The Modification of Dietary Protein with Ammonium Hydroxide Enhancement Improves Longevity and Metabolic Outcomes in a Sex-Dependent Manner

(1) Background: Dietary protein is a key component of all dietary patterns. It has been demonstrated that there are subtle differences in health implications associated with the source of dietary protein consumed. This study examined dietary protein sources (DPSs) in a long-term study of diet-induced obesity ± ammonium hydroxide enhancement (AHE) and its role in improving long-term health outcomes. (2) Methods: Over 18 months, 272 C3H/HeJ mice (136 male and 136 female) were monitored on high-fat diets with varying DPSs ± AHE. Mice were monitored for weekly change in total mass, as well as 6-month assessments of lean and fat mass. At each assessment, a cohort (~8 mice per diet per sex) was censored for a cross-sectional examination of organ function. (3) Results: Longevity was improved in females fed AHE diets, regardless of DPSs. Females' measures of fat and lean mass were markedly elevated with casein protein diets compared to beef protein diets regardless of AHE. Females fed a beef protein diet + AHE demonstrated reduced fat mass and increased lean mass with aging. In males, AHE beef protein diet-fed mice showed marked improvement to longevity and increased lean mass at 6 months. (4) Conclusions: This study demonstrates that dietary protein modification by AHE attenuates the negative impacts of HF diets in both males and females in a sex-dependent manner. Furthermore, the results from this study emphasize the importance of identifying the differences in the utilization of dietary proteins in both a sex- and age-related manner and demonstrate the potential of DPS modification by AHE as a dietary intervention.