Abstracts are listed in alphabetical order of presenting author (underlined).
Biofilm and its implication in ageing via « cold inflammation »
Patrizia d’Alessio, MD PhD
Introduction
Inflammation is characterized by rubor, tumor, calor, dolor and loss of function. Chronic “silent” inflammation promotes accelerated cell senescence speeding up ageing. Still, some forms of inflammation even lack fever and sometimes pain, in a new type we propose to name “cold inflammation”.
Biofilms are a form of habitat of microorganisms nesting bacterial cells within a polymeric matrix. Their development is initiated by environmental signals or by bacterial cells themselves.
Material and methods
The monoterpen, d-Limonene, shown to display a sustained anti-inflammatory activity in pre-clinical and clinical studies, was tested for its ability to modify the gut microbiome and act on monolayers of colonic epithelial cells H29/B6 mimicking the intestinal barrier.
Results
d-Limonene induced a decrease of serum IL-6 in healthy ageing humans as well as in pre-clinical models of colitis and dermatitis in rodents. In the Ristomed study probiotic supplementation tended to increase the ratio of Clostridium/Bifidobacteria in patients with low baseline inflammation and to decrease it in patients with baseline mild or high inflammation. Supplementation with d-Limonene has the reverse effect, acting on the microbiome and concomitantly on the barrier function of the gut epithelium.
Conclusions
In the gut, immune tolerance is nested in the biofilm, also a potential source of long-lasting asymptomatic chronic inflammation based on re-routing the immune system by the microflora. This microbiome imbalance impairing immune function precedes a dissemination of the inflammatory reaction to other organs. Major age-associated ailments could thus relate to the crucial point were imbalance of the microbiome favors a “leaky-gut”.
Patrizia d’Alessio, MD PhD
Introduction
Inflammation is characterized by rubor, tumor, calor, dolor and loss of function. Chronic “silent” inflammation promotes accelerated cell senescence speeding up ageing. Still, some forms of inflammation even lack fever and sometimes pain, in a new type we propose to name “cold inflammation”.
Biofilms are a form of habitat of microorganisms nesting bacterial cells within a polymeric matrix. Their development is initiated by environmental signals or by bacterial cells themselves.
Material and methods
The monoterpen, d-Limonene, shown to display a sustained anti-inflammatory activity in pre-clinical and clinical studies, was tested for its ability to modify the gut microbiome and act on monolayers of colonic epithelial cells H29/B6 mimicking the intestinal barrier.
Results
d-Limonene induced a decrease of serum IL-6 in healthy ageing humans as well as in pre-clinical models of colitis and dermatitis in rodents. In the Ristomed study probiotic supplementation tended to increase the ratio of Clostridium/Bifidobacteria in patients with low baseline inflammation and to decrease it in patients with baseline mild or high inflammation. Supplementation with d-Limonene has the reverse effect, acting on the microbiome and concomitantly on the barrier function of the gut epithelium.
Conclusions
In the gut, immune tolerance is nested in the biofilm, also a potential source of long-lasting asymptomatic chronic inflammation based on re-routing the immune system by the microflora. This microbiome imbalance impairing immune function precedes a dissemination of the inflammatory reaction to other organs. Major age-associated ailments could thus relate to the crucial point were imbalance of the microbiome favors a “leaky-gut”.
The effects and dose-response relationships of resistance training on circulating BDNF and inflammatory cytokines in older persons.
Ivan Bautmans¹ ² ³
1 Gerontology department, Vrije Universiteit Brussel (VUB), Brussels, Belgium
2 Frailty in Ageing research department, Vrije Universiteit Brussel (VUB), Brussels, Belgium
3 Geriatrics department, Universitair Ziekenhuis Brussel, Brussels, Belgium
[email protected]
Introduction
Ageing is associated with a chronic low-grade inflammation, which could be counteracted with physical exercise by influencing circulating inflammatory mediators and neurotrophic growth factors.
Methods
In 4 intervention studies including 243 elderly individuals we assessed the effects and dose-response relationships of resistance training (RT) on circulating BDNF and inflammatory cytokines (IL-6, IL-1beta, L-1ra, sTNFR1, IL-8, GM-CSF, IL-10):
1) n=31 aged 68±5 yrs, 6 weeks RT (3x10 repetitions @ 80% 1RM),
2) n=40 aged 67±7 yrs, 12 weeks RT (3x10 repetitions @ 80% 1RM) compared to matched controls,
3) n=56 aged 68±5 yrs, 12 weeks HIGH (2x10-15 repetitions @ 80%1RM), LOW (1x80-100 repetitions @ 20%1RM), or LOW+ (1x60 repetitions @ 20%1RM followed by 1x10-20 repetitions @ 40%1RM), followed by 24 weeks detraining,
4) n=116 aged 71±5 yrs, 12 weeks IST (3x10 repetitions @ 80%1RM), SET (2x30 repetitions at 40%1RM) or FT (4x60seconds muscle stretching),
Results
We observed significant RT-induced effects on inflammatory markers and BDNF in a dose-dependent and gender-specific manner. After 24 weeks detraining, effects on BDNF returned back to baseline.
Conclusion
6-12 weeks RT has considerable neurotrophic and anti-inflammatory effects in older persons. We suggest that exercising until volitional fatigue is the main trigger for exercise-induced responses. Continuous exercise adherence seems to be needed to sustain the training-induced effects on BDNF in older persons.
COI
None
Ivan Bautmans¹ ² ³
1 Gerontology department, Vrije Universiteit Brussel (VUB), Brussels, Belgium
2 Frailty in Ageing research department, Vrije Universiteit Brussel (VUB), Brussels, Belgium
3 Geriatrics department, Universitair Ziekenhuis Brussel, Brussels, Belgium
[email protected]
Introduction
Ageing is associated with a chronic low-grade inflammation, which could be counteracted with physical exercise by influencing circulating inflammatory mediators and neurotrophic growth factors.
Methods
In 4 intervention studies including 243 elderly individuals we assessed the effects and dose-response relationships of resistance training (RT) on circulating BDNF and inflammatory cytokines (IL-6, IL-1beta, L-1ra, sTNFR1, IL-8, GM-CSF, IL-10):
1) n=31 aged 68±5 yrs, 6 weeks RT (3x10 repetitions @ 80% 1RM),
2) n=40 aged 67±7 yrs, 12 weeks RT (3x10 repetitions @ 80% 1RM) compared to matched controls,
3) n=56 aged 68±5 yrs, 12 weeks HIGH (2x10-15 repetitions @ 80%1RM), LOW (1x80-100 repetitions @ 20%1RM), or LOW+ (1x60 repetitions @ 20%1RM followed by 1x10-20 repetitions @ 40%1RM), followed by 24 weeks detraining,
4) n=116 aged 71±5 yrs, 12 weeks IST (3x10 repetitions @ 80%1RM), SET (2x30 repetitions at 40%1RM) or FT (4x60seconds muscle stretching),
Results
We observed significant RT-induced effects on inflammatory markers and BDNF in a dose-dependent and gender-specific manner. After 24 weeks detraining, effects on BDNF returned back to baseline.
Conclusion
6-12 weeks RT has considerable neurotrophic and anti-inflammatory effects in older persons. We suggest that exercising until volitional fatigue is the main trigger for exercise-induced responses. Continuous exercise adherence seems to be needed to sustain the training-induced effects on BDNF in older persons.
COI
None
Advanced glycation end-product crosslinking in ageing skeletal tissues
Helen Birch
Institute of Orthopaedics and Musculoskeletal Science
UCL, London
[email protected]
Increasing age is a well-known major risk factor for tendon injuries and although tendon injuries are not life threatening, they cause considerable pain and disability. The WHO has recognised the promotion of physical activity as one of the greatest potentials to achieve gains in health in older age, highlighting the importance of musculoskeletal fitness. Despite this, relatively little is understood about the ageing process and the underlying changes that result in a decline in the functional ability of tendons.
The turnover of collagen, the predominant protein in tendon, is remarkably slow and half-life increases further with increasing chronological age. The long-lived nature of tendon collagen renders it susceptible to the formation of advanced glycation end-products (AGE) following attack by reactive carbonyl groups on sugars such as glucose (glycation). A series of spontaneous chemical re-arrangements and further reactions results in AGE crosslinks, the most abundant of which is thought to be glucosepane. Our current research is focused on understanding the formation, extent and location of AGE crosslinks, particularly glucosepane, in type I collagen and the effect these crosslinks have on the mechanical and biological properties of tendon. Our studies have shown that glucosepane levels increase with increasing age in human tendon. The sites we have identified as preferential sites for glucosepane formation overlap with other important bioactive interactions sites.
