A dietary sterol trade-off determines lifespan responses to dietary restriction in Drosophila melanogaster females

Abstract

Diet plays a significant role in maintaining lifelong health. In particular, lowering the dietary protein: carbohydrate ratio can improve lifespan. This has been interpreted as a direct effect of these macronutrients on physiology. Using Drosophila melanogaster, we show that the role of protein and carbohydrate on lifespan is indirect, acting by altering the partitioning of limiting amounts of dietary sterols between reproduction and lifespan. Shorter lifespans in flies fed on high protein: carbohydrate diets can be rescued by supplementing their food with cholesterol. Not only does this fundamentally alter the way we interpret the mechanisms of lifespan extension by dietary restriction, these data highlight the important principle that life histories can be affected by nutrient-dependent trade-offs that are indirect and independent of the nutrients (often macronutrients) that are the focus of study. This brings us closer to understanding the mechanistic basis of dietary restriction.

Drosophila melanogaster females prioritise dietary sterols for producing high quality eggs

“…These findings indicate that the responses of the traits to cholesterol supplementation on the holidic diet (Figure 2) are not apparent when some dietary sterols are available to the mother (Figure 3) -even though those levels that are available are insufficient to support full lifespan (Zanco et al, 2021). Together, these data indicate that mothers prioritise sterols for use in producing viable eggs rather than maintaining the mother's soma, supporting the Nutrient Recycling Hypothesis.…”

“…Under both of these models, supplementing sterols in a high P:C (high yeast) diet should increase the mothers' lifespan, which is what has been observed (Zanco et al, 2021), but they predict different effects on egg-to-adult viability. In the Nutrient Recycling Hypothesis (Adler and Bonduriansky, 2014), because the flies already prioritise sterols for reproduction, adding more to the diet would not markedly increase egg-to-adult viability, as it should already be high.…”

“…Specifically, across a broad range of species higher protein : carbohydrate (P:C) ratios are associated with short lifespan and high reproduction, while low P:C diets are associated with longer life, but lower levels of reproduction (Maklakov et al, 2008;Piper et al, 2011;Fanson and Taylor, 2012;Simpson et al, 2012Simpson et al, , 2017. Our recent work provides a new nutritional explanation for this phenomenon by demonstrating that while P:C ratio does positively associate with female reproduction in Drosophila, it is the abundance of a different nutritional component, dietary sterols, that dictates length of life (Zanco et al, 2021). Importantly, the dietary P:C ratio manipulates the availability of sterols accessible for somatic maintenance, by either inhibiting or driving reproductive output, of which sterols are required for.…”

“…The previous experiment used diets without sterols to assess the mothers' commitment to producing high-quality eggs when faced with extreme nutrient stress. To test the extent of maternal sterol prioritisation under more natural conditions, we exposed flies to a standard sugar/yeast diet, which we have previously shown to be sterol limiting for female egg production and lifespan (Zanco et al 2021), and supplemented it with sufficient sterols to overcome these limitations (0.3g/l cholesterol).…”

“…Based on our previous data, we proposed that in Drosophila, dietary P:C ratio is monitored to set the level of egg laying, while sterols, which determine length of life, are constitutively prioritised for reproduction (Zanco et al, 2021). Thus, when reproduction is low (on low P:C food) the diet supplies sufficient sterols to meet the relatively low demands for reproduction and this spares the mother from drawing on her own sterol reserves, which leaves her soma intact to sustain longer life.…”