European Innovation Partnership on Active and Healthy Ageing
Bringing added value through collaborative innovation
Authors: Orsolya Nagi, Policy Officer , SANCO.DG.02 - Innovation for Health and Consumers, DG Health and Consumers, European Commission. Brussels.
. The pilot European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) is a new stakeholder-driven approach to research and innovation. The overarching target is to add two years to the average number of healthy life years in the European Union by the year 2020. The Partnership is moving ahead at full speed with its implementation phase to bring added value by joining up efforts, bridging the gaps between public and private actions and instruments, facilitating scaling up of results and improving the framework conditions.
The concrete actions to be undertaken between now and 2015 to improve the quality of life of four million European senior citizens are set out in six Action Plans. These were presented at the Conference of Partners on the 6th November and cover:
- Better prescription and adherence through communication and patient empowerment, improvements in the healthcare system, and more research and methodology development on ageing and adherence.
- Launching/scaling-up operational programmes for early diagnosis and the prevention of falls in at least 10 European countries.
- Developing and implementing sustainable interventions for the prevention and comprehensive management of functional/cognitive decline and frailty that will reach at least 1.000 care providers.
- Deploying integrated care for chronic diseases to meet the needs of older persons and enhance system efficiency, focusing on e-care records, ICT and tele-services, through a European Integrated Care Collaboration.
- Promoting solutions for independent living by gathering information, developing reports, guidelines, recommendations and best practice.
- Implementing innovative age-friendly practices at regional and local level, and fostering physical /environmental innovation and practice, including the use of ICT.
Reference sites:
54 organisations applied to be candidate Reference sites in order to showcase and exchange best practices that implement elements from all areas of the Partnership in an integrated way. The candidates include regions, cities, integrated hospitals or care organisations that are able to demonstrate good practice in innovative care delivery and to highlight opportunities to transfer such practices to other regions (scaling-up). Reference sites will undertake a self-assessment starting from the beginning of 2013.
Visit the online Marketplace of the EIP on AHA!
Keywords: European Innovation Partnership, Active and Healthy Ageing, Healthy Life Years
Category: Invited
Bringing added value through collaborative innovation
Authors: Orsolya Nagi, Policy Officer , SANCO.DG.02 - Innovation for Health and Consumers, DG Health and Consumers, European Commission. Brussels.
. The pilot European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) is a new stakeholder-driven approach to research and innovation. The overarching target is to add two years to the average number of healthy life years in the European Union by the year 2020. The Partnership is moving ahead at full speed with its implementation phase to bring added value by joining up efforts, bridging the gaps between public and private actions and instruments, facilitating scaling up of results and improving the framework conditions.
The concrete actions to be undertaken between now and 2015 to improve the quality of life of four million European senior citizens are set out in six Action Plans. These were presented at the Conference of Partners on the 6th November and cover:
- Better prescription and adherence through communication and patient empowerment, improvements in the healthcare system, and more research and methodology development on ageing and adherence.
- Launching/scaling-up operational programmes for early diagnosis and the prevention of falls in at least 10 European countries.
- Developing and implementing sustainable interventions for the prevention and comprehensive management of functional/cognitive decline and frailty that will reach at least 1.000 care providers.
- Deploying integrated care for chronic diseases to meet the needs of older persons and enhance system efficiency, focusing on e-care records, ICT and tele-services, through a European Integrated Care Collaboration.
- Promoting solutions for independent living by gathering information, developing reports, guidelines, recommendations and best practice.
- Implementing innovative age-friendly practices at regional and local level, and fostering physical /environmental innovation and practice, including the use of ICT.
Reference sites:
54 organisations applied to be candidate Reference sites in order to showcase and exchange best practices that implement elements from all areas of the Partnership in an integrated way. The candidates include regions, cities, integrated hospitals or care organisations that are able to demonstrate good practice in innovative care delivery and to highlight opportunities to transfer such practices to other regions (scaling-up). Reference sites will undertake a self-assessment starting from the beginning of 2013.
Visit the online Marketplace of the EIP on AHA!
Keywords: European Innovation Partnership, Active and Healthy Ageing, Healthy Life Years
Category: Invited
Theories of ageing
Authors: Diana van Heemst
Leyden Academy on Vitality and Ageing
Ageing can be described by functional decline resulting in increased vulnerability to disease and death. Two separate and complementary classes of theories of ageing can be discerned. Ultimate ageing theories provide evolutionary explanations for why we age. These theories include the mutation accumulation theory, the theory of antagonistic pleiotropy and the disposable soma theory. Proximate ageing theories provide mechanistic explanations for how we age. With ageing, different types of damage accumulate. However, it is still illusive which type(s) of damage and which the underlying mechanisms are the principal drivers of human ageing. Candidate mechanisms include reactive oxygen species (oxidative damage theory) and cellular hypertrophy (theory of quasi-programmed senescence).
Keywords: ageing, evolutionary explanations, mechanistic explanations, damage, hyperfunction
Category: Invited
Authors: Diana van Heemst
Leyden Academy on Vitality and Ageing
Ageing can be described by functional decline resulting in increased vulnerability to disease and death. Two separate and complementary classes of theories of ageing can be discerned. Ultimate ageing theories provide evolutionary explanations for why we age. These theories include the mutation accumulation theory, the theory of antagonistic pleiotropy and the disposable soma theory. Proximate ageing theories provide mechanistic explanations for how we age. With ageing, different types of damage accumulate. However, it is still illusive which type(s) of damage and which the underlying mechanisms are the principal drivers of human ageing. Candidate mechanisms include reactive oxygen species (oxidative damage theory) and cellular hypertrophy (theory of quasi-programmed senescence).
Keywords: ageing, evolutionary explanations, mechanistic explanations, damage, hyperfunction
Category: Invited
Increased damage to proteins in ageing – wear and tear potentially avoidable by extending preventive maintenance of life’s essential machinery
Authors: Naila Rabbani and Paul J Thornalley
Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
Proteins undergo continual spontaneous modifications in physiological systems leading to change in their structure and function. This increases with age. Proteins are modified by glycation, oxidation and nitration leading to formation of glycation, oxidation and nitration adducts residues in proteins – including formation of non-disulfide crosslinks. Damaged proteins undergo proteolysis to form glycated, oxidised and nitrated amino acids or free adducts that are then metabolised or excreted. Protein damage adduct residues and free adducts may be robustly quantified by stable isotopic dilution analysis tandem mass spectrometry. Data of protein damage is now being combined to produce refined dynamic, multi-compartmental mathematical models of in-life protein damage. Accumulation of protein damage in ageing, that is, increased steady-state levels of damaged proteins occurs as a consequence of: (i) increased rates of protein damage – linked to increased rate of damaging agent formation and decreased anti-glycation and oxidant defences, (ii) decreased rates of repair of damaged proteins, and (iii) decreased rates of proteolysis of damaged proteins. Oxidative and non-oxidative mechanisms are involved. Antistress gene transcriptional responses also decline with age leaving the proteome particularly vulnerable in periods of oxidative, metabolic and lipogenic stress. Healthy ageing has been achieved in transgenic animals through manipulation of oxidative and non-oxidative mechanisms. Healthy ageing may be available for people through dietary supplements which prevent decline in expression in adulthood of a battery of genes protective against multi-modal stresses. Such interventions are designed to maintain vascular, metabolic, skeleto-muscular and other aspects of health, in part, through preventing increased flux of damage to proteins and increased steady-state levels of damaged proteins.