The author has no financial interests to disclose.
Helen Birch
Institute of Orthopaedics and Musculoskeletal Science
UCL, London
[email protected]
Increasing age is a well-known major risk factor for tendon injuries and although tendon injuries are not life threatening, they cause considerable pain and disability. The WHO has recognised the promotion of physical activity as one of the greatest potentials to achieve gains in health in older age, highlighting the importance of musculoskeletal fitness. Despite this, relatively little is understood about the ageing process and the underlying changes that result in a decline in the functional ability of tendons.
The turnover of collagen, the predominant protein in tendon, is remarkably slow and half-life increases further with increasing chronological age. The long-lived nature of tendon collagen renders it susceptible to the formation of advanced glycation end-products (AGE) following attack by reactive carbonyl groups on sugars such as glucose (glycation). A series of spontaneous chemical re-arrangements and further reactions results in AGE crosslinks, the most abundant of which is thought to be glucosepane. Our current research is focused on understanding the formation, extent and location of AGE crosslinks, particularly glucosepane, in type I collagen and the effect these crosslinks have on the mechanical and biological properties of tendon. Our studies have shown that glucosepane levels increase with increasing age in human tendon. The sites we have identified as preferential sites for glucosepane formation overlap with other important bioactive interactions sites.
The author has no financial interests to disclose.
Supercentenarians and the immunobiome
Victor Björk
Supercentenarians are people living to 110 or more, less than 1% of them live to 116. Mortality is often due to declining function of the immune system resulting in pneumonia or infectious disease. More and more research point to inflammaging and the microbiome as being a factor in extreme longevity.
The author has no financial interests to disclose.
Victor Björk
- Heales vzw
- Gerontology Research Group
Supercentenarians are people living to 110 or more, less than 1% of them live to 116. Mortality is often due to declining function of the immune system resulting in pneumonia or infectious disease. More and more research point to inflammaging and the microbiome as being a factor in extreme longevity.
The author has no financial interests to disclose.
The ageing biotech industry
Sven Bulterijs1,2
The first biotech companies working on ageing got established in the 1990s (examples include Geron Corporation, Alteon Corporation, Sierra Sciences, and Elixir Pharmaceuticals). The success of Sirtis Pharmaceuticals (founded in 2004) and sold to GlaxoSmithKline in 2008 for $720 million inspired a wave of new companies such as Calico, Human Longevity Inc., Chronos Therapeutics, and many others. In this talk I will analyse the strategies used by biotech companies working on ageing and the unique challenges that such companies face. No regulatory path has been created for the approval of geroprotective drugs or interventions. Furthermore, as human clinical trials, using life span as an end point, are unfeasible due to the long time period that such studies would involve and the lack of clear and robust biomarkers of ageing, it remains problematic to prove that a geroprotective intervention is able to successfully delay human ageing. While the ageing biotech industry is blooming investments are still insufficient due to the challenges described above.
The author is an employee of Aging Analytics inc.
Sven Bulterijs1,2
- Heales vzw
- Aging Analytics inc.
The first biotech companies working on ageing got established in the 1990s (examples include Geron Corporation, Alteon Corporation, Sierra Sciences, and Elixir Pharmaceuticals). The success of Sirtis Pharmaceuticals (founded in 2004) and sold to GlaxoSmithKline in 2008 for $720 million inspired a wave of new companies such as Calico, Human Longevity Inc., Chronos Therapeutics, and many others. In this talk I will analyse the strategies used by biotech companies working on ageing and the unique challenges that such companies face. No regulatory path has been created for the approval of geroprotective drugs or interventions. Furthermore, as human clinical trials, using life span as an end point, are unfeasible due to the long time period that such studies would involve and the lack of clear and robust biomarkers of ageing, it remains problematic to prove that a geroprotective intervention is able to successfully delay human ageing. While the ageing biotech industry is blooming investments are still insufficient due to the challenges described above.
The author is an employee of Aging Analytics inc.
Longevity and artificial intelligence (A.I.)
Didier Coeurnelle
Heales vzw
Developing research for longevity is one of the most important ways to save lives. Indeed, every day, around 110,000 people die of diseases related to old age (around 70 % of all deaths in the world and about 90 % of all deaths in "rich" countries). Developing research for longevity is (very) complicated. Indeed, we already defeated most causes of diseases and death, who were easy to combat. Difficult work is ahead. Developing research for longevity would be (much) easier with (a better) use of artificial intelligence. The speech will approach the companies working on A.I., the work they already accomplished, the perspectives of the medical research accomplished by A.I. on short and middle-term and risks related to A.I.
Didier Coeurnelle
Heales vzw
Developing research for longevity is one of the most important ways to save lives. Indeed, every day, around 110,000 people die of diseases related to old age (around 70 % of all deaths in the world and about 90 % of all deaths in "rich" countries). Developing research for longevity is (very) complicated. Indeed, we already defeated most causes of diseases and death, who were easy to combat. Difficult work is ahead. Developing research for longevity would be (much) easier with (a better) use of artificial intelligence. The speech will approach the companies working on A.I., the work they already accomplished, the perspectives of the medical research accomplished by A.I. on short and middle-term and risks related to A.I.
Ageing as modulator and target of cell based therapies
Claire Fabian¹, Yahaira Naaldijk¹, Lusine Danielyan², Alexandra Stolzing¹⁺³
Regenerative medicine is investigating (stem) cell transplantations as a treatment for many diseases of the elderly. Cell therapies often show promising results in animal models, however the translation into large clinical trials are difficult. This might be in part because we do not know much about the mechanisms of action of the used cells, the optimal cell dose, the best delivery route but partly because we do not take the donor age of the cells into account and pre-clinical trials are mostly run in young animals only. I will discuss the role of ageing in stem cell therapies but also show initial results on the use of cell therapy to delay brain ageing.
I have shown that mesenchymal stem cells decrease functional activity if they are derived from older donors or have been expanded in vitro. One question is therefore if donor age has an impact on cell therapy outcomes. In addition the recipient age also has to be investigated as it changes the environment in which the cells are transplanted into.
Material & Methods: We transplanted mouse mesenchymal stem cells or microglia into mice (young, aged and Alzheimer). Cells were either from young or mature donors. Cells were tracked either using eGFP or the y-chromosome. Histology and real time PCR were performed to analyse the status of inflammation.
Results: We find that aged donor cells were not engrafting well, with this being more pronounced for microglia then for MSC. Interestingly more cells were found in aged/diseased brains compared to young brains and this was linked to the amount of chemo-attractant MCP-1 expression. Young cells minimise inflammation levels in the brain of AD mice and in aged mice, however this was not found for aged cells.
Conclusion: Donor age as well as recipient age modifies cell migration and engraftment and has to be taken into consideration when investigating cell therapies. Different cell types seem to be able to minimise inflammation in aged or diseases brains, also translating into improved animal behaviour.
Claire Fabian¹, Yahaira Naaldijk¹, Lusine Danielyan², Alexandra Stolzing¹⁺³
- Leipzig University, Germany
- Tubingen University, Germany
- Loughborough University, Centre for Biological Engineering, Wolfson School, UK
Regenerative medicine is investigating (stem) cell transplantations as a treatment for many diseases of the elderly. Cell therapies often show promising results in animal models, however the translation into large clinical trials are difficult. This might be in part because we do not know much about the mechanisms of action of the used cells, the optimal cell dose, the best delivery route but partly because we do not take the donor age of the cells into account and pre-clinical trials are mostly run in young animals only. I will discuss the role of ageing in stem cell therapies but also show initial results on the use of cell therapy to delay brain ageing.
I have shown that mesenchymal stem cells decrease functional activity if they are derived from older donors or have been expanded in vitro. One question is therefore if donor age has an impact on cell therapy outcomes. In addition the recipient age also has to be investigated as it changes the environment in which the cells are transplanted into.
Material & Methods: We transplanted mouse mesenchymal stem cells or microglia into mice (young, aged and Alzheimer). Cells were either from young or mature donors. Cells were tracked either using eGFP or the y-chromosome. Histology and real time PCR were performed to analyse the status of inflammation.
Results: We find that aged donor cells were not engrafting well, with this being more pronounced for microglia then for MSC. Interestingly more cells were found in aged/diseased brains compared to young brains and this was linked to the amount of chemo-attractant MCP-1 expression. Young cells minimise inflammation levels in the brain of AD mice and in aged mice, however this was not found for aged cells.
