# Analysis of Cell and Molecular Phenotypes of the Longevity Associated FOXO3 Variant

> **NIH NIH P20** · KUAKINI MEDICAL CENTER · 2020 · $250,512

## Abstract

ABSTRACT
The United States is facing a boom in the proportion of its population over the age of 65. This
will put enormous strain on the health care system for decades to come unless the impact of
age-related diseases can be reduced in the short term. The process of aging is associated with
the development of all age-related diseases; telomere length, adult stem cell frequency and
function, all decline with age. A variant of the FOXO3 gene at SNP rs2802292 associates with
longevity in many human populations. This FOXO3 variant specifically confers a substantially
reduced risk of dying of coronary artery disease (>26%), similar in magnitude to common
cardiovascular risk factors, such as hypertension, diabetes, smoking. FOXO3 also impacts other
age-related diseases, physical and possibly cognitive function.
The maintenance of adult hematopoietic- and neural- stem cells is dependent on FOXO3.
Despite these associations it is unknown by what cellular and molecular mechanisms FOXO3
influences human longevity and healthy aging. Current studies of potential mechanisms have
mostly been limited to cell and animal models; thus, the proposed project will make use of a
large, longitudinal clinical cohort to attempt to fill this gap in our understanding.
The specific aims proposed to assess the mechanisms which FOXO3 operates via to impact
human longevity are: 1 - Test the hypothesis that the most robust protective FOXO3 variant
(SNP rs 2802292) affects telomere dynamics in a longitudinal study of a human cohort with
several decades of follow up and in cross-sectional studies of male and female offspring; 2 -
Test the hypothesis that the protective FOXO3 variant affects blood stem cell numbers and
function; and 3: - Test the hypothesis that the longevity-associated FOXO3 variant affects the
maintenance of stem cells in the brain and neurological health as a function of age.
Telomere attrition with age is variable between individuals, and the rate of attrition is associated
with cardiovascular disease risks and mortality. If FOXO3 affects genome stability via an impact
on the rate of telomere attrition, or changes in telomere maintenance via telomerase levels or
expression, it will be evident in the proposed longitudinal and cross-sectional analyses of
telomere dynamics spanning several decades of life. Stem cell populations act as a reserve for
replenishment of tissues throughout adulthood, and these populations decline in number and
function with age. If the FOXO3 longevity variant contributes to improved maintenance of these
cells it should be reflected in the frequency and function of stem cells from the peripheral blood
and brain, and with healthier phenotypes of brain aging, such as higher neural stem cell count,
reduced accumulation of senescent cells, fewer plaques/tangles, more robust dendrite/spine
branching, and/or better cognitive function.
The proposed study will perform the first clinical assessment of the relationship between
longitudinal telome...

## Key facts

- **NIH application ID:** 10015318
- **Project number:** 5P20GM125526-02
- **Recipient organization:** KUAKINI MEDICAL CENTER
- **Principal Investigator:** Philip M C Davy
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $250,512
- **Award type:** 5
- **Project period:** 2019-09-10 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10015318

## Citation

> US National Institutes of Health, RePORTER application 10015318, Analysis of Cell and Molecular Phenotypes of the Longevity Associated FOXO3 Variant (5P20GM125526-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10015318. Licensed CC0.

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