# Ketogenic Oscillations and Neurometabolic Healthspan

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $385,204

## Abstract

SUMMARY
Caloric restriction, intermittent fasting, time restricted feeding/eating, fasting mimicking diet, and the fuel-
switching linked to exercise have all shown evidence of improving metabolic and brain health. Studies funded
through the parent grant will be the first to directly address the specific roles of ketone metabolism upon the
metabolic, energetic, neuromodulatory, and cognitive benefits conferred by intermittent metabolic switching,
which has pleiotropic effects, including augmentation of ketone metabolism. Although focused on neurometabolic
declines associated with aging, none of the studies funded through the parent grant directly addresses the role
of nutrient oscillations, fuel switching, or ketone metabolism in Alzheimer’s Disease (AD). However, extensive
literature shows aberrant energy metabolism occurs in AD, including reduced glucose utilization during
neurodegeneration. Mild cognitive impairment/AD also is associated with impaired insulin sensitivity and reduced
VO2max compared to controls, factors both linked to mitochondrial function. A logical extension of impaired
glucose metabolism is the understudied hypothesis that a ketogenic diet could symptomatically benefit AD
subjects. Thus, multiple trials are targeting ketogenic diets to treat cognitive decline in neurodegenerative
diseases, and other interventional approaches that provoke intermittent metabolic switching are also of great
interest for AD therapy, including intermittent fasting. The central hypothesis of this supplemental application is
that integrated ketone metabolism is responsible for the improvement in AD outcomes attributable to intermittent
metabolic switching. The single Specific Aim is to use an accepted mouse model of AD to determine if oscillations
in ketogenic flux via intermittent fasting not only provide fuel to the brain, but also improve molecular and
histopathological outcomes. The rTg4510 (tauP301L bitransgenic) mouse model will be used to study the formation
of neurofibrillary tangles associated with Alzheimer's disease. The effects of intermittent fasting, versus ad
libitum-fed control, on metabolic and histopathological outcomes will be quantified in mice with hepatic ketogenic
sufficiency and compared to those of mice with genetically programmed ketogenic insufficiency. Cutting edge
metabolomics and metabolic flux analyses will be used to quantify brain glucose and ketone utilization, and
molecular and histopathological approaches will be used to reveal effects on AD pathogenesis. IMPACT: The
benefits of ketogenic therapies on health span are commonly presumed to occur through ketone metabolism,
but this has never been proven. The experiments proposed for the Supplement will determine if ketone synthesis
in liver for utilization in brain plays a mechanistic role in clinically relevant interventions for AD. Moreover, this
work will elucidate specific therapeutic targets for individuals who cannot perform this lifestyle intervention but
fo...

## Key facts

- **NIH application ID:** 10294352
- **Project number:** 3R01AG069781-01S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Peter A Crawford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,204
- **Award type:** 3
- **Project period:** 2020-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10294352

## Citation

> US National Institutes of Health, RePORTER application 10294352, Ketogenic Oscillations and Neurometabolic Healthspan (3R01AG069781-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10294352. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*