Conclusion: Donor age as well as recipient age modifies cell migration and engraftment and has to be taken into consideration when investigating cell therapies. Different cell types seem to be able to minimise inflammation in aged or diseases brains, also translating into improved animal behaviour.
Signatures of longevity and biomarkers of biological versus chronological age
Claudio Franceschi
University of Bologna and IRCCS Institute of Neurological Sciences of Bologna, Italy
I’ll present the last data produced in my laboratory on the genetics, epigenetics and N-glycomics of centenarians (100+), semi-supercentenarians (105+) and their offspring. I’ll describe new loci correlated with human longevity paying particular attention to population genetics and data on an the epigenetic signature of 105+ and their decelerated rate of ageing. A particular attention will be devoted to mechanisms underpinning the lifelong changes of DNA methylation of ELOVL2, a top epigenetic biomarker of ageing. Data showing that 100+ and 105+ are apparently younger than their chronological age according to the analysis on plasma N-glycans will also be presented and discussed. Finally I’ll present data on the lifelong trajectory and remodeling of human microbiome in subjects from 20 to 109 years of age. All these data are pieces of a puzzle we are trying to reconstruct within the perspective of a systems biology of ageing and longevity.
Claudio Franceschi
University of Bologna and IRCCS Institute of Neurological Sciences of Bologna, Italy
I’ll present the last data produced in my laboratory on the genetics, epigenetics and N-glycomics of centenarians (100+), semi-supercentenarians (105+) and their offspring. I’ll describe new loci correlated with human longevity paying particular attention to population genetics and data on an the epigenetic signature of 105+ and their decelerated rate of ageing. A particular attention will be devoted to mechanisms underpinning the lifelong changes of DNA methylation of ELOVL2, a top epigenetic biomarker of ageing. Data showing that 100+ and 105+ are apparently younger than their chronological age according to the analysis on plasma N-glycans will also be presented and discussed. Finally I’ll present data on the lifelong trajectory and remodeling of human microbiome in subjects from 20 to 109 years of age. All these data are pieces of a puzzle we are trying to reconstruct within the perspective of a systems biology of ageing and longevity.
A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease
Rosie Freer¹, Pietro Sormanni¹, Prajwal Ciryam¹ ², Christopher M. Dobson¹ and Michele Vendruscolo¹
1, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
2, Department of Molecular Biosciences, Northwestern University, Evanston IL 60208, USA
In Alzheimer’s disease, aberrant aggregates primarily composed of amyloid-beta and tau develop progressively across brain tissues following a specific spatio-temporal pattern. Although this pattern has been characterised for more than two decades [1], the mechanisms that govern the selective vulnerability of tissues remain under debate. To address this problem, we use transcriptional analysis of normal brains to identify an expression signature that predicts the vulnerability of different tissues to disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the specific expression patterns of the proteins that co-aggregate with amyloid-beta and tau, together with protein homeostasis components that regulate amyloid-beta and tau. Our analysis provides an explanatory link between a tissue-specific risk of protein aggregation and a corresponding vulnerability to Alzheimer’s disease [2].
1. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta neuropathologica 82, 239-259 (1991).
2. Freer et al. Science Advances (2016)
Rosie Freer¹, Pietro Sormanni¹, Prajwal Ciryam¹ ², Christopher M. Dobson¹ and Michele Vendruscolo¹
1, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
2, Department of Molecular Biosciences, Northwestern University, Evanston IL 60208, USA
In Alzheimer’s disease, aberrant aggregates primarily composed of amyloid-beta and tau develop progressively across brain tissues following a specific spatio-temporal pattern. Although this pattern has been characterised for more than two decades [1], the mechanisms that govern the selective vulnerability of tissues remain under debate. To address this problem, we use transcriptional analysis of normal brains to identify an expression signature that predicts the vulnerability of different tissues to disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the specific expression patterns of the proteins that co-aggregate with amyloid-beta and tau, together with protein homeostasis components that regulate amyloid-beta and tau. Our analysis provides an explanatory link between a tissue-specific risk of protein aggregation and a corresponding vulnerability to Alzheimer’s disease [2].
1. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta neuropathologica 82, 239-259 (1991).
2. Freer et al. Science Advances (2016)
New discoveries about ageing in C. elegans
David Gems, Alexandre Benedetto, Marina Ezcurra, Ann Gilliat and Yuan Zhao
Institute of Healthy Ageing, University College London
Arguably, C. elegans ageing studies have stalled slightly in recent years. Life span genetics identifies ever more new genes and pathways, yet the proximate mechanisms of ageing that such genes influence remain largely unclear. Recent work in my lab is using new ideas from M.V. Blagosklonny to develop and test novel hypotheses about the primary causes of ageing in C. elegans. These ideas link G.C. Williams’s evolutionary concepts (particularly antagonistic pleiotropy) with recent findings on the role of insulin/IGF-1 signaling in ageing. They suggest that senescent pathologies that limit lifespan may be driven primarily by late life run-on of wild-type gene function, rather than damage accumulation (e.g. due to reactive oxygen species). They motivate a new, pathology-centred approach to understanding senescence, particularly via the study of how pathologies develop ("developmental pathology"), and how they cause mortality. This has enabled the discovery of several new mechanisms by which senescent pathologies originate in C. elegans, including intestinal and gonadal atrophy, yolky pool formation (a form of senescent obesity), and uterine tumours. These mechanisms provide clues to the origins of several senescent pathologies in humans. It has also yielded insights into the causes and mechanisms of organismal death in C. elegans.
David Gems, Alexandre Benedetto, Marina Ezcurra, Ann Gilliat and Yuan Zhao
Institute of Healthy Ageing, University College London
Arguably, C. elegans ageing studies have stalled slightly in recent years. Life span genetics identifies ever more new genes and pathways, yet the proximate mechanisms of ageing that such genes influence remain largely unclear. Recent work in my lab is using new ideas from M.V. Blagosklonny to develop and test novel hypotheses about the primary causes of ageing in C. elegans. These ideas link G.C. Williams’s evolutionary concepts (particularly antagonistic pleiotropy) with recent findings on the role of insulin/IGF-1 signaling in ageing. They suggest that senescent pathologies that limit lifespan may be driven primarily by late life run-on of wild-type gene function, rather than damage accumulation (e.g. due to reactive oxygen species). They motivate a new, pathology-centred approach to understanding senescence, particularly via the study of how pathologies develop ("developmental pathology"), and how they cause mortality. This has enabled the discovery of several new mechanisms by which senescent pathologies originate in C. elegans, including intestinal and gonadal atrophy, yolky pool formation (a form of senescent obesity), and uterine tumours. These mechanisms provide clues to the origins of several senescent pathologies in humans. It has also yielded insights into the causes and mechanisms of organismal death in C. elegans.
Protein carbamylation: hallmark of ageing
Philippe Gillery
Laboratory of Medical Biochemistry and Molecular Biology, UMR CNRS/URCA n°7369, Faculty of Medicine, Reims, France
Among age-related processes are the chemical reactions referred to as "nonenzymatic post-translational modifications" (NEPTM), which are responsible for protein molecular ageing. Carbamylation is a recently described NEPTM due to the binding of isocyanate, derived from urea dissociation or from myeloperoxidase-mediated catabolism of thiocyanate, to amino groups of proteins. The most characteristic carbamylation-derived product (CDP) is homocitrulline generated from lysine residues. Carbamylation induces adverse alterations of protein structure, functions and interactions with cells.
Clinical studies have shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes. However, nothing was known about tissue protein carbamylation during ageing. To address this issue, we have evaluated the evolution of homocitrulline content over time in skin of three mammalian species with different life expectancies. Carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of CPDs, especially in extracellular matrix proteins with long half-life like type I collagen and elastin. The accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. Besides, homocitrulline accumulates in tissues more intensely than carboxymethyl-lysine, one of the major advanced glycation end-product generated by another NEPTM, glycoxidation. Thus, protein carbamylation may be considered a hallmark of ageing in mammalian species and may significantly contribute in the structural and functional tissue damages encountered during ageing.
Financial interest disclosure: none to declare.
Philippe Gillery
Laboratory of Medical Biochemistry and Molecular Biology, UMR CNRS/URCA n°7369, Faculty of Medicine, Reims, France
Among age-related processes are the chemical reactions referred to as "nonenzymatic post-translational modifications" (NEPTM), which are responsible for protein molecular ageing. Carbamylation is a recently described NEPTM due to the binding of isocyanate, derived from urea dissociation or from myeloperoxidase-mediated catabolism of thiocyanate, to amino groups of proteins. The most characteristic carbamylation-derived product (CDP) is homocitrulline generated from lysine residues. Carbamylation induces adverse alterations of protein structure, functions and interactions with cells.
