Macronutrient balance, reproductive function, and lifespan in aging mice

Abstract

In invertebrates, reproductive output and lifespan are profoundly impacted by dietary macronutrient balance, with these traits achieving their maxima on different diet compositions, giving the appearance of a resource-based tradeoff between reproduction and longevity. For the first time in a mammal, to our knowledge, we evaluate the effects of dietary protein (P), carbohydrate (C), fat (F), and energy (E) on lifespan and reproductive function in aging male and female mice. We show that, as in invertebrates, the balance of macronutrients has marked and largely opposing effects on reproductive and longevity outcomes. Mice were provided ad libitum access to one of 25 diets differing in P, C, F, and E content, with reproductive outcomes assessed at 15 months. An optimal balance of macronutrients exists for reproductive function, which, for most measures, differs from the diets that optimize lifespan, and this response differs with sex. Maximal longevity was achieved on diets containing a P:C ratio of 1:13 in males and 1:11 for females. Diets that optimized testes mass and epididymal sperm counts (indicators of gamete production) contained a higher P:C ratio (1:1) than those that maximized lifespan. In females, uterine mass (an indicator of estrogenic activity) was also greatest on high P:C diets (1:1) whereas ovarian follicle number was greatest on P:C 3:1 associated with high-F intakes. By contrast, estrous cycling was more likely in mice on lower P:C (1:8), and the number of corpora lutea, indicative of recent ovulations, was greatest on P:C similar to those supporting greatest longevity (1:11).

Keywords: aging; lifespan; macronutrients; nutrition; reproduction.

Fig. 1.

Macronutrient balance influences female gamete stock. Response surfaces showing the relationship between macronutrient intake (kJ/d) and (A) uterine mass, an indicator of steroid production, and (B) total number of follicles and (C) total number of corpora lutea, both indicators of gametogenesis which were counted across three sections in each ovary. Three 2D slices are presented to show the interactive effects of all three macronutrient dimensions (protein, carbohydrate, and fat). In each 2D slice, the third factor is set at its median. For all response surfaces, areas shown in red indicate the greatest value for each response and fall away as the colors shift from red to blue. The red lines indicate the ratio of macronutrients that maximizes each response. Shown are representative sections of ovaries when (D) high fat is consumed and (E) high carbohydrate is consumed. Yellow asterisks show follicles, and black asterisks show corpora lutea.

Fig. 2.

Estrous cycling is optimized at a high P:C ratio. Response surfaces showing the interactive relationship between macronutrient intake vs. the number of estrous cycles over 11 days. For response surfaces, the third dimension is sliced at the median. Areas shown in red indicate the greatest value for the average number of cycles and fall away as the colors shift from red to blue.

Fig. 3.

The effects of macronutrient intake on male reproduction. The relationship between testes mass and (A) total sperm count and (B) body mass. Response surfaces showing the relationship between macronutrient intake and (C) testes mass, as indicators of gametogenesis, and (D) seminal vesicle mass and (E) ventral prostate mass, as indicators of testosterone production and (F) plasma testosterone levels. For response surfaces, the third dimension is sliced at the median. Areas shown in red indicate the greatest value for each response and fall away as the colors shift from red to blue.

Fig. 4.

Median lifespan (LS) and reproductive function are optimized at different macronutrient niches. Response surfaces showing median lifespan of (A) females and (B) males. The red lines indicate the P:C ratio at which median lifespan is maximized (1:11 and 1:13, respectively). The green solid line indicates the ratio at which the average number of cycling was maximized (CY; P:C 1:8). Black dotted lines represent indicators of gametogenesis, showing either corpora lutea (CL; P:C 1:13) or testes mass (TS; P:C 1:1). Brown lines represent bioassays for steroid-dependent reproductive parameters and show uterus masses (UT; P:C 1:1) for females and seminal vesicle masses (SV; P:C 1:1) for males. For all response surfaces, areas shown in red indicate the greatest value for each response and fall away as the colors shift from red to blue.