Conference on Precision Medicine and Ageing...

Conference on Precision Medicine and Ageing 2018

3-4 September 2018 | King’s College LondonProgramme Book

www.pmageing.org

PM and Ageing programme.indd 1 24/08/2018 12:04

General Information

Venue

King’s College London New Hunt’s House Guy’s Campus London SE1 1UL

Registration Please make your way to the registration desk upon your arrival at the Conference. The registration desk will be located outside of Lecture Theatre 1 in New Hunts House, Guy’s Campus. The conference organisers will be pleased to assist you with any queries throughout the conference.

Conference Packs and BadgesYou will receive your name badge at registration. This must be worn at all times throughout the meeting. For reasons of security, any participant not wearing a name budge will be denied access to sessions. Participants will also receive a conference bag, a printed programme, along with a notebook and a pen.

Luggage StorageIf you arrive at the conference and require luggage storage, please speak to a conference organiser who will show you to the storage room. Please note, this will be unlocked and left at your own risk.

Internet AccessComplimentary Wi-Fi is available throughout King’s College, Guy’s Campus. To connect, log onto The Cloud on your device and you will be directed to The Cloud landing page. Simply click, ‘Get Online’.

Lunch and Refreshments The catering point is in the G.4 classroom of New Hunt’s House. If you have advised us you have a dietary requirement please make yourself known to a member of the catering team who will be happy to assist you.

Speaker Preview FacilitiesPlease bring your PowerPoint presentation on a USB memory stick. There will be a ‘Speaker Preview Room’ (G.3 in New Hunt’s House) which will be available during all session times. G.3 is located towards the right of the reception area in New Hunt’s House and there will be signage to help direct.

All oral presenters should meet with the audio-visual technician in the relevant lecture theatre control room at the earliest opportunity and at the very latest, two hours before the start of the session will take place. The control rooms are located at the back of the lecture theatres.

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During the conference we will be using the hashtag #PMAgeing on twitter to share insights from the discussions taking place.


Welcome

Dear Participants and Speakers,

I am delighted to welcome you all to the UK-Israel Precision Medicine and Ageing conference. This event is part of our ambitious programme of academic partnerships and collaborations. That programme has brought together more than 1,000 leading British and Israeli academics over the last four years.

Precision medicine has huge potential to improve people’s lives. The scientific community has a key role to play in developing new tools to prevent, diagnose and remedy diseases. This is relevant for all parts of our society, but particularly for the growing ageing population.

Precision medicine and big data are priority areas for the first call of our flagship UK/Israel research programme, known as BIRAX Ageing. This conference is a great opportunity to lay the groundwork for collaborative research between the UK and Israel in this field. I look forward to seeing the results in the years to come.

Sincerely,

HMA David Quarrey British Ambassador to Israel

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On behalf of the British Council, a very warm welcome.

Science and technology are two of Israel’s most developed sectors. Israel is well aligned with the UK in terms of priority sectors and international engagement, and in the last decade science has become one of the cornerstones of the bilateral UK-Israel relationship. This is important for both countries, as future prosperity will be materially affected by how successfully researchers and innovators are able to collaborate internationally and find solutions to the 21st century biggest challenges.

The British Council is pleased to support this platform for British and Israeli researchers to meet and collaborate in the field of Precision Medicine and Ageing. In the last four years, we have invested in developing scientific links between the two countries in key research areas, including neuroscience, nanotechnology, stem-cell research and antimicrobial resistance, to name a few. There is an appetite to intensify even more the bilateral scientific relations, and we are working on an ambitious set of initiatives for the years to come.

I am very grateful to Prof Valery Krizhanovsky, Dr Masashi Narita, Dr Richard Siow, Dr Liran Shlush and Prof Kevin Talbot for assisting us along the way, as well as to the Ageing Research Centre at King’s College London for hosting us.

I wish you all a very successful conference and hope the meeting will lead to fruitful collaboration.

Sincerely,

Christian Duncumb Director, British Council Israel



Dear Colleagues,

We are very pleased to welcome you all to the UK-Israel Precision Medicine and Ageing conference.

Precision medicine is rapidly evolving, both as a goal in basic sciences as well as in translational research. New and more precise technologies have the potential to revolutionise and shape the way age-related diseases are prevented or treated in the coming decades.

Precision medicine and ageing are broad and multidisciplinary fields, attracting Biologists, Mathematicians, Bio-engineers, Neuroscientists, Immunologists and Public Health researchers, to name a few, and addressing topics with widely diverse levels of complexity, ranging from genomics to stem-cell biology and computer science. The interdisciplinary nature of precision medicine was evident when designing the programme of this conference, the outcome being an excellent line up of leading British and Israeli speakers from different disciplines. We hope the diversity of topics presented will lead to fruitful and creative discussions.

Beyond the value of information exchange, the conference also aims to support the establishment of new links between British and Israeli academics. We hope this will translate into concrete collaborations, including applications to the new BIRAX Ageing call that will fund bilateral research.

We would like to thank all the speakers for accepting our invitation, and particularly grateful to King’s College London for their generous support in hosting this meeting.

We wish you all an exciting and productive meeting.

Kind regards,

Scientific Committee

Prof Valery Krizhanovsky Dr Masashi Narita Dr Liran Shlush Dr Richard Siow Prof Kevin Talbot

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Programme Schedule

DAY ONE Monday 3 September

08:00-08:30 New Hunt’s House, G.4 Morning Refreshments and Networking

New Hunt’s House, Lobby Registration

08:30-08:50 Lecture Theatre 2 Introduction and Greetings

08:50-09:20 Lecture Theatre 2 Keynote Speaker: Kevin Talbot, University of Oxford The nature of neurodegenerative disease

09:20-10:35 Lecture Theatre 2 Session I Chair: Valery Krizhanovsky, Weizmann Institute of Science

09:20-09:45 – Yaniv Assaf, Tel Aviv University MRI of brain plasticity

09:45-10:10 – Stephen Smith, University of Oxford Brain imageing in UK Biobank

10:10-10:35 – Hermona Soreq, Hebrew University of Jerusalem Non-coding RNAs and antagonistic pleiotropism in ageing

10:35-11:05 New Hunt’s House, G.4 Refreshments and Networking

11:05-12:45 Lecture Theatre 2 Session II Chair: Liran Shlush, Weizmann Institute of Science

11:05-11:30 – Wolf Reik, Babraham Institute Epigenetic ageing clock including in single cells

11:30-11:55 – Yehudit Bergman, The Hebrew University Medical School Epigenetic regulation of intestinal infl ammation

11:55-12:20 – Maya Leventer-Roberts, Clalit Research Institute Data driven care: innovation in practice

12:20-12:45 – Davide Danovi, King’s College London Precision Medicine at cell level through collaborative phenotyping:

HipSci and the Stem Cell Hotel

12:45-13:45 New Hunt’s House, G.4 Lunch and Networking



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13:45-15:25 Lecture Theatre 2 Session III Chair: Hermona Soreq, Hebrew University of Jerusalem

13:45-14:10 – Masashi Narita, Cancer Research UK, University of Cambridge Autophagy in senescence and ageing

14:10-14:35 – Valery Krizhanovsky, Weizmann Institute of Science Targeting senscent cells in age-related diseases

14:35-15:00 – Nitzan Rosenfeld, Cancer Research UK, University of Cambridge Circulating tumour DNA as a non-invasive tool for Precision Oncology

15:00-15:25 – Nathan Karin, Technion – Israel Institute of Technology What can regulatory T cells teach us about future medicine

15:25-15:50 New Hunt’s House, G.4 Refreshment Break and Networking

15:50-16:20 Lecture Theatre 2 Keynote Speaker: Uri Alon, Weizmann Institute of Science Senescent cells and the dynamics of Ageing

16:20-17:45 Lecture Theatre 2 Session IV Chair: Kevin Talbot, University of Oxford

16:20-16:55 – Yifat Merbl, Weizmann Institute of Science Utilizing proteolytic signatures in Precision Medicine

16:55-17:20 – Tali Cukierman-Yaff e, Endocrinology Institute, Sheba Medical Center The challenge of healthy ageing with diabetes

17:20-17:45 - Manuel Mayr, King’s College London A proteomics approach to cardiovascular ageing?