Clinical studies have shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes. However, nothing was known about tissue protein carbamylation during ageing. To address this issue, we have evaluated the evolution of homocitrulline content over time in skin of three mammalian species with different life expectancies. Carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of CPDs, especially in extracellular matrix proteins with long half-life like type I collagen and elastin. The accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. Besides, homocitrulline accumulates in tissues more intensely than carboxymethyl-lysine, one of the major advanced glycation end-product generated by another NEPTM, glycoxidation. Thus, protein carbamylation may be considered a hallmark of ageing in mammalian species and may significantly contribute in the structural and functional tissue damages encountered during ageing.
Financial interest disclosure: none to declare.
The role of type I IFN signaling at the choroid plexus during ageing
Gorlé Nina¹, Balusu Sriram¹, Van Wonterghem Elien¹, Van Imschoot Griet¹, Hoeijmakers Jan², Libert Claude¹, Vandenbroucke Roosmarijn¹
1: Inflammation Research Center, VIB Ghent University
2: Molecular Genetics, Erasmus Medical Center, Rotterdam.
The blood-cerebrospinal fluid (CSF) barrier is formed by choroid plexus epithelial epithelium, a unique single cell layer at the interface between blood and the CSF containing ventricular cavities. Malfunctioning of the blood-CSF barrier can cause serious damage to the CNS. Ageing is a complex, multifactorial process, characterized by progressive loss of physiological integrity and associated with several morphological changes at the choroid plexus epithelium. Here, we studied the role of the type I interferon signaling in the age-associated morphological changes at the blood-CSF barrier.
Financial interest disclosure: none to declare.
Gorlé Nina¹, Balusu Sriram¹, Van Wonterghem Elien¹, Van Imschoot Griet¹, Hoeijmakers Jan², Libert Claude¹, Vandenbroucke Roosmarijn¹
1: Inflammation Research Center, VIB Ghent University
2: Molecular Genetics, Erasmus Medical Center, Rotterdam.
The blood-cerebrospinal fluid (CSF) barrier is formed by choroid plexus epithelial epithelium, a unique single cell layer at the interface between blood and the CSF containing ventricular cavities. Malfunctioning of the blood-CSF barrier can cause serious damage to the CNS. Ageing is a complex, multifactorial process, characterized by progressive loss of physiological integrity and associated with several morphological changes at the choroid plexus epithelium. Here, we studied the role of the type I interferon signaling in the age-associated morphological changes at the blood-CSF barrier.
Financial interest disclosure: none to declare.
Testimony of an effective altruist
Arthur Helstein
Arthur is a Gold Sponsor for the Major Mouse Testing Program (MMMTP). He will speak about his social mission, his work and Life Extension.
Arthur Helstein
Arthur is a Gold Sponsor for the Major Mouse Testing Program (MMMTP). He will speak about his social mission, his work and Life Extension.
The impact of DNA damage and repair on ageing and sustained health
J. Hoeijmakers
Molecular Genetics, Erasmus Medical Center, Rotterdam.
The molecular basis underlying ageing and ageing-related diseases is one of the main unsolved questions in biology. Ageing in various model organisms appears remarkably plastic: e.g. suppressing insulin signalling extends lifespan in worms flies and mice. On the other hand, virtually all premature ageing syndromes in man provide a link with genome instability. We have generated mouse models which strikingly mimic human DNA repair deficiency syndromes and display wide-spread accelerated ageing. For instance, DNA repair-deficient Ercc1∆/- mice defective in 3 or more repair pathways show numerous accelerated ageing features limiting lifespan to 4-6 month. Simultaneously they exhibit an anti-ageing ‘survival response’, which suppresses growth and enhances maintenance, resembling the longevity response induced by dietary restriction (DR). Interestingly, subjecting these progeroid, dwarf mutants to actual DR resulted in the largest lifespan increase recorded in mammals. Thirty percent DR tripled median and maximal remaining lifespan, and drastically retarded numerous aspects of accelerated ageing, e.g. DR animals retained 50% more neurons and maintained full motoric function. Repair-deficient Xpg-/- mice also showing many premature ageing symptoms responded similarly to DR, extending this observation beyond Ercc1. The DR response in Ercc1∆/- mice resembled DR in wild type animals including reduced insulin signaling. Interestingly, ad libitum Ercc1∆/- liver expression profiles showed gradual preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. Phenotypes of conditional DNA repair models targeting ageing to selected organs will be presented exhibiting striking parallels with Alzheimer’s disease. Our findings strengthen the link between DNA damage and ageing, establish Ercc1∆/- mice as powerful model for identifying interventions to promote healthy ageing, reveal untapped potential for reducing endogenous damage, provide new venues for understanding the molecular mechanism of DR, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and DR-like interventions for preventing neurodegenerative diseases.
J. Hoeijmakers
Molecular Genetics, Erasmus Medical Center, Rotterdam.
The molecular basis underlying ageing and ageing-related diseases is one of the main unsolved questions in biology. Ageing in various model organisms appears remarkably plastic: e.g. suppressing insulin signalling extends lifespan in worms flies and mice. On the other hand, virtually all premature ageing syndromes in man provide a link with genome instability. We have generated mouse models which strikingly mimic human DNA repair deficiency syndromes and display wide-spread accelerated ageing. For instance, DNA repair-deficient Ercc1∆/- mice defective in 3 or more repair pathways show numerous accelerated ageing features limiting lifespan to 4-6 month. Simultaneously they exhibit an anti-ageing ‘survival response’, which suppresses growth and enhances maintenance, resembling the longevity response induced by dietary restriction (DR). Interestingly, subjecting these progeroid, dwarf mutants to actual DR resulted in the largest lifespan increase recorded in mammals. Thirty percent DR tripled median and maximal remaining lifespan, and drastically retarded numerous aspects of accelerated ageing, e.g. DR animals retained 50% more neurons and maintained full motoric function. Repair-deficient Xpg-/- mice also showing many premature ageing symptoms responded similarly to DR, extending this observation beyond Ercc1. The DR response in Ercc1∆/- mice resembled DR in wild type animals including reduced insulin signaling. Interestingly, ad libitum Ercc1∆/- liver expression profiles showed gradual preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. Phenotypes of conditional DNA repair models targeting ageing to selected organs will be presented exhibiting striking parallels with Alzheimer’s disease. Our findings strengthen the link between DNA damage and ageing, establish Ercc1∆/- mice as powerful model for identifying interventions to promote healthy ageing, reveal untapped potential for reducing endogenous damage, provide new venues for understanding the molecular mechanism of DR, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and DR-like interventions for preventing neurodegenerative diseases.
Human genetics and the causal role of lipoprotein(a) for cardiovascular disease
Florian Kronenberg, MD
Division of Genetic Epidemiology; Department of Medical Genetics, Molecular and Clinical Pharmacology; Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, AUSTRIA
Abstract
Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein that is under strong genetic control by the LPA gene locus. Genetic variants including a highly polymorphic copy number variation of the so called kringle IV repeats at this locus have a pronounced influence on Lp(a) concentrations. High concentrations of Lp(a) as well as genetic variants which are associated with high Lp(a) concentrations are both associated with cardiovascular disease which is a very strong support of causality between Lp(a) concentrations and cardiovascular disease. This method of using a genetic variant that has a pronounced influence on a biomarker to support causality with an outcome is called Mendelian randomization approach and was applied for the first time two decades ago with data from Lp(a) and cardiovascular disease. This approach was also used to demonstrate a causal association between high Lp(a) concentrations and aortic valve stenosis. Considering the high frequency of these genetic variants in the population makes Lp(a) the strongest genetic risk factor for cardiovascular disease identified so far. Promising drugs that lower Lp(a) are on the horizon but their efficacy in terms of reducing clinical outcomes has still to be shown.
Disclosures: nothing to disclose
Florian Kronenberg, MD
Division of Genetic Epidemiology; Department of Medical Genetics, Molecular and Clinical Pharmacology; Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, AUSTRIA
Abstract
Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein that is under strong genetic control by the LPA gene locus. Genetic variants including a highly polymorphic copy number variation of the so called kringle IV repeats at this locus have a pronounced influence on Lp(a) concentrations. High concentrations of Lp(a) as well as genetic variants which are associated with high Lp(a) concentrations are both associated with cardiovascular disease which is a very strong support of causality between Lp(a) concentrations and cardiovascular disease. This method of using a genetic variant that has a pronounced influence on a biomarker to support causality with an outcome is called Mendelian randomization approach and was applied for the first time two decades ago with data from Lp(a) and cardiovascular disease. This approach was also used to demonstrate a causal association between high Lp(a) concentrations and aortic valve stenosis. Considering the high frequency of these genetic variants in the population makes Lp(a) the strongest genetic risk factor for cardiovascular disease identified so far. Promising drugs that lower Lp(a) are on the horizon but their efficacy in terms of reducing clinical outcomes has still to be shown.