Keywords: glycation, protein damage, proteolysis
Category: Invited
Authors: Naila Rabbani and Paul J Thornalley
Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
Proteins undergo continual spontaneous modifications in physiological systems leading to change in their structure and function. This increases with age. Proteins are modified by glycation, oxidation and nitration leading to formation of glycation, oxidation and nitration adducts residues in proteins – including formation of non-disulfide crosslinks. Damaged proteins undergo proteolysis to form glycated, oxidised and nitrated amino acids or free adducts that are then metabolised or excreted. Protein damage adduct residues and free adducts may be robustly quantified by stable isotopic dilution analysis tandem mass spectrometry. Data of protein damage is now being combined to produce refined dynamic, multi-compartmental mathematical models of in-life protein damage. Accumulation of protein damage in ageing, that is, increased steady-state levels of damaged proteins occurs as a consequence of: (i) increased rates of protein damage – linked to increased rate of damaging agent formation and decreased anti-glycation and oxidant defences, (ii) decreased rates of repair of damaged proteins, and (iii) decreased rates of proteolysis of damaged proteins. Oxidative and non-oxidative mechanisms are involved. Antistress gene transcriptional responses also decline with age leaving the proteome particularly vulnerable in periods of oxidative, metabolic and lipogenic stress. Healthy ageing has been achieved in transgenic animals through manipulation of oxidative and non-oxidative mechanisms. Healthy ageing may be available for people through dietary supplements which prevent decline in expression in adulthood of a battery of genes protective against multi-modal stresses. Such interventions are designed to maintain vascular, metabolic, skeleto-muscular and other aspects of health, in part, through preventing increased flux of damage to proteins and increased steady-state levels of damaged proteins.
Keywords: glycation, protein damage, proteolysis
Category: Invited
DNA damage as a driver of aging
Authors: Jan Vijg, Martijn Dolle
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA
The capacity to repair DNA damage and prevent genetic or epigenetic alterations in differentiated tissues has been implicated as a major longevity assurance mechanism in higher eukaryotes. While under normal conditions DNA damage from natural sources such as oxidation and hydrolysis is swiftly repaired, errors during repair can result in genetic or epigenetic mutations. Such events are essentially irreversible and likely to contribute to a gradual divergence of the genetic and epigenetic information content among cells in an aging tissue. In turn, this could lead to random alterations in gene regulatory patterns. Using transgenic mouse and fly models harboring lacZ mutation reporter genes we demonstrated that DNA mutations accumulate with age in a tissue-specific manner. Some tissues, most notable the brain, proved highly resistant to mutation accumulation while in others, such as intestine, liver and heart in mice and abdomen and thorax in flies, the rate of genetic alteration was must faster. To assess genomic and epigenomic integrity in brain and other organs during aging in a genome-wide manner we have begun to explore the extraordinary power of massively parallel sequencing. Some results will be presented at the conference.
Keywords: DNA damage, epigenetic mutations, genetic mutations
Category: Invited
Authors: Jan Vijg, Martijn Dolle
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA
The capacity to repair DNA damage and prevent genetic or epigenetic alterations in differentiated tissues has been implicated as a major longevity assurance mechanism in higher eukaryotes. While under normal conditions DNA damage from natural sources such as oxidation and hydrolysis is swiftly repaired, errors during repair can result in genetic or epigenetic mutations. Such events are essentially irreversible and likely to contribute to a gradual divergence of the genetic and epigenetic information content among cells in an aging tissue. In turn, this could lead to random alterations in gene regulatory patterns. Using transgenic mouse and fly models harboring lacZ mutation reporter genes we demonstrated that DNA mutations accumulate with age in a tissue-specific manner. Some tissues, most notable the brain, proved highly resistant to mutation accumulation while in others, such as intestine, liver and heart in mice and abdomen and thorax in flies, the rate of genetic alteration was must faster. To assess genomic and epigenomic integrity in brain and other organs during aging in a genome-wide manner we have begun to explore the extraordinary power of massively parallel sequencing. Some results will be presented at the conference.
Keywords: DNA damage, epigenetic mutations, genetic mutations
Category: Invited
Alternative Perspectives on Ageing in the Nematode Caenorhabditis elegans: Reactive Oxygen Species or Hyperfunction?
Authors: David Gems and Yila de la Guardia
Institute of Healthy Ageing, University College London, Gower Street, London, UK
The biological mechanisms at the heart of the ageing process are a long-standing mystery. An influential theory has it that ageing is the result of an accumulation of molecular damage, caused in particular by reactive oxygen species (ROS) produced by mitochondria. This theory also predicts that processes that protect against oxidative damage (involving detoxification, repair and turnover) protect against ageing and increase lifespan. However, recent tests of the oxidative damage theory, many using the short-lived nematode worm C. elegans, have often failed to support the theory1-3. This motivates consideration of alternative models. One new theory, conceived by M.V. Blagosklonny, proposes that ageing is caused by hyperfunction, i.e. over-activity during adulthood of processes (particularly biosynthetic) that contribute to development and reproduction4,5. Such hyperfunction can lead to hypertrophy-associated pathologies, which cause the age increase in mortality. Here we assess whether the hyperfunction theory is at all consistent with what is know about C. elegans ageing, and conclude that it is6. In particular, during ageing C. elegans show a number of changes that may reflect pathology and/or hyperfunction, including high density packing of oocytes in the proximal gonad, oocyte hypertrophy to form tumour-like masses, massive yolk accumulation, cuticular hypertrophy and neurite outgrowth. Such changes appear to contribute to mortality in at least some cases (e.g. yolk accumulation). Our assessment implies that the hyperfunction theory is a plausible alternative to the molecular damage theory to explain ageing in C. elegans.
1Genes Develop 22, 3236 2008. 2Cell Metab 6, 280 2007. 3Proc Natl Acad Sci USA 109, 5785 2012.4Cell Cycle 5, 2087 2006. 5Cell Cycle 7, 3344 2008. 6Antiox Redox Signal Sep 24. [Epub ahead of print] 2012.
