Determining the critical relationship between human epidermal lipids and microbiota in sustaining healthy skin ageing

Lead Research Organisation: University of Manchester
Department Name: Manchester Pharmacy School

Abstract

Improvements in health care and reductions in birth rates have increased the proportion of older people in the UK and worldwide. As we grow older, there are significant changes in how organ systems within the body function; research is needed to understand how an ageing body adapts to remain healthy. Such understanding will help us define healthy ageing and will support efforts to reduce the risk of developing age-related health problems.

Skin is an important organ that protects the body from the environment. The outer layer of the skin, called the epidermis, forms a barrier that regulates the loss of water and electrolytes from the body, and provides an immunological barrier through specialist immune cells that are part of the body's defence against infections. The surface of the skin is covered by myriad microorganisms, collectively known as the 'microbiota'. These microorganisms are important for skin health as they can protect it from other potentially pathogenic microorganisms. The microbiota can also interact with immune cells and, in this way, strengthen the skin's ability to protect itself from infection.

As we age the natural changes that occur in human skin reduce its ability to maintain this barrier function; skin becomes thinner and more fragile, less resistant to infections, and more susceptible to develop ulcers and chronic wounds (i.e. wounds that fail to heal). In young skin, the structure and function of this epidermal barrier is dependent upon specialist skin lipids; as ageing occurs, there is a reduction in the lipid content of the epidermis. Skin microbiota also decline with increasing age, both in terms of the number of microorganisms and the number of species resident on the skin. Interestingly, skin lipids and microbiota have a dynamic relationship where lipids act both as nutrients and control factors for the microorganisms, whilst the microbiota can change the skin's lipid environment. As ageing affects both epidermal lipids and microbiota, we believe that if we study their association we will gain important new information on the processes that control healthy skin ageing.

In this project we propose to explore the hypothesis that ageing brings about changes in the lipid content of the skin (termed lipidome), and that these changes affect the skin-resident microorganisms, leading to reduced function of the epidermal barrier in the elderly. Therefore, in undertaking this project we aim to identify the baseline relationship between epidermal lipids and the skin microbiome, how this relationship is different in young and elderly individuals, and what effect these changes have on how the skin barrier functions in the elderly. Our research has three specific objectives:

1. How does the lipid composition of the epidermis and the function of the epidermal barrier change as the human body ages?
2. What is the impact of chronological ageing on the number and type of microbiota that are found on the skin at different body sites?
3. What is the association between the epidermal lipids and microbiota, how does this relationship change as we grow older, and what is the sequence of events that bring about the age-related changes?

By completing this project we will be able to show for the first time the exact details of the relationship that exists between skin lipids and microbiota, and how their association changes during the process of ageing. This information will provide a unique understanding of the natural state of a healthy epidermal barrier. Furthermore, this valuable insight will give us the ability to design interventions to prevent changes that make aged skin more prone to ailments, and to promote health. Such interventions have the potential to ease the burden of ill health for the individuals, and also have a positive financial impact on health care systems by keeping older skin healthier for longer.

Technical Summary

Chronologically aged skin is fragile, less resistant to infection and has a reduced capacity for repair when challenged - changes related to reduced epidermal barrier function. Two major barrier components are epidermal lipids and skin-resident microbiota, both of which are directly affected by ageing. Epidermal lipids are vital for the structural integrity and function of the barrier, and sustain and control the number and type of skin-resident biota. In turn, microbiota can alter the cutaneous lipid environment and impact host resistance and immunity.
The project aims to establish the baseline relationship between epidermal lipids and skin microbiota, determine age-related changes in both of these features, and the effect these changes have on barrier function in healthy chronologically aged skin. Our cross-sectional study will use young and elderly healthy human volunteers, and analyse epidermal lipids, microbiota, and barrier function, to evaluate the state of skin ageing and seek the link between age-induced perturbations and their impact on skin function.
Trans-epidermal water loss will be assessed as a measure of skin barrier function, mass spectrometry-based lipidomic analyses will provide qualitative and quantitative information on epidermal lipids, and high-throughput nucleic acid sequencing will provide comprehensive assessment of microbiota. Skin biopsies from a subset of volunteers will be used to further assess the functional age of skin based on markers of senescence, apoptosis, proliferation and pro-inflammatory infiltrates by immunohistochemistry. The data will be interrogated by unsupervised clustering analyses to explore their associations using a systems biology approach (KNIME environment for numerical analytics).
The project will provide for the first time a detailed understanding of the dynamic relationship between skin lipids and microbiota, and support new approaches to prevent age-related skin conditions and promote skin health.

