# Regulation of epigenome stability by SIRT6 during aging. Supplement: Does centenarian variant of SIRT6 or bowhead whale SIRT6 confer protection from Alzheimer's disease?

> **NIH NIH R37** · UNIVERSITY OF ROCHESTER · 2020 · $385,000

## Abstract

SUMMARY
 Centenarians, people that live to 100 years of age, are remarkably protected from dementias, despite
their advanced age. Understanding factors that protect centenarians from Alzheimer’s disease (AD) may provide
new leads for successful treatment. Our parent grant application investigates the role of SIRT6 protein in
epigenome stability, genome maintenance and suppression of LINE1 (L1) transposable elements. Importantly,
SIRT6 deficient mice show neurodegeneration, and SIRT6 levels are reduced in patients with AD. We discovered
that L1s are activated during aging, especially in the brain, and the cytoplasmic DNA copies of L1s trigger type
I interferon response. We hypothesize that the neuroinflammation induced by L1 activity contributes to the
development of AD. Recently, a coding variant of SIRT6 has been identified in centenarians. Our preliminary
data shows that the centenarian variant of SIRT6 has higher mono-ADP-ribosylation activity, enhances DNA
repair, and provides stronger suppression of L1 transposable elements. Our recent study also demonstrates that
long-lived mammalian species possess more active SIRT6 protein.
 Our hypothesis is that SIRT6 from long-lived animals or long-lived humans confers protection
against AD by promoting genome and epigenome stability, and by reducing neuroinflammation.
 Bowhead whale is the longest-lived mammal with the maximum lifespan of 211 years. Here we propose
to examine whether overexpressing bowhead whale SIRT6, or human centenarian SIRT6 variants in AD model
mice delays the disease progression. These experiments will serve as a proof of principle that activating SIRT6
may be used as therapeutic strategy against AD.

## Key facts

- **NIH application ID:** 10123596
- **Project number:** 3R37AG046320-07S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Andrei Seluanov
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 3
- **Project period:** 2014-04-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123596

## Citation

> US National Institutes of Health, RePORTER application 10123596, Regulation of epigenome stability by SIRT6 during aging. Supplement: Does centenarian variant of SIRT6 or bowhead whale SIRT6 confer protection from Alzheimer's disease? (3R37AG046320-07S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10123596. Licensed CC0.

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