2016 ICAD Abstracts

Non-Cell Autonomous Control of Metabolism by Neuronal mTORC1


Veronica Galvan, Ph.D.

Department of Physiology and The Barshop Institute for Longevity and Aging Studies/Nathan Shock Aging Center, University of Texas Health Science Center at San Antonio, USA    


Abstract: The mechanistic/mammalian target of rapamycin (mTOR) is a major regulator of cellular and organismal metabolism. Reduction of TOR signaling by rapamycin is known to alter organismal metabolism and increase lifespan and healthspan. In invertebrate models, selective reduction of function of mTOR in the nervous system is sufficient to extend life. We hypothesized that attenuating mTOR signaling in mature mammalian neurons would extend lifespan by altering critical aspects of metabolism non-autonomously. To test this hypothesis, we knocked down the mTOR complex 1 (mTORC1)-specific companion protein, Raptor, in neurons of adult mice.  Reduction of mTORC1 formation in neurons by 35% or 60% did not affect body weight but increased lean mass while reducing metabolism. This was associated with enhanced exercise endurance and absent post-exercise hypoglycemia, even though glucose and insulin tolerance were unchanged.  In vitro studies showed that factor(s) missing from serum in 35% KD animals may act to repress liver gluconeogenesis and increase glycogen levels in muscle.  To determine cell-autonomous effects of mTORC1 knockdown in neurons we measured spatial learning and memory. While 60% mTORC1 knockdown impaired cognitive plasticity, 35% reduction in mTORC1 complex formation resulted in enhanced spatial memory. Consistent with these observations, 60% neuronal mTORC1 KD reduced brain glucose metabolism and cerebral blood flow, while 35% KD increased brain glucose uptake with no changes in cerebral blood flow. Taken together, our data suggest that reduction of neuronal mTORC1 complex formation may have significant non-cell autonomous effects on basal and exercise glucose metabolism and endurance through factor(s) secreted in serum. Furthermore, our data indicate that the relationship between levels of mTORC1 in neurons and spatial memory is not linear. Rather, and in agreement with prior studies using rapamycin, our data suggest that spatial memory may be maximal when neuronal mTORC1 levels are moderately lower than WT, but may decrease with further reductions in mTORC1, mirroring the effects of mTORC1 knockdown on glucose metabolism. mTORC1 reduction had no effect on lifespan, ruling out delayed aging as a proximal cause for increased exercise endurance, adapted glucose metabolism, and enhanced memory in neuronal mTORC1 knockdown mice.




Deep-learned blood biochemistry and transcriptomic biomarkers of aging


Alex Zhavoronkov, PhD.

In Silico Medicine, Johns Hopkins University Eastern Campus, Baltimore, MD 21218, USA


Abstract: Using a data set of over 100,000 samples of routine blood tests consisting of 41 normalized parameters from reasonably healthy individuals we improved the accuracy of the previously published deep-learned biomarker of aging (www.Aging.AI) from the mean absolute error (MAE) of 5.55 years to 5.1 years. We also developed a deep-learned biomarker of aging using transcriptomic data from human peripheral blood with 4.9 MAE and R2 of 0.79.






Classifying Aging as a Disease in International Disease Classification Registries


Alex Zhavoronkov, PhD.

In Silico Medicine, Johns Hopkins University Eastern Campus, Baltimore, MD 21218, USA


Abstract: Aging is a complex multifactorial process contributing to the broad spectrum of pathologies and leading to functional decline and death of the organism. However, there is disagreement in the scientific and medical communities regarding whether aging itself can be classified as a disease. In order to attract more resources and attention to aging research and encourage pharmaceutical companies to develop actionable preventative interventions, multiple groups worldwide are preparing proposals to include aging and aging-associated conditions into the national and international disease classification registries. To facilitate the exchange of ideas and strategies, we developed a MediaWiki-driven system available at and invited scientists and medical professionals to contribute their approaches and proposals for public discussion.






Translating Geroscience: focus on bone


Simon Melov


Buck Institute for Research on aging, California, USA


Abstract: There is considerable interest in determining whether chemical compounds or interventions shown to significantly increase longevity in invertebrate models will also affect aging in mammals. To explore this concept, we tested three compounds and one element for their ability to slow age-related bone micro-architecture in older mice. We chronically treated mice from 19 months of age and used a repeated measures experimental design to evaluate a number of structural and functional indices in bone over late life. We focused on the aging skeleton, primarily the femur, because it can be accurately observed by computed tomography (CT) in living animals. Findings in this tissue may provide important insights into a major health issue, age-related bone loss and fracture in humans. We observed that with age there was increased inter-animal variation in bone structure despite the genetically identical nature of the test population. We also discovered complex changes in femoral bone loss and architecture during late life; the latter, osteopenic changes being similar to those observed in humans. In addition, we were able to document that the incidence of spontaneous fractures in aged mice is similar to that for humans. Finally, we report that in the mid-cortical shaft of the femur, one of the four interventions tested reduced the rate of bone loss to a level similar to that seen with anti-osteoporotic drugs in humans. Our results demonstrate that selecting interventions on the basis of lifespan extension in invertebrates may be predictive of positive healthspan effects in aging mammals.


Key words: Aging, phenotype, function, intervention







Hypothalamic inflammation in neural control of aging


Dongsheng Cai, Ph.D., M.D.


Molecular Pharmacology, Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, NY, USA


Abstract: In this talk, I will discuss the relationship between hypothalamic inflammation and neuroendocrine pathways in aging development as well as related metabolic syndrome. First, I will provide an overview on neuronal control of aging and lifespan in different species. Second, I will describe the involvement of hypothalamic pro-inflammatory IKK-beta and NF-kappaB pathway and related stress response in the development of aging and metabolic syndrome. Finally, I will discuss the impact of hypothalamic inflammation on hypothalamic neuroendocrine systems and therefore the influence on hypothalamic regulation of physiology which contributes to aging and lifespan changes. Altogether, inflammation-induced hypothalamic dysfunction represents a neural mechanism of aging. 