Planned Impact

As the demographics of the global population are shifting in favour of an ageing population, our understanding of what constitutes healthy ageing becomes particularly important. The structure and function of chronologically-aged skin changes; it becomes more fragile and less able to resist infections, while barrier function is also reduced. Epidermal lipids and skin microbiota are two key players in skin health, involved in maintaining skin's correct structure and function. This research will explore the relationship between epidermal lipids and microbiota in healthy skin, how this changes with age, and how this influences skin barrier function. This will provide a detailed profile of chronologically-aged skin, and establish a baseline definition of healthy aged skin, making it possible to monitor how changes in lipids or microbiota from this reference point impact on skin health. Our research will generate impact in the following ways:

1. Academic impact: The project outputs will benefit academic and industrial researchers working in the areas of ageing, skin and lipid biology as it will deliver a significant advancement in our understanding of the age-induced changes in cutaneous lipidome, microbiome, and barrier function. We will reach this audience and promote the results of our research through high quality peer-reviewed publications, seminars and conference presentations.

2. Public engagement: We will actively seek to increase awareness around skin health, and discuss the role epidermal lipids and skin-resident microbiota play in maintaining health in both the young and the elderly, and across the life course. We will do so through public engagement events organised by the University of Manchester and affiliated research interest groups. Our target audience (including school children, adults and the elderly) will gain insight into the importance of skin lipids and microbiota in healthy skin ageing, and the university students enrolled in healthcare courses that we will train to deliver these events will learn about how emerging research can impact health care product development as well as population health. Press releases, personal web pages and social media will be used to create further impact.

3. Business engagement and knowledge transfer: We will be actively involved in business engagement and knowledge transfer activities, primarily with our industrial partner (SkinBioTherapeutics PLC). The company has a very strong record in developing bespoke skin products and are uniquely placed to take forward any relevant findings. Potential applications are expected to reach beyond healthy ageing to restoring skin ailments, and will bolster the company's existing product portfolio. Further to this, we will continue interacting with the personal care and pharmaceuticals sectors in the UK and abroad, pursuing knowledge transfer activities since the relevant technologies can be applied to product testing and assay development. The University of Manchester has a strong tradition in using its research to make positive impacts on real world challenges, and the University of Manchester Intellectual Property (UMIP) service will support commercialisation of intellectual property and our efforts.

4. Training of young scientists: The project will generate further impact though training and development of new skills, increasing employment, and retaining young scientists in the locality. Our research niche in skin lipidomics, and expertise in microbiota and skin ageing, has attracted funds to employ and train young scientists. This project will allow us to continue this trend and retain local talent, and we aim to generate further impact though the recruitment and training of postgraduate students. Finally, the public and business engagement activities of the project will further enhance the skills of the young researchers involved in the project, improving their career prospects.

Publications

10 25 50
 
Description Ageing affects both the lipids of the epidermal barrier and the profile of microorganisms found on the the skin. These changes are somewhat different in men and women, and depend on the body site. The prevalence of certain lipid classes correlate with ageing, while both lipid classes and individual lipid species correlate with certain microorganisms. Our findings could potentially lead to the development of interventions which could support skin function in older individuals
Exploitation Route we are still analysing data and exploring potential IP protection
Sectors Healthcare

Pharmaceuticals and Medical Biotechnology

 
Description The project team organised and presented a public engagement event with the support of Manchester Institute for Collaborative Research on Ageing (31October 2019). The event featured three speakers covering the impact of ageing on skin structure and function and role of cutaneous lipids and microbiota (details below). The event attracted a large audience and was very well received; MICRA have asked us to repeat the activity next year. Understanding our skin - what happens as we age? Our skin acts as an important barrier to the environment, but as we age it grows thinner and becomes more susceptible to damage, infection and chronic wounds. We believe that some of these changes may relate to lipids found within the skin, as well as microorganisms living on the skin surface. We aim to get a better understanding of the changes that ageing skin goes through, and are conducting a research study comparing young and older skin. We hope that by learning more about these age-related changes, we can understand how to intervene to keep older skin healthier for longer. Presenters Professor Rachel Watson: What happens to our skin as we age? Professor Andrew McBain: Understanding the microorganisms that live on our skin Dr Alex Kendall: Why lipids are so important for our skin?
First Year Of Impact 2019
Sector Healthcare
Impact Types Societal

 
Description BB/X006859 Determining the specificity of vesicle traffic at the Golgi apparatus
Amount £540,000 (GBP)
Funding ID BB/X006859 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2023 
End 07/2026
 
Description Developing an in silico model of the scalp keratinocyte lipidome in dandruff
Amount £120,000 (GBP)
Funding ID 2449792 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2020 
End 09/2024
 
