Male reproduction and lifespan: the role of dietary sterols

Aim: Understand why eating cholesterol boosts the lifespan of male flies when they mate, but not when they are celibate. Hypotheses: Males lose sterols in sperm and seminal fluid when they mate. A lack of dietary cholesterol leads to sterol depletion, changes in hormone production, and early death. Outcome: A step-change in understanding how reproduction determines male dietary needs to avoid early death. Context: food, sex and death are intimately linked Diets that boost reproduction can often accelerate ageing. Macronutrients (proteins, fats and carbohydrates) are well known to be important. Contrastingly, whilst we know micronutrients have key roles in biochemistry and cell biology, we know much less about their impact on fertility and ageing. There are a multitude of micronutrients, and each can vary in quantity and interact with other nutrients, making it hard to unravel their effects. Challenge: understanding how dietary sterols and reproduction determine male lifespan Cholesterol is a micronutrient and a type of sterol, chemicals that are found in all plants and animals. Animals use sterols to form hormones and cell membranes, and they are found in many tissues, including sperm and seminal fluid. In our recent experiments we made an unexpected discovery: dietary cholesterol makes male fruit flies (Drosophila melanogaster) live longer when they mate regularly, but not if they never mate (and in some scenarios even shortens lifespan). This experiment suggests that males prioritise sterols for reproduction over using them to maintain their body. Now we want to understand why this happens. Aims Our hypothesis is that males face a trade-off between using sterols for reproduction (in the ejaculate), versus survival. Question 1. Do males lose sterols in sperm and seminal fluid when they mate, leading to harmful sterol depletion and reduced lifespan? Question 2. Is disrupted hormone production, due to mating-induced sterol depletion, the cause of reduced male lifespan? Objectives To answer the questions we will: 1a) Track the movement of sterols from food to different body tissues, and the loss of sterols when males mate, using cutting-edge lipid mass spectrometry techniques. 1b) Reveal what causes males to need cholesterol when they mate frequently, using male flies that genetically lack sperm or seminal fluid, or the ability to absorb sterols normally. 2a) Manipulate hormone levels by replacing cholesterol with sterols that are less efficient at – or completely incapable of – being made into hormones 2b) Directly feed hormones to flies Applications, benefits, and relevance to BBSRC priorities The research underpins our fundamental understanding of the links between diet, reproduction and lifespan. Sterols have the same biological functions across animals, including humans (in the formation of cell membranes and hormones), proteins that move sterols around the body are very similar, and sterols are found ubiquitously in sperm and semen. Our work in flies will thus have wide relevance, including to human diseases such as hypercholesterolemia (and drugs that treat it) and different diet choices (e.g. vegan vs omnivore). Our findings will ultimately help us understand the role of dietary sterols in reproduction and healthy ageing in animals and people. The project will benefit from and develop a highly skilled existing team to work on leading-edge bioscience spanning core themes in BBSRC’s strategy: increasing healthy life expectancy; the biological mechanisms of health; and ageing, diet, nutrition, and health.