# Mechanisms of the signaling metabolite β-hydroxybutyrate in Alzheimer's disease and the aging brain

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2022 · $63,102

## Abstract

PROJECT SUMMARY
 Signaling metabolites are small molecules with routine functions in cellular energy metabolism that also
act as signals to regulate diverse cellular pathways in response to a changing energy state. Signaling
metabolites link nutrition to aging. Many of the emerging geroscience therapies that target mechanisms of
aging have come from the discovery and understanding of signaling metabolites. The ketone body β-
hydroxybutyrate (BHB) is a new signaling metabolite. It is produced during fasting, dietary restriction, exercise,
or carbohydrate restriction to keep the body’s tissues supplied with energy when glucose is scarce. We now
have growing evidence that it also functions as a signal, by inhibiting enzymes, binding directly to proteins as a
post-translational modification, and activating receptors. Through its signaling activities, BHB regulates gene
expression, inflammation, metabolism, senescence, and other cellular activities important to both aging and
Alzheimer’s disease (AD).
 We recently showed for the first time that ketogenic diet (KD), which stimulates endogenous production
of BHB similar to fasting, improves survival in aging mice and prevents age-related declines in memory. We
also found that KD improves memory in the hAPPJ20 AD mouse model, and reduces abnormal epileptiform
discharges that contribute to memory decline. KD is a complex intervention, and though it is now being studied
in clinical trials of AD, a better understanding of which aspects of KD are most helpful should lead to better
targeted and more effective therapies. We have successfully developed an innovative toolset of dietary,
chemical, and genetic tools to isolate the individual components of KD, including carbohydrate restriction, BHB,
energy provision by BHB, and cellular signaling activities of BHB. We will use these tools to uncover the
specific mechanisms by which BHB improves memory in normal aging and in AD mice (Aim 1), and reduces
epileptiform discharges in AD mice (Aim 2). We will characterize key molecular changes that BHB causes in
the proteomic landscape of the brain, including mapping the acetylome and new BHBylome (Aim 3).
 This project combines expertise in both geroscience and AD with a deep understanding of BHB biology
to carry out closely aligned mechanistic studies using both aging and AD models. It examines the intersection
of a molecular mechanism that is broadly relevant to aging (ketone bodies as metabolic signals) with one
highly specific to AD (aberrant epilepsy-like network hypersynchrony). It is highly likely to stimulate further
progress on AD because the mechanistic framework it generates will directly inform translational studies
involving ketone body compounds and ketogenic diets. These data will help establish criteria for designing
effective interventions, provide relevant intermediate biomarkers, and permit deeper investigation into the
downstream molecular targets most relevant to AD.

## Key facts

- **NIH application ID:** 10469290
- **Project number:** 3R01AG067333-02S1
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** John C Newman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $63,102
- **Award type:** 3
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469290

## Citation

> US National Institutes of Health, RePORTER application 10469290, Mechanisms of the signaling metabolite β-hydroxybutyrate in Alzheimer's disease and the aging brain (3R01AG067333-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10469290. Licensed CC0.

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