Disclosures: nothing to disclose
Introduction to Kappa, a rule-based language for modeling protein-protein and gene-protein networks based on the DNA repair model
Anton Kulaga
1. ILA (International Longevity Alliance)
2. IRIF (Institute of fundamental research in Informatics), PPS team (Proofs, Programs and Systems), Université Paris Diderot, Paris, France
3. Computer Science Department of École normale supérieure, Paris, France
DNA damage accumulation is an important hallmark of biological ageing. Once a certain level of DNA damage is reached, cells may undergo a wide range of phenotypic changes, from cell cycle arrest, apoptosis, or cellular senescence [1]. Understanding DNA repair process is also important for the development of genetic therapies against ageing and other diseases because Homology Directed Repair (HDR) is actively used for insertions of DNA sequences and Base excision repair (BER) is required for targeted nucleotide editing method [2].
According to PubMed there are more than 10 000 papers dealing with mutations and ageing and this number is growing rapidly due to increasing interest in the topic and extensive use of high-throughput methods in experiments. As a consequence, it became hard for researchers to remain up-to-date with all relevant information. To counter this problem, about 2000 review paper has been written in the field...
As an alternative to classical reviews, which are static objects with a natural obsolescence, we propose to use kappa rule-based modeling to designing formal updatable reviews that are at the same time executable [3]. Kappa is a rule-based language for modeling protein-protein and gene-protein interactions.
I will present Kappa-Notebook, an open-source software, that allows to collaboratively develop executable models by linking kappa code to papers, databases, plasmid maps and other artifacts.
In my presentation, using DNA-repair model, I will:
* demonstrate core features of Kappa language
* highlight the ways how researchers can benefit from kappa modeling and will show its limitations
* share intermediate results of the ongoing HDR modeling project (in collaboration with Maurice Kanbar center of biomedical engineering )
REFERENCES
1. Erol, A., 2011. Deciphering the intricate regulatory mechanisms for the cellular choice between cell repair apoptosis or senescence in response to damaging signals. Cell. Signal. 23, 1076–1081.
2. Nishida K. et al. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems //Science. – 2016. – С. Aaf8729., 2-3
3. Danos, V., Feret, J., Fontana, W., Krivine, J.: Scalable simulation of cellular signaling networks. In: Proceedings of APLAS 2007. Volume 4807 of LNCS. (2007) 139–157
Anton Kulaga
1. ILA (International Longevity Alliance)
2. IRIF (Institute of fundamental research in Informatics), PPS team (Proofs, Programs and Systems), Université Paris Diderot, Paris, France
3. Computer Science Department of École normale supérieure, Paris, France
DNA damage accumulation is an important hallmark of biological ageing. Once a certain level of DNA damage is reached, cells may undergo a wide range of phenotypic changes, from cell cycle arrest, apoptosis, or cellular senescence [1]. Understanding DNA repair process is also important for the development of genetic therapies against ageing and other diseases because Homology Directed Repair (HDR) is actively used for insertions of DNA sequences and Base excision repair (BER) is required for targeted nucleotide editing method [2].
According to PubMed there are more than 10 000 papers dealing with mutations and ageing and this number is growing rapidly due to increasing interest in the topic and extensive use of high-throughput methods in experiments. As a consequence, it became hard for researchers to remain up-to-date with all relevant information. To counter this problem, about 2000 review paper has been written in the field...
As an alternative to classical reviews, which are static objects with a natural obsolescence, we propose to use kappa rule-based modeling to designing formal updatable reviews that are at the same time executable [3]. Kappa is a rule-based language for modeling protein-protein and gene-protein interactions.
I will present Kappa-Notebook, an open-source software, that allows to collaboratively develop executable models by linking kappa code to papers, databases, plasmid maps and other artifacts.
In my presentation, using DNA-repair model, I will:
* demonstrate core features of Kappa language
* highlight the ways how researchers can benefit from kappa modeling and will show its limitations
* share intermediate results of the ongoing HDR modeling project (in collaboration with Maurice Kanbar center of biomedical engineering )
REFERENCES
1. Erol, A., 2011. Deciphering the intricate regulatory mechanisms for the cellular choice between cell repair apoptosis or senescence in response to damaging signals. Cell. Signal. 23, 1076–1081.
2. Nishida K. et al. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems //Science. – 2016. – С. Aaf8729., 2-3
3. Danos, V., Feret, J., Fontana, W., Krivine, J.: Scalable simulation of cellular signaling networks. In: Proceedings of APLAS 2007. Volume 4807 of LNCS. (2007) 139–157
Goals for the life extension community: Advancing LE R&D and awareness of the topic
Myriam Ji Sun Leis
International Longevity Alliance
International Society on Ageing and Disease (ISOAD)
Myriam Ji Sun Leis
International Longevity Alliance
International Society on Ageing and Disease (ISOAD)
- Advancing LE R&D and awareness of the topic
- Networking within and extending the LE-Communities, also into the “mainstream”
- Financial support for conferences (e.g. EHA, ROSYBA, SENS, ISOAD etc.)
- Funding Longevity summer schools and student/researchers exchange programs
- Generating scientific, political, economic and public interest in biogerontology, longevity and LE-R&D, regenerative medicine and related fields
PARENTAL LONGEVITY AND THE MULTIPLE PROTECTIVE FACTOR MODEL OF HUMAN AGEING
David Melzer
University of Exeter Medical School (UK) and University of Connecticut Center on Ageing (USA)
Offspring of longer lived parents tend to have much better health status, including dramatically lower incidence of cancers, cardiovascular disease and dementia. In our analyses in the Health and Retirement study, with each decade mothers or fathers survived after age 65, all-cause mortality in offspring declined by 19% and 14% per decade respectively: i.e. the health advantage of longer lived parents increased linearly and was not confined to the exceptionally long-lived.
In our analysis of 186,151 non-adopted UK Biobank participants with deceased parents, we found that increasing parental longevity was associated with participant education, higher income, more physical activity, plus lower rates of smoking and obesity. Offspring of longer-lived parents had lower incidence of multiple circulatory conditions including atrial fibrillation and heart failure. For cancer associations were modest except for lung cancer. In our GWAS analysis of 75,000 UKB participants we found three genome significant variants, including a novel DNA repair variant associated with extreme (top 1%) parental survival. We also showed that offspring of longer-lived parents had fewer common genetic risk alleles (lower genetic risk scores) for coronary artery disease, systolic blood pressure, body mass index, cholesterol levels, plus autoimmune conditions and Alzheimer's. Associations were similar for extreme survival, but with an additional association with HDL cholesterol raising variants.
These findings suggest a 'multiple risk and protective factor' model of human ageing, influenced by many different pathways. For several pathways, preventive strategies already exist.
David Melzer
University of Exeter Medical School (UK) and University of Connecticut Center on Ageing (USA)
Offspring of longer lived parents tend to have much better health status, including dramatically lower incidence of cancers, cardiovascular disease and dementia. In our analyses in the Health and Retirement study, with each decade mothers or fathers survived after age 65, all-cause mortality in offspring declined by 19% and 14% per decade respectively: i.e. the health advantage of longer lived parents increased linearly and was not confined to the exceptionally long-lived.
In our analysis of 186,151 non-adopted UK Biobank participants with deceased parents, we found that increasing parental longevity was associated with participant education, higher income, more physical activity, plus lower rates of smoking and obesity. Offspring of longer-lived parents had lower incidence of multiple circulatory conditions including atrial fibrillation and heart failure. For cancer associations were modest except for lung cancer. In our GWAS analysis of 75,000 UKB participants we found three genome significant variants, including a novel DNA repair variant associated with extreme (top 1%) parental survival. We also showed that offspring of longer-lived parents had fewer common genetic risk alleles (lower genetic risk scores) for coronary artery disease, systolic blood pressure, body mass index, cholesterol levels, plus autoimmune conditions and Alzheimer's. Associations were similar for extreme survival, but with an additional association with HDL cholesterol raising variants.
These findings suggest a 'multiple risk and protective factor' model of human ageing, influenced by many different pathways. For several pathways, preventive strategies already exist.