Exercise and antioxidants: together is not better


Nathalie Sumien


Center for Neuroscience Discovery, Institute for Healthy Aging, UNT Health Science Center, Fort Worth, Texas, USA


Abstract: Popular interventions such as antioxidant intake or moderate exercise are often recommended to attain healthy brain aging and reduce oxidative stress.  Furthermore, these two interventions are often coupled together in anticipation of additive effects based on the rationale that each intervention alone activates anti-aging mechanisms ameliorating brain function.  However, the nature of the interaction between exercise and antioxidants remains unclear with evidence of potential antagonistic action of antioxidant on the beneficial effects of exercise.  Male C57BL/6 mice of different ages were assigned to one of the following experimental groups: Sedentary- Control Diet; Sedentary- Antioxidant (Aox) Diet; Exercised- Control Diet; Exercised- Aox Diet.  The Aox Diet was supplemented with 1.65 mg ascorbate /g diet and 0.825 mg α-tocopheryl acetate/ g diet and fed ad libitum.  The exercised mice received a forced exercise regimen training of 1h using an inclined treadmill.  The respective treatments were followed for 8 weeks pre-treatment period and throughout behavioral testing, which measured spontaneous activity, musculoskeletal reflexes, strength, balance, coordination, spatial learning and memory, anxiety, learning and cognitive flexibility.  Overall, our studies did not reveal any major additive or antagonistic effect of moderate exercise and antioxidant intake, supporting that each intervention most likely improves aspects of brain function via independent pathways.






Vasodegenerative Disease: Lessons from The Nervous System


David A. Greenberg, M.D., Ph.D.

Buck Institute for Research on Aging, Novato, CA, USA


Abstract: Vasodegenerative diseases, such as atherosclerosis and hypertensive and diabetic vasculopathies, share many features with neurodegenerative diseases. These include complex and poorly understood etiologies; common risk factors; chronic progression; involvement of distinctive functional systems, regions and cell types; presence of extracellular deposits or intracellular inclusions; gradual spread to contiguous and sometimes distant sites; and a tendency to present clinically in later life. These commonalities may provide clues regarding pathophysiology and approaches to treatment.


Key words: vasodegeneration , neurodegeneration, atherosclerosis, hypertension, diabetes






Role of microRNAs in Mitochondrial Decline in Aging and Alzheimer’s Disease


James W. Simpkins, PhD


The Highland Professor of Stroke/Neurology, Center for Basic and Translational Stroke Research

West Virginia University, Morgantown, WV 26506, USA


Abstract: Polygenetic risk factors and reduced expression of many genes in late-onset Alzheimer’s disease (AD) impedes identification of a target(s) for disease-modifying therapies. MicroRNAs are short non-coding RNA that targets many genes and concomitantly down regulates multiple biological pathways by repressing mRNA translation/or degradation. We identified a novel microRNA, miR-34a that is over expressed in specific brain regions of AD patients as well as in the 3xTg-AD mouse model. Specifically, increased miR-34a expression in the temporal cortex region compared to age matched healthy control correlates with severity of AD pathology. miR-34a over expression in patient’s tissue and forced expression in primary neuronal culture correlates with concurrent repression of its target genes involved in synaptic plasticity, oxidative phosphorylation and glycolysis. The repression of oxidative phosphorylation and glycolysis related proteins correlates with reduced ATP production and glycolytic capacity, respectively. We also found that miR-34a overexpressed neurons secrete miR-34a containing exosomes that are taken up by neighboring neurons. Furthermore, miR-34a targets dozens of genes whose expressions are known to be correlated with synchronous activity in resting state functional networks. Our analysis of human genomic sequences from the tentative promoter of miR-34a gene shows the presence of NFκB, STAT1, c-Fos, CREB and p53 response elements. Together, our results raise the possibilities that pathophysiology-induced activation of specific transcription factor may lead to increased expression of miR-34a gene and miR-34a mediated concurrent repression of its target genes in neural networks may result in dysfunction of synaptic plasticity, energy metabolism, and resting state network activity. Thus, our results provide insights into polygenetic AD mechanisms and disclose miR-34a as a potential therapeutic target for AD. (This work was supported by the National Institutes of Health grants P20 GM109098, P01 AG022550, P01 AG027956, U54 GM1049492.)





Parkin and α-synuclein in dopamine or iron induced death of SHSY5Y cells: relevance in the pathogenesis of Parkinson's disease.

Sasanka Chakrabarti1, Upasana Ganguly2, Anirban Ganguly2, Oishimaya Sen2 and Gargi Ganguly2

1Department of Biochemistry, ICARE Institute of Medical Sciences and Research, Haldia 721645, India

2Department of Biochemistry, Institute of Post-Graduate Medical Education and Research. Kolkata 700020, India

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease in the aged population causing progressive motor deficits and other features including dementia. The most conspicuous clinical features are bradykinesia, muscular rigidity and tremor which result from the degeneration of dopaminergic cells of substantia nigra projecting to striatum. Most cases of PD appear sporadically, but the pathway of neurodegeneration in this disease condition is largely unknown.  However, a proteotoxic mechanism through the accumulation of α-synuclein is considered to play a central role in the neurodegenerative process. Studies in our lab and elsewhere have established that α-synuclein accumulation through overexpression or inhibition of proteasomal degradation leads to a loss of viability in cultured cells of neural origin via several mechanisms, and this could be an important experimental model of PD neurodegeneration. We are attempting to identify various endogenous molecules that in concentrations relevant to physiological condition may lead to an accumulation of α-synuclein within the cells and subsequent cell death.  We have observed that dopamine (DA) induces an accumulation of α-synuclein in SHSY5Y cells which impairs mitochondrial functions leading to cell death through apoptosis and secondary necrosis, and the phenomenon is prevented markedly by the transfection of cells with SiRNA specific for α-synuclein.  An exposure of SHSY5Y cells to iron (10 to 100 µM) also causes a significant accumulation of α-synuclein intracellularly, but with much less cell death. This is presumably because iron causes an overexpression of parkin which has neuroprotective functions. However, under conditions of DA exposure with significant cell death, the induction of parkin is much less conspicuous.  The mechanisms of overexpression of α-synuclein and parkin by iron and their interactions with mitochondria are being actively studied, and the results may provide important clues in understanding the mechanisms of PD neurodegeneration and identifying new neuroprotective drugs.    