Keywords: Oxidative damage, hyperfunction, C. elegans
Category: Invited
Authors: David Gems and Yila de la Guardia
Institute of Healthy Ageing, University College London, Gower Street, London, UK
The biological mechanisms at the heart of the ageing process are a long-standing mystery. An influential theory has it that ageing is the result of an accumulation of molecular damage, caused in particular by reactive oxygen species (ROS) produced by mitochondria. This theory also predicts that processes that protect against oxidative damage (involving detoxification, repair and turnover) protect against ageing and increase lifespan. However, recent tests of the oxidative damage theory, many using the short-lived nematode worm C. elegans, have often failed to support the theory1-3. This motivates consideration of alternative models. One new theory, conceived by M.V. Blagosklonny, proposes that ageing is caused by hyperfunction, i.e. over-activity during adulthood of processes (particularly biosynthetic) that contribute to development and reproduction4,5. Such hyperfunction can lead to hypertrophy-associated pathologies, which cause the age increase in mortality. Here we assess whether the hyperfunction theory is at all consistent with what is know about C. elegans ageing, and conclude that it is6. In particular, during ageing C. elegans show a number of changes that may reflect pathology and/or hyperfunction, including high density packing of oocytes in the proximal gonad, oocyte hypertrophy to form tumour-like masses, massive yolk accumulation, cuticular hypertrophy and neurite outgrowth. Such changes appear to contribute to mortality in at least some cases (e.g. yolk accumulation). Our assessment implies that the hyperfunction theory is a plausible alternative to the molecular damage theory to explain ageing in C. elegans.
1Genes Develop 22, 3236 2008. 2Cell Metab 6, 280 2007. 3Proc Natl Acad Sci USA 109, 5785 2012.4Cell Cycle 5, 2087 2006. 5Cell Cycle 7, 3344 2008. 6Antiox Redox Signal Sep 24. [Epub ahead of print] 2012.
Keywords: Oxidative damage, hyperfunction, C. elegans
Category: Invited
Mitochondrial Theory of Ageing: Dead or Alive(?)
Authors: Trifunovic A
CECAD Cologne - Excellent in Aging Research at the Institute for Genetics, Cologne University, Germany
Although mitochondria have long been anticipated as a perpetrator of aging, there was little experimental evidence to link these changes directly with the cellular pathology of aging. MtDNA mutator mouse was the first model showing that collective amount of somatic mtDNA mutation could cause ageing in experimental animals. Before this mtDNA mutations and especially random mtDNA point mutations were seen more as a consequence than the driving force of ageing. The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature ageing phenotype. High levels of apoptotic cells were detected in both proliferating and postmitotic tissues in mtDNA mutator mice. Proposed loss of vital cells in which mtDNA mutations have accumulated beyond a critical threshold could also be consequence of the disruption of stem cell pools.
Mitochondrial DNA damage is believed to lead to increased ROS production. Surprisingly, we showed that increased levels of mtDNA mutations were not associated with increased oxidative stress in mtDNA mutator mice. In agreement with this, we now show that mtDNA mutator produce significantly less net ROS than WT mitochondria, when energized by an optimal mixture of substrates that allow maximal oxidative capacity. This argues against a direct role of oxidative stress in the ageing process. Although ROS production is lower in the mtDNA mutator mice, the lack of sufficient ability to protect against oxidation may allow existing ROS to still cause a great harm. Increase stress conditions in conjunction with the cells inability to produce enough ATP might very well conspire to overwhelm the capacity of the mtDNA mutator mice to maintain their tissue homeostasis, leading to the observed premature aging phenotypes. Therefore, the role of oxidative stress in development of premature ageing phenotypes still cannot be lightly dismissed.
Keywords: Mitochondria, mtDNA, oxidative stress, mutator mice
Category: Invited
Authors: Trifunovic A
CECAD Cologne - Excellent in Aging Research at the Institute for Genetics, Cologne University, Germany
Although mitochondria have long been anticipated as a perpetrator of aging, there was little experimental evidence to link these changes directly with the cellular pathology of aging. MtDNA mutator mouse was the first model showing that collective amount of somatic mtDNA mutation could cause ageing in experimental animals. Before this mtDNA mutations and especially random mtDNA point mutations were seen more as a consequence than the driving force of ageing. The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature ageing phenotype. High levels of apoptotic cells were detected in both proliferating and postmitotic tissues in mtDNA mutator mice. Proposed loss of vital cells in which mtDNA mutations have accumulated beyond a critical threshold could also be consequence of the disruption of stem cell pools.
Mitochondrial DNA damage is believed to lead to increased ROS production. Surprisingly, we showed that increased levels of mtDNA mutations were not associated with increased oxidative stress in mtDNA mutator mice. In agreement with this, we now show that mtDNA mutator produce significantly less net ROS than WT mitochondria, when energized by an optimal mixture of substrates that allow maximal oxidative capacity. This argues against a direct role of oxidative stress in the ageing process. Although ROS production is lower in the mtDNA mutator mice, the lack of sufficient ability to protect against oxidation may allow existing ROS to still cause a great harm. Increase stress conditions in conjunction with the cells inability to produce enough ATP might very well conspire to overwhelm the capacity of the mtDNA mutator mice to maintain their tissue homeostasis, leading to the observed premature aging phenotypes. Therefore, the role of oxidative stress in development of premature ageing phenotypes still cannot be lightly dismissed.
Keywords: Mitochondria, mtDNA, oxidative stress, mutator mice
Category: Invited
Autophagy and neurodegeneration
Authors: David C Rubinsztein
Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, U.K.
Intracellular protein aggregation is a feature of many late-onset neurodegenerative diseases, including Parkinson’s disease, tauopathies, and polyglutamine expansion diseases (like Huntington’s disease (HD)). Many of these mutant proteins, like that causing HD, cause disease via toxic gain-of-function mechanisms. Therefore, the factors regulating their clearance are crucial for understanding disease pathogenesis and for developing rational therapeutic strategies.
The two major intracellular protein degradation pathways are the ubiquitin-proteasome system and (macro)autophagy. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. I will describe our recent studies that implicate the plasma membrane as a source for autophagosomes, before focussing on the roles of autophagy in neurodegeneration.
We showed that the autophagy inducer, rapamycin, reduced the levels of mutant huntingtin and attenuated its toxicity in cells, and in Drosophila and mouse HD models. We have extended the range of intracellular proteinopathy substrates that are cleared by autophagy to other related neurodegenerative disease targets and have provided proof-of-principle in cells, Drosophila and mice. In order to induce autophagy long-term, we have been striving to identify safer alternatives to the mTOR inhibitor, rapamycin. To this end, we have been trying to discover novel components of the autophagy machinery and new signalling pathways and drugs that impact on autophagy. While autophagy induction is protective in models of various neurodegenerative diseases, certain other conditions, including lysosomal storage disorders, are associated with compromised autophagy. I will review these data and then describe how impaired autophagy compromises cellular processes, including the ubiquitin-proteasome system.
Keywords: Autophagy, rapamycin, intracellular protein aggregation, proteasome
Category: Invited
Authors: David C Rubinsztein
Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, U.K.
