# Investigations of targets, mechanisms, and optimal delivery of therapeutic ketosis for functional longevity and treatment of Alzheimer's disease

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $2,236,723

## Abstract

Project Summary – Overall
'Investigation of targets, mechanisms, and optimal delivery of therapeutic ketosis for functional
longevity and treatment of Alzheimer's disease'
We recently demonstrated, for the first time anywhere, that the isocaloric continuous Ketogenic diet extends
cognitive and memory and muscle functions in mice, and significantly increases median longevity by 13%1. In
the same issue of Cell Metabolism, others showed that the intermittent Ketogenic diet (iKD) preserves many
late life functions in mice. These simultaneously-published findings have profound mechanistic (for
understanding the biology of aging) and translational (for US public health) implications. Mechanistically, they
suggest the hypothesis that 'ketosis delays aging'. The PPG application is designed to identify mechanistic
targets and biomarkers by which therapeutic ketosis delays aging in mice, and are consistent with the
geroscience concept, i.e. that interventions that delay aging should delay age related disease, in this case AD,
Alzheimer's. By identifying the KD mechanisms and biomarkers in mice, this study will lay the ground work for
future human studies. In order to serve these mechanistic and translational goals, we propose these four
projects. 1, Cortopassi, involves the mechanistic dissection of the ketolongevity mechanism, using
transcriptomics, protein arrays and knockout mice, and Shc antagonists for Alzheimer's disease. 2, Pelicci,
maps the epigenetic consequences of aging, and how the KD reverses them, and to what extent these overlap
with aging and Alzheimer's. 3, Baar, addresses KAT and acetylation mechanisms by which improved muscle
function delays brain aging in wild-type and Alzheimer's mouse model. 4, Ramsey, identifies the
'ketotherapeutic envelope' necessary for preservation of late-life functions and longevity, and with respect to an
Alzheimer's mouse model. These Projects are all interactive as shown in the text. They are also supported by
an outstanding Animal Core C, led by Kent Lloyd DVM PHD and Lee-Way Jin MD PHD with stellar experience
in mouse biology and Alzheimer's disease, brilliant support by Biostatistics Core B, Kyoungmi Kim, and a well-
organized Administrative Core A. The completion of this project will lead to new mechanistic inside into the
therapeutic ketosis longevity mechanism, and identify biomarkers of ketotherapeutic effect that could be
relevant to preservation of functions and longevity in aging Americans, and those with Alzheimer's disease.

## Key facts

- **NIH application ID:** 9955153
- **Project number:** 5P01AG062817-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Gino A Cortopassi
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,236,723
- **Award type:** 5
- **Project period:** 2019-06-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955153

## Citation

> US National Institutes of Health, RePORTER application 9955153, Investigations of targets, mechanisms, and optimal delivery of therapeutic ketosis for functional longevity and treatment of Alzheimer's disease (5P01AG062817-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9955153. Licensed CC0.

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