuals aging with HIV-1-infection. The CDC estimates the majority of HIV-1 infected individuals will be over 50 years old by 2015. Many of the mechanisms dysregulated during aging are also contributing to the development of HIV-associated neurocognitive disorders (HAND) in 20–70% of infected individuals. Despite its discovery as a TNFa/HIV-1-inducible gene in astrocytes, little is known about the role of astrocyte elevated gene-1 (AEG-1) in astrocyte responses during HIV-1 CNS infection and whether it contributes to the development of HAND. In a well-characterized human cohort, AEG-1 levels in the pre-frontal cortex increased in an age-dependent manner in non-infected individuals, and were also significantly elevated in age-matched HIV+ individuals. Further, in mouse models, astrocyte AEG-1 was upregulated during brain injury and HIV-1 TAT expression. Our studies in primary human astrocytes and astrocytoma cell line U87MG have shown that AEG-1 regulates aspects of reactive astrogliosis, a key pathological feature of HIV-1 CNS disease. HAND-relevant stimuli induced AEG-1 expression and nuclear translocation via activation of the NF-kB pathway, indicating AEG-1 may serve as a novel transcriptional cofactor during neuroinflammation. Further, AEG-1 dysregulates the expression of EAAT2 and YY1, an EAAT2 repressor, leading to reduced glutamate clearance and neuronal excitotoxicity. Manipulating AEG-1 expression revealed AEG-1 regulation of astrocyte migration and proliferation during wound healing along with AEG-1-mediated protection against oxidative stress. AEG-1 may mediate protection from oxidative stress through interactions with the master regulator of cellular antioxidant responses, Nrf-2. Interestingly, during oxidative stress and wound healing, despite total AEG-1 levels remaining unchanged, AEG-1 localization in nucleolus increased significantly. Together, our studies indicate that AEG-1 may play a critical role in neurodegenerative mechanisms by regulating astrocyte migration, proliferation, cytokine secretion, excitotoxicity and antioxidant responses during HAND and aging.
KEY WORDS: astrocyte elevated gene-1, HIV-associated neurocognitive disorders, aging, astrogliosis, neuroinflammation, oxidative stress, excitotoxicity
Post and Abstract
Calorie Restriction Delay Renal Senescence through SIRT6 Mediated Signaling Pathway
Nannan Zhang, Zhongchi Li, Zhuoran Wang, Liyuan Li, Yaru Liang and Zhao Wang
MOE Key Laboratory of Protein Sciences, Department of Pharmacology, School of Medicine, Tsinghua University, Beijing 100084, China
ABSTRACT: The aggravating trend of aging population has bring us with great medical challenges. Renal senescence related disease continues to be of critical importance for its high morbidity rates and huge cost of treatment. Calorie restriction (CR) has various beneficial effects on health, including lifespan prolongation and functional improvement of multiple organisms. SIRT6, a member of the sirtuins family of NAD+-dependent histone deacetylases, has been shown to play a key role in mediating the effects of CR. Here we show how CR-triggered SIRT6-dependent pathways affect renal senescence and the critical role of SIRT6 on aging. Aged mice with 6-month of CR had improved renal pathology and enhanced SIRT6 expression compared with ad libitum (AL) group. In addition, we took low FBS (LF) cultured WI38 human fibroblasts as a model to simulate CR in vitro. Compared with normal FBS (NF) group, LF group has prolonged lifespan and increased expression of SIRT6. Furthermore, we stably overexpressed or knockdown SIRT6 in WI38. Increased SA-β-gal+ staining were observed in SIRT6-deficient cells even though in LF condition, while the overexpression of SIRT6 can delay the replicative senescence effectively. NF-κB is involved in the SIRT6 mediated longevity control. SIRT6 overexpressed WI38 had low translocate rate into the nucleus and SIRT6 can attenuate the NF-κB signaling by deacetylating the RelA subunit of NF-κB complex. This work is funded by the National Basic Research Program of China (973 Program, 2013CB530802).
