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

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.

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.

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.