NIH Research Festival
FARE Award Winner
Insulin Resistance (IR) is implicated in brain aging and Alzheimer‚Äôs disease (AD) pathogenesis. An extensive animal literature suggests pro-cognitive and beneficial systemic and brain effects of intermittent calorie restriction (CR). We conducted a Randomized Controlled Trial of 5-2 CR (2 days 480 Kcal/day; 5 non-restricted days) compared to low-intensity ‚Äúhealthy living‚Äù (HL) diet by USDA recommendations for 8 weeks, in 40 overweight cognitively intact individuals > 55 years old with peripheral IR. After 8 weeks, both diets decreased BMI, weight and waist circumference suggesting high compliance. 5-2 CR but not HL diet increased blood beta-hydroxybutyrate and acetoacetate suggesting increased ketogenesis and decreased HOMA2-IR indicating IR alleviation. 5-2 CR but not HL diet improved executive function and cued memory. 5-2 CR but not HL diet decreased sedentary behavior by actigraphy. Moreover, 5-2 CR but not HL diet decreased brain glucose by magnetic resonance spectroscopy (MRS) indicating increased glucose metabolism. Both diets decreased equally regional BrainAGE (brain-age-gap on structural magnetic resonance imaging (MRI)) in the anterior cingulate cortex. Many effects varied by APOE e4 genotype. However, in cerebrospinal fluid (CSF) and neuron-derived extracellular vesicles (NDEVs), no changes were observed for Abeta42, Abeta40, total Tau and P181-Tau with either diet, and no change in neuronal IR, as assessed by NDEV-associated P-S312-insulin receptor substrate (IRS)-1. Overall, both diets had beneficial systemic and brain effects, with 5-2 CR showing additional positive effects on IR, ketogenesis, cognition, and brain glucose metabolism, potentially contributing to healthier brain aging. However, no biomarker evidence emerged indicating AD cascade modulation.
Scientific Focus Area: Clinical Research
This page was last updated on Monday, September 25, 2023