Intracellular protein aggregation is a feature of many late-onset neurodegenerative diseases, including Parkinson’s disease, tauopathies, and polyglutamine expansion diseases (like Huntington’s disease (HD)). Many of these mutant proteins, like that causing HD, cause disease via toxic gain-of-function mechanisms. Therefore, the factors regulating their clearance are crucial for understanding disease pathogenesis and for developing rational therapeutic strategies.
The two major intracellular protein degradation pathways are the ubiquitin-proteasome system and (macro)autophagy. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. I will describe our recent studies that implicate the plasma membrane as a source for autophagosomes, before focussing on the roles of autophagy in neurodegeneration.
We showed that the autophagy inducer, rapamycin, reduced the levels of mutant huntingtin and attenuated its toxicity in cells, and in Drosophila and mouse HD models. We have extended the range of intracellular proteinopathy substrates that are cleared by autophagy to other related neurodegenerative disease targets and have provided proof-of-principle in cells, Drosophila and mice. In order to induce autophagy long-term, we have been striving to identify safer alternatives to the mTOR inhibitor, rapamycin. To this end, we have been trying to discover novel components of the autophagy machinery and new signalling pathways and drugs that impact on autophagy. While autophagy induction is protective in models of various neurodegenerative diseases, certain other conditions, including lysosomal storage disorders, are associated with compromised autophagy. I will review these data and then describe how impaired autophagy compromises cellular processes, including the ubiquitin-proteasome system.
Keywords: Autophagy, rapamycin, intracellular protein aggregation, proteasome
Category: Invited
Epigenetic regulation of aging
Authors: Mario F. Fraga1,2
1Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, Madrid E-28049, Spain, 2Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain
Epigenetics of aging is an emerging field that promises exciting revelations in the near future. Epigenetic mechanisms, including DNA methylation and histone modification, are determinants of normal development and can change during aging. Some of the epigenetic alterations described during aging, as hypermethylation at specific promoters and decrease of global DNA methylation, are also associated with tumour development. The epigenetic alterations occurring during development and aging can be stochastic and depend on genetic (intrinsic) and environmental (extrinsic) factors. Future challenges in the field involve the determination of the role of these epigenetic alterations in the establishment of aging-associated phenotypes.
Keywords: Epigenetics, DNA methylation, histone modifications
Category: Invited
Authors: Mario F. Fraga1,2
1Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, Madrid E-28049, Spain, 2Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain
Epigenetics of aging is an emerging field that promises exciting revelations in the near future. Epigenetic mechanisms, including DNA methylation and histone modification, are determinants of normal development and can change during aging. Some of the epigenetic alterations described during aging, as hypermethylation at specific promoters and decrease of global DNA methylation, are also associated with tumour development. The epigenetic alterations occurring during development and aging can be stochastic and depend on genetic (intrinsic) and environmental (extrinsic) factors. Future challenges in the field involve the determination of the role of these epigenetic alterations in the establishment of aging-associated phenotypes.
Keywords: Epigenetics, DNA methylation, histone modifications
Category: Invited
Lessons from the Blue Zones where people are living longer
Authors: Michel Poulain
Université catholique de Louvain, Belgium
We find places on earth where people are living longer and we named these places Blue Zones after discovering the first one in the mountainous part of Sardinia (Poulain et al. 2004). So far we identified three other Blue Zones in Okinawa (Japan), Nicoya (Costa Rica) and Ikaria (Greece). We surveyed oldest olds in the different settings in order to discover longevity determinants. Concretely investigations on population longevity are more appropriate to find common traits that could help to live longer. The presentation will compare the four BZ’s in order to identify common longevity determinants. Life style, nutrition, physical activity and both physical and social environment are considered. Thereafter our findings are discussed to see which message can be brought to post-industrial societies in order to improve the quality of life in oldest ages. What can BZ’s stories tell us to support healthy ageing in Europe?
Keywords: blue zones, longevity, Sardinia, Okinawa, Nicoya, Ikaria
Category: Invited
Authors: Michel Poulain
Université catholique de Louvain, Belgium
We find places on earth where people are living longer and we named these places Blue Zones after discovering the first one in the mountainous part of Sardinia (Poulain et al. 2004). So far we identified three other Blue Zones in Okinawa (Japan), Nicoya (Costa Rica) and Ikaria (Greece). We surveyed oldest olds in the different settings in order to discover longevity determinants. Concretely investigations on population longevity are more appropriate to find common traits that could help to live longer. The presentation will compare the four BZ’s in order to identify common longevity determinants. Life style, nutrition, physical activity and both physical and social environment are considered. Thereafter our findings are discussed to see which message can be brought to post-industrial societies in order to improve the quality of life in oldest ages. What can BZ’s stories tell us to support healthy ageing in Europe?
Keywords: blue zones, longevity, Sardinia, Okinawa, Nicoya, Ikaria
Category: Invited
Glucose regulation and familial longevity
Authors: Diana van Heemst
Department of Gerontology and Geriatrics, Leiden University Medical Center
We included families with exceptional longevity in the Leiden Longevity Study. Over the last years, metabolic features were compared between the offspring of nonagenarian siblings and their current living partners. After exclusion of subjects with diabetes, we observed several differences in glucose regulation, including lower levels of non-fasted and fasted glucose, better oral glucose tolerance and higher peripheral insulin sensitivity. These differences between groeps could not be explained by differences in body composition. Our current research is aimed at further unraveling the mechanism of glucose regulation in familial longevity with emphasis on the role of the brain.
Keywords: familial longevity, glucose regulation
Category: Invited
Authors: Diana van Heemst
Department of Gerontology and Geriatrics, Leiden University Medical Center
We included families with exceptional longevity in the Leiden Longevity Study. Over the last years, metabolic features were compared between the offspring of nonagenarian siblings and their current living partners. After exclusion of subjects with diabetes, we observed several differences in glucose regulation, including lower levels of non-fasted and fasted glucose, better oral glucose tolerance and higher peripheral insulin sensitivity. These differences between groeps could not be explained by differences in body composition. Our current research is aimed at further unraveling the mechanism of glucose regulation in familial longevity with emphasis on the role of the brain.
Keywords: familial longevity, glucose regulation
Category: Invited
Healthy life extension by calorie restriction
Authors: Sven Bulterijs
Heales VZW
Calorie restriction (CR) is the best researched method for delaying the ageing process. The origins of experimental research in the effects of a reduced food intake on lifespan date back a century ago. The studies show a remarkable evolutionary conservation of the 'CR response' from yeast to mice. Calorie restriction has also been found to have beneficial effects on serveral age-related diseases such as Alzheimer's disease, cancer, cardiovascular disease, hypertension, and type 2 diabetes. The mechanism of calorie restriction is still illusive although several mechanisms have been suggested including Ins/IGF-1 signaling, mitochondria changes, apoptosis, antioxidant protection mechanisms, hormesis and reduction in inflammation. The holy grail of CR research is the development of a drug that could mimick the health benefits of CR without reducing food intake. Several potential candidates have been discovered so far, of which metformin is currently the most promesing.
