Dietary Optimisation for Male Fertilisation Success and Healthy Reproductive Ageing

男性的生育能力是由精子和精液决定的，统称为射精。老龄化有影响：射精的质量和性能随着年龄的增长而下降，这是老年夫妇受精成功率降低的重要原因。饮食也有影响：营养不良对射精和男性生育能力（以及健康的许多其他方面）不利。我们也知道饮食会影响衰老。饮食优化（通常涉及一些食物限制）可以延长许多动物的健康寿命。我们还不知道的是，什么样的饮食最能防止射精随着年龄的增长而恶化。“精确营养”（精心定制的饮食）能否延缓衰老，从而提高年长男性的受精成功率？我们需要了解这些问题，这既是为了获得基础科学知识--了解食物如何影响生育和衰老--也是为了将这些想法应用于动物和人类，以改善生殖健康。为了解决这个问题，我们将测试不同的饮食如何影响老年男性的生殖。我们将使用一种易于操作的模式物种，果蝇，黑腹果蝇。雄性生殖在所有动物中基本相似，生育力、衰老和营养加工的许多核心遗传机制都是共享的，因此我们对果蝇的研究将具有广泛的可翻译性。我们将进行新的实验，使用最先进的技术来系统地改变饮食，并通过检查生育能力和射精来分析对男性生殖年龄的影响。首先（1）我们将测试饮食中碳水化合物，蛋白质和脂肪的比例如何影响不同年龄段的男性受精成功。我们知道，精子和精液中含有的蛋白质对生育力特别重要，所以我们更进一步，改变蛋白质的组成部分（氨基酸）。我们将调整食物中特定氨基酸的比例，以匹配精液中精子和蛋白质的预测最佳值，并测试这些匹配的饮食是否有助于延缓男性生殖衰老。第二（2），我们将测试对男性生育力有益的饮食是否也对寿命有益。如果没有，我们将看到在不同年龄段之间切换饮食是否可以通过暂时提高生育能力但保持长寿来为男性提供“两全其美”。最后（3）我们将比较优化的射精与非优化的射精的成分，以了解射精的特征如何随饮食和年龄而变化。为此，我们将使用蛋白质组学来揭示精子和精液中蛋白质的混合，并研究其对高生育力和低生育力精子代谢的影响。因此，拟议的工作将深入调查饮食、衰老和生育能力之间的联系。为什么这项工作很重要？首先，这项工作将扩大我们对营养、衰老和生殖生物学的基本知识，鉴于这些主题的普遍意义，这是有价值的。但我们的技术在应用于其他物种时也可能有用，这可能具有经济或社会效益。控制携带疾病或破坏作物的昆虫物种的一个关键方法是释放精子不能存活的不育雄性昆虫，这些雄性昆虫与野生雌性昆虫交配，防止它们产生后代。这种技术有效性的一个主要因素是男性的受精成功。我们也许能够将我们在果蝇身上获得的知识应用于其他昆虫，以提高被释放的雄性的生殖寿命，这可能最终有助于对抗疾病和提高粮食安全。对于人类，牲畜和濒危物种，我们通常也希望延长生殖健康。同样，如果我们可以应用类似的技术为这些物种开发优化的饮食，它可能代表一种简单，具有成本效益和非侵入性的方法，用于改善男性生育能力随年龄的恶化。

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.