# UNDERSTANDING CELLULAR AND TRANSCRIPTIONAL REGULATORY CHANGES IN HUMAN AGING

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $149,398

## Abstract

The process of aging is believed to involve progressive loss of control of transcriptional regulation, in particular
involving regulatory mechanisms referred to as “epigenetic”. These changes have been mostly characterized
as an increase in variability of DNA methylation with age, referred to as epigenetic drift, with a subset of loci
showing an intriguing, progressive change of DNA methylation that appears to act as an “epigenetic clock”.
We note, however, that a DNA methylation assay reports much more than the transcriptional regulatory state
of the cells studied. DNA methylation differences between individuals are now appreciated to indicate, for
example, cell subtype compositional or DNA sequence differences, without any cells necessarily having
changed their transcriptional regulation. DNA methylation is thus both a readout of transcriptional regulation
and of other molecular and cellular processes, all generating changes in DNA methylation of the same modest
magnitude.
To perform a study that allows DNA methylation changes to be interpreted with confidence, we need to
understand the sources of variability affecting this transcriptional regulator. A rigorous study should therefore
include test genotypes, cell subtype proportions, and transcriptional variability, all of which can change DNA
methylation values in a cell population. Furthermore, understanding the cis-regulatory landscape in the cells
tested is essential, as this allows a focused analysis at loci informative for DNA methylation changes.
An ideal cell type to use in an aging study is CD4+ T lymphocytes. Not only is this a cell type that appears to
mediate a number of age-related phenotypes, and is accessible from peripheral blood for genome-wide assays
of cohorts, it can also be tested for repertoire diversity using T cell receptor assays, and for cell subtype
composition using multiple orthogonal techniques. We will use the strengths of our institution’s Nathan Shock
Center of Excellence in the Biology of Aging to collect a well-phenotyped cohort for this study.
Our data will reveal whether age-associated epigenetic changes occur independently of confounding
influences, but will also allow us to uncover the other cellular and molecular events taking place in CD4+ T
cells. An innovative goal is the identification of age-labile functional sequence variants, loci that change their
ability to influence gene expression with age, a unique insight into the relationship between DNA sequence
polymorphism and aging. We will also test the hypothesis that epigenetic clock CpGs represent loci mediating
age-associated glucocorticoid receptor resistance, a separate model for age-associated compromise in cellular
function.
The outcome of this project will be the most rigorous and definitive study to date of epigenetic changes in
aging. We expect human aging to involve a combination of cellular and molecular events. These findings will
allow new, comprehensive insights into how CD4+ T cells are ...

## Key facts

- **NIH application ID:** 10141372
- **Project number:** 3R01AG057422-04S1
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** John Greally
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $149,398
- **Award type:** 3
- **Project period:** 2018-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141372

## Citation

> US National Institutes of Health, RePORTER application 10141372, UNDERSTANDING CELLULAR AND TRANSCRIPTIONAL REGULATORY CHANGES IN HUMAN AGING (3R01AG057422-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10141372. Licensed CC0.

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