Therapeutic Mechanism of Endothelial Progenitor Cell Transplantation for Ischemic Stroke

Guo-Yuan Yang

The Center of Neuroscience and Neuroengineering,Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, 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 14daysof focal cerebral ischemia in mice (p<0.05). Administration of glycyrrhizin (10mg/kg/d) blocked the beneficial effect of EPC transplantation (p<0.05). Further investigation showed GFP+ exogenous endothelial progenitor cells accumulated in perifocal region following14 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 HMGB1hyperexpression is an important factor for the trigger the repairing and remodeling during post-ischemia.







Somatotropic signalling, methionine metabolism and DNA methylation in aging

H.M. Brown-Borg

Department of Biomedical Sciences, University of North Dakota School of Medicine & Health Sciences, USA

Abstract: Endocrine hormones play a significant role in aging and longevity. Growth hormone (GH) affects not only somatic growth but also drives aspects of metabolism and stress resistance.  We have shown that GH modulates oxidative and methionine metabolism, and longevity in GH mutant mice.  Our current studies focus on delineating the relationships between the methionine metabolic pathway and plasma GH levels as they relate to epigenetic stability.  Components of the methionine pathway were differentially affected by dietary methionine level.  Underlying GH status also influenced the metabolic responses to alterations of this amino acid.  Long-living somatotropic signalling-deficient (Ames, GHRKO) mice were not able to discriminate differences in dietary methionine in terms of lifespan, food consumption and body weight.  GH transgenic mice and the wild type mice from each line lived longer when fed methionine-restricted but not methionine-supplemented diets as previously reported.  In addition, we have examined DNA methylation differences between Ames dwarf and wild type mice.  Ames mice exhibit a more stable methylation pattern across the genome over time when compared to wild type mice supporting the notion that epigenetic stability contributes to longevity.   These studies indicate that GH status impacts dietary methionine sensing and downstream aspects of metabolism including DNA methylation, health and overall lifespan.




Global Efforts supporting Aging Research:  Sustainable Development Goals – Progress and Pitfalls


Jack Kupferman

Gray Panthers, NYC Network; the Stakeholder Group on Ageing at the UN; and the Executive Committee of the NGO Committee on Ageing at the United Nations


Abstract: The world’s recently adopted blueprint for social, economic and environmental development, Sustainable Development Goals  includes a huge component concerning health and aging.  Because the SDGs require attention to health care delivery, medical research, and attention to longevity, advocates in each nation of the world have an opportunity to find ways to encourage public and private efforts to fund research.  This discussion will detail how the concerns of aging and older persons were incorporated in this important global effort; how ageism continues to be an impediment; and how you can potentially encourage progress at the national and global level regarding medical research and health care delivery; longevity and more. 





Rejuvenation biotechnology: paradoxically, undoing aging will be easier than slowing it


Aubrey de Grey


SENS Research Foundation, California, USA

Abstract: It may seem premature to be discussing the comprehensive medical conquest of human aging when so little progress has yet been made in even postponing it. However, two facts undermine this assessment. Firstly, aging happens throughout our lives but only causes ill-health after middle age: this shows that we can postpone that ill-health without knowing how to prevent aging completely, but instead by molecular and cellular repair. Secondly, regenerative medicine is now advancing from a futuristic twinkle in a few visionaries' eyes to a realistic strategy for addressing numerous medical conditions. I will explain why therapies that can add 30 healthy years to the remaining lifespan of typical 60-year-olds may well arrive within the next few decades.





Decreased consumption of specific macronutrients promotes metabolic health and longevity


Dudley Lamming

Department of Medicine, University of Wisconsin-Madison, and William S. Middleton Memorial Veterans Hospital, Madison, WI, USA

Abstract: Low protein, high carbohydrate diets can increase lifespan and improve metabolic health in both rodents and humans, but the specific aspects of a low protein diet that promote health and longevity have not been identified. Here, we demonstrate that a specific reduction in dietary branched chain amino acids (BCAAs) is sufficient to improve metabolic health, improving glucose tolerance and decreasing adiposity in both young and middle-aged mice, and promoting leanness and insulin sensitivity in mouse models of diet-induced obesity. Further, we find that diets with decreased protein or BCAA content can promote the longevity of progeroid mice. Reduced consumption of BCAAs does not induce the production of FGF21, a reputed endocrine signal of protein restriction and fasting, but does result in specific inhibition of the mechanistic Target Of Rapamycin Complex 1 (mTORC1). Our results suggest that a reduction in dietary branched chain amino acids promotes metabolic health and longevity, and may represent a highly translatable option for the treatment of diabetes and other age-related diseases.







Geroscience as a trans-NIH effort focused on late life health


Felipe Sierra

Division of Aging Biology, NIA/NIH, USA


Abstract: Aging is by far the major risk factor for most chronic diseases. This has been common knowledge since times immemorial, yet it is only recently that research into the basic molecular and cellular mechanisms of aging has led to potential interventions, not just behavioral (diet and exercise), but also pharmacological. Geroscience is an interdisciplinary field that aims to understand the relationship between aging and age-related diseases, and the Geroscience hypothesis posits that manipulation of the rate of aging might delay the appearance of not one, but many chronic diseases. This would lead to health improvements not possibly matched by the current approach of addressing one disease at a time.

With the elderly showing the fastest population growth worldwide, it is imperative to accelerate efforts to fulfill their biomedical needs, including a reduction in the overall burden of age-related diseases and disabilities. The elderly are often afflicted by multiple comorbidities and therefore resolving one disease at a time is not the best strategy when it comes to this burgeoning population. Geroscience offers an attractive alternative approach to supplement the current model in biomedicine.