DAY TWO Tuesday 4 September 08:00-08:30 New Hunt’s House, G.4 Morning Refreshments and Networking

08:30-09:00 Lecture Theatre 2 Keynote speaker Haim Cedar, Hebrew University of Jerusalem DNA Methylation

09:00-10:15 Lecture Theatre 2 Session V Chair: Yehudit Bergman, The Hebrew University Medical School

09:00-09:25 – Joao Pedro De Magalhaes, University of Liverpool Integrative genomics of ageing

09:25-09:50 – Karl Skorecki, Technion – Israel Institute of Technology Genomic Precision in drug discovery for challenging targets: applications to chronic

kidney disease

09:50-10:15 – Asaf Vivante, Tel Aviv University History of childhood kidney disease and risk of adult end-stage renal disease

10:15-10:45 New Hunt’s House, G.4 Coff ee, Networking

10:45-12:35 Lecture Theatre 2 Session VI Chair: Masashi Narita, Cancer Research UK, University of Cambridge

10:45-11:10 – Katja Simon, University of Oxford Autophagy & immune senescence

11:10-11:35 – George Vassiliou, Wellcome Sanger Institute Clonal haematopoiesis and ageing

11:35-12:00 – Liran Shlush, Weizmann Institute of Science The early evolution of Leukaemia

12:00-12:25 – John Marioni, European Bioinformatics Institute Heterogeneity in immune activation during Ageing

Closing remarks by the British Council and Scientifi c Committee

12:35-13:45 New Hunt’s House, G.4 Lunch

Henriette Raphael Building, Main Function Room Registration to BIRAX Ageing Conference

13:45-14:45 Lecture Theatre 2 Joint Session - Introduction and Greetings

1. Greetings - opening of BIRAX Conference to be held from 13:45pm on 4 September - Thursday 6 September. 2. Keynote Speaker – Janet Lord, University of Birmingham Immunesenescence and its contribution to the Ageing phenotype

Conference Concludes



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Professor Uri Alon Weizmann Institute of Science

Senescent cells and the dynamics of Ageing Monday 3 September 2018, 15:50-16:20 Keynote Session Lecture Theatre 2

Prof Uri Alon earned his BSc in physics and mathematics, and his MSc in physics from the Hebrew University of Jerusalem. He was awarded his PhD in physics from the Weizmann Institute of Science and was a postdoctoral fellow in experimental biology in the Departments of Physics and Molecular Biology at Princeton University. Prof Alon works at the interface between physics and biology and is one of the founders of the field of systems biology. Prof Alon has received many awards including the 2014 Nakasone prize, the Jacques Solvay Chair in Physics in 2017 and the Michael Bruno Memorial Award in 2009 and many more.


Professor Yaniv Assaf Tel Aviv University

MRI of brain plasticityMonday 3 September 2018, 09:20-09:45 Session I Lecture Theatre 2

Prof Assaf is a member of the Dept. of Neurobiology, George S. Wise Faculty of Life Sciences at Tel Aviv University and the Sagol School of Neuroscience. His main research interest is measuring brain micro-structure with magnetic resonance imageing (MRI) in humans and rodents. He studies the anatomical characteristics of brain tissue as well as structural aspects of neuro-plasticity and behavioral correlates. Prof Assaf has developed several novel MRI methodologies to study brain micro-structure including AxCaliber that measures the in-vivo axon diameter and CoLI that measure the cortical layers arrangement in the human brain.

Abstract

At every aspect of our lives – function determines structure. Just as new roads are built between developing cities, network wires are laid to adjust to faster communication demand and social networks are formed under a common goal of individuals, also the brain needs to remodel it’s connectome to adapt to the daily and continuous change in functional demands.

The connectome refers to several functional and structural characteristics of brain connectivity that span from the micron level (neural circuits) to the macroscopic level (long scale pathways). This complex network (which includes the white matter but not only) is responsible for the information passage through different regions. If the integrity of the connectome is affected, the brain functions abnormally. Hence, the connectome is intrinsic to everything that the brain does.

Without the ability to explore the connectome in-vivo, it was traditionally considered to be stable and fixed. Indeed, most effort in white matter research was invested in describing the geographical appearance of the network and the areas it connects.

Magnetic resonance imageing (MRI) and specifically diffusion MRI opened, for the first time, a window into the in-vivo physiology of white matter and the connectome. By measuring micro-structural features of white matter there is a new opportunity to explore also its physiology and dynamics. In the presentation we will demonstrate how the connectome can be measured and what are its macro and micro-structural features, we will describe its evolutional characteristics and demonstrate the role of the connectome in brain plasticity and ageing.



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Professor Yehudit Bergman The Hebrew University Medical School

Epigenetic regulation of intestinal inflammation Monday 3 September 2018, 11:30-11:55 Session II Lecture Theatre 2

Yehudit Bergman is a Full Professor at the Hebrew University Medical School in Jerusalem where she holds The Dr Emanuel Rubin Chair in Medical Science. She studied for her Ph.D. degree at The Weizmann Institute of Science, spent her post gradual work at Stanford University with Dr Ronald Levy, and at MIT with Dr David Baltimore. She chaired the Department of Experimental Medicine and Cancer Research and the Developmental Biology Program. She is a member of EMBO, Academia Europaea and a recipient of The Helmholtz International Fellow Award, and The TEVA Award for Excellence in Science. She sees as one of her goals to inspire young students and researchers. Several of her students have taken up positions as principal investigators worldwide. Her current scientific interest is in understanding the mechanistic basis for epigenetic regulation; both during normal development as well as in cancer. Her research focuses on the role of epigenetics in the development of the immune system, and its involvement in stem cells, inflammation and cancer.

Abstract

Inflammation has been linked to the pathogenesis of tumors in a significant fraction of human cancers. Inflammatory bowel disease (IBD) patients have a significantly higher risk of developing colorectal cancer. The disease has seen a steep rise in incidence over the past decades that can be explained by the drastic environmental changes throughout the last century. Epigenetic mechanisms are known to respond to environmental cues and therefore play important roles in the pathogenesis of inflammation and cancer. We are studying the in vivo genome-wide impact of gut commensal microbiota on the epigenetic landscape of intestinal epithelial cells under homeostasis and pathogenic conditions.