Cell-cell communication in senescence
Masashi Narita
Cancer Research UK, Cambridge Institute
University of Cambridge
Cellular senescence is a highly stable state of cell cycle arrest induced by various pathophysiological stimuli. Senescent cells typically exhibit distinct morphological changes, and a number of biochemical and molecular markers of senescence have been described, which are typically associated with the effector mechanisms of senescence. Our group is interested in various aspects of such senescence effectors, and how they are related with each other. Senescence is recognised as an ‘autonomous’ tumour suppressor mechanism, and we speculate that the stable nature of the senescence arrest might be, in part, regulated through a fundamental re-organisation of the high-order chromatin structure. Accumulating evidence indicates that senescent cells also have ‘non-autonomous’ activities that exhibit diverse effects upon neighbouring cells and the surrounding tissues through the senescence-associated secretory phenotype (SASP). In addition, our recent evidence suggests that direct cell-cell contact also plays a role in the non-autonomous functions of senescence. Importantly, some aspects of the senescence phenotype can be transmitted to neighbouring ‘normal’ cells through the cell-cell contact. Thus the SASP and cell-cell contact in combination might be a target for modulating senescence and its associated disorders.
I have no financial relationships to disclose
Masashi Narita
Cancer Research UK, Cambridge Institute
University of Cambridge
Cellular senescence is a highly stable state of cell cycle arrest induced by various pathophysiological stimuli. Senescent cells typically exhibit distinct morphological changes, and a number of biochemical and molecular markers of senescence have been described, which are typically associated with the effector mechanisms of senescence. Our group is interested in various aspects of such senescence effectors, and how they are related with each other. Senescence is recognised as an ‘autonomous’ tumour suppressor mechanism, and we speculate that the stable nature of the senescence arrest might be, in part, regulated through a fundamental re-organisation of the high-order chromatin structure. Accumulating evidence indicates that senescent cells also have ‘non-autonomous’ activities that exhibit diverse effects upon neighbouring cells and the surrounding tissues through the senescence-associated secretory phenotype (SASP). In addition, our recent evidence suggests that direct cell-cell contact also plays a role in the non-autonomous functions of senescence. Importantly, some aspects of the senescence phenotype can be transmitted to neighbouring ‘normal’ cells through the cell-cell contact. Thus the SASP and cell-cell contact in combination might be a target for modulating senescence and its associated disorders.
I have no financial relationships to disclose
Epigenetics and ageing. Correlations with demographic and genetic data.
Giuseppe Passarino, Dina Bellizzi, Serena Dato, Francesco de Rango, Alberto Montesanto, Giuseppina Rose.
Department of Biology, Ecology and Earth Science, University of Calabria, Rende, Italy
The epigenetic profile of an individual is the result of the unique combination of the genetic background and of the environmental factors he/she went through. DNA methylation, represents the most widely studied epigenetic modification. In fact, high throughput technologies allowed to analyze the methylation across DNA, leading to epidemiological studies of the epigenome profile in numerous samples with specific traits.
The studies which investigated the correlation of epigenetic profiles with age have probably summarized the different forces acting on these profiles. Indeed, although some sites have proved to be very precise molecular clock, probably due to genetic determinants, most of the methylation sites have shown to be correlated to the quality of the ageing. In particular, we showed that frailty of the elderly is associated to global hypomethylation. On the other hand, a mitochondrial DNA site (bp932) was found to have higher levels of methylation in subjects with a lower survival chance. Horvarth et al (2015) have shown that 105+ subjects, have a methylation profile which does not follow the molecular epigenetic clock.
On the whole, the analysis of methylation profiles shows that a remodeling of the methylome occurs with age and can be an excellent biomarker of ageing and the individual age related modification of homeostasis; however, we need to better understand if we can modulate ageing by modulating specific epigenetic features.
The authors have no financial interests related to the presented work.
Giuseppe Passarino, Dina Bellizzi, Serena Dato, Francesco de Rango, Alberto Montesanto, Giuseppina Rose.
Department of Biology, Ecology and Earth Science, University of Calabria, Rende, Italy
The epigenetic profile of an individual is the result of the unique combination of the genetic background and of the environmental factors he/she went through. DNA methylation, represents the most widely studied epigenetic modification. In fact, high throughput technologies allowed to analyze the methylation across DNA, leading to epidemiological studies of the epigenome profile in numerous samples with specific traits.
The studies which investigated the correlation of epigenetic profiles with age have probably summarized the different forces acting on these profiles. Indeed, although some sites have proved to be very precise molecular clock, probably due to genetic determinants, most of the methylation sites have shown to be correlated to the quality of the ageing. In particular, we showed that frailty of the elderly is associated to global hypomethylation. On the other hand, a mitochondrial DNA site (bp932) was found to have higher levels of methylation in subjects with a lower survival chance. Horvarth et al (2015) have shown that 105+ subjects, have a methylation profile which does not follow the molecular epigenetic clock.
On the whole, the analysis of methylation profiles shows that a remodeling of the methylome occurs with age and can be an excellent biomarker of ageing and the individual age related modification of homeostasis; however, we need to better understand if we can modulate ageing by modulating specific epigenetic features.
The authors have no financial interests related to the presented work.
The use of anti-ageing drug combinations in life extension investigations: the experience of crowdfunding research.
Iryna Pishel, PhD, D.Sc., Victoria Darchyk, Olga Horobets
D. F. Chebotaryov State Institute of Gerontology NAMS of Ukraine, Kyiv
Today the campaign for the approval of ageing as a disease initiated worldwide. And now, anti-ageing therapy begins to be developed actively. Development of such anti-ageing drug composition is the purpose of this study.
For this study, we used two different approaches. First - we selected 10 well-known drugs that have different mechanisms of action, with the most proven effect on life expectancy; and have used 3 different combinations of these drugs for anti-ageing research: combination “A” - Aspirin, Everolimus, Metoprolol Tartrate, Metformin Hydrochloride, Simvastatin, Ramipril; combination “B” - Simvastatin, Hydrochlorothiazide, Losartan Potassium, Amlodipine besylate; and a combination “C” - Aspirin, Everolimus, Metformin Hydrochloride. Second - we began testing the effect of a C60 olive oil (C60OO) solution on the life span of mice.
Preliminary data suggest two main results. First, chronic administration of these drug combinations to mice from the age of 23 months (~ 60-70 years for a man) has led to the opposite effect - the lifespan of mice tended to decrease. This fact might indicate the ineffectiveness of initiation of anti-ageing therapy in such a late age. Second, chronic administration of these drug combinations to mice from the age of 16-18 months (~ 50-60 years for a man) has led to the trend of increasing life expectancy. The report discusses the preliminary results of the study.
Iryna Pishel, PhD, D.Sc., Victoria Darchyk, Olga Horobets
D. F. Chebotaryov State Institute of Gerontology NAMS of Ukraine, Kyiv
Today the campaign for the approval of ageing as a disease initiated worldwide. And now, anti-ageing therapy begins to be developed actively. Development of such anti-ageing drug composition is the purpose of this study.
For this study, we used two different approaches. First - we selected 10 well-known drugs that have different mechanisms of action, with the most proven effect on life expectancy; and have used 3 different combinations of these drugs for anti-ageing research: combination “A” - Aspirin, Everolimus, Metoprolol Tartrate, Metformin Hydrochloride, Simvastatin, Ramipril; combination “B” - Simvastatin, Hydrochlorothiazide, Losartan Potassium, Amlodipine besylate; and a combination “C” - Aspirin, Everolimus, Metformin Hydrochloride. Second - we began testing the effect of a C60 olive oil (C60OO) solution on the life span of mice.
Preliminary data suggest two main results. First, chronic administration of these drug combinations to mice from the age of 23 months (~ 60-70 years for a man) has led to the opposite effect - the lifespan of mice tended to decrease. This fact might indicate the ineffectiveness of initiation of anti-ageing therapy in such a late age. Second, chronic administration of these drug combinations to mice from the age of 16-18 months (~ 50-60 years for a man) has led to the trend of increasing life expectancy. The report discusses the preliminary results of the study.
How can we persuade and educate the wider public about the importance of ageing research?
Robert James Powles
BGRF, UK and Longevity Reporter, UK
There have been great strides in recent research, but while the science is consistently improving the greatest barrier to rapid progress remains lagging public interest. Many people remain baffled or at best vaguely interested in longevity efforts. We must therefore find ways to educate and persuade the public that tackling aging is feasible and beneficial to wider society. This can be achieved through projects such as The Longevity Reporter; explaining complex science in a clear and relatable manner to those without a scientific background.
