# Comparative genomics and epigenomics of aging

> **NIH NIH P01** · UNIVERSITY OF ROCHESTER · 2022 · $418,943

## Abstract

SUMMARY: The aging process can be naturally accelerated and decelerated during evolution leading to
significant diversity in lifespan among related species. Mammals represent a particularly convenient system to
examine this diversity at the molecular level, because these animals are characterized by a nearly hundred-fold
difference in lifespan and their tissues and cultured cells are readily available. Unbiased characterization of
genes and processes that are associated with natural changes in lifespan within mammals may lead to the
development of approaches that target the aging process and possibly delay it. We hypothesize that mammalian
lifespan is adjusted through a combination of common and lineage-specific processes and provide preliminary
data in support of this idea. In the ongoing phase of the PPG we generated exciting data that support our general
approach to lifespan control. We generated comprehensive molecular profiles across mammals, including
species of exceptional longevity. These datasets include RNAseq, metabolite profiling, and chemical element
profiling as well as the genomes of long-lived naked mole rat and beaver. We also generated a DNA methylation
clock for mice and found that it correctly reports the effects of longevity interventions. We propose to utilize these
tools and approaches to address, in close collaboration with other Projects and Cores, critical questions in our
understanding of natural control of mammalian lifespan. Specifically, we propose to examine: (1) Molecular
features underlying longevity in mammals. We will utilize the profiles we generated to identify molecular features
and their combinations, with a focus on gene expression and metabolites, linked with longevity, ultimately
building molecular signatures of long-lived species (with Core C). We will also carry out gene expression and
metabolite profiling analyses of beaverized SIRT6 mice (with Project 1 and Core B), naked mole rat HAS2
transgenic mice, and mice treated with hyaluronidase inhibitors (with Project 2 and Core B), providing critical
molecular insights into the mechanisms by which these genes promote longevity. (2) Genomics of long-lived
rodents. We will carry out comprehensive annotation of new, much improved assemblies of naked mole rat and
beaver genomes (with Core C), in turn providing critical resources for Projects, 1, 2 and 3. We will also focus on
the evolution of DNA repair and chromatin remodeling genes and characterization of gene loss and gain in these
species. (3) Applications of the epigenetic clock to mouse models of longevity. We have recently developed a
mouse DNA methylation clock, which we will apply to the animal and cell culture models examined in the PPG
(with Projects 1, 2, and 3, and Cores B and C). (4) Development and application of the naked mole rat epigenetic
clock. We will utilize naked mole rats differing in age (with Project 2 and Core B), quantify age-dependent patterns
of DNA methylation, and develop and ap...

## Key facts

- **NIH application ID:** 10399524
- **Project number:** 5P01AG047200-09
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Vadim N. Gladyshev
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,943
- **Award type:** 5
- **Project period:** 2014-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399524

## Citation

> US National Institutes of Health, RePORTER application 10399524, Comparative genomics and epigenomics of aging (5P01AG047200-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399524. Licensed CC0.

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