Professor Haim Cedar Hebrew University of Jerusalem

DNA Methylation Tuesday 4 September 2018, 08:30-09:00 Keynote Session Lecture Theatre 2

Haim Cedar was born in New York in 1943. He received his B.Sc. in Mathematics (M.I.T.) and an M.D. and Ph.D. from N.Y.U. (1970). He did postdoctoral research with Eric Kandel and then with Gary Felsenfeld (N.I.H.). In 1973 he immigrated to Israel where he joined the faculty of the Hebrew University, becoming a full professor in 1981. He is a member of EMBO (1982), the Israel Academy of Sciences (2003). He has received the Israel Prize (1999), the Wolf Prize in Medicine (2008), the Gairdner International Award (2011) and the Louisa Gross Horwitz Prize (2016).

Abstract

DNA methylation serves as an annotation system for marking the DNA text. During development, this chemical modification first plays a role in setting up the basal genome structure that determines overall gene accessibility, while further fine tuning is accomplished by programmed methylation changes in each individual cell type. It appears that DNA methylation continues to modulate gene expression profiles after birth, both as a function of normal physiological adaptation and as a response to environmental influences. These epigenetic events then serve as a type of memory that marks past experience. In this context, we will examine the dynamics of DNA methylation during ageing and attempt to understand its role in cancer predisposition.



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Dr Tali Cukierman-Yaffe Endocrinology Institute, Sheba Medical Center

The challenge of healthy ageing with diabetes Monday 3 September 2018, 16:55-17:20 Session IV Lecture Theatre 2

Tali Cukierman-Yaffe is an endocrinologist and a clinical epidemiologist. She is a senior physician in the Endocrinology Institute, head physician of the Centre for Successful Ageing with Diabetes in the Sheba Medical Centre and has a senior lecturer position in the Epidemiology department at Tel-Aviv University. She also is a PHRI (Population Health Research Institute, McMaster University, Canada) international fellow. She has extensive experience in epidemiological clinical studies in the area of cognition and diabetes. She is the principal investigator (PI) of the cognitive sub-study of the ORIGIN study (Outcome Reduction with Initial Glargine Intervention) a 12,500 person multi-centre randomized controlled study. She is a co-investigator in the ACCORD-MIND study (Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes) a ~3000 person randomized controlled study. She is also PI of several Israeli studies related to diabetes and cognitive function. She is the founder of the Centre for Successful Ageing with Diabetes a research and clinical platform that strives for better treatment and healthy/successful ageing of older people with diabetes utilizing a multi-disciplinary approach.

Abstract

The prevalence of diabetes increases with age. In the US for example it has been reported that 25-30% of those over the age of 65 have a diagnosis of diabetes. Diabetes is a disease of accelerated ageing. Data from the last several years has shown that it is a risk factor for cognitive dysfunction, dementia and disability. There are many explanations for this. Glucose has been implicated as a culprit. However there are also studies suggesting a bidirectional relationship with cognitive dysfunction or a common pathway.

This has several important clinical implications. First, cognitive dysfunction & physical, functional impairment should be considered chronic complications of the disease & prevention of these is important in older age. Thus, a) It is important to understand the effect of current diabetes treatment modalities on these complications; unfortunately few of the cardiovascular outcome trials that have been conducted in the last several years measured cognitive/functional outcomes; b) identifying pre-clinical stages & preventive strategies may enable slowing of progression to these states. One such strategy could be routine measurement of cognitive/physical function. Indeed studies have demonstrated that cognitive function/decline are good predictors of progression to dementia. Second, cognitive dysfunction & physical/ functional impairment impede self-care capacity which is a cornerstone in diabetes treatment. At the Center for Successful Ageing with Diabetes a novel comprehensive evaluation that incorporates cognitive, physical and emotional assessments that together enable the tailoring of a personalized treatment plan to the capabilities of the individual is offered. The Center is a clinical, training and research platform. Serving as an “idea generator” and a platform to test interventions. The data gathered has enabled answering pertinent questions such as risk factors for disability, the optimal cognitive tool to be used in the primary clinic and the effect of a multi domain intervention on physical indices in older people with diabetes.


Dr Davide Danovi King’s College London

Precision Medicine at cell level through collaborative phenotyping: HipSci and the Stem Cell HotelMonday 3 September 2018, 12:20-12:45 Session II Lecture Theatre 2

Davide Danovi holds an MD from University of Milan, a PhD in Molecular Oncology from the European Institute of Oncology and completed his postdoctoral training with Austin Smith at the University of Cambridge and Steve Pollard at University College London where he developed a screening platform to isolate compounds active on human neural stem cells from normal or brain tumour samples. At King’s he has been working in the framework of the Human Induced Pluripotent Stem Cells Initiative (HipSci). Leverageing on this research, he is now developing the Stem Cell Hotel project, implementing a dedicated laboratory space for collaborative phenotyping.

Abstract Modern medicine aims to understand the drivers of response to drugs and clinical outcomes linking these to cell behaviour in vitro in the context of different genetic backgrounds. Projects such as the human induced pluripotent stem cells initiative (hipsci.org) offers the scientific community access to a large cell line resource from healthy volunteers and patients affected by several genetic diseases. Importantly within the framework of this project, we have developed methods to characterise cells and identify drivers of variance in cell phenotype integrating stem cell biology, high content analysis and artificial microenvironments. Leverageing from this expertise to characterise cells for cell therapy and drug discovery, the Stem Cell Hotel is now providing to external scientists from academia and industry a dedicated collaborative phenotyping space.



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Dr Joao Pedro De Magalhaes University of Liverpool

Integrative genomics of ageingTuesday 4 September 2018, 09:00-09:25 Session V Lecture Theatre 2

Dr de Magalhaes graduated in Microbiology in 1999 from the Escola Superior de Biotecnologia in his hometown of Porto, Portugal, and then obtained his PhD in 2004 from the University of Namur in Belgium. Following a postdoc with genomics pioneer Prof George Church at Harvard Medical School, in 2008 Dr de Magalhaes was recruited to the University of Liverpool. He is now a reader and leads the Integrative Genomics of Ageing Group (http://pcwww.liv.ac.uk/~ageing/). The group’s research focuses on understanding the genetic, cellular, and molecular mechanisms of ageing.

Abstract

Age-related conditions are the leading causes of death and healthcare costs. Retarding the ageing process would have enormous medical and financial benefits. A large number of genes and drugs extending lifespan in model organisms already exist, yet given long validation times, only a small fraction of them can be explored for humans clinical applications. Therefore, prioritizing drugs and gene targets is imperative. In this talk, I will present network and machine learning approaches for predicting longevity genes and compounds, which we validated experimentally. I will also present integrative, multi-dimensional approaches that provide insights into longevity pathways and their role in age-related diseases. Overall, our computational approaches allow us to identify and prioritize further compounds with potential life-extending properties.


