# Ketone ester diet to ameliorate age-related decline in memory and muscle mass

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $226,781

## Abstract

Project Summary (Abstract):
The global proportion of individuals 65 and older is growing and is expected to reach nearly 17% by 2050. Aging
is associated with a progressive decline in organ and tissue function resulting in alterations in cognition and
physical function. In particular, brain aging is manifested as impairments in executive function, working memory,
and episodic memory, and age-related sarcopenia leads to muscle weakness and impaired mobility. Both of
these can have a profound impact on the quality of life, particularly for those suffering from Alzheimer’s disease.
Ketone bodies, 3-hydroxybutyrate and acetoacetate, are important molecules providing energy to the brain
during development, fasting, and exercise. Our work has shown that levels of ketone bodies decrease with aging.
This is significant as glucose transport into the brain is impaired with aging. Interestingly, while the abundance
of GLUT1 (which transports glucose into the brain) declines, MCT1 (which transport ketone bodies into the brain)
has been shown to increase in the hippocampus of aged rats, the brain region essential for learning and
formation of new long-term memories. Recent studies have shown that a ketogenic diet results in beneficial
effects on age-related memory, which suggest ketones serve as an alternate fuel source when glucose uptake
and catabolism is impaired. Additionally, 3-hydroxybuyrate has been shown to inhibit the NLRP3 inflammasome,
activation of which has been linked with age-related sarcopenia. A major issue with the ketogenic diet is the low
long-term adherence, and its restrictive nature with respect to fiber and essential nutrient intake. Increasing
ketone concentrations in the blood through a supplement would therefore be of benefit for an aging population.
In aim 1, we propose to determine the effect of supplementation of a ketone monoester ((R)-3-hydroxybutyl-(R)-
3-hydroxybutyrate (3-HBHB)), which has been shown to increase circulating 3-hydroxybutyrate concentrations,
on long-term memory in aged mice through a series of cognitive tests at baseline and after 7 weeks on the diet.
We will then determine how hippocampal transporters, metabolic enzymes, and metabolites change in response
to increased levels of ketones in the blood to provide a mechanistic understanding of how ketone esters impact
hippocampal function. In our second aim, we will compare the muscle mass, strength, and voluntary physical
activity of mice provided 3-HBHB with mice on a control diet, and then determine mechanistically how skeletal
muscle mass and metabolism is affected by the ketone ester diet. The knowledge gained from this study could
have important implications for the aging population, and could represent a foundation on which to develop
robust therapeutic treatments to prevent age-related memory decline and sarcopenia.

## Key facts

- **NIH application ID:** 10142745
- **Project number:** 1R21AG071156-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** JON J. RAMSEY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $226,781
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142745

## Citation

> US National Institutes of Health, RePORTER application 10142745, Ketone ester diet to ameliorate age-related decline in memory and muscle mass (1R21AG071156-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10142745. Licensed CC0.

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