# SIRT6 role in facilitating more efficient genome and epigenome maintenance in long-lived species.

> **NIH NIH P01** · UNIVERSITY OF ROCHESTER · 2021 · $388,306

## Abstract

SUMMARY: The long-term goal of Project 1 is to identify mechanisms responsible for more efficient genome
and epigenome maintenance in long-lived animal species. Genome instability, including genomic
rearrangements arising from errors during repair of DNA breaks, and dysregulation of epigenetic landscapes are
believed to be contributing causes of aging. In the current period of support, we demonstrated that the efficiency
of DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), correlates positively with
maximum lifespan. Furthermore, we demonstrated that SIRT6 protein, which serves as an upstream regulator
of DSB repair, is a major factor responsible for the differences in DSB repair efficiency between species. SIRT6
ability to promote DSB repair correlated strongly with maximum lifespan. By dissecting SIRT6 sequence variation
across rodents with large differences in lifespan, we identified five amino acids fully responsible for the
differences in SIRT6 activity in promoting DSB repair, as well as the differences in SIRT6 deacetylation and
mono-ADP-ribosylation activities. Other preliminary studies identified SIRT6 as a key factor in epigenome
stability during aging. We found that SIRT6 suppresses activation of transposable elements in aged mice,
restores inducibility of NRF2 target genes, and confers more youthful expression signatures to senescent cells.
Based on these findings, our objectives are to expand our analysis of SIRT6 changes responsible for improved
DSB repair to other long-lived species; test whether long-lived species have more stable epigenome
maintenance upon DNA damage and characterize the role of SIRT6 in this process; and finally, test whether the
identified five amino acid changes that improve mouse SIRT6 to the level found in long-lived species result in
lifespan extension. Our overarching hypothesis is that longevity is associated with improved DSB repair and
epigenome maintenance and stimulation of SIRT6 activity can improve these processes and extend the lifespan.
We propose to: (1) Integrate data from multiple long-lived species to determine the landscape of amino acid
changes in SIRT6 that are associated with longevity and improved DSB repair; (2) Test whether the ability to
recover epigenome organization following DNA damage correlates with maximum lifespan, and identify the role
of SIRT6 in this process. We will collaborate with Project 2 to test the effect of hyaluronan on epigenome
maintenance, and with Project 3 to compare genome and epigenome maintenance in different rodent species
upon DNA damage. (3) Construct a “beaverized” SIRT6 mouse containing five beaver amino acid substitutions
responsible for enhanced SIRT6 activity and with Core C test whether these mice show improved health and
lifespan. We will work with Project 3 to characterize genome and epigenome stability in these mice and with
Project 4 to determine whether improved DNA repair in these mice results in more youthful meta...

## Key facts

- **NIH application ID:** 10152477
- **Project number:** 5P01AG047200-08
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Vera Gorbunova
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,306
- **Award type:** 5
- **Project period:** 2014-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152477

## Citation

> US National Institutes of Health, RePORTER application 10152477, SIRT6 role in facilitating more efficient genome and epigenome maintenance in long-lived species. (5P01AG047200-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10152477. Licensed CC0.

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