Key Words: SIRT6, Calorie restriction, kidney, aging
Aging - The Role of Microelement Balance
Lygovaya E.1 , Stambler I.2 , Blokh D.3 , Gorbachev A.4
1 - Scientific_Research Center “Arktika” FEB RAS, Magadan, Russia
2 – Department of Science, Technology and Society, Bar Ilan University, Israel
3 – C.D. Technologies Ltd., Israel
4 – North-East State University, Magadan, Russia
One of the main problems in the biology of aging is the question of causal relations between age-related impairment of metabolic processes and the aging process itself. With reference to microelements and mineral metabolism, the question can be stated as follows: Is aging a consequence of age-related deterioration of mineral metabolism (impaired absorption of essential elements, slow elimination and accumulation of toxic elements), or is the imbalance of microelements status of an aging person one of the side effects of programmed diseases of aging?
According to a number of studies, the deficit of microelements in an aged organism is related to chronic diseases, leading to excretion of elements. This concerns, first of all, Zink, Copper, Iron, Selenium, Chromium (Ermekcioglu, 2001). At the same time, the deficit of essential elements or excess of toxic elements, produced via impairment of metal-ligand complexes, is a recognized trigger of pathological processes.
Apparently, the elements imbalance and the development of pathology are parallel yet interrelated processes. In any case, the level and interaction of certain microelements in the human organism can be a clear indicator of personal health or predisposition to pathology. In the course of massive clinical and population studies, conducted under the WHO auspices, there was established an array of microelements associated with cardiovascular pathology, cancer, diabetes and other diseases of old age.
During aging, as a result of selective absorption of certain elements, their selective concentration and selective elimination, the organism either requires an elevated input of certain elements, or on the contrary becomes more sensitive to their toxic effects. If age-related impairment of microelement homeostasis is a primary cause of diseases of aging, then this may create a range of possibilities for prevention of premature aging. The elimination of certain excessive elements from the organism is a difficult task. Yet, the replenishment of deficient elements and thus the elimination of the deficiency is feasible, and opens a wide range of possibilities for preventing microelements impairment, including prevention of diseases of aging. This approach has been practically validated by the use of microelement supplements in the aged (Dror et al., 2001).
We have analyzed the microelements status of aged persons (aged 75-90), living in the circumpolar areas of Russia. We have established both the common patterns of age-related changes in the content of several elements (Calcium, Magnesium, Selenium, Zink, Phosphorus), as well as regional differences in the content of certain elements (Aluminum, Boron, Iodine, Silicon). We consider the role of natural (bio-geo-chemical) factors, affecting the age-related modifications of the microelements status, and the possible involvement of the microelements imbalances in the development of diseases of aging.
Key words: Aging, Microelement Balance, Microelement Toxicity, Microelement Deficit
Identification of aging-related genes using mouse genetics
Rong Yuan1, 2*, Gary Churchill2, Luanne Peters2, David Harrison2 and Beverly Paigen2
1The Geriatric Research Division, Department of Medicine, Southern Illinois University School of Medicine, 801 N. Rutledge St., Springfield, IL 62794, USA
2The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA
ABSTRACT: To identify genes related to aging, we systematically characterized 32 mouse inbred strains in longitudinal and cross sectional study designs. We observed significant correlations of both the age of female sexual maturation (FSM) and circulating IGF1 at 6 months with longevity. We further found that C57BL/6J females had 9% lower IGF1, 6% delay in age of sexual maturation and 24% extended longevity compared to a congenic strain, which carries a C3H/HeJ allele on C57BL/6J background. These results confirm the correlation between age of FSM and longevity, and support the hypothesis that IGF1 plays an important role in regulating the association. Next, using quantitative trait loci (QTL), mapping in conjunction with haplotype and single nucleotide polymorphism analyses, we identified candidate genes for aging-related phenotypes, including nuclear receptor interacting protein 1 (Nrip1) and proprotein convertase subtilisin/kexin type 2 (Pcsk2). We obtained transgenic mice with deletions of Nrip1 and Pcsk2, observed significantly reduced IGF1 and delayed the age of FSM. We found that Nrip1-deficient female mice had significantly extended longevity. In addition, Nrip1 mice showed reduced cancer incidence and improved metabolism, including increased insulin sensitivity, enhanced mitochondrial function and improved profile of inflammatory cytokines. The longevity of Pcsk2 knockout mice is still under observation. Discovery of aging-related genes using mouse genetics represents a powerful and effective strategy for uncovering new genes and pathways for validation in human studies.