Structural and functional rejuvenation of the aged brain by inhibition of leukotriene receptors


Julia Marschallinger, PhD


Tony Wyss-Coray lab, Stanford University, VAPAHCS, Palo Alto, CA 94304



Abstract: Leukotrienes are eicosanoid mediators of inflammation that are well-studied in asthma and allergy, and leukotriene receptor antagonists such as the drug montelukast have been successfully developed to treat asthmatic patients. In the brain, elevated leukotriene levels have been recently demonstrated in acute as well as chronic lesions (e.g. Alzheimer´s disease) and are suggested to mediate neuroinflammatory processes. Interestingly, increasing concentrations of leukotrienes and of the leukotriene-producing enzyme 5-LOX have also been reported in the aging brain. The role of leukotriene signaling in brain aging, in particular in neuroinflammation and age-related cognitive impairments, however, remained to be elucidated.

Here, we examined the effects of a 6-week oral treatment with the leukotriene receptor antagonist montelukast (10 mg kg-1) on brain structure and cognitive functions in aged (20 months) rats. First, we analyzed CNS pharmacology and showed that, after oral administration, montelukast entered the brain of the treated animals. Next, neuroinflammation, adult neurogenesis, blood-brain barrier integrity and neuronal activity were assessed, and several cognitive tests were performed to study the effects of montelukast on the aged brain.

Our results demonstrated that inhibition of leukotriene receptors by montelukast reduced neuroinflammation and elevated hippocampal neurogenesis in aged rats. Most intriguingly, treatment with montelukast led to a significant improvement of learning and memory skills in the aged animals to a level that was comparable to the cognitive skills of young adult rats.

Thus, inhibition of the leukotriene signaling pathway is a promising target for structural and functional brain rejuvenation in the elderly. Treatment with the approved anti-asthmatic drug montelukast provides a safe and druggable approach to restore cognitive functions in old individuals and paves the way to future clinical translation of leukotriene receptor inhibition for the treatment of dementias.






Recognizing degenerative aging as a treatable medical condition:

methodology and policy


Ilia Stambler, PhD

Department of Science, Technology and Society, Bar Ilan University, Israel


Abstract: It is becoming increasingly clear that in order to accomplish healthy longevity for the population, there is an urgent need for the research and development of effective therapies against degenerative aging or senescence processes underlying major aging related diseases, including heart disease, neurodegenerative diseases, type 2 diabetes, cancer, pulmonary obstructive diseases, as well as aging-related complications and susceptibilities of infectious communicable diseases.  Yet, an important incentive for the research and development of such therapies appears to be the development of clinically applicable and scientifically grounded definitions and criteria for the multifactorial degenerative aging process (“senescence” or “senility” using the existing ICD category), underlying those diseases, as well as for the safety and effectiveness of interventions against it. Such generally agreed definitions and criteria are currently absent. The devising of such criteria is important not only for the sake of their scientific value and their utility for the development of therapeutic solutions for the aging population, but also implicitly to comply with and implement major existing national and international programmatic and regulatory requirements. This presentation will examine some methodological suggestions and potential pitfalls for the development of such criteria. Some of the methodological issues involved in potential clinical diagnosis and treatment of senescence as a medical condition may include: Clinical benefits; Focus on older persons; Selection of diagnostic criteria; Integration, interrelation and balance of diagnostic parameters; Long term consideration; Pluralism and rigor of approaches; Affordability of testing and intervention. Methods of information-theoretical analysis can help address some of these methodological issues.

Key words: Senescence, Aging, Aging-related Diseases, Diagnosis, Regulation





Slowing and reversing cognitive declines with age – a two-pronged approach.


Kang W1, Gronska M1, Krzyspiak J1, Kamatkar N1, Galinski B1, Ghosh H1,2, Kee S1, McKeehan N1, Belalcazar H1, Alvina K1, Kong Y1, Francesca Balordi3, Su N4, Lin Chen4, Weiser D1, Levy M1, Castillo P1, Fishell G3, Khodakhah K1, Hébert JM1.


1 Albert Einstein College of Medicine, Bronx, USA

2 Tata Institute for Fundamental Research, Bangalore, India

3 New York University Langone Medical Center, New York, USA

4 Third Millitary Medical University, Chongqing, China


Abstract: A major concern with advancing age is the decline in cognitive function that progressively occurs even in the healthiest individuals and that occurs more precipitously in individuals with neurodegenerative diseases. At present, little can be done to curb, halt, or reverse age-related neurodegeneration or the accompanying decline in mental function. Using mouse models, our group has been focused on developing two potential therapeutic approaches to slow or reverse these age-related declines. In one approach we are manipulating the FGF signaling pathway a) to reduce the chronic inflammatory state of astrocytes, allowing better support for neurons and delaying their degeneration; and b) to increase neurogenesis in the hippocampus of aged animals. In a second independent approach, we are developing neural cell transplant paradigms that will allow new neurons to integrate into existing circuits to bolster their function and reverse age-related functional declines.    








Aging deteriorate central neuritic dystrophy and cognitive deficits in diabetic rats.


Feng-Yan Sun


Department of Neurobiology, School of Basic Medical Sciences, Shanghai Medical college; Research Center of Aging and Medicine, Fudan University, Shanghai 2000032, China


Abstract: Dementia is one of the complications of diabetes mellitus. The increase of cognitively impaired subjects with the progression of aging in the population is an urgent worldwide issue. In our previous study, we had demonstrated that the diabetic rats with an impairment of spatial learning and memory showed the occurrence of RTN3-immunoreactive dystrophic neurites in the cortex. Biochemical examinations revealed the increase of a high molecular weight form of RTN3 (HW-RTN3) in diabetic brains. The corresponding decrease of monomeric RTN3 was correlated with the reduction of its inhibitory effects on the activity of ß-secretase (BACE1), a key enzyme for generation of ß-amyloid peptides. The results from immunoprecipitation combined with protein carbonyl detection showed that carbonylated RTN3 was significantly higher in cortical tissues of diabetic rats compared with control rats, indicating that diabetes-induced oxidative stress led to RTN3 oxidative damage. In neuroblastoma SH-SY5Y cells, high glucose and/or H2O2 treatment significantly increased the amounts of carbonylated proteins and HW-RTN3, whereas monomeric RTN3 was reduced. Thus, diabetes-induced cognitive deficits and central neuritic dystrophy are correlated with the formation of aggregated RTN3 via oxidative stress. Besides, we used D-galactose-induced aging model to study the effects on diabetes-induced central neuritic dystrophin in rat brains. We interestingly found that aging rats showed increased in the formation of HW-RTN3 in diabetic rat brains with more dystrophic neurites in the cortical pyramidal neurons. Meanwhile, we also observed that Ser139 phosphor-histone H2A.X was highly expressed in the neurons of cerebral cortex of rat brains in aging alone and aging plus diabetes, but not in diabetes alone. Therefore, aging could deteriorate central neuritic dystrophy and cognitive deficits in diabetic rats. 







