Senescence is the process of biological ageing that takes place in living cells and the abundance of senescent cells increase in our bodies as we age. As many people will be aware, age is one of the biggest risk factors for a number of diseases, and it is thought that senescent cells and the factors that they secrete may drive the ageing process. Controlled and targeted clearance of the senescent cell burden may have considerable health benefits and is an attractive strategy for extending our healthspan. This research programme seeks to identify new gene that can be targeted for clearance of senescent cells and identify novel compounds to achieve this aim. Until very recently it was not possible to perform targeted gene knockdown in senescent cells. However, the applicant has successfully developed a technique to turn individual genes off in senescent cells. This has enabled us to screen for genes that senescent cells have become 'addicted to' and find those that can be targeted to specifically kill these aged cells. Using this strategy, we have identified 16 such genes. Excitingly, these genes appear to be functionally related, interact with key drivers of senescence and are observed to increase their expression in a range of cells and tissues with biological ageing. Our bodies are made up of lots of different cell types, and an important first step will be to determine if turning these genes off in different cell types also results in the specific clearance of senescent cells. This will involve the culture of epithelial cells and fibroblasts from two different tissues, breast and skin. These cells have already been grown and aged in our laboratory. We will also validate the reported increase in expression with age using skin biopsies. Throughout this work, we will examine a range of known senescence markers, determine the precise cell death pathways that are engaged and check that our approaches are well tolerated by 'healthy' young cells. We will use a mixture of sophisticated, automated microscopy techniques coupled with molecular biology and others assays to achieve these aims. It is anticipated that future strategies for the targeted removal of senescent cells (so call senolytic therapies) will involve intermittent administration during periods of good health. We will test a range of different regimes to model the optimal treatment strategy for human senescent cell clearance. In addition to turning off our selected genes, we will perform a small-scale compound screen to see if we can identify senolytic compounds which inhibit our genes of interest. Next, we will use state of the art 3D co-culture systems to generate 'skin in a dish' and determine the impact of senescent cell clearance on skin ageing phenotypes. Finally, we will perform a high-throughput compound screen to identify novel compounds that can achieve targeted senescent cell clearance in cells in a dish and in our 3D models. Results of this research programme will therefore provide much needed information about the route to senescent cell clearance, identify novel senolytic compounds and bespoke treatment regimes. We hope our research will pave the way for the development of future treatments for senescent cell clearance.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Deodorants and antiperspirants are among the most important personal care products used every day. As consumers are demanding more from their personal care products, healthcare companies are constantly trying to improve the end-user experience of their products. Unilever, is the market leader with >40% market share, driven by sales of its 3 main brands, Rexona (Sure), Axe (Lynx) and Dove. Current product technology is based mainly on aluminium-containing antiperspirant salts (which also act as antimicrobials), antimicrobial solvents (ethanol, glycols) and fragrance. There is a demand for more targeted interventions, such as interfering directly with the formation of malodour at the molecular level. The production of body odour (BO) occurs during the normal growth of harmless bacterial communities that live on underarm skin, often called skin commensals or the skin microbiota. These bacteria acquire nutrients through the uptake of molecules secreted from the eccrine, sebaceous and apocrine glands in our skin. One of these molecules is a sulphur-conjugated peptide, which is secreted from the apocrine gland and recognised by a transport system designed to move peptides into the bacterial cell. Once inside the cell, the sulphur part of the molecule is split from the peptide and escapes from the bacteria, either through active transport or simple diffusion. Once on the skin, this volatile compound evaporates from the body and enters the air surrounding the individual as body odour. Inhibiting the bacterial transporter responsible for the uptake of the key precursor to thiol-based malodour represents a completely novel approach that holds great potential. For safety reasons, the market potential for a new odour-control technology lies, at least initially, in the non-aerosol segment, which represents about 10% of Unilever's business. The aim of this collaborative LINK award is therefore focused on developing a set of targeted inhibitors against the transport system responsible for the uptake of the odourless sulphur-conjugated peptide, thus eliminating one of the main causes of BO in the underarm. A commercialised peptide transporter inhibitor could potentially create a ~Euro200K per annum business for the new technology manufacturer. Furthermore, given the radical nature of the technology, its launch would be expected to result in significant market growth. This might mean growth of ~10% pa in the first 3 years for Unilever's non-aerosol business, equivalent to ~Euro300 million in cash turnover. There is thus clear potential to benefit the UK economy and to create new jobs for both the chemical supplier and Unilever, which has a global development and manufacturing site in Seacroft near Leeds.

When you eat a foodstuff or a pill (i.e. a pharmaceutical drug) it is important that the relevant molecules go to the places where they will be of most benefit. How nutrients and drugs are absorbed and distributed (and eventually excreted) is thus a topic of high importance. When it goes wrong in the case of drugs they may not work properly or may even be toxic; this latter is known as an Adverse Drug Reaction, and they account for more than 5% of hospital admissions. Cells are bounded by cell membranes, whose job it is to stop them letting in any old rubbish. Instead, these membranes contain proteins called transporters that serve to ferry small molecules into and out of cells as part of the day-to-day reactions (metabolism) that keep us alive. Such transporters account for fully one third of the gene products involved in these biochemical networks. It turns out in general terms that, since all they recognise is a molecule, without knowing its 'purpose' (nutrient, drug, vitamin, etc), just these same transporters are involved in transporting nutrients, vitamins and pharmaceutical drugs into cells; the problem is that we do not tend to know which transporters transport which substances, and this correlation-based assessment is what we wish to find out here. To do this we shall study how transporter levels and the extent of small molecule uptake vary together between different cells and tissues; given enough of these paired measurements we can work out which changes in which transporters best account for the changes in small molecule uptake, including molecules not used in the learning phase, and can then test directly that they do indeed transport the molecules we claim. Because the transporter levels naturally vary between tissues they must naturally be controlled, and several substances (such as vitamin D) are known to affect these levels dramatically. This means that we can expect to be able to modulate the expression of transporters and different tissues by adding a second molecule (a so-called 'binary weapon'), and thereby 'force' particular substances to go only to those tissues. We shall test this by adding a library of small artificial (man-made) molecules (so-called 'fragments') and seeing which of them can do this (at least to some degree). Computer methods help us to find larger and more potent molecules that possess these same fragment signatures and that would therefore be predicted to have the desired targeting effects. Importantly, we shall curate all of the data in a web-accessible database.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.