L-glutamic acid (monosodium glutamate, MSG) decrease lifespan in Drosophila melanogaster.
Woong Seo1, Shin-Hae Lee1, Bora Lee1, Dea-Sub Song2, Seok-Woo Go2, Tae-Hyun Kim2, Jun-Hyuk Moon2, Kuk-Young Jang2, Ah-Young Ham2, Kyung-Jin Min1
1Department of Biological Sciences, Inha University, Incheon 402-751, Korea.
2Hakik high school, Incheon Korea 402-041
ABSTRACT: L-glutamic acid (monosodium glutamate, MSG) is one of the famous artificial seasonings and commonly exists in nature as sodium salt of glutamic acid. There are many debates regarding the effects of MSG on human health. MSG feeding in mice caused hypothalamus damage and vision impairment in some trials, but no detectable detrimental changes in other trials. Moreover, there has been not much information regarding the long term effects of MSG like the effects of MSG on life span and development. In this study, we examined the physiological effects of MSG using Drosophila melanogaster. The eclosion and pupation rate was not changed when less than 200mM MGS was treated, but flies were not eclosed when 500mM MSG was treated. MSG treatment on adult flies decreased life span by almost tested concentrations except 500mM MSG. In addition, MSG decreased motility of male flies. When the flies fed MSG from the larval stage were switched to feed normal food from adult stage, the lifespan is reduced. Interestingly, the flies fed MSG from the larval to adult stage increased the lifespan compared to flies fed MSG in larval or adult stage only. In conclusion, MSG may affect the physiology of Drosophila in high concentrations.
Key words: MSG, Drosophila, Lifespan
Maternal effects of dietary restriction on offspring fitness in Drosophila melanogaster
Bora Lee, Eun-Ji Lee and Kyung-Jin Min
Department of Biological Sciences, Inha University, Incheon 402-751, Republic of Korea.
ABSTRACT: Dietary restriction has been found to increase the longevity and stress resistance in a wide array of eukaryotic species and it has been known that protein, rather than carbohydrate restriction is important to increase the lifespan in fruit flies. However, it has never been tested whether the effects of parental dietary restriction on offspring fitness. Adult flies were exposed to a regular diet or dietary restricted diet. We then measured the pupation/eclosion frequency, longevity, and stress resistance in the offspring of these flies. Compared to control flies, flies held on a protein-restricted diet were more likely to develop from eggs to pupae, and from pupae into adults. Female offspring of flies fed a restricted diet showed a consistent increase in resistance to starvation and oxidative stress. The effect of parental diet on male offspring was less consistent. Parental diet also seemed to affect the longevity of offspring. Offspring of flies fed a protein-restricted diet tended to outlive offspring of flies held on a regular diet, although results varied somewhat among trials. This study suggests that the impact of diet restriction can extend beyond exposed individuals to their offspring, and should be considered in both theoretical and empirical studies of senescence.
Key words: Dietary restriction, Caloric Restriction, Aging/physiology, Longevity, Parental effects, Drosophila melanogaster
Autoimmune Diseases in Europe- Mechanisms and Treatment
LILE Editions, Brussels, Belgium; HLEB- Healthy Life Expectancy Bulgaria
ABSTRACT: Chronic respiratory diseases are an important cause for mortality in the developed countries. In this study we have analysed and compared data on chronic respiratory diseases and some other autoimmune diseases with demographic data on aging in Europe. We investigated the proven and potential mechanisms as well as the existing methods of treatment of autoimmune diseases. On the basis of our study we suggest a thorough research on the mechanisms of the aging process as the most reliable way to develop a targeted treatment for the autoimmune diseases.
Large elastic artery stiffness with aging: Molecular mechanisms to translational interventions
Bradley S. Fleenor
University of Kentucky, Kentucky, USA
ABSTRACT: Older age is the major risk factor for cardiovascular diseases, which is, in part, attributable to dysfunctional arteries. Large elastic artery stiffness, one expression of arterial dysfunction, is worsened with aging and is an independent predictor of cardiovascular events. Both oxidative stress and inflammation within the artery are important signaling pathways in the development of age-related arterial stiffening. Recent evidence, however, has also shown a causal role for periaortic adipose-related oxidative stress and inflammatory signaling to promote arterial stiffness with aging. Importantly, translational nutraceutical and functional food interventions may de-stiffen arteries that, in turn, reduce cardiovascular risk in older adults by ameliorating oxidative stress and inflammation.