Epigenetic Mechanisms of Stem Cell Aging and Rejuvenation


Thomas A. Rando


Stanford University, Stanford, California, USA


Abstract: There is an age-dependent decline in stem cell functionality in many tissues. Many molecular, biochemical, and functional features of stem cells have been characterized, and these changes have been assumed to be largely irreversible and inevitable accompaniments of aging. Supported by data from studies of heterochronic parabiotic pairings of mice, it is clear that the aged phenotype can be modified when aged cells are exposed to a youthful systemic milieu. These findings raise the question as to what extent, the aged phenotype is epigenetically determined. We have found changes in patterns of chromatin modification that occur during the aging of quiescent muscle stem cells (MuSCs). In particular, there is a marked increase in the enrichment of the repressive mark, H3K27me3, at transcription sites along the genome, and a corresponding decrease in the expression of a subset of genes. Among these, we have found a decrease in histone gene expression at the transcript and protein levels. There is also a corresponding reduction in nucleosome occupancy in aged MuSCs. These changes in histone expression are reverted to a more youthful state in the setting of heterochronic parabiosis. Elucidating the underlying epigenetic features of aged stem cells will provide a framework for understand the fundamental molecular mechanisms of aging and the mechanisms by which environmental influences can reverse the aged phenotype.



Remote ischemic conditioning to prevent geriatric cerebro-cardiovascular diseases

Xunming Ji, MD PhD MBA

Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China

Abstract: With the rapid growth of older populations throughout the world, cardiovascular disease and stroke are the leading cause of adult death and disability respectively, and their disease burden continues to increase. In some low- and middle-income countries (i.e. China), stroke has been the leading cause of death, followed by cardiovascular diseases. Fortunately, most of the cardiovascular and cerebrovascular diseases are preventable and treatable. However, some of the strategies used for preventing and treating these diseases are not cost-effective and may result in severe adverse effects. Therefore, how to prevent cerebro-cardiovascular diseases and improve their prognosis in cost-effective and safe ways has become a world-challenging issue.

Ischemic conditioning confers protection against subsequent more severe ischemic insults by periodically exerting ischemia-reperfusion in an organ or tissue of the subject. This far-reaching phenomenon was first demonstrated by Murry et al. in 1986 and it has been widely studied thereafter. However, the major disadvantage of ischemic conditioning in situ is that it requires an intervention therapy to the target organs directly, which is not always feasible in clinical practice. As an alternative strategy, applying this protective stimulus to an organ or tissue remote from the target organs may be far more attractive during clinical applications. Ischemia was initially applied to a separate region by Przyklenk et al. as a new method to carry out ischemic conditioning, which was later named remote ischemic conditioning (RIC). The strategy of performing RIC on limbs is generally conducted by blood-pressure cuffs that inflated to a pressure blocking unilateral or bilateral limbs blood perfusion, which is now considered as the most convenient, safe, and feasible method to be used in clinical settings.





Same lineage but different susceptibility to immunosenescence: lessons from T cells


Ng Tze Pin 1, Hassen Kared 2, Weili Xu 2,3, Anteneh Tizazu 2,4, Anis Larbi 2,3,4


1 Gerontological Programme, YLL School of Medicine, NUS, Singapore

2Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Singapore

3 School of Biological Science, NTU, Singapore

4 Department of Microbiology and Immunology, NUS, Singapore


Abstract: Aging is often referred as a continuous loss of reserve and the immune system is also affected. By definition immunosenescence includes all the age-related functional alterations. Practically, this term is not always correctly used. For instance, for any years the reduced capacity to produce IL-2 by T cells from elderly was considered as a hallmark of immunosenescence. We know now that it just reflects the shirt from naïve to memory cells during T cell differentiation. This shift is expected to be very high in elderly due to the multiple antigenic encounters. We have studied the T cell family in order to understand how the various members are effected by age and by strong driving forces such as persistent infections. We are showing that terminal-effector CD8+ T cells (Tte) are pushed further in the differentiation stage due to cytomegalovirus infection and that aging was a lower driving force. While naïve T cell (Tn) number decreased we show that the reduced functionality of stem cell memory T cells (Tscm) is mainly due to the homeostatic proliferation of naïve T cells. Inhibition of specific pathways could restore the Tscm stemness. The gamma/delta (Tg/d) belong of the unconvential T cell family. We found that Vdelta1+ T cells follow similar phenotype and function as CD8+ T cells while the Vdelta2+ T cells show no susceptibility to age- or CMV-related "senescence". This provides with a potential model to study resistance to senescence in immune cells.




ASPP2 involvement in p53 mediated HIV-1 envelope glycoprotein gp120 neurotoxicity in mice cerebrocortical neurons

Yulin Zhang, Zhiying Liu, Luxin Qiao1, Yabo Ouyang and Dexi Chen

Department of Infectious Diseases, Capital Medical University affiliated Beijing You An Hospital, Beijing Institute of Hepatology, Beijing 100069, China.


