The metabolic - epigenetic axis in ageing, cognitive impairment and stress
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Research
Overview Ageing is the major risk factor for a variety of diseases such as cancer, diabetes, dementia and others. Currently, millions of elderly people are suffering from such maladies, which generally lack therapeutic interventions to completely reverse their course. This is partially because little is known about the molecular mechanisms that are involved during the very early stages of these diseases. While much research is focused on treating advanced forms of age-associated maladies, the focus of my research is to find novel molecular mechanisms that are deregulated during early middle age (preventive approach). Such deregulations precede the prevalence of the more advanced age-associated maladies but maybe underlying mechanisms that eventually drive their appearance. Previous work in various organisms has shown that the DNA transcriptome starts to alter during middle aged. Recent work, including my own, has supported the notion that attenuating such age-associated transcriptome deregulation leads to increase a healthy life span. Interestingly, DNA transcription is known to be regulated, at least partially, by epigenetic factors such as histone modifications. For example, histone acetylation has been extensively linked with promoting gene expression. Intriguingly, various age-associated diseases such as cancer, infertility, cognitive decline and others are accompanied by deregulated levels of histone acetylation. While the mechanisms leading to deregulated histone acetylation in ageing remain poorly understood, recent studies support the notion that the process of acetylation of histone is dependent on metabolic activity. For example, the metabolic enzyme ATP citrate lyase (ACL) was shown to generate acetyl-CoA (from mitochondrial citrate) that is required for acetylation reactions. To note, recent work has suggested that the activity of various metabolic enzymes, including ACL, can be regulated by acetylation as well. As metabolic activity, including acetyl-CoA metabolism, is known to alter with ageing, it is possible that such metabolic changes may cause epigenetic alterations during ageing. Therefore, it is important to understand how acetyl-CoA metabolism itself is regulated and altered during early ageing. |
Current projects
Metabolism and epigenetic in 45 years selected Titan mice
Metabolism and epigenetic in 45 years selected Titan mice
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Characterizing altered metabolism and epigenetic connectivity in Titan mice. These mice were selected for 45 years based on their weight. As such, they are world-wide unique and exist only at the FBN. Strikingly, they are 3 times the size of a normal mouse (120 grams average), making them the biggest mouse model that exists. Furthermore, they display rapid aging process. To this end, we apply novel mass spectrometry tools (Proteomics and metabolomics), whole genome sequencing and other biochemical tools. In this project, we also collaborating with the German Mouse Clinic. |
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The metabolism - epigenetic axis in early ageing and response to environmental stress
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We are currently working on characterising changes in metabolic regulation and histone acetylation associated transcription during environmental stress in Drosophila flies. We also test how response to stress is altered during the course of aging
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Metabolic induced epigenetic changes during memory formation and impairment
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Our previous results suggest that metabolic inflexibility during early ageing maybe causally involved with age-associated memory impairment in mice. We wish to better understand the causes of such metabolic inflexibility and its downstream affects on the epigenome. In this project, we apply novel mass spec imaging tools (Collaboration with BMC, Munich) and proteomics with mice behaviour such as fear conditioning and water maze.
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