Key words: periaortic adipose, oxidative stress, inflammation
Prevention of age-related hearing loss by the modulation of NAD+/NADH ratio by -lapachone
Hyung-Jin Kim1, Gi-Su Oh1, Ai Hwa Shen1,3, Tae Hwan Kwak2, Raekil Park1 and Hong-Seob So1*
1Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, 344-2 Shinyong-dong Iksan, Jeonbuk 570-749, Korea. 2Mazence Institute, Suwon, Korea
ABSTRACT: Age-related hearing loss (ARHL) is a predominant neurodegenerative disease with age. Here, we demonstrate for the first time that, in the aging process, the levels and activities of SIRT1 and SIRT3 are suppressed by reduction of intracellular NAD+ levels. We provide evidence that the decline in SIRT1 and SIRT3 levels aggravates ARHL by increasing acetylation of NF-kB and p53, suggesting ARHL may occur through the induction of inflammatory responses and oxidative stress as well as the mitochondrial dysfunctions, playing an essential role for the apoptotic cell death in cochlear tissues. Moreover, we show that the simultaneous induction of the cytosolic and mitochondrial NAD+ levels using β-lapachone, whose intracellular target is NQO-1, prevents mice from ARHL and its deleterious effects through the maintenance of the mitochondrial structure and function. These results suggest that direct modulation of the cellular NAD+ level by pharmacological agents could be a promising option for treating ARHL.
Key Words: Age-related hearing loss (ARHL), NAD+/NADH ratio ratio , Sirtuins, NQO-1, β-lapachone
Intestinal bacteria: The real "Fountain of Youth"?
Serbian Association of geriatricians and gerontologist, Belgrade, Serbia
ABSTRACT: Ageing today is quite different from what it was just a few decades ago. It is also poles apart from what it used to be in centuries preceding the modern era. It appears that the only thing unchanged is a man’s desire to find the Fountain of Youth. Even scientists found the temptation hard to resist. More or less; but the majority of scientists are looking for a unique principle in a complex and interdependent system – or simply: “one cure for the old age”. So, the causes of ageing are both genetic and environmental. Recently, there are a lot of references that support the theory of infective cause of aging. Ageing is "hyperinflamation". The immune system is not only the most convenient model for studying ageing, but immunity deficiency is a significant factor in ethiopathogenesis of many diseases of old age. First and foremost, the practical problem is not just in increased sensitivity to infections, but it also appears in the attempt to protect the elderly by immunization. Deregulation appears to be the main disorder of the immune system in old age. While certain clones of immune cells do not react to antigens, others produce auto antibodies and homogeneous immunoglobulines according to the type of benign monoclonal gamapathies. It is a fact that, although not diseases in themselves, these disorders are significant in the development of many other diseases. Auto antibodies may cause initial lesion of a blood vessel that continues with the known mechanism of development of arteriosclerosis. In any case, prognostic significance is essential, because it is generally known that higher frequency of auto antibodies means shorter survival. Interindividual heterogeneity is one of the ageing symbols. Intestinal bacteria display also great interindividual variation. There is a link between inflammation, intestinal bacteria and ageing process. Life styles and diet change gut microbiota. Nutrition (and starvation) affect life span. Epidemiologists say, however, that it was the immunisation that made the true quantum leap for medicine. Vaccination extended the lifespan of human beings on average for 28 years. With the current global epidemic of obesity, eradication of malignant and cardio-vascular diseases would give us another 7 years of life. So, is it possible to find “a vaccine against ageing”?
Longevity privilege can be caused by probiotics effects not only regarding harmonization of the immune system in the elderly, but as result of “good” bacteria prevalence.