Keywords: calorie restriction, disease, life span extension,
Category: Invited
Authors: Sven Bulterijs
Heales VZW
Calorie restriction (CR) is the best researched method for delaying the ageing process. The origins of experimental research in the effects of a reduced food intake on lifespan date back a century ago. The studies show a remarkable evolutionary conservation of the 'CR response' from yeast to mice. Calorie restriction has also been found to have beneficial effects on serveral age-related diseases such as Alzheimer's disease, cancer, cardiovascular disease, hypertension, and type 2 diabetes. The mechanism of calorie restriction is still illusive although several mechanisms have been suggested including Ins/IGF-1 signaling, mitochondria changes, apoptosis, antioxidant protection mechanisms, hormesis and reduction in inflammation. The holy grail of CR research is the development of a drug that could mimick the health benefits of CR without reducing food intake. Several potential candidates have been discovered so far, of which metformin is currently the most promesing.
Keywords: calorie restriction, disease, life span extension,
Category: Invited
Geroprotectors
Authors: Stephen Spindler
University of California, Riverside
To screen for compounds capable of extending the healthy lifespan of humans, we screened several hundred potential therapeutics, some individually and many groups, for their effects on lifespan using mice and Drosophila. In mice, dose-response longevity studies are expensive and time consuming. To circumvent these limitations, we used dosages with well-defined surrogate endpoints in mice, gleaned from the scientific literature. To avoid caloric restriction-related artifacts, mice were fed daily, food consumption was monitored, and mice were weighed regularly. Fifty-eight treatment groups were used in our Cohort 1 study, now completed. Most of these received chemical supplements cold packed in their food. A second cohort of 68 treatment groups of mice is now undergoing testing. In the completed Cohort 1 study, 9 of the 58 groups experienced statistically significant lifespan extension (15.5% of the groups). Of these, most, but not all of the compounds also extended the lifespan of Drosophila. Many compounds did not increase mouse lifespan, including blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, Pycnogenol, quercetin, and taxifolin. Most of these extracts or compounds were reported to increase the longevity of Drosophila and/or C. elegans, and two of them were previously reported to extend the lifespan of mice. These results suggest compound screening in lower eucaryotes produces a high proportion of false positives, and that mouse lifespan studies can be confounded by caloric restriction-related artifacts. The positive results we found suggest that compounds already in our armamentarium are capable of extending mammalian lifespan.
Keywords: Drugs, lifespan tests, screening
Category: Invited
Authors: Stephen Spindler
University of California, Riverside
To screen for compounds capable of extending the healthy lifespan of humans, we screened several hundred potential therapeutics, some individually and many groups, for their effects on lifespan using mice and Drosophila. In mice, dose-response longevity studies are expensive and time consuming. To circumvent these limitations, we used dosages with well-defined surrogate endpoints in mice, gleaned from the scientific literature. To avoid caloric restriction-related artifacts, mice were fed daily, food consumption was monitored, and mice were weighed regularly. Fifty-eight treatment groups were used in our Cohort 1 study, now completed. Most of these received chemical supplements cold packed in their food. A second cohort of 68 treatment groups of mice is now undergoing testing. In the completed Cohort 1 study, 9 of the 58 groups experienced statistically significant lifespan extension (15.5% of the groups). Of these, most, but not all of the compounds also extended the lifespan of Drosophila. Many compounds did not increase mouse lifespan, including blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, Pycnogenol, quercetin, and taxifolin. Most of these extracts or compounds were reported to increase the longevity of Drosophila and/or C. elegans, and two of them were previously reported to extend the lifespan of mice. These results suggest compound screening in lower eucaryotes produces a high proportion of false positives, and that mouse lifespan studies can be confounded by caloric restriction-related artifacts. The positive results we found suggest that compounds already in our armamentarium are capable of extending mammalian lifespan.
Keywords: Drugs, lifespan tests, screening
Category: Invited
Metformin in cancer therapy: a new perspective for an old antidiabetic drug
Authors: Frédéric Bost
INSERM U1065, Nice, France
Metformin is a widely used anti-diabetic drug prescribed for more than 30 years for the treatment of type II diabetes. In diabetic patients, it reduces hepatic glucose production, increases insulin sensitivity and glucose utilization by muscles and adipocytes resulting in decreased insulinemia and amelioration of insulin sensitivity. At the molecular level, metformin regulates the AMPK/mTOR signalling pathway which controls protein synthesis, cell proliferation and is an emerging regulator of ageing. This leads to the hypothesis that metformin could affect tumor growth and reduce the risk of cancer. In a pioneer work Evans et al. demonstrated that metformin decreases the incidence of cancer in diabetic patients. Since then, several concordant studies have shown that metformin exerts anti-neoplasic effects in cancer cells and animal models. If one of the indirect benefits of metformin is a decrease in insulin, a growth promoting hormone, cellular studies demonstrate that metformin can also directly affect cancer cell proliferation and the AMPK/mTOR axis.
We will review here the recent advances concerning metformin and cancer at the molecular and cellular level. We will also recapitulate the preclinical and clinical evidences demonstrating a beneficial contribution of metformin in cancer.
Keywords: Metformin, cancer, AMPK, mTOR
Category: Invited
Authors: Frédéric Bost
INSERM U1065, Nice, France
Metformin is a widely used anti-diabetic drug prescribed for more than 30 years for the treatment of type II diabetes. In diabetic patients, it reduces hepatic glucose production, increases insulin sensitivity and glucose utilization by muscles and adipocytes resulting in decreased insulinemia and amelioration of insulin sensitivity. At the molecular level, metformin regulates the AMPK/mTOR signalling pathway which controls protein synthesis, cell proliferation and is an emerging regulator of ageing. This leads to the hypothesis that metformin could affect tumor growth and reduce the risk of cancer. In a pioneer work Evans et al. demonstrated that metformin decreases the incidence of cancer in diabetic patients. Since then, several concordant studies have shown that metformin exerts anti-neoplasic effects in cancer cells and animal models. If one of the indirect benefits of metformin is a decrease in insulin, a growth promoting hormone, cellular studies demonstrate that metformin can also directly affect cancer cell proliferation and the AMPK/mTOR axis.
We will review here the recent advances concerning metformin and cancer at the molecular and cellular level. We will also recapitulate the preclinical and clinical evidences demonstrating a beneficial contribution of metformin in cancer.
Keywords: Metformin, cancer, AMPK, mTOR
Category: Invited
Authors: Dr David Wald
Queen Mary, University of London
The 20th Century saw the emergence of a major epidemic of occlusive vascular disease. Heart attacks and ischaemic strokes were rare in the 19th century. They now represent the commonest cause of premature death throughout the world. Most of this burden of disease and premature mortality is avoidable and much is now known on how it can be avoided. While major changes in diet, exercise and smoking could, in principle, have a major impact, to achieve this has proved difficult. A new approach to prevention is needed in which preventive medicine and pharmacology are combined into a single prevention strategy. The concept will be illustrated in this talk by reference to the polypill a combination pill capable of reducing serum cholesterol and blood pressure simultaneously and reducing the risk cardiovascular disease by about 75%.