Abstract: The mechanism of HIV-1 associated neurocognitive disorders is still unclear. ASPP2 is a damage-inducible p53-binding protein that stimulates p53-mediated apoptosis and transactivates proapoptotic and cell cycle regulatory genes. It is reported that ASPP2 controls cell proliferation, polarity and tissue organization in the CNS, and has a specific regulatory function in the death of retinal ganglion cells and the development of Alzheimer's disease. In this study, we used p53 and ASPP2 genes knockout mice and primary cerebrocortical neuron culture to analyze the role of ASPP2 interaction with p53 in HIV-1 envelope glycoprotein gp120 induced neurotoxicity. The results showed that 10ng/ml gp120 protein might stimulate p53 overexpression and translocation to nuclear and 30 ng/ml gp120 protein could stimulate both p53 and ASPP2 translocation to nuclear but only p53 overexpression. The primary cultured neurons of p53-/-ASPP2+/-mice had a higher survival rate than that of p53-/-mice in gp120 protein stress. ASPP2 interaction with P53 induced by high dose of gp120 stimulated Bax transcription and contributed to caspase-3 cleavage, and ASPP2-siRNA attenuated gp120 induced neuron death through inhibition Bax expression. These results suggest that ASPP2 plays an important role in p53 mediated neuronal apoptosis at gp120 stress. Further research is necessary to investigate the exact regulatory pathway of this process.

Key word: ASPP2; p53; gp120; neurotoxicity; HIV-1 associated neurocognitive disorders






The mitochondrial metabolic checkpoint and reversing stem cell aging

Danica Chen

UC Berkeley, Berkeley, California, USA

Abstract: Cell cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. Recent advances in hematopoietic stem cell (HSC) biology highlight a mitochondrial metabolic checkpoint that is essential for HSCs to return to the quiescent state. As quiescent HSCs enter the cell cycle, mitochondrial biogenesis is induced, which is associated with increased mitochondrial protein folding stress and mitochondrial oxidative stress. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow HSCs to exit the cell cycle and return to quiescence. Other mitochondrial maintenance mechanisms include mitophagy and asymmetric segregation of aged mitochondria. Because loss of HSC quiescence results in the depletion of the HSC pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in HSCs will increase our understanding of hematopoiesis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions. 

Key words: mitochondria, stem cell, aging, sirtuin, SIRT3, SIRT7, oxidative stress, mitochondrial UPR




Proteostasis, cellular senescence, and age-related neurodegenerative diseases

Shankar J. Chinta, Georgia Woods, Manish Chamoli, Judy Campisi, Gordon J. Lithgow, and Julie K. Anderse

Buck Institute for Research in Aging, California, USA

Abstract: Dr. Andersen is pursuing a wide array of leads toward treatments for complex disorders including Alzheimer’s and Parkinson’s disease. Recently, the laboratory has joined efforts with the Lithgow laboratory at the Buck institute as part of a collaborative project aimed at identifying novel drugs that eliminate neurotoxic protein deposits in patients diagnosed with these devastating disorders. This would fill critical unmet need for drugs that can block disease progression in the brains of patients already impacted by these conditions.  Lysosomes are organelles that serve as the garbage disposal of the cell. Damaged proteins and other cellular components are broken down by lysosomes in a process known as autophagy. Autophagy has recently been found to be a crucial factor in the removal of damaged neurotoxic proteins associated with several age-related neurodegenerative diseases including Alzheimer’s and Parkinson’s. Joint research from the Andersen-Lithgow laboratory has recently identified a factor called TFEB as being critical to this process.  A recent drug screen performed by our laboratories has identified a novel series of potent, structurally-related compounds that activate TFEB and prevent neurodegenerative phenotypes in C. elegans models of Alzheimer’s and Parkinson’s disease. Independent bioinformatic analysis suggests that these compounds have favorable characteristics for CNS-acting drugs in humans including high brain availability and low toxicity. We propose that these drugs have the wide-ranging potential to impact on all patients diagnosed with age-related neurodegenerative disease. Current efforts are towards pre-clinical studies in order to provide appropriate proof-of-principle to move forward into human phase I trials. A recent independent study from the Andersen laboratory has also identified lysosomal dysfunction as a prime driver of elevated toxic iron levels which occur in these disorders and suggests that thes drugs may provide additional benefit by preventing associated brain metal toxicity. In a recent collaborative effort with the Campisi lab, the Andersen lab has shown that a process known as cellular senescence, previously associated primarily with aging in peripheral tissues, may also play an important role in age-related brain pathologies. The laboratory is working to identify novel 'senolytics', compounds which preent age-related brain senescence, as a novel potential cure.   

Key words: proteostasis, cellular senescence, aging, Alzheimer’s Parkinson's





Articulating the Case for Aging Science


Stuart Jay Olshansky


School of Public Health, University of Illinois at Chicago, Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, USA


Abstract: The extension of life achieved in the last century as a product of advances in public health and medical technology, represents a monumental achievement for humanity. Most people born today will live past age 65, and many of them will survive past age 85, but life extension comes with a Faustian trade. Modern medical advances will no doubt endure, but it is possible that continued success in attacking fatal diseases could expose the saved population to an elevated risk of conditions of extreme frailty and disability. This occurs because of a phenomenon known as competing risks – that is, fatal and disabling diseases accumulate in aging bodies within which biological aging remains unaltered. The longer we live, the more these diseases cluster within us. It is distinctly possible that life extension in the future may no longer be an appropriate goal for medicine and public health. Instead, health extension may become the new mantra. If this happens, and there is reason to believe it will, understanding the various behavioral, biological, and environmental risk factors that contribute to inequality in healthy life extension will soon dominate the rationale supporting aging science, public health, and future advances in medical technology. In this presentation I will discuss the compelling rationale for why aging science needs to become the new model of health promotion and disease prevention in this century.







Björn Schumacher


Institute for Genome Stability in Aging and Disease, Medical Faculty, and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany


Abstract: The causal contribution of DNA damage in driving the aging process has become evident in a variety of progeroid syndromes that are caused by defects in DNA repair systems. Congenital defects in genome maintenance mechanisms cause complex disease phenotypes characterized by developmental growth failure, cancer susceptibility, and premature aging. The distinct human disease outcomes of DNA repair defects become particularly apparent in syndromes caused by mutations in nucleotide excision repair (NER). While transcription-coupled (TC-) NER defects lead to growth and mental retardation and premature ageing in Cockayne syndrome (CS) patients, global-genome (GG-) NER mutations lead to highly skin cancer prone Xeroderma pigmentosum (XP). Intriguingly, the distinct outcomes of NER deficiencies are conserved in the simple metazoan C. elegans. TC-NER deficiency renders worms highly susceptible to DNA damage during developmental growth and with aging, while GG-NER defects give rise to genome instability in proliferating germ cells.