Description Exploring interventions to maintain and prolong healthy skin function for an ageing population
Amount £720,542 (GBP)
Funding ID BB/W006022/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2022 
End 09/2025
 
Description The cutaneous lipidome Does ethnicity impact skins lipid barrier
Amount £105,984 (GBP)
Funding ID BB/X511511/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2022 
End 09/2026
 
Description The role of phospholipases in human skin lipid metabolism and epidermal barrier function
Amount £2,876 (GBP)
Funding ID BB/T004770/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2019 
End 07/2019
 
Description Understanding and treating neurogenic conditions related to the Kennedy pathway
Amount £600,000 (GBP)
Funding ID MR/Y014251 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2024 
End 12/2027
 
Description Can skin-resident yeasts alter the lipidome of the epidermis and modulate immune responses? 
Organisation Agency for Science, Technology and Research (A*STAR)
Department Genome Institute of Singapore
Country Singapore 
Sector Academic/University 
PI Contribution discussions, experimental design, PhD student supervision
Collaborator Contribution discussions, experimental design, materials, PhD student supervision
Impact no outputs yet
Start Year 2022
 
Description International Interlaboratory Trial initiated by the International Lipidomics Society and NIST 
Organisation National Institute of Standards & Technology (NIST)
Country United States 
Sector Public 
PI Contribution My laboratory is participating in an international interlaboratory trial using NIST materials, organised and overviewed by the International Lipidomics Society
Collaborator Contribution Materials and protocols
Impact publications planned
Start Year 2023
 
Description Long chain fatty acids in atopic dermatitis 
Organisation Møreforsking
Country Norway 
Sector Private 
PI Contribution Discussions on a clinical study design and analysis of clinical samples. The clinical study has started in Norway. A research agreement is currently under review and a research contract is expected to be in place shortly.
Collaborator Contribution The partners will conduct a clinical study using a new fish oil preparation; the partners have secured favourable research ethics and the study has started recruitment. The partners have secured funding from local funders (Norway) to support the analysis of clinical sample at the University of Manchester using our skin lipidomics platform.
Impact no outputs yet
Start Year 2023
 
Description Research Collaboration with AstraZeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Successful joint application for a BBSRC-DTP CASE studentship; the project will start September 2023
Collaborator Contribution discussions; research design
Impact successful studentship grant application
Start Year 2022
 
Description Research Grant Application: HFSP; not funded 
Organisation University of Tokyo
Country Japan 
Sector Academic/University 
PI Contribution I was the PI for a project grant application to HFSP together with Murakami (Japan) and Boilard (Canada). The proposal was entitled: High dimensional lipid networks controlling communication between biological barrier interfaces. Although we were shortlisted for a full proposal, the submission was not successful.
Collaborator Contribution I was PI to this multidisciplinary project.
Impact n/a
Start Year 2019
 
Description Research collaboration with WBA/BOOTS 
Organisation Boots UK
Country United Kingdom 
Sector Private 
PI Contribution Designing and performing research; discussions and knowledge transfer; writing grant proposal; writing papers
Collaborator Contribution discussions; in kind contribution to research
Impact BBSRC IPA GRANT INCOME PUBLICATIONS
Start Year 2019
 
Description MICRA webinar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The project team presented three short talks and took part in a Q&A session on 'Skin Lipids and Ageing'. The event was organised by MICRA (Manchester Institute for Collaborative Research in Ageing). The audience were members of the general public. Feedback was positive and MICRA invited us to organise a further event in the near future.
Year(s) Of Engagement Activity 2021
 
Description Manchester Institute for Collaborative Research on Aging (MICRA) event: Understanding our skin - what happens as we age? 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact More that 60 members of the public, mostly older adults, attended this event. The event comprised three short talks and a Q&A session. The audience actively engaged with the researchers and the feedback was extremely good. The participants complemented the team on a very interesting a relevant to their health area of science that they do not hear much about. MICRA - the Manchester based Institute for Collaborative Research into Ageing - have invited the team to repeat the event in 2020.
Year(s) Of Engagement Activity 2019
 
Description School Visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Girls STEM career event, speed dating event, Matthew Moss High School, Rochdale.
Year 10 girls attended a speed-dating style event to discuss; the pupils were from different backgrounds and had many different aspirations and career ideas. They were very much interested to find out about science careers, university education, working at a university and conducting research.
Year(s) Of Engagement Activity 2024
 
Description Webinar- Manchester Institute for Collaborative Researh on Ageing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Webinar organised by MICRA; the audience were mainly older individualts; 4 members of the project team presented an update of our research project; a Q&A session followed; MICRA received very positive feedback and we have been asked to present another seminar next year; the webinar sparked an interest in our research study.
Year(s) Of Engagement Activity 2021