Project Summary
Age-related diseases are the major causes of morbidity and mortality in the US. Many elderly people
suffer from multiple age-related diseases simultaneously; while the risk of almost every individual disease rises
with age, they also interact. For example, diabetes and obesity are risk factors for neurodegenerative diseases
including Alzheimer’s disease (AD). Calorie restriction (CR), a dietary intervention which extends lifespan while
delaying or preventing age-related disease, is one plausible approach to lessen the burden of multiple age-
related diseases simultaneously, but reduced-calorie diets are notoriously difficult to sustain. Recent studies
have highlighted an important role for dietary protein in health and longevity, with protein restriction (PR) shown
to promote longevity and to mimic the metabolic, frailty, and cognitive benefits of CR.
During the initial project period, we found that specifically reducing dietary consumption of the three
branched-chain amino acids (BCAAs) – leucine, isoleucine, and valine – has sex-specific benefits for frailty and
lifespan in C57BL/6J mice. We determined that the metabolic and molecular effects of PR are both sex and
strain dependent, and that the role of a specific hormone proposed to mediate the effects of PR may be more
limited than previously suspected and also differ between sexes and strains. Finally, we found that the BCAAs
have distinct roles on metabolism, with restriction of isoleucine being necessary and sufficient for the metabolic
benefits of PR. In preliminary experiments, we have also found that isoleucine restriction has sexually dimorphic
effects on healthspan and longevity in genetically heterogenous mice, and that PR has beneficial effects on
cognition and disease pathology in a mouse model of Alzheimer’s disease.
Here, we will rigorously test the ability of graded restriction of isoleucine to promote health and longevity
in DBA/2J and C57BL/6J mice of both sexes, examining the effects on metabolic health, frailty, cognition and
lifespan as well as the effects on pathology and at the molecular level. We will identify the role of a specific
hormone, FGF21, in the metabolic response to isoleucine restriction. Finally, we will test if restriction of individual
BCAAs is necessary and sufficient for the ability of a PR diet to prevent or delay AD.
The proposed work will examine the role of the BCAA isoleucine on health and longevity in multiple
genetic backgrounds for the first time and answer long-standing questions regarding how dietary composition
impacts healthy aging. Importantly, we will gain new insight into the mechanisms that drive the potent effects of
isoleucine restriction on healthy aging, and break new ground identifying how individual BCAAs impact the
progression of AD. In the long term, this work will enable our lab and others to develop a mechanistic
understanding of how dietary BCAAs and other macronutrients regulate health and disease vulnerability, and to
identify new targets for pharmacological treatments to promote healthy aging.