# Mechanisms of longevity in the naked mole rat: high molecular weight hyaluronan and stable epigenome. Supplement: Hyaluronan from naked mole rats as potential Alzheimer's disease therapy.

> **NIH NIH P01** · UNIVERSITY OF ROCHESTER · 2020 · $385,000

## Abstract

Summary
 The overarching goal of our funded program project grant (PPG) is to understand the mechanisms of
longevity that evolved in long-lived mammalian species. Project 2 led by Dr. Andrei Seluanov focuses on the
mechanisms of longevity and cancer resistance of the naked mole rat. Naked mole rat is the longest-lived rodent
with the maximum lifespan of 32 years. Naked mole rats are a model of healthy aging as they do not display
age-related pathologies almost until death. Remarkably, naked mole rats brains contain high levels of Aβ, similar
to what is found in 3xTg Alzheimer’s disease (AD) model mice, but they do not form plaques and do not show
any signs of neurodegeneration. Our group has found that naked mole rat tissues, including brain, contain very
high levels of high molecular weight hyaluronan (HA). HA is a linear polysaccharide that is the main non-protein
component of extracellular matrix. HA has potent cytoprotective, anti-inflammatory and antioxidant properties,
and, as we discovered, plays important role in cancer resistance and longevity of naked mole rat. Core B of the
PPG maintains colonies of naked mole rats at the University of Rochester and recently developed transgenic
mouse model that overexpresses naked mole rat hyaluronan synthase 2 gene.
 In this Administrative supplement we propose to expand our research into the field of AD. We
hypothesize that HA protects naked mole rat brain from AD by counteracting aging related
neurodegeneration, inflammatory processes and neuropathology triggered by Aβ. To test this hypothesis,
we propose the following three aims: (1) Test whether high molecular weight HA is protective against aging
related phenotypic and morphological changes in mice over 2 years of age. We will test for signs of
neurodegeneration, aging-related inflammation and age-related degradation in central nervous system (CNS) of
our transgenic mice overexpressing naked mole rat hyaluronic acid synthase 2 (nmrHAS2). (2) Assess the effect
of endogenous high molecular weight HA on acute and chronic neuroinflammation in young mice. By subjecting
mice to LPS induced inflammation we will be able to assess whether HA is protective against acute and chronic
states of inflammation in nmrHAS2 mice. (3) Test the protective effect of high molecular weight HA in transgenic
AD mouse models expressing nmrHAS2. We will develop a transgene of nmrHAS2 and AD mice model, MAPT
and 5xFAD, in order to test if endogenous HA is protective against AD pathologies in these models.
 This work will be conducted by Project 2 and supported by the Animal Core. In addition, the proposed
work will facilitate Projects 3 and 4 of the PPG that analyze the effects of HA on mutagenesis and on global
transcriptome changes triggered by HA. The proposed studies will open new avenues for developing drugs for
AD. If HA is protective, small molecule inhibitors of hyaluronan degrading enzymes could be developed to
increase the levels of HA in the brains.

## Key facts

- **NIH application ID:** 10123573
- **Project number:** 3P01AG047200-07S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Vera Gorbunova
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 3
- **Project period:** 2014-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123573

## Citation

> US National Institutes of Health, RePORTER application 10123573, Mechanisms of longevity in the naked mole rat: high molecular weight hyaluronan and stable epigenome. Supplement: Hyaluronan from naked mole rats as potential Alzheimer's disease therapy. (3P01AG047200-07S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10123573. Licensed CC0.

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