# Discriminating between causes of age-related variegated gene expression

> **NIH NIH R00** · ALTIUS INSTITUTE FOR BIOMEDICAL SCIENCES · 2022 · $249,000

## Abstract

Project Summary:
Cells in the same tissue can express the exact same gene at different levels, and this cell-to-cell variation
tends to increase with age. Cells in tissues need to coordinate gene expression to maintain homeostasis.
Thus, dysregulated variation may be related to, or causative of, the loss of physiological capacities with age.
However, the causes and consequences of this increased gene expression variation are not known. In this
project I propose to use C. elegans and human tissue culture as model systems to study age-related variation
in gene expression between homologous cells in controlled environments. In our prior study, we found strong,
cell-specific expression patterns for many reporter genes in young C. elegans animals; that is, for many genes
in young animals, the ratio of gene A to gene B expression was fixed in cell type X, and different than in cell
type Y. We found that this fixed expression pattern deteriorates with age; in a given cell type genes become
expressed at variable stoichiometry in individual animals. Similarly, in mammals, cell-to-cell variation in gene
expression observed during aging or senescence is also uncorrelated. Thus, I propose that growing
dissimilarity between homologous cells with age may be a conserved phenomenon of aging. I refer to increase
of uncorrelated gene expression variation with age as age-related variegated gene expression (VGE). In the
proposed project, I will harness both the power of C. elegans and human cell culture to investigate how
homologous cells become more dissimilar with age. In the K99 phase of the project I will learn techniques for
quantitative microscopy, single cell RNAseq and aging-focused human cell culture methods. Throughout the
K99 and R00, I will be investigating potential causes that contribute to age-related VGE. K99-Aim1: I will
determine if changes of allele access with age contribute into VGE in C. elegans by analyzing expression from
of identical promoters integrated at the identical loci on sister chromosomes. K99-Aim2: I will learn and use
single-cell RNA-seq to determine if prevalence of allele bias/monoallelism rises in human fibroblasts with age.
R00-Aim3: I will determine what genes and pathways become highly variably expressed with age. I will
examine if variable expression of these genes is stochastic or adaptive by determining if expression levels of
reporters of these genes predict stress resistance, health or lifespan. These experiments will address the
hypothesis that adaptive physiological responses of individual cells to age-related stress contribute to VGE.
R00-Aim 4: Using human cell culture, I will determine if cell-to-cell communications propagate VGE among
cells with youthful expression patterns – that is, cells without VGE.

## Key facts

- **NIH application ID:** 10542536
- **Project number:** 4R00AG061216-03
- **Recipient organization:** ALTIUS INSTITUTE FOR BIOMEDICAL SCIENCES
- **Principal Investigator:** Nikolay Burnaevskiy
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2022-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10542536

## Citation

> US National Institutes of Health, RePORTER application 10542536, Discriminating between causes of age-related variegated gene expression (4R00AG061216-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10542536. Licensed CC0.

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