# Mechanisms of epigenome stability in long-lived species.

> **NIH NIH P01** · UNIVERSITY OF ROCHESTER · 2024 · $688,674

## Abstract

Summary: Long-lived species evolved efficient mechanisms of genome and epigenome maintenance, which
can be adapted to extend human lifespan and healthspan. Furthermore, genomic instability has been implicated
in Alzheimer's Disease (AD) and Related Dementias (ADRD). Investigating long-lived species provides us with
an unparallelled opportunity to discover novel longevity adaptations perfected over millions of years of evolution.
In the current period of support, we made several discoveries that shed light onto the mechanisms responsible
for more efficient genome and epigenome maintenance in long-lived mammals. We demonstrated that DNA
double-strand break (DSB) repair strongly correlates with species maximum lifespan. We showed that SIRT6 is
responsible for the major part of this correlation. We demonstrated that a SIRT6 variant with enhanced mono-
ADP-ribosylation activity is enriched in human centenarians. We demonstrated that somatic mutation rates
inversely correlate with maximum lifespan of species. We found that transposable elements become
derepressed with age and contribute to inflammation and epigenetic drift. Finally, we developed transcriptomic
signatures of short- and long-lived species and demonstrated DNA DSB repair genes are more highly expressed
in long-lived species, while inflammation and cytoplasmic DNA sensing pathways are dampened in long-lived
species. We discovered that the longest-lived mammal, the bowhead whale, has extremely efficient and accurate
DNA DSB repair, mediated by high levels of cold-induced RNA binding protein (CIRBP). Our unpublished data
demonstrates that several bat species have highly efficient DNA DSB repair mediated by yet unknown
mechanisms. We also obtained preliminary data that long-lived species have a more stable epigenome when
subjected to DNA damage and identified combinatorial histone modifications (PTMs) that correlate with longevity.
These findings put us in an excellent position to identify the fundamental mechanisms of longevity and develop
antiaging interventions based on targeting these newly identified pathways. Our aims are: (1) Understand
epigenetic determinants of longevity. We will identify genes controlled by longevity-associated PTMs, identify
reader and writer enzymes and test whether these PTMs can be manipulated to extend lifespan; (2) Understand
the mechanisms of genome and epigenome stability in long-lived species; we will identify proteins that promote
more efficient DNA repair in long-lived species and identify DNA and RNA modifications associated with longer
lifespan using state-of-the-art mass spectrometry approaches; (3) Test whether interventions targeting longevity
adaptations, i.e. SIRT6, CIRBP and cytoplasmic DNA sensing pathways improve genome and epigenome
stability, delay AD onset, and increase lifespan in mice. We will collaborate with Project 2 to test the relationship
between genome stability and AD, with Project 3 to measure mutation rates and with Project 4 to t...

## Key facts

- **NIH application ID:** 10848566
- **Project number:** 2P01AG047200-11
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Vera Gorbunova
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $688,674
- **Award type:** 2
- **Project period:** 2014-05-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848566

## Citation

> US National Institutes of Health, RePORTER application 10848566, Mechanisms of epigenome stability in long-lived species. (2P01AG047200-11). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10848566. Licensed CC0.

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