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4. Aging and drug discovery

Author

Bakula, Daniela, Aliper, Alexander M, Mamoshina, Polina, Petr, Michael A, Teklu, Amanuel, Baur, Joseph A, Campisi, Judith, Ewald, Collin Y, Georgievskaya, Anastasia, Gladyshev, Vadim N, Kovalchuk, Olga, Lamming, Dudley W, Luijsterburg, Martijn S, Martín-Montalvo, Alejandro, Maudsley, Stuart, Mkrtchyan, Garik V, Moskalev, Alexey, Olshansky, S Jay, Ozerov, Ivan V, Pickett, Alexander, Ristow, Michael, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Clinical Sciences, Biological Sciences, Aging, 5.1 Pharmaceuticals, 5.9 Resources and infrastructure (treatment development), Generic health relevance, Good Health and Well Being, aging, drug discovery, Physiology, Oncology and Carcinogenesis, Developmental Biology
Abstract

Multiple interventions in the aging process have been discovered to extend the healthspan of model organisms. Both industry and academia are therefore exploring possible transformative molecules that target aging and age-associated diseases. In this overview, we summarize the presented talks and discussion points of the 5th Annual Aging and Drug Discovery Forum 2018 in Basel, Switzerland. Here academia and industry came together, to discuss the latest progress and issues in aging research. The meeting covered talks about the mechanistic cause of aging, how longevity signatures may be highly conserved, emerging biomarkers of aging, possible interventions in the aging process and the use of artificial intelligence for aging research and drug discovery. Importantly, a consensus is emerging both in industry and academia, that molecules able to intervene in the aging process may contain the potential to transform both societies and healthcare.

Published
2018

5. Animal models of obesity and diabetes mellitus

Author

Kleinert, Maximilian, Clemmensen, Christoffer, Hofmann, Susanna M, Moore, Mary C, Renner, Simone, Woods, Stephen C, Huypens, Peter, Beckers, Johannes, de Angelis, Martin Hrabe, Schürmann, Annette, Bakhti, Mostafa, Klingenspor, Martin, Heiman, Mark, Cherrington, Alan D, Ristow, Michael, Lickert, Heiko, Wolf, Eckhard, Havel, Peter J, Müller, Timo D, and Tschöp, Matthias H

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Biotechnology, Nutrition, Obesity, Neurodegenerative, Diabetes, Metabolic and endocrine, Animals, Body Mass Index, Diabetes Mellitus, Type 2, Disease Models, Animal, Dogs, Fishes, Haplorhini, Humans, Mice, Rats, Risk Assessment, Sensitivity and Specificity, Swine, Endocrinology & Metabolism, Clinical sciences
Abstract

More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.

Published
2018

11. Rosmarinic Acid Improves Cognitive Abilities and Glucose Metabolism in Aged C57Bl/6N Mice While Disrupting Lipid Profile in Young Adults in a Sex-Dependent Fashion

Author

Musillo, Chiara, primary, Giona, Letizia, additional, Ristow, Michael, additional, Zarse, Kim, additional, Siems, Karsten, additional, Di Francesco, Alessia, additional, Collacchi, Barbara, additional, Raggi, Carla, additional, Cirulli, Francesca, additional, and Berry, Alessandra, additional

Published
2023
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18. Consuming Fructose‐sweetened Beverages Increases Body Adiposity in Mice

Author

Jürgens, Hella, Haass, Wiltrud, Castañeda, Tamara R, Schürmann, Annette, Koebnick, Corinna, Dombrowski, Frank, Otto, Bärbel, Nawrocki, Andrea R, Scherer, Philipp E, Spranger, Jochen, Ristow, Michael, Joost, Hans‐Georg, Havel, Peter J, and Tschöp, Matthias H

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Health Sciences, Nutrition, Obesity, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Cardiovascular, Metabolic and endocrine, Cancer, Stroke, Adipose Tissue, Animals, Beverages, Body Composition, Body Constitution, Carbonated Beverages, Energy Intake, Energy Metabolism, Fructose, Liver, Male, Mice, Oxidation-Reduction, Sweetening Agents, Weight Gain, fructose, soft drink, energy balance, energy expenditure, rodent, Endocrinology & Metabolism
Abstract

ObjectiveThe marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To determine if and how fructose might promote obesity in an animal model, we measured body composition, energy intake, energy expenditure, substrate oxidation, and several endocrine parameters related to energy homeostasis in mice consuming fructose.Research methods and proceduresWe compared the effects of ad libitum access to fructose (15% solution in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metabolism in mice.ResultsExposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased respiratory quotient, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic pericentral pattern.DiscussionThese data are compatible with the conclusion that a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.