Professor Nathan Karin Technion - Israel Institute of Technology

What can regulatory T cells teach us about future medicineMonday 3 September 2018, 15:00-15:25 Session III Lecture Theatre 2

The laboratory of Nathan Karin focuses on exploring basic mechanisms of immunological tolerance. Among its major findings is the discovery of the key adhesion molecule that directs leukocyte accumulation at inflammatory sites (Nature 1992), which led to the development of the first biological drug for Multiple Sclerosis (Tysabri). Recently NK identified a novel subtype of FOXp3+ regulatory T cells (Tregs) that are CCR8+ and are master drivers of immune regulation (Brashest et al PNAS 2017). Based on its MOA, NK developed a novel platform for precession medicine aiming at evaluating Tregs function along ageing and identifying best candidates for immunotherapy.

AbstractThe biological function of effector CD4+ T cells and effector CD8+ T cells is tightly regulated by different types of regulatory cells. Among these cells, the CD4+CD25+Foxp3+ regulatory T cells (Treg) are the major subset that regulate immunity to self. The mechanism of action of these cells includes upregulation of the metabolic receptor CD39, secretion of Granzyme B that targets effector T cells, and production of the suppressor cytokine IL-10. It is believed that selective amplification of the biological function of these cells would be beneficial for treating a variety of autoimmune diseases.

CCR8 is a chemokine receptor that binds four ligands, including CCL1. Recently NK and his lab identified a novel subtype of Treg cells that produce CCL1 and express CCR8. Activation of these cells through a CCL1 autocrine loop potentiates their suppressive activity, making them master drivers of immune regulation (Brashest et al PNAS 2017). NK’s team at the Rappaport Institute are collaborating with GSK’s Discovery Partnerships with Academia group to maximise the translational potential of this discovery in treating immuno-inflammatory diseases in specific patient populations based on their Treg status. This could be further extended to examine the effect of ageing on T cell function and it’s biological consequences.



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Professor Valery Krizhanovsky Weizmann Institute of Science

Targeting senscent cells in age-related diseasesMonday 3 September 2018, 14:10-14:35 Session III Lecture Theatre 2

Prof Krizhanovsky received his PhD in Biology at the Hebrew University of Jerusalem in 2005. He then did his postdoctoral training at Cold Spring Harbor Laboratory, USA. In 2010 Prof Krizhanovsky joined Weizmann Institute of Science where he is now Associate Professor at the Department of Molecular Cell Biology. During his career, he discovered the role of cellular senescence in tissue damage, established the role of NK cells in the immune surveillance of senescent cells, presence of senescence in the placenta and discovered senolytic pathways allowing specific elimination of senescent cells in vivo. His laboratory studies the role of senescent cells in ageing, age-related diseases and cancer. Web: http://www.weizmann.ac.il/mcb/valery/

Abstract

Senescent cells are present in pre-malignant lesions, tumors following therapy and sites of tissue damage where they limit tumorigenesis and aid tissue repair. However, when senescent cells accumulate in tissues they contribute to pathology of age-related diseases. The accumulation of senescent cells in tissues can result from the resistance of these cells to pro-apoptotic stimuli. We showed that senescent cells upregulate the anti-apoptotic proteins members of Bcl-2 family. Joint knockdown or inhibition of these proteins by a small molecule induced selective apoptosis of senescent cells. Notably, treatment of mice with the small molecule eliminated senescent cells from tissues and led to subsequent entrance of tissue stem cells into cell cycle. Yet another molecular mechanism that limits cell death of senescent cells is dependent on the CDK inhibitor p21 (CDKN1A). Upon p21 knockdown, senescent cells die in a caspase- and JNK-dependent manner. Notably, p21 knockout in mice eliminated liver senescent stellate cells and alleviated liver fibrosis and collagen production. With age, when senescent cells gradually accumulate in tissues, they promote a chronic “sterile” inflammation via secreted pro-inflammatory and matrix-remodeling factors. These factors lead to immune-cell recruitment and senescent-cell clearance. We show that mice with impaired immune surveillance of senescent cells exhibit both higher senescent-cell tissue burden and chronic inflammation. Consequently, they exhibit multiple pathologies and significantly lower survival than control animals. Altogether, these studies focus on elimination of senescent cells as a promising strategy for extension of healthspan and lifespan, and uncover the molecular mechanisms of the effect of senescent cells.


Dr Maya Leventer-Roberts Clalit Research Institute

Data driven care: innovation in practiceMonday 3 September 2018, 11:55-12:20 Session II Lecture Theatre 2

Maya Leventer-Roberts, MD, MPH is currently the Deputy Director of the Clalit Research Institute in Tel Aviv, Israel. She completed her residency in pediatrics at Mount Sinai. She has an undergraduate degree in physics from Wesleyan University, an MD from the Yale School of Medicine, and her MPH from the Harvard School of Public Health in Family and Community Health. She completed her fellowship in Pediatric Environmental Health at Mount Sinai, and is also dually appointed as Adjunct Assistant Professor in Preventive Medicine and Pediatrics at Mount Sinai. She has worked previously with the NYC Department of Health on epidemiological methods and developing and tracking interventions in public health outcomes and chronic disease prevention. She now oversees over a hundred active projects which bring data-driven insights for risk prediction and population level intervention directly into one of the world’s largest payer/provider healthcare systems.

Abstract

Data-driven innovation is hailed as a unique opportunity to fill the aim of improving health care delivery and patient experience while reducing overall costs. The Clalit Research Institute (CRI) takes this theoretical ideal into dramatic real world practice by creating insights out of raw data and translational health policy out of insights. CRI drives the data-driven health care policy of Clalit Health Services, Israel’s largest healthcare organization that provides a comprehensive basket of services across the entire patient journey and through the full life span to over 50% of the population, or approximately 4.5 million people. Our team, world renowned experts in clinical medicine, data science, epidemiology, and advanced analytics, uses clinically relevant real world evidence to promote precision medicine in high-risk groups.



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Professor Janet Lord University of Birmingham

Immunesenescence and its contribution to the Ageing phenotypeTuesday 4 September 2018, 13:45-14:45 Joint Session – BIRAX Opening Lecture Theatre 2

Professor Janet Lord is Director of the Institute for Inflammation and Ageing at Birmingham University and is also Director of the MRC-Arthritis Research UK Centre for Musculoskeletal Ageing Research. Her primary research focus is in the effect of ageing upon immune function and how this limits the ability of older adults to resolve inflammation and predisposes them to chronic inflammatory disease such as Rheumatoid Arthritis. In 2013 she was awarded the Lord Cohen medal for her outstanding research in human ageing by the British Society for Research into Ageing. She was elected a Fellow of the Academy of Medical Sciences in 2015.


Dr John Marioni European Bioinformatics Institute

Heterogeneity in immune activation during Ageing Tuesday 4 September 2018, 12:00-12:25 Session VI Lecture Theatre 2

John Marioni is a Research Group Leader at the EMBL-European Bioinformatics Institute, a Senior Group Leader at the CRUK Cambridge Institute within the University of Cambridge and an Associate Faculty member of the Wellcome Sanger Institute. John read for his PhD at the University of Cambridge under the supervision of Professor Simon Tavaré before becoming a postdoctoral scholar under the supervision of Professor Matthew Stephens at the University of Chicago. John’s lab has pioneered the development of methods for the analysis of single-cell genomics data. Subsequently, his lab has applied them, in conjunction with outstanding experimental collaborators, to understand cell fate decisions in early mammalian development.

