Dietary Optimisation for Male Fertilisation Success and Healthy Reproductive Ageing

Male fertility is determined by sperm and seminal fluid, collectively known as the ejaculate. Ageing has an impact: the quality and performance of the ejaculate declines with age and is an important contributor to reduced fertilisation success in older couples. Diet also has an impact: malnutrition is bad for the ejaculate and male fertility (and many other aspects of health). We also know that diet influences ageing. Dietary optimisation (typically involving some food limitation) can extend healthy lifespan in many animals. What we don't yet know is what diet is best for preventing the ejaculate from deteriorating with age. Could 'precision nutrition' (carefully tailored diets) delay the decline with age, leading to improved fertilisation success older males? We need to understand these problems both for fundamental scientific knowledge - to know how food affects fertility and ageing - but also if we want to apply the ideas to animals and people to improve reproductive health.
To tackle this problem we will test how different diets affect reproduction in ageing males. We will use an easy to manipulate model species, the fruit fly, Drosophila melanogaster. Male reproduction is fundamentally similar across animals, and many core genetic mechanisms of fertility, ageing and nutrient processing are shared, so our studies in the fly will be widely translatable. We will perform novel experiments, using state-of-the-art techniques to systematically vary diets, and analyse the effects on male reproductive ageing by examining fertility and the ejaculate. First (1) We will test how the ratios of carbohydrates, protein and fat in the diet affect male fertilisation success across different ages. We know that proteins contained in sperm and seminal fluid are especially important in fertility, so we go further, varying the building blocks of proteins (amino-acids). We will tailor the ratio of specific amino-acids in the food to match the predicted optima for sperm and proteins in the seminal fluid, and test whether these matched diets help delay male reproductive ageing. Second (2) we will test whether diets that are good for male fertility are also good for lifespan. If not, we will see whether switching between diets at different ages can provide males with the 'best of both worlds' by temporarily enhancing fertility but retaining a long life. Finally (3) we will compare the composition of optimised ejaculates with those of non-optimal ejaculates, to understand how the characteristics of the ejaculate vary with diet and age. To do this we will use proteomics to reveal the mix of proteins in the sperm and seminal fluid, and we will look at the effects on metabolism in high and low fertility sperm. The proposed work will therefore provide a deep investigation into the links between diet, ageing and fertility.
Why is this work important? First, the work will expand our fundamental knowledge of nutritional, ageing and reproductive biology, which is valuable given the ubiquitous significance of the topics. But our techniques might also be useful when applied to other species, which may have economic or social benefits. A key method for controlling insect species that carry disease or destroy crops is the release of sterile male insects with inviable sperm, who mate with wild females preventing them from producing offspring. A major factor in the effectiveness of this technique is the male's fertilisation success. We may be able to apply the knowledge we gain in Drosophila to other insects, to improve the reproductive longevity of released males, which may ultimately help fight disease and improve food security. For humans, livestock and endangered species, we often also desire extended reproductive health. Again, if we can apply similar techniques to develop optimised diets for these species, it may represent a simple, cost-effective and non-invasive method for ameliorating male fertility deterioration with age.

The health of the ejaculate, formed by sperm and seminal fluid, is essential for full male fertilisation success. Malnutrition and ageing are known to decrease male ejaculate performance, across a broad range of taxa. However, we understand little about nutritional optimisation for male reproductive ageing: whether diet can be tailored combat age-related declines in sperm and seminal fluid. We need to know the answer to this for both the our basic understanding of the links between nutrition, reproduction and ageing, and for potential applications of precision nutrition to animals and people. To address the problem, we have assembled an interdisciplinary team who bring state-of the art techniques from the fields of nutrition, reproduction, and mass spectrometry. We will use Drosophila model, which shares many fundamental mechanisms of metabolism, ageing, and the ejaculate with other animals, including humans. We will combine multidimensional precision nutrition manipulations, with assays of fertilisation success, male reproductive ageing, and cell and molecular analyses of sperm and seminal fluid quality, to address three key aims: (1) to characterise dietary macronutrient and amino-acid ratios that optimise fertilisation success across different male ages; (2) to test whether nutritional optimisation can simultaneously enhance male fertilisation success and lifespan; (3) to map the cellular and molecular makeup of nutritionally optimised and compromised ejaculates from males of different ages. Overall, this project provides the first high-resolution, systematic experimental investigation of the links between nutrition and male healthy ageing. As such, the project advances our fundamental understanding of the link between three universal pillars of fitness - food, fertility and survival - and lays the foundations for developing nutritional tools to promote male reproductive health.