Mechanism of Metals Homeostasis Regulation in AD Disease
Institutes of Biomedical Sciences & Department of Chemistry, Fudan University, Shanghai 200043, China
ABSTRACT: Alzheimer’s Disease (AD) is a kind of neurodegenerative diseases. The characteristic pathological features of AD are senile plaques, neurofibrillary tangles, the loss of neurons and granulovacuolar degeneration. Though the mechanism of AD is very complicated, the metal homeostasis regulater by amyloid beta, amyloid precursor protein and metallothionein-III is associated with the AD. The aberrant of metal homeostasis is one of the reasons that induced AD. Herein the transitional metal homeostasis of copper, zinc and iron, regulated by related protein amyloid beta, amyloid precursor protein, and metallothionein-IIIwill be describer and discussed.
Figure 1, Metal homeostasis regulation in neuronal cells (left) and the model for the role of APP in cellar iron export and its inhibition in AD.
Key words: Metals Homeostasis, MT3, AD, Aβ, APP
Objectives: Aging is often accompanied by cognitive decline. Magnetic resonance spectroscopy (MRS) can explore aging at a molecular level. In this study, we investigated in the relationship between regional concentrations of metabolites and normal aging in Chinese using quantitative 1H-MRS.
Methods: Experiments were performed on thirty cognitively normal (Mini-mental-state-examination ≥28) subjects (mean=49.87±18.33 years) using 3.0T MR scanner (Achieva, Philips Healthcare). Single-voxel-spectroscopy with short echo-time (TE) 38ms, repetition time (TR) 2000ms were employed. Single voxels with size of 2cmx2cmx2cm were placed in the anterior and posterior cingulate cortices. MRS spectra were processed with offline Java-based version of jMRUI (4.0) using QUEST (quantification based on quantum estimation). Choline (Cho), creatine (Cr), N-acetyl-aspartate (NAA), glutamate (Glu) and myo-inositol (mI) were measured and quantified. Cerebrospinal fluid normalization was done using voxel based morphometry (VBM5). Absolute concentrations of various metabolites were calculated. Bivariate linear regression in SPSS version 20.0 was used for statistical analysis. The level of significance was set at 0.05.
Anterior cingulate cortex
Posterior cingulate cortex
Key: ↑, significant increase; -, no significant change; [ ], absolute concentration expressed in mmol/kg; * indicates p<0.05, ** p<0.01
In aging, increases in Cho and Cr might suggest glial proliferation. Increases in NAA and Glu, which is a neurotransmitter, might indicate neuronal hypertrophy. Such findings highlight the metabolic changes of the anterior and posterior cingulate cortices with age, which could be compensatory to an increased energy demand coupled with lower cerebral blood supply.
Interleukin-4-mediated activation of M1/M2 microglia improves functional recovery after intracerebral hemorrhage in rats
Jianjing Yang, Weilong Huang, Zhenxing Li, Jiannan Hu, Shengwei Huang,
Xialong Gu and Qichuan Zhuge
Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
ABSTRACT: Neuroinflammatory play a critical role in post-stroke brain injury, yet microglia is brain resident myeloid cells and have emerged as a key driver of the neuroinflammatory responses, which included anti-proimflammatory M2 proinflammatory M1 macrophages/microglia. Currently, little is known about the mechanisms underlying microglial activation. Here, our study are to determine whether intracerebral administration of interleukin-4 (IL-4) affected the activation of M1/M2 microglia and the corresponding outcome after ICH. Rat ICH model was induced by intracerebral injection of collagenase IV into the striatum, and IL-4 was then intracerebrally injected after ICH. We found that after intracerebral injection of IL-4, M1 polarization markers iNOS, IL-6, IL-1β and TNF α were significantly reduced and M1 polarization markers Arg 1 and IL-13 were increased, along with improved neurobehavioral deficit induced by ICH. In conclusion, our study shows that early intracerebral injection of IL-4 promotes the functional recovery after, which may associated with a protective inflammatory milieu via inhibiting M1, but promoting M2 polarization.