Keywords: cardiovascular disease, polypill, cholesterol, blood pressure
Category: Invited
Queen Mary, University of London
The 20th Century saw the emergence of a major epidemic of occlusive vascular disease. Heart attacks and ischaemic strokes were rare in the 19th century. They now represent the commonest cause of premature death throughout the world. Most of this burden of disease and premature mortality is avoidable and much is now known on how it can be avoided. While major changes in diet, exercise and smoking could, in principle, have a major impact, to achieve this has proved difficult. A new approach to prevention is needed in which preventive medicine and pharmacology are combined into a single prevention strategy. The concept will be illustrated in this talk by reference to the polypill a combination pill capable of reducing serum cholesterol and blood pressure simultaneously and reducing the risk cardiovascular disease by about 75%.
Keywords: cardiovascular disease, polypill, cholesterol, blood pressure
Category: Invited
KEHLY: Innovative know-how to live healthy longer
Authors: Edouard Debonneuil
Heales VZW
Health care business models so far essentially rely on cures for specific diseases. But when an old person starts to need long term care following a cold, a fall, or other events that would not matter at younger ages: is the cold the main culprit? Would we have transformed the life of the person for long if we had tackled the cold on time?
The last decades have shown that there is another path, a very promising one. That life expectancy and healthy life expectancy are very malleable, because some things we do and take have large long term effects, negative or positive. Knowing such long term effects is the key for long healthy lives.
Business models are yet to be defined. Two practical approaches to know such long term effects are animal lifespan tests (or HLY tests) and statistical inference of long term effects of drugs in humans. A "long term health" label on drugs would be one incentive to have the business of long term health knowledge grow, for the benefits of all.
Keywords: long term health, knowledge, healthy life years, drugs, label, lifespan tests, rodents, ICT
Category: Invited
Authors: Edouard Debonneuil
Heales VZW
Health care business models so far essentially rely on cures for specific diseases. But when an old person starts to need long term care following a cold, a fall, or other events that would not matter at younger ages: is the cold the main culprit? Would we have transformed the life of the person for long if we had tackled the cold on time?
The last decades have shown that there is another path, a very promising one. That life expectancy and healthy life expectancy are very malleable, because some things we do and take have large long term effects, negative or positive. Knowing such long term effects is the key for long healthy lives.
Business models are yet to be defined. Two practical approaches to know such long term effects are animal lifespan tests (or HLY tests) and statistical inference of long term effects of drugs in humans. A "long term health" label on drugs would be one incentive to have the business of long term health knowledge grow, for the benefits of all.
Keywords: long term health, knowledge, healthy life years, drugs, label, lifespan tests, rodents, ICT
Category: Invited
Strategies to target corrective RNAs to mitochondria
Authors: Carla Koehler, Michael Teitell, Geng Wang, and Eriko Shimada
UCLA, Los Angeles, CA
Mammalian polynucleotide phosphorylase (PNPase) is an evolutionarily conserved 3’ to 5’ RNA exonuclease related to RNase PH that is involved in mRNA degradation in bacteria and chloroplasts. We have shown that PNPase is a peripheral membrane protein in the mitochondrial intermembrance space (IMS), a surprising location for an RNA processing enzyme since this compartment is devoid of RNA. However, the detailed characterization of PNPase function shows that it is the first component in mammalian mitochondria to mediate the import of a subset of RNAs into the mitochondrial matrix, including the RNA components of RNase P and Mrp1, tRNAs, and the 5S ribosomal RNA. Surprisingly, mammalian PNPase can still degrade RNA. We have also characterized the import properties of mitochondrial RNAs in more detail and show that a stem-loop region in Mrp1 and RNase P guides the RNA into mitochondria. This stem loop region can be appended to non-imported RNAs and subsequently guide these RNAs into the mitochondria. This approach supports that this pathway may be used to directly target RNAs of interest to the organelle. We propose that PNPase acts as a gatekeeper in the IMS to guide RNAs with the correct import properties into mitochondria and may use the degradation function to degrade RNAs that are not destined for import. Moreover, studies are underway to exploit this pathway as a potential therapeutic for mitochondrial diseases caused by mutations in the mitochondrial genome and as a strategy to correct deleterious mitochondrial DNA mutations that may accumulate as one ages.
Keywords: PNPase, mitochondria, RNA import
Category: Invited
Authors: Carla Koehler, Michael Teitell, Geng Wang, and Eriko Shimada
UCLA, Los Angeles, CA
Mammalian polynucleotide phosphorylase (PNPase) is an evolutionarily conserved 3’ to 5’ RNA exonuclease related to RNase PH that is involved in mRNA degradation in bacteria and chloroplasts. We have shown that PNPase is a peripheral membrane protein in the mitochondrial intermembrance space (IMS), a surprising location for an RNA processing enzyme since this compartment is devoid of RNA. However, the detailed characterization of PNPase function shows that it is the first component in mammalian mitochondria to mediate the import of a subset of RNAs into the mitochondrial matrix, including the RNA components of RNase P and Mrp1, tRNAs, and the 5S ribosomal RNA. Surprisingly, mammalian PNPase can still degrade RNA. We have also characterized the import properties of mitochondrial RNAs in more detail and show that a stem-loop region in Mrp1 and RNase P guides the RNA into mitochondria. This stem loop region can be appended to non-imported RNAs and subsequently guide these RNAs into the mitochondria. This approach supports that this pathway may be used to directly target RNAs of interest to the organelle. We propose that PNPase acts as a gatekeeper in the IMS to guide RNAs with the correct import properties into mitochondria and may use the degradation function to degrade RNAs that are not destined for import. Moreover, studies are underway to exploit this pathway as a potential therapeutic for mitochondrial diseases caused by mutations in the mitochondrial genome and as a strategy to correct deleterious mitochondrial DNA mutations that may accumulate as one ages.
Keywords: PNPase, mitochondria, RNA import
Category: Invited
Senescent cell clearance extends healthspan
Authors: 1,2,3Baker D.J., 1,4Wijshake T., 3Tchkonia T., 3,5LeBrasseur N.K., 1Childs B.G., 4van de Sluis B., 3Kirkland J.L., 1,2,3van Deursen J.M.
1Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. 2Molecular Biology and Biochemistry, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. 3Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. 4Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen University, Groningen 9700 RB, The Netherlands. 5Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive aging remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Senescent cells accumulate in various tissues and organs with aging and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug. By utilizing the hypomorphic BubR1 progeroid mouse background, the INK-ATTAC transgene removes p16Ink4a-positive senescent cells upon drug treatment. In tissues, such as adipose tissue, skeletal muscle, and eye, in which p16Ink4a contributes to the acquisition of age-related pathologies, removal of p16Ink4a-expressing cells delayed the onset of these phenotypes. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction, and extend healthspan.