Published
2005

20. Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists

Author

Umapathysivam, Mahesh M, primary, Araldi, Elisa, additional, Hastoy, Benoit, additional, Dawed, Adem Y, additional, Vatandaslar, Hasan, additional, Sengupta, Shahana, additional, Kaufmann, Adrian, additional, Thomsen, Søren, additional, Hartmann, Bolette, additional, Jonsson, Anna E, additional, Kabakci, Hasan, additional, Thaman, Swaraj, additional, Grarup, Niels, additional, Have, Christian T, additional, Færch, Kristine, additional, Gjesing, Anette P, additional, Nawaz, Sameena, additional, Cheeseman, Jane, additional, Neville, Matthew J, additional, Pedersen, Oluf, additional, Walker, Mark, additional, Jennison, Christopher, additional, Hattersley, Andrew T, additional, Hansen, Torben, additional, Karpe, Fredrik, additional, Holst, Jens J, additional, Jones, Angus G, additional, Ristow, Michael, additional, McCarthy, Mark I, additional, Pearson, Ewan R, additional, Stoffel, Markus, additional, and Gloyn, Anna L, additional

Published
2023
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21. Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists

Author

Umapathysivam, Mahesh M, Araldi, Elisa, Hastoy, Benoit, Dawed, Adem Y, Vatandaslar, Hasan, Sengupta, Shahana, Kaufmann, Adrian, Thomsen, Søren, Hartmann, Bolette, Jonsson, Anna E, Kabakci, Hasan, Thaman, Swaraj, Grarup, Niels, Have, Christian T, Færch, Kristine, Gjesing, Anette P, Nawaz, Sameena, Cheeseman, Jane, Neville, Matthew J, Pedersen, Oluf, Walker, Mark, Jennison, Christopher, Hattersley, Andrew T, Hansen, Torben, Karpe, Fredrik, Holst, Jens J, Jones, Angus G, Ristow, Michael, McCarthy, Mark I, Pearson, Ewan R, Stoffel, Markus, Gloyn, Anna L, Umapathysivam, Mahesh M, Araldi, Elisa, Hastoy, Benoit, Dawed, Adem Y, Vatandaslar, Hasan, Sengupta, Shahana, Kaufmann, Adrian, Thomsen, Søren, Hartmann, Bolette, Jonsson, Anna E, Kabakci, Hasan, Thaman, Swaraj, Grarup, Niels, Have, Christian T, Færch, Kristine, Gjesing, Anette P, Nawaz, Sameena, Cheeseman, Jane, Neville, Matthew J, Pedersen, Oluf, Walker, Mark, Jennison, Christopher, Hattersley, Andrew T, Hansen, Torben, Karpe, Fredrik, Holst, Jens J, Jones, Angus G, Ristow, Michael, McCarthy, Mark I, Pearson, Ewan R, Stoffel, Markus, and Gloyn, Anna L

Abstract

UNLABELLED: Patients with type 2 diabetes vary in their response to currently available therapeutic agents (including GLP-1 receptor agonists) leading to suboptimal glycemic control and increased risk of complications. We show that human carriers of hypomorphic T2D-risk alleles in the gene encoding peptidyl-glycine alpha-amidating monooxygenase (PAM), as well as Pam- knockout mice, display increased resistance to GLP-1 in vivo . Pam inactivation in mice leads to reduced gastric GLP-1R expression and faster gastric emptying: this persists during GLP-1R agonist treatment and is rescued when GLP-1R activity is antagonized, indicating resistance to GLP-1's gastric slowing properties. Meta-analysis of human data from studies examining GLP-1R agonist response (including RCTs) reveals a relative loss of 44% and 20% of glucose lowering (measured by glycated hemoglobin) in individuals with hypomorphic PAM alleles p.S539W and p.D536G treated with GLP-1R agonist. Genetic variation in PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D. (Funded by the Wellcome, Medical Research Council, European Union, NIHR Oxford Biomedical Research Centre, United Kingdom, Registered on ClinicalTrials.gov, NCT02723110 .). SUMMARY PARAGRAPH: Type 2 diabetes (T2D) is a leading cause of morbidity and mortality globally 1 . Current management of T2D patients focuses on lowering glycemic exposure and reducing complications with lifestyle and pharmacological interventions 2 . Despite the availability of multiple medications to lower glycated hemoglobin (HbA1c), only 53% of individuals with T2D reach the glycemic target (HbA1c <7%) 3, 4 . There is potential to improve medication selection through "precision medicine" where patient specific factors (e.g. genetic markers) are used to indicate whether a patient is more or less likely to respond to a medication. Here we show that human carriers of hypomorphic T2D-risk alleles in the gen

