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The molecular basis underpinning Inflamm-aging

  • Project No: KTPS-NC-11
  • Intake: 2021 KTPS-NC

PROJECT OUTLINE

Age is the biggest single risk factor for many chronic diseases, from cardiovascular disease to neurodegeneration. One of the major contributing factors is chronic low-grade inflammation, also called inflamm-aging, the excess production of inflammatory cytokines. Inflamm-aging is also likely to contribute to fatal immune pathology that can occur in response to infections, particularly affecting older adults such as in severe COVID19. Autophagy, a pathway activated when cells are stressed, clears away debris accumulated over time, recycling building blocks for re-use. It has been shown in model organisms and other tissues that autophagy maintains a healthy lifespan and a young immune system 1. Our hypothesis is that declining autophagy levels with age underpin ageing of the immune system, in particular inflamm-aging. We will focus on macrophages in this project, the main inflammatory cell in the body.

We have discovered that autophagy prevents premature aging of the macrophage 2. Indeed, we have found in mice and human cells that autophagy decreases with age. We will investigate to what extent this contributes to inflamm-aging in macrophages and identify in which type of macrophages (tissue-resident versus bone marrow-derived) autophagy is required to prevent inflamm-aging. Then we aim to understand what autophagy needs to degrade to prevent inflamm-aging in macrophages. For this, we have generated a novel mouse model, in which the autophagic cargo is directly proximity-labelled in primary cells (unpublished). The cargo may for example include dysfunctional mitochondria or the machinery that makes cytokines (inflammasome). This knowledge will help us to better understand the dysfunctional cell biology behind the cellular aging process.

Our second aim is to understand the contribution of the microenvironment in which macrophages live. During aging, fat tissue increases, which contributes to a major extent to the increased inflammation, and it contain large numbers of macrophages. We have found that autophagy of the fat cells themselves prevents inflammation, by providing nutrients to the anti-inflammatory macrophages, while in the absence of autophagy the inflammatory macrophages prevail. Here we are to explore if this contributes to inflamm-aging. We will measure if there is an age-related decline in autophagy in fat cells, what exactly does autophagy provide to the neighbouring macrophage (for example fatty acids which are stored by fat cells) 3 and can those be used to reverse inflamm-aging in macrophages.

Lastly, we have discovered a new signalling pathway for autophagy, which is downregulated with age. A molecule called spermidine, which can be found in every cell (but less so in cells from aged organisms) maintains basic autophagy levels in lymphocytes via this novel signalling pathway (involving the translation factor eIF5A) and the transcription factor TFEB 4 5. In this last aim we want to explore if spermidine or other drugs that can modulate this pathway can be used to prevent aging and inflamm-aging of macrophages.

Treating age-related illnesses puts many health care systems under enormous economic pressure. Novel pathways targeting processes underlying age-related metabolic and molecular damage provide an opportunity to prevent or slow the emergence of chronic pathologies.

KEYWORDS

Inflamm-aging, autophagy, macrophages, ageing

TRAINING OPPORTUNITIES

Training will be provided in techniques including proteomics and RNAseq and their analysis, confocal microscopy, immunological techniques such as multi parameter flow cytometry. You will attend regular seminars within the department and in the wider University. You will be expected to present data regularly in lab meetings and in departmental progress report seminars and in national and international conferences.  You will have the opportunity to work closely with collaborating groups interested in inflammation (Fiona Powrie, KIR, Jelena Bezbradica-Mirkovic, KIR, Claudia Waskow, Jena, Christian Behrends, Munich). A senior postdoc in the lab will initially supervise you. A core curriculum of lectures is offered in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis, statistics and the microbiome.

Environment

The Kennedy Institute is a world-renowned research centre, housed in a brand new, state-of-the-art facility at the University of Oxford. The Simon lab consists currently of 4 postdocs, 3 DPhil students (tow in their final year and one first year) and we will recruit a bioinformatician and research assistant with recently funded Wellcome Investigator award. It is a small, friendly and very international lab. While lab members are ambitious and working each on different projects, team work is being encouraged. Every DPhil student in my lab (10 so far) had the opportunity to write a review, and has published a first author primary paper. We regularly welcome MSc students and other short-term students in the lab, so there will be opportunities to train your supervision skills 

KEY PUBLICATIONS

  1. Zhang H, Puleston DJ, Simon AK. Autophagy and Immune Senescence. Trends Mol Med 2016; 22:671-86.
  2. Stranks AJ, Hansen AL, Panse I, Mortensen M, Ferguson DJ, Puleston DJ, et al.,.. Simon AK. Autophagy Controls Acquisition of Aging Features in Macrophages. J Innate Immun 2015; 7:375-91.
  3. Riffelmacher T, Clarke A, Richter FC, Stranks A, Pandey S, Danielli S, et al. ….Simon AK. Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation. Immunity 2017; 47:466-80 e5.
  4. Zhang H, Alsaleh G, Feltham J, Sun Y, Napolitano G, Riffelmacher T, et al. ….Simon AK. Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. Mol Cell 2019; 76:110-25 e9.
  5. Alsaleh G, Panse I, Swadling L, Zhang H, Meyer A, Lord J, et al…. Simon AK Translational control of autophagy is key to T cell vaccine responses in older adults. eLife; under review.

CONTACT INFORMATION

Contact: Prof Katja Simon, Kennedy Institute, University of Oxford

Email: katja.simon@kennedy.ox.ac.uk