Abstract With recent technological developments it has become possible to characterize a single cell’s genome, epigenome, transcriptome and proteome. In particular, single-cell RNA-sequencing (scRNA-seq) has been widely applied to study heterogeneity in populations of neurons, in the immune system and in early development, revealing the existence of new populations of cells and differentiation trajectories. Fully exploiting such data requires the development of novel computational methods, with many of the tools developed for bulk RNA-sequencing not being appropriate for scRNA-seq. In this presentation I will describe some of the methods we have developed to address these challenges, and will illustrate their application in the context of ageing of the the immune system.



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Manuel Mayr King’s College London

A proteomics approach to cardiovascular ageing?Monday 3 September 2018, 17:20-17:45 Session IV Lecture Theatre 2

Manuel Mayr qualified in Medicine from the University of Innsbruck (Austria) in 1999. He then moved to London to undertake a PhD. Upon completion of his PhD, he achieved promotion to Professor in 2011. He has been awarded a prestigious British Heart Foundation Personal Chair in 2017. His academic achievements have been recognised by the inaugural Michael Davies Early Career Award of the British Cardiovascular Society (2007), the inaugural Bernard and Joan Marshall Research Excellence Prize of the British Society for Cardiovascular Research (2010), and the Outstanding Achievement Award by the European Society of Cardiology Council for Basic Cardiovascular Science (2013).

Abstract

Objectives: To explore the role of a family of metalloproteases known as ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) in regulating vascular proteoglycan content. Background: Ageing is a major risk factor for cardiovascular diseases. Continuous extracellular matrix remodelling (ECM) remodelling occurs in response to pulsatile blood flow changes, vascular injury or during vascular ageing. Methods: We have established proteomics approaches for studying the ECM (www.cardiovascularproteomics.eu). Results: ADAMTS-1, -4 and -5 are the main enzymes responsible for cleavage of large aggregating proteoglycans such as versican and aggrecan. ADAMTS-5 activity affects proteoglycan-mediated lipoprotein retention in the murine aorta predisposing to atherosclerosis (Didangelos et al, J Biol Chem 2012). Upon vascular injury, a reduction in ADAMTS-1 and ADAMTS-5 contributes to an increase of aggrecan and versican in stented porcine coronary arteries (Suna et al, Circulation 2018). In a model of aortic dilatation by angiotensin II (AngII) infusion, mice lacking the catalytic domain of ADAMTS-5 (Adamts5Δcat) showed an attenuated rise in blood pressure whilst displaying increased dilatation of the ascending aorta (Fava et al, Arterioscl Thromb Vasc Biol 2018). Interestingly, a comparison of the aortic ECM from AngII-treated wildtype and Adamts5Δcat mice revealed versican as the most up-regulated ECM protein in Adamts5Δcat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine) and a decrease of low-density lipoprotein-related protein 1 (LRP1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS-5, attenuated the generation of versikine but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5Δcat mice, but was not sufficient to maintain versican processing and prevent aortic dilatation. Thus, ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. Conclusions: Our results support the emerging role of ADAMTS proteases in age-associated cardiovascular diseases


Dr Yifat Merbl Weizmann Institute of Science

Utilizing proteolytic signatures in Precision Medicine Monday 3 September 2018, 16:20-16:55 Session IV Lecture Theatre 2

Dr Yifat Merbl completed her BS summa cum laude in Computational Biology at Bar Ilan University in 2003. She earned an MSc in Immunology at the Weizmann Institute in 2005 with Prof. Irun Cohen. She joined the first PhD program in Systems Biology at Harvard Medical School, completing her PhD there in 2010. She stayed on at Harvard as a postdoctoral fellow until joining the Department of Immunology at the Weizmann Institute in 2014. Dr Merbl’s research explores the many modifications that proteins undergo in the human body. Drawing on her background in computational biology, cell biology, biochemistry, and immunology, Dr Merbl developed a high-throughput system that enabled her to monitor post-translational modifications of thousands of proteins in parallel, under conditions that are relatively close to those of the complex cellular environment. In addition, she developed a profiling system using protein microarrays that allow her to identify the changes that occur to thousands of individual proteins, simultaneously. In her new lab, Dr Merbl wants to zero in how the ubiquitin system, one of the most important post-translation modifiers in proteostasis regulation in cancer and immune regulation. Dr Merbl is the recipient of numerous awards for her scholastic and academic excellence, including an ERC Starting Grant (2015), the Alon Scholarship (2015), the Gruber Foundation Young Scientist Award (2015), and the Israeli Centers of Excellence Young Investigator Award (2014). She is also listed as a co-inventor on several pending patent applications for her proteomics techniques.

Abstract Cellular function is critically regulated by targeting substrates to proteasomal degradation in response to intracellular and extracellular signals. Yet, direct analysis of naturally cleaved proteasomal peptides under physiological conditions is still lacking. Here, we established Mass Spectrometry Analysis of Proteolytic Peptides (MAPP) as a novel proteomic approach for the detection of peptides that are cleaved by cellular proteasomes through proteasomal footprinting. Using MAPP we analyzed changes in the proteolytic landscape in response to stimuli such as pro-inflammatory signals and revealed dynamic modulation of the cellular proteome in response to different signals. We further demonstrated the proficiency of MAPP to human clinical samples and uncovered disease-associated signatures of proteasomally-cleaved peptides in patients. Taken together, our approach may be broadly applicable to reveal novel insight into the degradation landscape in various cellular conditions as well as human diseases that are associated with aberrations in proteasomal degradation, ranging from protein aggregation to autoimmunity and cancer. Importantly, it may be utilized for numerous aspects of personalized medicine from clinical and molecular diagnostics to the development of new therapies.



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Dr Masashi Narita Cancer Research UK, University of Cambridge

Autophagy in senescence and ageingMonday 3 September 2018, 13:45-14:10 Session III Lecture Theatre 2

Masashi Narita has been a group leader at the Cancer Research UK Cambridge Institute (University of Cambridge) since 2006. He obtained his MD in 1992 (Osaka, Japan) and finished his PhD (Osaka, Japan) in 2000. He then joined Scott Lowe’s group as a postdoc at the Cold Spring Harbor Laboratory, where he worked on senescence-associated heterochromatic foci (SAHF). Currently his group studies diverse senescence effector programs, with particular emphasis on chromatin architecture and autophagy, to understand how senescence modulates tumorigenesis and ageing.

Abstract

Autophagy is a bulk cellular degradation system, playing a critical role in the quality control of macromolecules and metabolic homeostasis. Autophagy activity declines with age and, at least in lower eukaryotes, an autophagy defect promotes ageing. While ‘basal’ autophagy is anti-ageing machinery, the precise role of ‘stress-induced’ autophagy in senescence is not entirely clear. Here, we have generated mice with a doxycycline (dox) inducible knockdown of a key autophagy gene, Atg5 (called Atg5i mice), enabling temporal control of autophagy levels in vivo. In contrast to typical knockout mouse models for autophagy genes, due to the limited permeability of dox through the blood-brain-barrier, dox-fed Atg5i mice do not show the rapid lethality associated with neurotoxicity, allowing us to do long-term experiments. They instead reveal accelerated tissue degenerative disorders. Autophagy restoration by removing dox after a prolonged period of autophagy inhibition alleviates some but not all of these phenotypes. The dynamic nature of autophagy-associated phenotypes will be discussed at a cellular, tissue, and organismal levels.


