# Reversing the epigenetic code of aging through ketogenic diets

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $259,200

## Abstract

Project Summary – Project 2
Reversing the epigenetic code of aging through ketogenic diets
The epigenetic modifications that cause aging and tissue degeneration are currently unknown. We measured
the methylated lysines of histone H3 in mouse livers with aging to identify the epigenetic signature of aging.
Caloric restriction (CR) intervention, which extends lifespan, preserved a younger epigenetic profile, reversing
multiple epigenetic marks. We plan to overlap the epigenetic signature of aging with ketogenic diet (KD) and
CR interventions, with metabolomic profiles and transcriptomic profiles prepared by Project 2. This will result in
a product of aging-responsive and KD-responsive and metabolically mapped epigenetic biomarkers that
reverse the epigenetic signature of aging. The hypothesis of Project 2 is that epigenetic marks drive the
program of aging and cognitive decline, and that determining the epigenetic signature of the KD will point out
genes and metabolic nodes that can serve as biomarkers of the KD functional effect to extend functional
longevity. A further hypothesis is that these biomarkers identified in mice could overlap those in humans,
thereby pointing to human biomarkers of aging as well as dietary amelioration. The goal of this study is to
determine the epigenetic effects of KD on aging and neurodegeneration. Specific Aims include the following: 1)
identify the epigenetic profile of aging through assessment of histone marks; 2) dissect the interaction between
diets and chromatin regulation during aging by overlapping metabolomics, transcriptomics and epigenomics;
and 3) overlap the mouse epigenetic signature of aging with humans to the extent possible to identify age-
related biomarkers. To achieve these aims, Project 2 will determine the histone code of aging in wild-type and
Alzheimer's model mice. We will overlap age- and diet-related epigenetic, transcriptomic and metabolomic
profiles and biomarkers, together with Project 1 and Core B, to identify functional biomarkers of aging and
cognitive decline that are reversed by the KD. We will also investigate the epigenetic signature of potential
biomarkers in the blood of aged individuals, and in Alzheimer's brain tissue chunks provided by Core C. Project
2 has the potential to identify functional biomarkers of aging and cognitive decline, and to identify which of
these biomarkers respond to the KD in mice. Because the same biomarkers can be tested in human samples,
there is the potential to identify novel human biomarkers of functional aging and how to reverse them through
dietary strategies.

## Key facts

- **NIH application ID:** 10685459
- **Project number:** 5P01AG062817-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Pier Giuseppe Pelicci
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $259,200
- **Award type:** 5
- **Project period:** 2019-06-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10685459

## Citation

> US National Institutes of Health, RePORTER application 10685459, Reversing the epigenetic code of aging through ketogenic diets (5P01AG062817-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10685459. Licensed CC0.

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