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).aging | macronutrients | lifespan | reproduction | nutrition N utrition profoundly influences reproduction and lifespan. Traditionally, dietary restriction has been the central focus of most research, with numerous studies showing that caloric restriction can improve age-related health and prolong lifespan across a wide range of taxa ranging from yeasts to humans (1-6). The extension of lifespan under caloric restriction has been explained by resource-mediated tradeoffs between reproduction (age of sexual maturity, number of offspring, and parental investment) and longevity (senescence and lifespan), with these outcomes titrated for maximum overall reproductive success under given levels of resource availability (7,8). However, the view that there is a simple constitutive tradeoff between reproduction and longevity has been challenged by accumulating experimental evidence from invertebrate models, beginning with experiments in Caenorhabditis elegans, demonstrating that lifespan in long-lived mutants was not affected by the ablation of germ cell and somatic gonad precursors, indicating that neither germ cells nor progeny production was directly responsible for increased longevity in the worm (9). Later, it was found that manipulating the insulin/insulin-like growth factor-1 (IGF1) pathway in adult worms can extend lifespan without the loss of fecundity (10). In beetles, the increased risk of death associated with high egg pr...