Professor Wolf Reik Babraham Institute

Epigenetic ageing clock including in single cells Monday 3 September 2018, 11:05-11:30 Session II Lecture Theatre 2

Wolf Reik obtained his MD from the University of Hamburg. He did his thesis work with Rudolf Jaenisch, and postdoctoral work with Azim Surani in Cambridge. He became a Fellow of the Lister Institute of Preventive Medicine at Cambridge and subsequently the Head of the Epigenetics Programme at the Babraham Institute in Cambridge and its Associate Director. He is honorary Professor of Epigenetics at the University of Cambridge and Associate Faculty at the Wellcome Trust Sanger Institute, where he is a founding member of the Centre for Single Cell Genomics. He is a Member of EMBO, Fellow of the Academy of Medical Sciences, Fellow of the Royal Society, and a Member of the Academia Europaea.

His research interests are in epigenetics, particularly in epigenetic reprogramming during mammalian development and its role in stem cell biology and inheritance. His current work addresses the mechanisms of genome-wide demethylation in the mammalian germ line, links between reprogramming and pluripotency, epigenetic regulation of cell fate decisions in early development, and the role of epigenetic mechanisms in ageing. His lab also develops new epigenomics technologies especially in single cells. He has published 244 research papers with an h-index of 109.

Abstract

Epigenetic information is relatively stable in somatic cells but is reprogrammed on a genome wide level in germ cells and early embryos. Epigenetic reprogramming appears to be conserved in mammals including humans. This reprogramming is essential for imprinting, and important for the return to naïve pluripotency including the generation of iPS cells, the erasure of epimutations, and perhaps for the control of transposons in the germ line. Following reprogramming, epigenetic marking occurs during lineage commitment in the embryo in order to ensure the stability of the differentiated state in adult tissues. Signalling and cell interactions that occur during these sensitive periods in development may have an impact on the epigenome with potentially long lasting effects. The epigenome changes in a potentially programmed fashion during the ageing process; this epigenetic ageing clock seems to be conserved in mammals.

Our recent work addresses the mechanisms and consequences of global epigenetic reprogramming in the germ line, and the role of passive and active mechanisms of DNA demethylation. Using single cell multi-epigenomics techniques, we are beginning to chart the epigenetic and transcriptional dynamics and heterogeneity during the exit from pluripotency, symmetry breaking, and initial cell fate decisions leading up to gastrulation. We are also interested in the potentially programmed degradation of epigenetic information during the ageing process and how this might be coordinated across tissues and individual cells.



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Dr Nitzan Rosenfeld Cancer Research UK, University of Cambridge

Circulating tumour DNA as a non-invasive tool for Precision OncologyMonday 3 September 2018, 14:35-15:00 Session III Lecture Theatre 2

Dr Nitzan Rosenfeld is a recognised expert in cell-free DNA analysis and its application for non-invasive cancer genomics. Originally trained in Physics, Dr Rosenfeld specialised in quantitative molecular biology, obtaining a Ph.D. from the Weizmann Institute of Science under the supervision of Prof. Uri Alon. In 2005 he joined Rosetta Genomics, where he was Head of Computational Biology and led development of molecular tests that are in clinical use for oncology. Since 2009 he has been focusing on applications of circulating tumour DNA (ctDNA), as a group leader at the Cancer Research UK Cambridge Institute, University of Cambridge. His research group pioneered the use of Next-Generation Sequencing of ctDNA, demonstrating its potential as a liquid biopsy through a series of widely-cited publications describing whole exome, hybrid capture, and amplicon-based sequencing of ctDNA. Dr Rosenfeld’s work is funded by research grants from CRUK, ERC and others, and has been recognised by distinguished awards including the CRUK Future Leaders in Cancer Research prize (2013), the British Association for Cancer Research Translational Research Award (2013), the Foulkes Foundation Medal (2015), and the Meyenburg Cancer Research Award (2017). In 2014, Dr Rosenfeld and colleagues founded Inivata, a global clinical cancer genomics company harnessing the potential of circulating DNA analysis to transform patient care. Its innovative InVision™ liquid biopsy platform is being employed by leading cancer institutes.


Dr Liran Shlush Weizmann Institute of Science

The early evolution of Leukaemia Tuesday 4 September 2018, 11:35-12:00 Session VI Lecture Theatre 2

Dr Liran Shlush received his BSc with honor from Technion Institute of Technology Haifa Israel in 1996. He completed his medical degree also in the Technion and his Internal Medicine and at the Rambam Healthcare Campus Haifa Israel. Dr Shlush completed a PhD in population’s genetics in 2012, at the Technion Faculty of Medicine Haifa Israel under the supervision of Prof Karl Skorecki. He has been a post-doctoral fellow in the laboratory of Dr John Dick in Toronto from 2012-2014. During this time he published a seminal paper in Nature on the early evolution of leukemia, a paper that was selected by the editors of Nature medicine as one of the most notable advancements in medicine for the year of 2014. Dr Shlush is currently a senior scientist at the immunology department at the WIS and a visiting physician in the leukemia group at Princess Margaret Cancer Centre, and the Hematology department at the Rambam healthcare campus. Dr Shlush’s research is focused on the evolution of hematological malignancies with special interest in the early stages of leukemia.



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Professor Katja Simon University of Oxford

Autophagy & immune senescenceTuesday 4 September 2018, 10:45-11:10 Session VI Lecture Theatre 2

Katja Simon is Professor at Oxford University and Principal Investigator at the Kennedy Institute of Rheumatology. She trained as an Immunologist under Avrion Mitchison at the DRFZ Berlin and showed in her PhD that TH1 cytokines are found in excess in rheumatoid arthritis (EULAR Award). As a postdoc at the Centre d’Immunologie Marseille Luminy, she investigated transcription factors regulating thymic cell death. During her second postdoc in Oxford she pursued her interest in cell fate, studying cell death molecules in thymic selection, inflammation and tumour immunity. As a Principal Investigator, she turned her attention to autophagy, and discovered that autophagy maintains healthy red blood cells, stem cells and memory T cells. It promotes differentiation and prevents ageing of the hematopoietic system. She is a Wellcome investigator.

Abstract

With extension of the average lifespan, ageing has become a heavy burden in society. Immune senescence is a key risk factor for many age-related diseases such as cancer, neurodegeneration and increased infections in the elderly, and hence, has elicited much attention in recent years. As our body’s guardian, the immune system maintains systemic health through removal of pathogens and damage. Autophagy is an important cellular “clearance” process by which a cell internally delivers damaged organelles and macromolecules to lysosomes for degradation. Here, we discuss the most current knowledge of how impaired autophagy can lead to cellular and immune senescence. We will provide an overview, with examples, of the clinical potential of exploiting autophagy to delay immune senescence and/or rejuvenate immunity to treat various age-related diseases.