We employed the nematode model to investigate distinct response mechanisms to genome instability in somatic tissues and in the germline. DNA damage that persists in somatic tissues leads to activation of the insulin-like growth factor signalling (IIS) effector DAF-16. The FoxO transcription factor DAF-16 is efficiently activated in response to DNA damage during development while its DNA damage responsiveness declines with aging. We demonstrated that DAF-16 alleviates growth arrest and enhances DNA damage resistance in somatic tissues even in the absence of DNA repair. We propose that IIS mediates DNA damage responses in somatic tissues and that DAF-16 activity enables developmental growth amid persistent DNA lesions and promotes tissue maintenance through enhanced tolerance of DNA damage that accumulates with aging.

DNA damage that persists in germ cells leads to enhanced stress resistance of somatic tissues. The “Germline DNA damage-induced systemic stress resistance” (GDISR) is mediated by the innate immune system that is triggered by genomically compromised germ cells and executed through elevated activity of the ubiquitin proteasome system (UPS) in somatic tissues. We propose that GDISR elevates somatic endurance to extend reproductive lifespan when germ cells require time to reinstate genome stability before resuming offspring generation.

Our findings suggest that somatic tissues adapt to distinct constraints of genome instability in the germline and the soma: Developmental growth of somatic tissues can be sustained despite genome instability by DAF-16-mediated DNA damage tolerance, while adult tissues adapt to the requirements of genomically compromised in germ cells through GDISR.


Key words: DNA damage response, aging, progeroid syndromes, nucleotide excision repair, C. elegans





Age-related Stem Cell Dysfunction: Lessons from Drosophila

Arshad Ayyaz, Hongjie Li, Lifen Wang, Linlin Guo, Hansong Deng, Jason Karpac, Heinrich Jasper

Buck Institute for Research on Aging, Novato, CA, USA

Abstract: Proliferation of stem cells has to be carefully controlled to maintain long-term regenerative capacity of high-turnover tissues while preventing cancer. We study the Drosophila intestine as a genetically accessible model in which to explore stem cell function. Intestinal stem cells (ISCs) over-proliferate in aging flies, limiting lifespan. In recent work, we have explored some of the underlying causes of this hyper-proliferative phenotype, and have established a role for age-related immunosenescence and associated commensal dysbiosis in this breakdown of homeostasis.

We are currently exploring the integration of oxidative stress and ER stress signaling in the control of ISC proliferation, as well as the interaction of ISCs with blood cells (hemocytes) in the regulation of tissue homeostasis. Our findings deepen our understanding of the regulation of proliferative homeostasis in aging barrier epithelia, and suggest potentially conserved mechanisms by which proliferative homeostasis can be preserved in the long term, extending lifespan.


  • Guo, L., Karpac, J., Tran, S.L., Jasper, H. (2014) PGRP-SC2 Promotes Gut Immune Homeostasis to Limit Commensal Dysbiosis and Extend Lifespan. Cell, 156:109-22.
  • Wang L, Zeng X, Ryoo HD, Jasper H. (2014) Integration of UPRER and Oxidative Stress Signaling in the Control of Intestinal Stem Cell Proliferation. PLoS Genet. 10:e1004568.





Signaling pathway activation drift in aging and photo aging


Alex Aliper, Alexey Moskalev, Fabianne Pohlman, Polina Mamoshina, Gene Makarev, Irina Fedulova, Anton Buzdin, Alex Zhavoronkov


Insilico Medicine, Inc., Baltimore, USA


Abstract: We analyzed multiple gene expression data sets in multiple skin cell types from both cell lines and tissue samples in young, middle-aged, old and very old patients as well as photoaged cell lines and tissue samples. We compared signaling pathway activation changes and will be presenting notable previously unpublished correlations between aging and photoaging.


Key words: aging, photoaging, UVA, pathway activation, signaling pathways, gene expression






Age-dependent negative effects and interactions of metabolic interventions on neurocognitive function


Michael J. Forster

Center for Neuroscience Discovery, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas, 76107.

Abstract: Commonly used laboratory rats and mice maintained under sedentary conditions exhibit significant weight gain, peaking at middle age and followed by a period of weight loss during old age. This pattern recapitulates age-related trends in energy balance in humans with mild obesity and prediabetes during middle age, and is associated with development of mild impairment of frontocortical function. Our laboratory has recently studied effects of metabolic interventions (metformin, caloric restriction, and curcumin) implemented in mice of different ages (young, middle-aged and old) to model differing conditions of energy balance. Metformin was studied based on its evaluation in humans in different age groups as an anti-aging intervention. Metformin treatment diminished weight gain when implemented for 12 weeks beginning at middle age (11 mo), but failed to improve impaired motor or neurocognitive function in this age group. Metformin significantly impaired spatial memory performance when implemented for the same period in young adults (4 mo) or senescent mice (22 mo). Caloric restriction (to 30% of ad libitum intake) or curcumin supplementation (which increased energy intake without weight gain), both improved neurocognitive function when introduced in middle aged mice, but these effects were absent in males when caloric restriction was combined with curcumin treatment. These results suggest that neurocognitive effects of health-promoting interventions may vary markedly depending on age and metabolic condition, in spite of overall positive health outcomes.





The impact of elimination of senescent cells on ageing and age-related disease


Valery Krizhanovsky


Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.