Robert James Powles
BGRF, UK and Longevity Reporter, UK
There have been great strides in recent research, but while the science is consistently improving the greatest barrier to rapid progress remains lagging public interest. Many people remain baffled or at best vaguely interested in longevity efforts. We must therefore find ways to educate and persuade the public that tackling aging is feasible and beneficial to wider society. This can be achieved through projects such as The Longevity Reporter; explaining complex science in a clear and relatable manner to those without a scientific background.
An integrative view of extracellular matrix ageing
Sylvie RICARD-BLUM
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires,
UMR 5246 CNRS - Université Lyon 1, 43 Boulevard du 11 novembre 1918,
69622 Villeurbanne cedex, France ([email protected])
The extracellular matrix (ECM) determines the shape and the organization of tissues, provides them with mechanical properties, and regulates numerous cellular processes (e.g. proliferation, migration, and differentiation). The ECM is remodeled in diseases such as fibrosis, cancer and diabetes, and in ageing, which modulates the release of bioactive fragments called matricryptins. ECM assembly and functions are mediated by protein-protein and protein-glycosaminoglycan interactions, which influence each other and form networks in vivo. We have developed a roadmap to build extracellular interaction networks in order to identify new functions of ECM proteins, and to determine how these interaction networks are rewired at the molecular level in ageing and disease with a focus on Alzheimer’s disease. We have created an interaction database, MatrixDB, (http://matrixdb.univ-lyon1.fr) to store ECM interaction data collected experimentally and by manual curation of the literature. We have built an ECM interaction network comprised of ECM and matricellular proteins, proteoglycans, matricryptins, cross-linking (lysyl oxidases, transglutaminase-2, and peroxidasin) and degrading enzymes, and receptors. We now integrate transcriptomics and proteomics data in this network and analyze it with computational tools to determine how it is rewired during ageing and if a few proteins connecting different molecular mechanisms (e.g. cross-linking and oxidative stress) play key roles in this process.
Sylvie RICARD-BLUM
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires,
UMR 5246 CNRS - Université Lyon 1, 43 Boulevard du 11 novembre 1918,
69622 Villeurbanne cedex, France ([email protected])
The extracellular matrix (ECM) determines the shape and the organization of tissues, provides them with mechanical properties, and regulates numerous cellular processes (e.g. proliferation, migration, and differentiation). The ECM is remodeled in diseases such as fibrosis, cancer and diabetes, and in ageing, which modulates the release of bioactive fragments called matricryptins. ECM assembly and functions are mediated by protein-protein and protein-glycosaminoglycan interactions, which influence each other and form networks in vivo. We have developed a roadmap to build extracellular interaction networks in order to identify new functions of ECM proteins, and to determine how these interaction networks are rewired at the molecular level in ageing and disease with a focus on Alzheimer’s disease. We have created an interaction database, MatrixDB, (http://matrixdb.univ-lyon1.fr) to store ECM interaction data collected experimentally and by manual curation of the literature. We have built an ECM interaction network comprised of ECM and matricellular proteins, proteoglycans, matricryptins, cross-linking (lysyl oxidases, transglutaminase-2, and peroxidasin) and degrading enzymes, and receptors. We now integrate transcriptomics and proteomics data in this network and analyze it with computational tools to determine how it is rewired during ageing and if a few proteins connecting different molecular mechanisms (e.g. cross-linking and oxidative stress) play key roles in this process.
In vivo regulation of mitochondrial ROS levels as a strategy to extend lifespan.
Alberto Sanz
Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
E-mail: [email protected]
Mitochondrial Reactive Oxygen Species (ROS) can cause oxidative damage and subsequently cell death. However, ROS are also essential messengers implicated in cellular signaling and therefore required to maintain homeostasis. It is usually accepted that their role as damaging or signaling agents is determined by their concentration. Here, I will discuss that where and how ROS are produced is as important as the amount of ROS to determine their physiological effects. For example, Drosophila ageing is characterized by the accumulation of damaged mitochondria and high levels of ROS. However, inducing high levels of ROS specifically stimulating reverse electron transport (RET) through respiratory complex I (CI) extends lifespan and protects mitochondrial function during ageing. On the other hand, knock-down of Sod2 increases superoxide levels, reduces mitochondrial respiration and dramatically shortens lifespan. Paradoxically, inducing RET protects mitochondrial function and rescues lifespan in spite of increasing total ROS levels. This indicates that the RET-ROS signaling is specifically recognized and activates mechanisms of protection. The ability of RET to modify the rate of ageing highlights a potential physiological role and the opportunity to delay ageing and age-related diseases through changes in the redox state of the CoQ pool that will induce RET in vivo.
Financial interest disclosure: none to declare.
Alberto Sanz
Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
E-mail: [email protected]
Mitochondrial Reactive Oxygen Species (ROS) can cause oxidative damage and subsequently cell death. However, ROS are also essential messengers implicated in cellular signaling and therefore required to maintain homeostasis. It is usually accepted that their role as damaging or signaling agents is determined by their concentration. Here, I will discuss that where and how ROS are produced is as important as the amount of ROS to determine their physiological effects. For example, Drosophila ageing is characterized by the accumulation of damaged mitochondria and high levels of ROS. However, inducing high levels of ROS specifically stimulating reverse electron transport (RET) through respiratory complex I (CI) extends lifespan and protects mitochondrial function during ageing. On the other hand, knock-down of Sod2 increases superoxide levels, reduces mitochondrial respiration and dramatically shortens lifespan. Paradoxically, inducing RET protects mitochondrial function and rescues lifespan in spite of increasing total ROS levels. This indicates that the RET-ROS signaling is specifically recognized and activates mechanisms of protection. The ability of RET to modify the rate of ageing highlights a potential physiological role and the opportunity to delay ageing and age-related diseases through changes in the redox state of the CoQ pool that will induce RET in vivo.
Financial interest disclosure: none to declare.
Advanced glycation endproducts and vascular AGEing.
Prof. dr. Casper Schalkwijk
Maastricht University Medical Centre,
Department of Internal Medicine,
P.O. Box 5800,
6202 AZ Maastricht,
The Netherlands.
[email protected].
The formation of advanced glycation endproducts (AGEs) is associated with the development of age-related diseases and is, at least in part, a likelymechanism accounting for vascular senescence.Protein glycation was viewed originally as a post-translational modification of proteins that accumulated slowly on long-lived proteins throughout life. In addition, glycation adducts are also formed in a fast manner on cellular and short-lived extracellular proteins and on DNA. The highly reactive methylglyoxal is a key compound involved in the very fast generation of glycation adducts on proteins, lipids and DNA. It has been demonstrated that the modification of proteins by methylglyoxal results in increased expression of adhesion molecules, growth factors and a sensitizing of cells to the effects pro-inflammatory cytokines. To counteract the deleterious effects of methylglyoxal, organisms contain glyoxalase I (GLO1), which concerts methylgyoxal to D-lactate.Several studies showed that there is a decline in the expression of GLO1 with age, which may contribute to increased risk of cardiovascular disease with ageing. Overexpression of the GLO1 gene (Glo1) not only counteracts the rise in methylglyoxal, AGEs and oxidative stress, but also prevents the development of endothelial dysfunction, and the microvascular complications. GLO1-transgenic aged rats showed amelioration of senescence.
In conclusion,GLO1belongs to the network of genes that influence longevity. The balance between the production of methylglyoxal and its detoxification by GLO1 can significantly contribute to the ageing process and to healthy ageing.
Prof. dr. Casper Schalkwijk
Maastricht University Medical Centre,
Department of Internal Medicine,
P.O. Box 5800,
6202 AZ Maastricht,
The Netherlands.
[email protected].
The formation of advanced glycation endproducts (AGEs) is associated with the development of age-related diseases and is, at least in part, a likelymechanism accounting for vascular senescence.Protein glycation was viewed originally as a post-translational modification of proteins that accumulated slowly on long-lived proteins throughout life. In addition, glycation adducts are also formed in a fast manner on cellular and short-lived extracellular proteins and on DNA. The highly reactive methylglyoxal is a key compound involved in the very fast generation of glycation adducts on proteins, lipids and DNA. It has been demonstrated that the modification of proteins by methylglyoxal results in increased expression of adhesion molecules, growth factors and a sensitizing of cells to the effects pro-inflammatory cytokines. To counteract the deleterious effects of methylglyoxal, organisms contain glyoxalase I (GLO1), which concerts methylgyoxal to D-lactate.Several studies showed that there is a decline in the expression of GLO1 with age, which may contribute to increased risk of cardiovascular disease with ageing. Overexpression of the GLO1 gene (Glo1) not only counteracts the rise in methylglyoxal, AGEs and oxidative stress, but also prevents the development of endothelial dysfunction, and the microvascular complications. GLO1-transgenic aged rats showed amelioration of senescence.