Published
2023

22. Publisher Correction: Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly

Author

Irizar, Peer Aramillo, Schäuble, Sascha, Esser, Daniela, Groth, Marco, Frahm, Christiane, Priebe, Steffen, Baumgart, Mario, Hartmann, Nils, Marthandan, Shiva, Menzel, Uwe, Müller, Jule, Schmidt, Silvio, Ast, Volker, Caliebe, Amke, König, Rainer, Krawczak, Michael, Ristow, Michael, Schuster, Stefan, Cellerino, Alessandro, Diekmann, Stephan, Englert, Christoph, Hemmerich, Peter, Sühnel, Jürgen, Guthke, Reinhard, Witte, Otto W., Platzer, Matthias, Ruppin, Eytan, and Kaleta, Christoph

Published
2019
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29. Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly

Author

Aramillo Irizar, Peer, Schäuble, Sascha, Esser, Daniela, Groth, Marco, Frahm, Christiane, Priebe, Steffen, Baumgart, Mario, Hartmann, Nils, Marthandan, Shiva, Menzel, Uwe, Müller, Jule, Schmidt, Silvio, Ast, Volker, Caliebe, Amke, König, Rainer, Krawczak, Michael, Ristow, Michael, Schuster, Stefan, Cellerino, Alessandro, Diekmann, Stephan, Englert, Christoph, Hemmerich, Peter, Sühnel, Jürgen, Guthke, Reinhard, Witte, Otto W., Platzer, Matthias, Ruppin, Eytan, and Kaleta, Christoph

Published
2018
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30. Ageing with elegans: a research proposal to map healthspan pathways

Author

Luyten, Walter, Antal, Peter, Braeckman, Bart P., Bundy, Jake, Cirulli, Francesca, Fang-Yen, Christopher, Fuellen, Georg, Leroi, Armand, Liu, Qingfei, Martorell, Patricia, Metspalu, Andres, Perola, Markus, Ristow, Michael, Saul, Nadine, Schoofs, Liliane, Siems, Karsten, Temmerman, Liesbet, Smets, Tina, Wolk, Alicja, and Rattan, Suresh I. S.

Published
2016
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44. Pollinator guilds respond contrastingly at different scales to landscape parameters of land-use intensity

Author

Bergholz, Kolja, Sittel, Lara-Pauline, Ristow, Michael, Jeltsch, Florian, and Weiß, Lina

Subjects
500 Naturwissenschaften und Mathematik, Ecology, ddc:570, ddc:500, Institut für Biochemie und Biologie, Ecology, Evolution, Behavior and Systematics, 570 Biowissenschaften, Biologie, Nature and Landscape Conservation
Abstract

Land-use intensification is the main factor for the catastrophic decline of insect pollinators. However, land-use intensification includes multiple processes that act across various scales and should affect pollinator guilds differently depending on their ecology. We aimed to reveal how two main pollinator guilds, wild bees and hoverflies, respond to different land-use intensification measures, that is, arable field cover (AFC), landscape heterogeneity (LH), and functional flower composition of local plant communities as a measure of habitat quality. We sampled wild bees and hoverflies on 22 dry grassland sites within a highly intensified landscape (NE Germany) within three campaigns using pan traps. We estimated AFC and LH on consecutive radii (60–3000 m) around the dry grassland sites and estimated the local functional flower composition. Wild bee species richness and abundance was positively affected by LH and negatively by AFC at small scales (140–400 m). In contrast, hoverflies were positively affected by AFC and negatively by LH at larger scales (500–3000 m), where both landscape parameters were negatively correlated to each other. At small spatial scales, though, LH had a positive effect on hoverfly abundance. Functional flower diversity had no positive effect on pollinators, but conspicuous flowers seem to attract abundance of hoverflies. In conclusion, landscape parameters contrarily affect two pollinator guilds at different scales. The correlation of landscape parameters may influence the observed relationships between landscape parameters and pollinators. Hence, effects of land-use intensification seem to be highly landscape-specific., Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe; 1298

Published
2021
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