Abstract: Senescent cells are present in pre-malignant lesions, tumors following therapy and sites of tissue damage.  At these sites cellular senescence limits tumorigenesis in response to activated oncogenes and DNA damage.  However, when senescent cells accumulate in tissues they can contribute to pathology of age-related diseases.  Quantitative identification of senescent cells in tissues is currently challenging, limiting our understanding of their physiological and pathophysiological impact.  We combined senescence-associated-beta-galactosidase assay, with staining for molecular markers for senescence to quantify senescent cells in tissues on a single cell basis.  Using this approach we quantified senescent cells in sites of tissue damage, fibrosis, pre-malignant lesions and different tissues during ageing in mice.  Our data demonstrate first tissue level quantitative examination of accumulation of senescent cells from different cell types in different tissues with age.  When senescent cells gradually accumulate in tissues they promote a chronic “sterile” inflammation which is a hallmark of unhealthy aging.  Pharmacological tools allowing efficient elimination of senescent cells in vivo is a promising strategy for treatment of age-related diseases associated with accumulation of senescent cells.  The accumulation of senescent cells in tissues can result from the resistance of these cells to pro-apoptotic stimuli.  Molecular mechanisms underlying this resistance are not well understood.  We show that senescent cells from both human and mouse origin upregulate the anti-apoptotic proteins Bcl-w and Bcl-xL.  Joint inhibition of Bcl-w and Bcl-xL by siRNAs or by a small molecule induced selective apoptosis of senescent cells.  Notably, treatment of mice with the small molecule efficiently eliminated senescent cells from sites of tissue damage and led to subsequent entrance of tissue stem cells into cell cycle.  Our results provide a possibility of quantitative identification of senescent cells in tissues, unravel a mechanism of resistance of senescent cells to apoptosis and indicate that senescent cells might be limiting tissue fitness by inhibiting stem cell proliferation.


Aging-induced p38 MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis

Brichkina A, Bertero T, Loh HM, Nguyen TMN, Emelyanov A, Rigade S, Ilie M2, Hofman P, Gaggioli C, Bulavin DV

IRCAN, 06107 Nice Cedex 02 France 


Abstract: Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Non-transformed cell types within the microenvironment continuously co-evolve with tumor cells to promote tumorigenesis. Here, we identify an aging-induced p38 MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, pro-tumorigenic signal in the tissue microenvironment. We find that lung cancer growth depends on short-distance cues produced by the cancer niche in a p38-dependent manner. We identify fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis, which regulates early stromal fibroblast activation, the conversion to Carcinoma-Associated Fibroblasts (CAF), and cancer cell proliferation. Systemic downregulation of p38MAPK signaling in a knock-in model with substitution of activating Tyr182 to phenylalanine or conditional ablation of p38 in fibroblasts has a significant tumor suppressive effect on K-ras lung tumorigenesis. Furthermore, both Kras-driven mouse lung tumors and orthotopically-grown primary human lung cancers show a significant sensitivity to both a chemical p38 inhibitor and an over-the-counter inhibitor of hyaluronan synthesis. We propose that p38 MAPK-hyaluronan-dependent reprogramming of the tumor microenvironment plays a critical role in driving lung tumorigenesis while blocking this process could have far-reaching therapeutic implications. 



Longevity and healthspan effects of ketogenic diet in mice


John C Newman, Ming Zhao, Xinxing Yu, and Eric Verdin


Gladstone Institutes/UCSF, San Francisco, CA 94158


Abstract: The ketone body beta-hydroxybutyrate (BHB) is produced during physiological states that are associated with improving health, including dietary restriction, fasting, and exercise. The emerging signaling functions of BHB, including deacetylase inhibition and inflammasome inhibition, suggest that it may be a molecular effector mechanism of some of the health benefits from these states. We sought to determine if long-term exposure to BHB through dietary manipulations would affect the longevity and healthspan of C57BL/6 male mice. As a proof of concept, we a control diet (AIN-93M, 10% calories from protein) with a zero-carbohydrate ketogenic (KD, 90% calories from fat), The ketogenic diet was markedly obesogenic, but cycling between KD and the control diet week prevented obesity. Overall caloric intake was similar between cycling groups and groups fed only control diet. In a small pilot study (N=10/group) started at 17 mo, cyclic-KD increased median lifespan by 10% over the control diet. Preliminary data from a larger study (N=36-71/group) started with mice aged 12 mo shows increased longevity from cyclic-KD. In healthspan testing, cyclic-KD results in enhanced cognition, maintenance of youthful exploratory behavior, and slowing of immune aging. In summary, non-obese exposure to ketogenic diets may enhance longevity and improves healthspan including enhancing cognition in old age.




Zinc contributes to acute cerebral ischemia-induced blood-brain barrier disruption


Zhifeng Qi, Jia Liang, Xunming Ji, Ke Jian Liu*


Cerebrovascular Diseases Research Institute, Xuanwu hospital of Capital Medical University, Beijing, 100053, China


*Corresponding author


Abstract: Zinc ions are stored in synaptic vesicles and cerebral ischemia triggers their release from the terminals of neurons. Zinc accumulation in neurons has been shown to play an important role in neuronal death following ischemia. However, almost nothing is known about whether zinc is involved in ischemia-induced blood–brain barrier (BBB) disruption. Herein, we investigated the contribution of zinc to ischemia-induced acute BBB disruption and the possible molecular mechanisms using both cellular and animal models of cerebral ischemia. Zinc greatly increased BBB permeability and exacerbated the loss of tight junction proteins (Occludin and Claudin-5) in the endothelial monolayer under oxygen glucose deprivation conditions. In cerebral ischemic rats, a dramatically elevated level of zinc accumulation in microvessels themselves was observed in isolated microvessels and in situ, showing the direct interaction of zinc on ischemic microvessels. Treatment with a specific zinc chelator N,N,Nʹ,Nʹ-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), even at 60-min post ischemia onset, could greatly attenuate BBB permeability in the ischemic rats as measured by Evan’s Blue extravasation, edema volume and magnetic resonance imaging. Furthermore, zinc accumulation in microvessels activated the superoxide/matrix metalloproteinase-9/-2 pathway, which leads to the loss of tight junction proteins (Occludin and Claudin-5) and death of endothelial cells in microvessels themselves. Our findings reveal a novel mechanism of cerebral ischemia-induced BBB damage, and implicate zinc as an effective and viable new target for reducing acute BBB damage following ischemic stroke.


Keywords: blood–brain barrier; brain ischemia; zinc; matrix metalloproteinases; tight junction proteins; cell death; microvessel.


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