In conclusion,GLO1belongs to the network of genes that influence longevity. The balance between the production of methylglyoxal and its detoxification by GLO1 can significantly contribute to the ageing process and to healthy ageing.
Is nanotechnology and stem cells a solution for treatment and replacement of damaged organs?
Alexander Marcus Seifalian¹*
Centre of Nanotechnology & Regenerative Medicine, University College London, UK.
*Current address: Nanotechnology Regenerative Medicine Ltd
The London Bioscience Innovation Centre, London, UK
Email: [email protected]
Nanoparticles, nanotechnology-based biomaterials and stem cells are the next generations of biotechnology under development for treatment and replacement of damaged organs.
Their research and development are based on a multidisciplinary team approach from basic science to the clinician. We have developed and patented a family of nanoparticles, nanocomposites materials and use stem cells in the development of human organs.
Using these novel materials, 3D scaffold is fabricated using 3D bioprinter, and then the scaffold is functionalised by peptides, antibodies and/or stem cells.
Practically, however, more knowledge needs to be revealed 1) biocompatibility and toxicology of scaffold in short and long term, 2) design and structure biomolecules as well as 3) stem cells application and its differentiation to mature cells before they can enter clinical trials.
These have proven to be barriers to clinical entry, seen even in both in vitro and preclinical studies due to inconsistency in results from a myriad of studies.
However, we can be assured that the field is indeed making advancements, demonstrated by the rapid development of smarter scaffold as well as work on stem cells and initial compassionates cases of implanted organs.
Conflict of Interests
The author declares that there is no conflict of interests regarding this research and development.
Alexander Marcus Seifalian¹*
Centre of Nanotechnology & Regenerative Medicine, University College London, UK.
*Current address: Nanotechnology Regenerative Medicine Ltd
The London Bioscience Innovation Centre, London, UK
Email: [email protected]
Nanoparticles, nanotechnology-based biomaterials and stem cells are the next generations of biotechnology under development for treatment and replacement of damaged organs.
Their research and development are based on a multidisciplinary team approach from basic science to the clinician. We have developed and patented a family of nanoparticles, nanocomposites materials and use stem cells in the development of human organs.
Using these novel materials, 3D scaffold is fabricated using 3D bioprinter, and then the scaffold is functionalised by peptides, antibodies and/or stem cells.
Practically, however, more knowledge needs to be revealed 1) biocompatibility and toxicology of scaffold in short and long term, 2) design and structure biomolecules as well as 3) stem cells application and its differentiation to mature cells before they can enter clinical trials.
These have proven to be barriers to clinical entry, seen even in both in vitro and preclinical studies due to inconsistency in results from a myriad of studies.
However, we can be assured that the field is indeed making advancements, demonstrated by the rapid development of smarter scaffold as well as work on stem cells and initial compassionates cases of implanted organs.
Conflict of Interests
The author declares that there is no conflict of interests regarding this research and development.
Using Deep Neural Networks trained on massive multi-modal inputs for ageing research
Quentin Vanhaelen
Insilico Medicine inc.
Ageing is a complex process and occurs at different rates and to different extents in various organ systems. One problem is that the evaluation of ageing changes and possible anti-ageing therapies requires a comprehensive set of robust biomarkers. However, most of these biomarkers are not representative of the health state of the entire organism or individual systems and are not easily measured or targeted with known interventions. Deep learning technique based on a modular ensemble of multiple Deep Neural Networks (DNNs) stacked into an ensemble and trained on tens of thousands of blood biochemistry samples can be used for predicting human chronological age. The analysis of relative feature importance within the DNNs helps to deduce the most important features that may shed light on the contribution of these systems to the ageing process. Albumin, glucose, alkaline phosphatase, urea and erythrocytes were identified as being the five most markers for predicting human chronological age.
Disclosure: The author is an employee of InSilico Medicine inc.
Quentin Vanhaelen
Insilico Medicine inc.
Ageing is a complex process and occurs at different rates and to different extents in various organ systems. One problem is that the evaluation of ageing changes and possible anti-ageing therapies requires a comprehensive set of robust biomarkers. However, most of these biomarkers are not representative of the health state of the entire organism or individual systems and are not easily measured or targeted with known interventions. Deep learning technique based on a modular ensemble of multiple Deep Neural Networks (DNNs) stacked into an ensemble and trained on tens of thousands of blood biochemistry samples can be used for predicting human chronological age. The analysis of relative feature importance within the DNNs helps to deduce the most important features that may shed light on the contribution of these systems to the ageing process. Albumin, glucose, alkaline phosphatase, urea and erythrocytes were identified as being the five most markers for predicting human chronological age.
Disclosure: The author is an employee of InSilico Medicine inc.
Repositioning Tolcapone as a potent inhibitor of transthyretin amyloidogenesis and its associated cellular toxicity
Salvador Ventura¹
1Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193-Bellaterra, Spain.
Background:
Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat the TTR amyloidoses.
Material and Methods:
Here, we used biophysical, cell biology and in vivo studies to repurpose Tolcapone, an FDA-approved molecule for Parkinson’s disease, as a very potent TTR aggregation inhibitor.
Results and Discussion:
Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. The crystal structures of Tolcapone bound to wild type TTR and to the V122I cardiomyopathy-associated variant explain why this molecule is a better amyloid inhibitor than Tafamidis, so far the only drug in the market to treat the TTR amyloidoses.
Conclusions:
Overall, Tolcapone, already in clinical trials, is a strong candidate for therapeutic intervention in these diseases, including those ocurring in the central nervous system, for which no small molecule approach exist.
Salvador Ventura¹
1Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193-Bellaterra, Spain.
Background:
Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat the TTR amyloidoses.
Material and Methods:
Here, we used biophysical, cell biology and in vivo studies to repurpose Tolcapone, an FDA-approved molecule for Parkinson’s disease, as a very potent TTR aggregation inhibitor.
Results and Discussion:
Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. The crystal structures of Tolcapone bound to wild type TTR and to the V122I cardiomyopathy-associated variant explain why this molecule is a better amyloid inhibitor than Tafamidis, so far the only drug in the market to treat the TTR amyloidoses.
Conclusions:
Overall, Tolcapone, already in clinical trials, is a strong candidate for therapeutic intervention in these diseases, including those ocurring in the central nervous system, for which no small molecule approach exist.
Scenarios for the future of healthy life extension
David W. Wood
Delta Wisdom, and London Futurists (UK)
This talk looks at four scenarios for the future of healthy life extension over the next 25 years – scenarios that can be termed “Optimistic”, “Realistic”, “Pessimistic”, and “Humanity+” (the latter can also be called “Abolitionist”). Each of these scenarios is a credible development from the status quo. The speaker will look at critical factors which will vary the likelihoods of the different outcomes.
Whereas the Optimistic scenario depends on the successful execution of a single significant disruption from existing mainstream medical practice, the Humanity+ (Abolitionist) scenario relies on a two-fold disruption taking place. Drawing on his extensive experience of disruptions taking place in other fields of business and technology, and on his studies of the history and philosophy of science, the speaker will clarify how the adoption of disruptions often depends as much on social factors as on technological ones.
The speaker will proceed to make suggestions for the best steps that can be taken by the community of healthy life extension enthusiasts, bearing in mind the risks of counter-productive steps. Recommendations include improved community-building, political alliances, and more sophisticated meme engineering, as well as increased support for citizen science.
David W. Wood
Delta Wisdom, and London Futurists (UK)
This talk looks at four scenarios for the future of healthy life extension over the next 25 years – scenarios that can be termed “Optimistic”, “Realistic”, “Pessimistic”, and “Humanity+” (the latter can also be called “Abolitionist”). Each of these scenarios is a credible development from the status quo. The speaker will look at critical factors which will vary the likelihoods of the different outcomes.
Whereas the Optimistic scenario depends on the successful execution of a single significant disruption from existing mainstream medical practice, the Humanity+ (Abolitionist) scenario relies on a two-fold disruption taking place. Drawing on his extensive experience of disruptions taking place in other fields of business and technology, and on his studies of the history and philosophy of science, the speaker will clarify how the adoption of disruptions often depends as much on social factors as on technological ones.
The speaker will proceed to make suggestions for the best steps that can be taken by the community of healthy life extension enthusiasts, bearing in mind the risks of counter-productive steps. Recommendations include improved community-building, political alliances, and more sophisticated meme engineering, as well as increased support for citizen science.
