Investigating the Mechanistic Role of Dietary Protein in Aging and in Alzheimer's Disease

Project Summary Dietary protein is a powerful determinant of the biological state and represents a vital element in a comprehensive geroprotective therapy. Several groups have demonstrated that the manipulation of dietary protein levels can directly influence the aging process. Specifically, the reduction of protein intake (PR) robustly enhances metabolic health, promotes healthspan, and extends lifespan. Unpublished data from the Lamming Lab further demonstrates in an early onset model of Alzheimer’s disease (3xTg-AD) that PR improves glucose tolerance, reduces tau hyperphosphorylation, and ameliorates cognitive deficits. However, a recent conflicting report suggests that a high protein diet can reduce the accumulation of Aβ in the brains of Alzheimer’s disease (AD) patients. This indicates that further understanding of PR’s molecular mechanisms is necessary to appreciate the true contribution of dietary protein in the aging process. In investigating the components of a PR diet, the Lamming Lab has reported that isoleucine restriction (IleR) alone can effectively recapitulate PR’s benefits and is required for a significant portion of PR’s effects. To further understand the role of IleR as a geroprotective therapy, young C57BL/6J male mice were fed an IleR diet and concurrently treated with rapamycin, which is a well-studied life-extending drug with proven benefits in AD mouse models. Surprisingly, rapamycin largely overtook the short-term effects of the diet, blocking IleR’s benefits in body composition, glucose tolerance, and energy expenditure. At the molecular level, rapamycin specifically prevented the induction of lipolytic programs and not of thermogenesis or lipogenesis in the inguinal white adipose tissue. Lipolysis and lipid regulation plays a critical role in the systemic state of metabolism. While the effect of PR on brain lipid regulation is unknown, recent publications have found that dysfunctions in lipolysis is associated with AD progression. As such, this proposal investigates the overarching hypothesis that lipolysis regulation is a critical mechanism of action in the physiological role of dietary protein, with a focus on healthspan, lifespan, and cognitive health. Aim 1 will define the metabolic and molecular interactions between rapamycin and various dietary restrictions and investigate the role of dietary protein concentrations on the life-extending effects of rapamycin. Aim 2 will leverage transgenic mouse lines with genetic ablation of putative rapamycin targets in order to dissect the molecular mechanisms responsible for the effects of PR. Aim 3 will determine the role of dietary protein on the development of AD symptoms and on the effects of rapamycin in the early onset 3xTg-AD and the late onset hAβ-AD mouse models. We will further characterize changes of the lipidomic profile in the serum and the brain. In summary, this research program seeks to provide significant advancements in our mechanistic understanding of the role of dietary protein in the biology of aging as well as in the manifestation of AD pathogenesis.