Key words: ICH, interleukin-4, M1/M2, microglia, inflammation, neurobehavioral
Reversal of Focal Cerebral Ischemia-induced Neurological Deficits in Aged Rats by Administration of from Young Plasma
Peng Wang1*, Chengcai Zheng1, Hongxia Zhang1, Mengxiong Pan1, Wei-Ming Zheng1, Kunlin Jin2
1Department of Neurosurgery, Wenzhou Medical University, Wenzhou, Zhenjiang Province 325000, China
2Department of pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76106, USA
ABSTRACT: Aging is associated with a striking increase in the incidence of stroke and neurodegenerative diseases, which may be due to structurally and functionally changing the adult brain. Recent study shows that young blood can reverse age-related impairments in cognitive function and synaptic plasticity in mice. However, little is known whether young blood can improve the functional outcome after ischemic stroke. Here, focal cerebral ischemia in young (3-months-old) and aged (20-months-old) rats was induced by occlusion of distal middle cerebral artery occlusion (dMCAO) and young or aged plasma was intraperitoneally injected into young and aged rat 30 min after focal ischemia respectively. The outcome was assessed at 3 and 15 days after injection. We found that the infarction volume and motor deficits were significantly improved in aged ischemic rats when young plasma was injected. Interestingly, the functional outcome was worsen in young rats if aged plasma was infused. However, not significant changes of functional outcome were observed in young-adult or aged rats if the plasma from same age rat was injected after focal ischemia. Our data suggest that environment plays a critical role in aging process and young blood may contain beneficial elements, which improve stroke outcome.
Key Words: ischemia, stroke, outcome, function, aging.
Cross-Talk between Human Neural Stem Cells and Peripheral Blood Mononuclear Cells in an Allogeneic Co-culture Model
Hongxia Zhang1, Bei Shao1*, Qichuan Zhuge1, Peng Wang1, Chengcai Zheng1, Chenqi Yang2, Brian Wang2, Dong-Ming Su1,2, Kunlin Jin1,2
1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 35000, China
2Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
ABSTRACT: Transplantation of human neural stem cells (hNSCs) as a regenerative cell replacement therapy in neurodegenerative diseases and the injured brain holds great promise. However, the underlying mechanisms remain unclear. One of the potential mechanisms includes hNSC-induced modulation of immune cells. To this end, we, here, focused on the interaction between hNSCs and allogeneic peripheral blood mononuclear cells (PBMCs) in a co-culture model with molecular and cellular analyses to determine the interplay between hNSCs and immune cells. After co-culturing hNSCs with PBMCs for 48 hr, we found that hNSCs could apparently decrease the proportion of CD3+ and CD8+ T cells, reduce the proportion of gamma delta T (γδT) cells and increase the proportion of regulatory T cells (Tregs), though there were no influences on proliferation and apoptosis of T cells. In addition, pro-inflammatory cytokines were reduced and anti-inflammatory cytokines were increased after co-culture. We also found that PBMCs, in turn, could significantly promote the proliferation and differentiation of hNSCs, but does not cause apoptosis of hNSCs. To conclude, our data suggest that neural stem cells (NSCs) cross-talk with immune cells, which may be one mechanism underlying NSCs-mediated cell protection after injury.
Key words: neural stem cells; peripheral blood mononuclear cells; immunomodulation; proliferation; apoptosis; differentiation
Mortality Kinetics at Advanced Ages
DavisHeart andLung ResearchInstitute, Departmentof InternalMedicine, The Ohio State University College of Medicine, 420 West 12th Avenue, Columbus, OH43210, USA
ABSTRACT: Gompertz law of mortality quantitatively describes the mortality rate of humans and almost all multicellular animals. However, its underlying kinetic mechanism is still unclear. In this study, the author proposed a reaction kinetic model with a time dependent rate coefficient to describe the survival and senescence processes based on a hypothesis regarding a vital chemical substance, such as the telomere, that is critical for life. A new mortality function was derived. The new mortality equation becomes the well-known Gompertz law of mortality and has the same relationship of parameters in the mortality function prescribed by Strehler-Mildvan correlation as age is smaller than a characteristic value. The new mortality equation, which is a function of temperature, predicts the mortality plateau appearing in the period of age greater than. This prediction is consistent with the most recently reported mortality trajectories for single-year birth cohorts. The simulated curves from the new mortality function fit the human survival curves with mortality plateau pretty well. A closed-form analytical expression for describing the relationship of average lifespan with temperature was derived, which is consistent with published experimental data. Some other equations are also derived from the new mortality equations. The derived equations can be used to estimate the limit of average lifespan, predict the maximal longevity, calculate the temperature coefficient of lifespan, and explain the tendency of survival curve. This study is exploring the connection between molecular mechanism and demography.