# UNDERSTANDING OF ESSENTIAL GENE FUNCTION IN AGING

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $360,279

## Abstract

PROJECT SUMMARY
Functional genomic studies have contributed enormously to our understanding of conserved genetic pathways
influencing aging in evolutionarily divergent organisms. The use of high throughput machinery and the
application of skilled manpower along with screening systematic gene knock-out in yeast and gene depletion
(RNA interference) in worm have led to the identification of several genes that influence life span. Some of
these genes have human orthologues and have been examined successfully in the context of invertebrate and
mammalian aging. Although, it is now clear that at least some aspects of cellular aging are highly conserved,
identification of conserved components of longevity pathways across evolutionarily divergent organisms has
lagged far behind. We will address this issue by analyzing the function of conserved essential genes in
regulation of longevity. Essential genes in yeast are approximately 5 times more likely to have human
orthologs than non-essential genes. For example, among the 1123 yeast essential genes, 856 of them have
both worm and human homologs. However, to date, despite the greater functional importance and high
conservation between species, there has been no comprehensive study to characterize the role of essential
genes in aging. Accordingly, the goal of this proposal is to test the hypothesis that essential genetic modifiers
of aging in yeast are more likely to play a conserved role in the aging process in multicellular eukaryotes. In a
complete screen of yeast and validation screen from worm strains with increased expression of one the
essential genes for which there is a clear human ortholog, we made the striking observation that essential
genes are much more likely than non-essential genes to play an important conserved role in lifespan
regulation. We propose to use recently developed tools to screen the conserved gene dosage effect on
lifespan using C. elegans (Aim 1). Next, we will identify genetic mechanisms of lifespan determination by
analyzing genome-scale patterns of age-associated mRNA expression changes in long living strains and
place new longevity genes into or out of known longevity pathways with genetic epistasis experiments (Aim 2).
In the last aim, we will provide proof of mechanistic concept by investigating the molecular mechanisms
underlying a promising, potentially conserved in humans, mode of longevity stemming from the overexpression
of conserved essential genes (Aim 3). Such genes are a rich, untapped source for understanding genetic
mechanisms of longevity determination. Thus, every hit represents a newly discovered longevity gene with a
conserved human ortholog. Successful completion of this proposal will yield a wealth of new information about
conserved mechanisms of molecular determination of aging and will identify dozens of candidate genes for
testing in higher eukaryotes with important ramifications for healthy human aging.

## Key facts

- **NIH application ID:** 10803044
- **Project number:** 1R01AG079944-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Alaattin Kaya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $360,279
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803044

## Citation

> US National Institutes of Health, RePORTER application 10803044, UNDERSTANDING OF ESSENTIAL GENE FUNCTION IN AGING (1R01AG079944-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10803044. Licensed CC0.

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