Professor Karl Skorecki Technion - Israel Institute of Technology

Genomic Precision in drug discovery for challenging targets: applications to chronic kidney disease Tuesday 4 September 2018, 09:25-09:50 Session V Lecture Theatre 2

Karl Skorecki is a 1977 MD graduate of the University of Toronto, who pursued postgraduate clinical and research training in internal medicine, nephrology and cell and molecular biology at the Brigham and Women’s and Massachusetts General Hospitals and Harvard Medical School. Karl and family moved to Haifa in Israel in 1995, where he has served in various clinical and academic leadership positions. These have included Director of Nephrology at Rambam Medical Center, Professor of Medicine at the Technion – Israel Institute of Technology, Director of the Rappaport Research Institute, and currently Director of Medical and Research Development at Rambam Medical Center. His research interests are in the genetic epidemiology of health disparities with a focus on chronic kidney disease.

Abstract

Chronic Kidney Disease (CKD), manifesting as declining glomerular filtration rate, proteinuria, and hypertension, is a well-studied feature of ageing with a large inter-individual and inter-population variability. Moreover, a striking inequality in the chronic kidney disease, with a 4-fold increased incidence and prevalence rates, and earlier onset in populations of recent African ancestry, led our group and others to identify causal disease risk variants for non-diabetic non-monogenic forms of CKD, at the APOL1 genetic locus. These variants rose to high allele frequency in Sub-Saharan Africa, under the strong evolutionary pressure exerted by virulent trypanosomal subspecies. A single parental copy of the identified APOL1 kidney disease risk variants confers protection against lethal parasitic illness, whereas two parental copies increase the risk of progressive chronic kidney disease by 7-50 fold. While this represents among the highest odds ratios ever reported for common non-monogenic disease risk causal variants, there is still a substantial proportion of the population of genotypic risk who reach an old age with well-preserved kidney function and without any evidence of CKD. This phenotypic heterogeneity can be attributed to epistatic or gene-by-environment interactions, with a number of environmental second hits which transform genotypic risk to clinical disease having been identified already, and others to be discovered. Currently, we are focusing our attention on an elderly cohort, who are at high genotypic risk, without manifestations of CKD, in a precision approach, to identify protective genetic and environmental influences. Mechanistic studies in kidney cells and experimental model systems point to altered autophagy flux rates, as well as mitochondrial dysfunction, as potential important modifiers of progressive chronic kidney disease. Accordingly, the current focus of attention is on environmental and genetic factors which impinge on these and related pathways. Since variable decline in kidney function is a feature of ageing, we view the current set of studies as an excellent opportunity for precision identification of preventive strategies and intervention to promote healthy ageing.



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Professor Stephen Smith University of Oxford

Brain imageing in UK BiobankMonday 3 September 2018, 09:45-10:10 Session I Lecture Theatre 2

Steve Smith is Professor of Biomedical Engineering and head of the Analysis Group at WIN/FMRIB. FMRIB’s Analysis Group, which he started in 1997, now comprises about 30 research fellows, postdocs, students and staff, carrying out functional and structural brain image analysis and statistics research. The group has produced the brain image analysis software package FSL (FMRIB Software Library) which is widely used in many laboratories across the world. Recent personal research has concentrated on resting state networks, showing that these correspond closely to explicit functional networks as seen in task FMRI (Smith, PNAS, 2009), showing new networks on the basis of distinct temporal dynamics (Smith, PNAS, 2012), and relating functional networks to behaviour and lifestyle (Smith, Nature Neuroscience, 2015). Currently, the FMRIB Analysis Group is playing a major role in the Human Connectome Project (Smith, TICS 2013; Smith, NeuroImage 2014), UK Biobank Imageing (Miller, Nature Neuroscience 2016), and the Developing Human Connectome Project.

Abstract

UK Biobank is a prospective epidemiological health study involving 500,000 participants, including rich baseline data (blood assays, genetics, lifestyle information, cognitive testing and much more). 100,000 of these volunteers are also coming back for brain and body imageing, with 26,000 already imaged. All UKB data is available for researchers upon application. We will describe the brain imageing component of UKB, and show some early results including associations with thousands of non-imageing variables and genetics.


Professor Hermona Soreq Hebrew University of Jerusalem

Non-coding RNAs and antagonistic pleiotropism in ageingMonday 3 September 2018, 10:10-10:35 Session I Lecture Theatre 2

Hermona Soreq was trained at The Weizmann Institute of Science and the Rockefeller University. She joined the faculty of The Hebrew University in 1986, where she holds a Chair in Molecular Neuroscience and is also a founding member of the ELSC Center of Brain Sciences. Soreq pioneered the application of molecular biology and genomics to the study of cholinergic signaling, with a recent focus on its microRNA regulation in mice and humans. Her work spans both basic and biomedical studies on cholinergic signaling in health and disease, particularly on anxiety-related topics.

Abstract

Background: Ageing associates with modified acetylcholine (ACh) signaling and altered metabolism, anxiety and inflammation, and recent reports show that long-term treatment of ageing patients with anti-cholinergic drugs exacerbates their risk of cognitive decline. This may reflect antagonistic pleiotropism, where genes play certain roles early in development but counter-acting ones in ageing. To seek the mechanisms underlying this phenomenon and ways to limit its impact we focus on the involvement in cholinergic signaling of non-coding RNAs, which rapidly emerge as global regulators of gene expression but their ageing-associated roles remain largely obscure.

Methods and Results: RNA-sequencing of patients’ blood cells revealed short microRNAs (miRs) and transfer RNA fragments (tRFs) that may co-attenuate the expression of cholinergic genes and appear to operate in cooperative groups of miRs and tRFs that coordinate modifications in the entire physiological landscape of cholinergic signaling. We found changed levels of these context-dependent RNA regulator groups to reflect modified anxiety, pain, metabolism and post-stroke recovery prospects, all of which associate with altered ACh signaling. Moreover, the impact of interactions between regulatory RNAs and coding transcripts may change with ageing, modifying the health-related consequences of unique or paired genomic single nucleotide polymorphisms (SNPs) that interrupt the binding of miRs to their cholinergic mRNA targets. Consequently, young carriers of inherited SNPs intercepting the interaction of the primate-specific hsa-miR-608 with acetylcholinesterase mRNA showed slightly elevated anxiety, blood pressure and inflammation biomarkers as well as apparent protection from acute stressful experiences. However, brain tissues from aged carriers of such SNPs presented considerably higher levels of acetylcholinesterase than matched controls, predicting suppressed cholinergic status and mal-responsiveness to the regular dose of Alzheimer’s disease therapeutics.

Take home Message: Our findings indicate causal involvement of non-coding RNAs in ageing-related processes and highlight the need for personalized medicine-based decisions when treating ageing patients with cholinergic-targeted drugs.



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Professor Kevin Talbot University of Oxford

The nature of neurodegenerative diseaseMonday 3 September 2018, 08:50-09:20 Keynote Session Lecture Theatre 2

Kevin Talbot is Professor of Motor Neuron Biology, and Head of the Division of Clinical Neurology in the Nuffield Department of Clinical Neurosciences, University of Oxford, UK. His research is focussed on in vitro and in vivo modelling of the earliest phases of pathogenesis in the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), to elucidate the basic mechanisms of motor neuron degeneration and accelerate the identification of disease modifying treatments. His team use spinal motor and cortical neuronal models based on induced pluripotent stem cells, and BAC-transgenic mice based on TDP-43 mutations. Current work is focussed using these models to identify drug targets using high and medium throughput screening. He also runs a specialist clinical service which provides clinical care to 10% of the UK ALS patient population.