Keywords: p16Ink4a, senescent cells,
Category: Invited
Authors: 1,2,3Baker D.J., 1,4Wijshake T., 3Tchkonia T., 3,5LeBrasseur N.K., 1Childs B.G., 4van de Sluis B., 3Kirkland J.L., 1,2,3van Deursen J.M.
1Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. 2Molecular Biology and Biochemistry, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. 3Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. 4Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen University, Groningen 9700 RB, The Netherlands. 5Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive aging remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Senescent cells accumulate in various tissues and organs with aging and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug. By utilizing the hypomorphic BubR1 progeroid mouse background, the INK-ATTAC transgene removes p16Ink4a-positive senescent cells upon drug treatment. In tissues, such as adipose tissue, skeletal muscle, and eye, in which p16Ink4a contributes to the acquisition of age-related pathologies, removal of p16Ink4a-expressing cells delayed the onset of these phenotypes. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction, and extend healthspan.
Keywords: p16Ink4a, senescent cells,
Category: Invited
Potential of telomerase in extending health span and longevity in mice
Authors: Bruno Miguel Bernardes de Jesus
Spanish National Cancer Research Centre, Spain
A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy.
Keywords: telomerase, TERT, gene therapy
Category: Invited
Authors: Bruno Miguel Bernardes de Jesus
Spanish National Cancer Research Centre, Spain
A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy.
Keywords: telomerase, TERT, gene therapy
Category: Invited
Computational Support for analyzing induction of pluripotency and other cell transitions
Authors: Georg Fuellen
Institute for Biostatistics and Informatics in Medicine and Ageing Research, Department Ageing, Faculty of Interdisciplinary Research, Rostock University, Germany
Medical School Rostock, Germany
Towards extending healthspan, decelerating universal ageing-related processes, preventing a whole range of diseases, and enabling the tackling of a range of diseases (all at the same time) are attractive research areas, because they do not subscribe to the commonplace and necessarily ineffective idea of finding cures for single diseases (cf. Olshansky, Science, 1990).
For example, towards repairing a range of organs by the patient's own cells, surprising progress has been made in the past years in manipulating cell fate, e.g. turning somatic cells into pluripotent ones that may proliferate, and redifferentiate (cf. the 2012 nobel prize).
I will describe a project idea where omics data (time series) describing induction of pluripotency will be analyzed differentially, in order to establish an intelligent screening campaign that tackles the challenge of finding small molecules inducing pluripotency.
I will also describe how such a project may be supported by knowledge formalization using ontologies, going far beyond the Gene Ontology. Essentially, I propose that we need to care more about formalizing knowledge about processes (occurrents) such as pluripotency induction, transdifferentiation and ageing, and less about formalizing descriptions of the corresponding cellular states (continuants).
Lastly, I'd like to highlight workshops I'm organizing in 2013, the 3rd Rostock Symposium on Systems Biology and Bioinformatics in Ageing Research, http://www.ibima.med.uni-rostock.de/IBIMA/symposium/2013/ and the 5th Bioinformatics and Stem Cells Satellite Workshop, http://www.ibima.med.uni-rostock.de/stemcellbioinf_2013/
Keywords: pluripotency, omics, transdifferentiation
Category: Invited
Authors: Georg Fuellen
Institute for Biostatistics and Informatics in Medicine and Ageing Research, Department Ageing, Faculty of Interdisciplinary Research, Rostock University, Germany
Medical School Rostock, Germany
Towards extending healthspan, decelerating universal ageing-related processes, preventing a whole range of diseases, and enabling the tackling of a range of diseases (all at the same time) are attractive research areas, because they do not subscribe to the commonplace and necessarily ineffective idea of finding cures for single diseases (cf. Olshansky, Science, 1990).
For example, towards repairing a range of organs by the patient's own cells, surprising progress has been made in the past years in manipulating cell fate, e.g. turning somatic cells into pluripotent ones that may proliferate, and redifferentiate (cf. the 2012 nobel prize).
I will describe a project idea where omics data (time series) describing induction of pluripotency will be analyzed differentially, in order to establish an intelligent screening campaign that tackles the challenge of finding small molecules inducing pluripotency.
I will also describe how such a project may be supported by knowledge formalization using ontologies, going far beyond the Gene Ontology. Essentially, I propose that we need to care more about formalizing knowledge about processes (occurrents) such as pluripotency induction, transdifferentiation and ageing, and less about formalizing descriptions of the corresponding cellular states (continuants).
Lastly, I'd like to highlight workshops I'm organizing in 2013, the 3rd Rostock Symposium on Systems Biology and Bioinformatics in Ageing Research, http://www.ibima.med.uni-rostock.de/IBIMA/symposium/2013/ and the 5th Bioinformatics and Stem Cells Satellite Workshop, http://www.ibima.med.uni-rostock.de/stemcellbioinf_2013/
Keywords: pluripotency, omics, transdifferentiation
Category: Invited
Induced pluripotent stem cells, aging and therapeutic applications
Authors: Alexandra Stolzing
Fraunhofer Institute for Cell Therapy and Immunology, Perlickstrasse 1, Leipzig, Germany
Reprogramming of somatic cells provides a unique opportunity to derive patient-specific stem cells with potential application in cell therapies. Cellular reprogramming can in addition contribute in many ways towards better understanding of the mechanisms of aging. The first iPS cell lines have been created from donors with premature aging disorders as well as from centenarians. Even if questions on the complete identity of iPSCs and embryonic stem cells (ESCs) remains unanswered, the established cell lines have shown relevant aspects of the disease phenotype and can now be used as in vitro models to study ageing aspects.
Although different studies suggest a similar differentiation potential between hiPSCs and hESC, it is unclear whether they can be expanded into homogeneous cell populations without early senescence, suitable for clinical translation. Reprogramming does not necessarily be rejuvenation. Some recent publications have flagged the problem of introducing additional mutations during the process, however others have shown a reset of telomere length, gene expression profiles and mitochondrial activity.
We have derived iPS from different donors (including healthy young/aged and Huntington donors) and analysed telomere extension and telomerase activity initiated through the reprogramming process. Changes in telomere length were observed during expansion as well as changed mitochondrial activity. Additionally, we have analysed fibroblasts derived from these iPS-lines for signs of aging, mitochondrial activity and compared them to donor fibroblasts. We found that telomere length get restored after reprogramming during the first 10 passages. In addition we observe a reduction in ROS production and a change in mitochondrial morphology.
Despite our observed telomere extension after reprogramming and no obvious accelerate aging in the iPS derived cells it still remains an open question if reprogramming can reset cell age or if reprogramming is a highly selective process allowing only un-damaged, young cells to be reprogrammed.
