# Validation and optimization of epigenetic clocks

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $621,176

## Abstract

Project Summary/Abstract
It has been challenging to find and validate molecular targets for extending human healthspan because most
clinical biomarkers are neither sufficiently mechanistic nor proximal to fundamental mechanisms of aging to
serve as indicators. To address the challenge of developing biomarkers of aging, we will primarily focus on
epigenetic alterations because it is highly likely that with this work DNA methylation (DNA) will come out as a
valid biomarker ready for clinical application. The overarching goals of this proposal are a) to realize the great
promise of DNAm based biomarkers of aging (known as epigenetic clocks) for human interventional studies
and b) to advance their mechanistic understanding. This proposal builds on our active research program
surrounding DNAm based biomarkers of aging and their relationship to markers of cellular senescence. We
and others have demonstrated that existing prototypes of DNAm biomarkers are predictive of lifespan and
many age-related conditions. We have established that some DNAm biomarkers relate to lifestyle interventions
and existing DNAm biomarkers are already being used in human clinical trials of anti-aging interventions. With
these proof-of-concept studies completed, we enter the next phase where these biomarkers need to be
optimized to track the effectiveness of interventions in human studies. Although it is widely acknowledged that
DNAm biomarkers are remarkably robust, they remain sensitive to technical variation. To minimize such
spurious variation, we will optimize all components within the workflow, from collection of human samples to
the final point of analysis.
In our previous planning grant, our network of researchers designed a study for evaluating the utility of DNAm
based biomarkers of aging in human longitudinal cohort studies. Building on these plans, we will test whether
DNAm biomarkers are indicators of a fundamental aging process underlying healthspan by carrying out human
longitudinal cohort studies, genetic studies, and interventional studies. We will relate DNAm biomarkers to
markers of cellular senescence and a battery of clinical biomarkers of aging in order to advance mechanistic
insights. We will evaluate whether a panel of biomarkers is more predictive of healthspan/multiple health
outcomes as opposed to a single marker. We will optimize DNAm biomarkers for use in human ex vivo studies
for testing responsiveness to various anti-aging or pro-aging interventions. The resulting optimized system also
serves as a potential high-throughput drug screening system, which will have the advantage of being controlled
for potential confounding factors and is of human origin. Collectively, these investigations will result in (a) the
optimization of the entire workflow process for the application of DNAm biomarkers in human interventional
studies and (b) context-of-use statements that fully describe the purpose and use of each biomarker.

## Key facts

- **NIH application ID:** 9950952
- **Project number:** 5U01AG060908-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Steve Horvath
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $621,176
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950952

## Citation

> US National Institutes of Health, RePORTER application 9950952, Validation and optimization of epigenetic clocks (5U01AG060908-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9950952. Licensed CC0.

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