Abstract

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis represent one of the principal public health challenges of our age. One third of people born in 2018 in the UK are predicted, assuming current demographic trends continue, to live to the age of 100 years. The burden of cognitive impairment and physical decline in this population will require one to one care for a significant proportion, with dire economic consequences. Research into neurodegenerative disease has so far failed to identify any treatments which significantly alter natural history and prevent progressive disability.

The identification in each of the main neurodegenerative diseases of mutations in distinct but specific genes indicates that each is a complex clinical syndrome with multiple biological causes. As with other areas of medicine such as cancer, progress in neurodegenerative disease therapy will require a precise molecular understanding of the key pathways which lead to cell stress and death in the nervous system, and how these interact with normal ageing. Evidence is accumulating in favour of a ‘multiple-hit’ model in which neurodegeneration manifests as the consequence of a combination of genetic susceptibility factors and age-dependent changes in cellular homeostasis, which are either environmentally determined or due to stochastic events. Neurodegenerative diseases also affect compartmentalised sub-systems of the brain and spinal cord, suggesting that there are inherent vulnerabilities in complex and probably recently evolved networks. Real progress in treating these diseases requires a precision-medicine approach underpinned by the detection of those at risk, by early diagnosis and treatment, and by the use of more realistic in vivo and in vitro models for drug discovery, which reflect more tractable upstream events early in disease initiation.


Dr George Vassiliou Wellcome Sanger Institute

Clonal haematopoiesis and ageingTuesday 4 September 2018, 11:10-11:35 Session VI Lecture Theatre 2

Dr George Vassiliou is a Cancer Research UK Senior Fellow and heads the Haematological Cancer Genetics Group at the Wellcome Trust Sanger Institute since 2011. He is also a member of Faculty at the Wellcome-MRC Cambridge Stem Cell Institute and practices as a Consultant Haematologist at Cambridge University Hospitals, where he treats patients with acute leukaemias and myeloma. His group studies the pre-clinical evolution, pathogenesis and treatment of acute myeloid leukaemia (AML), a disease with a survival below 30% and for which treatments have not changed significantly for more than 25 years. The group develop and study bespoke mouse models to investigate how particular gene mutations drive AML and related cancers and were one of the groups that described the phenomenon of clonal haematopoiesis (CH), believed to be the precursor of myeloid and other haematological malignancies. More recently, they and their collaborators showed that individuals at high risk of AML can be identified years in advance through the characteristic of their CH clones. Furthermore, they have pioneered a CRIPSR-Cas9 genome-wide screening platform for the identification of genetic vulnerabilities of cancer cells and used this to identify the RNA methyltransferase METTL3 as a novel therapeutic target in AML.

Abstract

Clonal haematopoiesis (CH) is a phenomenon in which individual hematopoietic stem cells (HSCs) acquire a fitness advantage over their peers and contribute disproportionately to peripheral blood cell production. CH is usually driven by leukaemias associated somatic mutations, which affect one of a small number of genes (>95% of cases are driven by mutations in 1 of 8 genes). We reported previously that the proportion of cases attributable to mutations in individual genes changes significantly with age. Most strikingly, we found that CH driven by mutations in spliceosome genes is almost exclusively seen in persons aged 70 years or older. Others have also reported that the prevailing types of mutations driving CH is influenced by non-mutation factors such as immunological disorders and exposure to cytotoxic agents. Also, we and others have reported that in most instances, the nature of the driver mutation does not predict the growth trajectory of the CH clone. To better understand the interaction of CH with ageing, we are studying a cohort of individuals aged 70-110 years-old from the ImmunoAgeing study (http://www.immunoageing.eu/). We recently completed targeted sequencing of the first 297 individuals and detected CH clones in 65%. Compared to younger cohorts, we identified an increased prevalence of CH driven by mutations in TET2 and splicing genes. We are currently searching for associations between a series of haematological, immunological and lifestyle variables and the presence of CH. In addition, we are studying a separate 300 individuals with samples taken serially over a period of 20 years, to understand factors involved in clonal progression.



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Dr Asaf VivanteTel Aviv University

History of childhood kidney disease and risk of adult end-stage renal diseaseTuesday 4 September 2018, 09:50-10:15Session VLecture Theatre 2

Dr Asaf Vivante, is a physician scientist, whose main research interests involve diff erent aspects of pediatric nephrology with a main focus on bioinformatics analysis of large datasets as well as on understanding the genetic basis of congenital renal malformations. He has extensive experience in clinical nephrology, genetics, developmental biology, and bioinformatics. His doctoral (Tel-Aviv university) and postdoc research (BCH, Harvard Medical School) focused on the genetics of kidney diseases. Dr Vivante is a recipient of multiple awards (Fulbright Scholar, Manton Center and the Mallinckrodt Research Award). Since 2010 he has initiated several national Israeli studies using large datasets, which investigated childhood and young adulthood chronic kidney diseases (CKD) etiologies (Vivante JAMA, 2011; Vivante JAMA, 2014; Calderon-Margalit NEJM, 2018). In addition, he led the fi rst Israeli national genetic screen among individuals with familial renal anomalies (Vivante JASN, 2013), and since then has characterized many novel kidney disease genes that elucidate pathogenic mechanisms and that directly contribute to patient care.

Abstract

In a recent study published in the New England Journal of Medicine, an Israeli research group led by Dr Asaf Vivante from Tel-Hashomer Hospital and in collaboration with Prof Calderon-Margalit and Prof Karl Skorecki, found that a history of childhood kidney disease increases the risk of end-stage renal disease (ESRD) in adulthood. The research group used two nationwide Israeli cohorts. At enrollment researchers drew the sample from the Israeli Defense Forces database and included 1.5 million adolescents who had routine health assessment between 1967 and 1997, at the army recruitment centers before mandatory military service. The cohort was then linked, with the Israeli end stage renal disease registry from 1980 to 2014 (mean duration of follow-up, 30 years).

There are reasonable parameters for kidney function, but relatively poor indicators for kidney reserve. Researchers hypothesized that even mild childhood kidney disease that has seemingly resolved may cause subclinical kidney damage. This damage may lead to reduction in kidney reserve and increase the risk of chronic kidney disease in adulthood. The group found that a history of mild/resolved childhood kidney disease, with no clinical or laboratory evidence of compromised glomerular fi ltration rate, hypertension or proteinuria in adolescence was associated with a signifi cantly increased risk of ESRD in adulthood (HR 4.19, 95% CI 3.52–4.99). The study results suggests that even subclinical degree of kidney parenchymal injury secondary childhood kidney conditions can lead to enhanced susceptibility to future chronic kidney disease (CKD). These fi ndings are clinically relevant in the current global CKD epidemic as the care for patients with chronic kidney disease is also aimed at identifying at risk individuals and asymptomatic patients in early disease stages - in order to timely initiate treatments and preventive measures which can mitigate prognosis. The study highlights mild childhood kidney diseases as a newly appreciated risk factor for future CKD.


We would like to thank you for joining us at the

Precision Medicine and Ageing Conference



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Conference on Precision Ageing and Medicine 2018 3-4 September 2018 | King’s College London

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