Keywords: pluripotent stem cells, centenarians, premature aging disorders, telomere length
Category: Invited
Authors: Alexandra Stolzing
Fraunhofer Institute for Cell Therapy and Immunology, Perlickstrasse 1, Leipzig, Germany
Reprogramming of somatic cells provides a unique opportunity to derive patient-specific stem cells with potential application in cell therapies. Cellular reprogramming can in addition contribute in many ways towards better understanding of the mechanisms of aging. The first iPS cell lines have been created from donors with premature aging disorders as well as from centenarians. Even if questions on the complete identity of iPSCs and embryonic stem cells (ESCs) remains unanswered, the established cell lines have shown relevant aspects of the disease phenotype and can now be used as in vitro models to study ageing aspects.
Although different studies suggest a similar differentiation potential between hiPSCs and hESC, it is unclear whether they can be expanded into homogeneous cell populations without early senescence, suitable for clinical translation. Reprogramming does not necessarily be rejuvenation. Some recent publications have flagged the problem of introducing additional mutations during the process, however others have shown a reset of telomere length, gene expression profiles and mitochondrial activity.
We have derived iPS from different donors (including healthy young/aged and Huntington donors) and analysed telomere extension and telomerase activity initiated through the reprogramming process. Changes in telomere length were observed during expansion as well as changed mitochondrial activity. Additionally, we have analysed fibroblasts derived from these iPS-lines for signs of aging, mitochondrial activity and compared them to donor fibroblasts. We found that telomere length get restored after reprogramming during the first 10 passages. In addition we observe a reduction in ROS production and a change in mitochondrial morphology.
Despite our observed telomere extension after reprogramming and no obvious accelerate aging in the iPS derived cells it still remains an open question if reprogramming can reset cell age or if reprogramming is a highly selective process allowing only un-damaged, young cells to be reprogrammed.
Keywords: pluripotent stem cells, centenarians, premature aging disorders, telomere length
Category: Invited
Collective advantages of a very long life. Should the State subsidize life extension?
Authors: Didier Coeurnelle
Heales VZW
A longer and healthier life is almost always enjoyed by the citizens who can benefit from it. But this evolution is also positive for the whole society, and a catalyst for non-violence. This speech gives a description of positive political,
economic and sociological aspects of a world with a largely delayed senescence: lower health costs, lower level of crime, higher level of happiness, ...
The following themes will be approached accompanied with statistical information:
- Economic advantages
- Sustainable society
- Harmonious society
- Political and sociological advantages
- Research funding
- Ethical aspects: life extension as a human right.
Keywords: long-term health, age-related diseases, economics, politics,
statistics, happiness,
Category: Invited
Authors: Didier Coeurnelle
Heales VZW
A longer and healthier life is almost always enjoyed by the citizens who can benefit from it. But this evolution is also positive for the whole society, and a catalyst for non-violence. This speech gives a description of positive political,
economic and sociological aspects of a world with a largely delayed senescence: lower health costs, lower level of crime, higher level of happiness, ...
The following themes will be approached accompanied with statistical information:
- Economic advantages
- Sustainable society
- Harmonious society
- Political and sociological advantages
- Research funding
- Ethical aspects: life extension as a human right.
Keywords: long-term health, age-related diseases, economics, politics,
statistics, happiness,
Category: Invited
Strategies to understand, prevent, and perhaps even reverse, human aging through exploration of Advanced Glycation End-Products
Authors: David A. Spiegel, M.D., Ph.D.
Yale University, Departments of Chemistry and Pharmacology
Recent scientific advances suggest that many age-related health problems result from long-term environmental and/or dietary exposure to common substances. These include carbohydrates found in foods (glucose, fructose, and others), and oxygen found in the air. Although these agents are essential for human survival, over time, they lead to the build up of toxic materials called Advanced glycation end-products (AGEs). Surprisingly, relatively little is known about AGEs, especially in terms of which ones are the most harmful, how they give rise to physical deficits, and how their formation can be prevented.
My laboratory has been successful in preparing many AGEs in chemically pure form, and in quantities sufficient for detailed study. Using these materials, we have also been able to study how AGEs may cause damage to cells and
tissues of the human body. Our current goal is to identify new drugs that can degrade these chemicals, thus reversing many of the physical problems associated with old age, including skin damage, joint and bone defects, and cardiovascular disease. This talk will provide an overview of how AGEs are believed to cause many age-related health problems, as well as our laboratory’s ongoing efforts to inhibit and/or reverse their formation. We are hopeful that our research has real potential to help rejuvenate the world’s elderly population.
Keywords: Advanced glycation end-products, Drugs, Age-related diseases
Category: Invited
Authors: David A. Spiegel, M.D., Ph.D.
Yale University, Departments of Chemistry and Pharmacology
Recent scientific advances suggest that many age-related health problems result from long-term environmental and/or dietary exposure to common substances. These include carbohydrates found in foods (glucose, fructose, and others), and oxygen found in the air. Although these agents are essential for human survival, over time, they lead to the build up of toxic materials called Advanced glycation end-products (AGEs). Surprisingly, relatively little is known about AGEs, especially in terms of which ones are the most harmful, how they give rise to physical deficits, and how their formation can be prevented.
My laboratory has been successful in preparing many AGEs in chemically pure form, and in quantities sufficient for detailed study. Using these materials, we have also been able to study how AGEs may cause damage to cells and
tissues of the human body. Our current goal is to identify new drugs that can degrade these chemicals, thus reversing many of the physical problems associated with old age, including skin damage, joint and bone defects, and cardiovascular disease. This talk will provide an overview of how AGEs are believed to cause many age-related health problems, as well as our laboratory’s ongoing efforts to inhibit and/or reverse their formation. We are hopeful that our research has real potential to help rejuvenate the world’s elderly population.
Keywords: Advanced glycation end-products, Drugs, Age-related diseases
Category: Invited
Geroprotective drugs for healthy life extension
Authors: Sven Bulterijs
Heales VZW
Drugs that decrease the rate of aging and consequently extend lifespan (named geroprotective drugs). The literature contains a long list of compounds that have been shown to, at least moderately, increase the lifespan in one model organism but only a few ones have been thoroughly validated in several model organisms. To these highly validated drugs belong metformin and rapamycin (sirolimus). Other drugs such as resveratrol have received lot's of hype in the popular media despite its disappointing results in several lifespan tests. Finally, simvastatin is a very widespread used drug to lower cholesterol levels but according to some studies might also increase lifespan.
Keywords: Metformin, Geroprotective drugs, CR mimetics
Category: Invited
Authors: Sven Bulterijs
Heales VZW
Drugs that decrease the rate of aging and consequently extend lifespan (named geroprotective drugs). The literature contains a long list of compounds that have been shown to, at least moderately, increase the lifespan in one model organism but only a few ones have been thoroughly validated in several model organisms. To these highly validated drugs belong metformin and rapamycin (sirolimus). Other drugs such as resveratrol have received lot's of hype in the popular media despite its disappointing results in several lifespan tests. Finally, simvastatin is a very widespread used drug to lower cholesterol levels but according to some studies might also increase lifespan.
Keywords: Metformin, Geroprotective drugs, CR mimetics
Category: Invited
