# A New Translational Rat Model for Evaluating Anti-Aging Interventions

> **NIH NIH R33** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $728,662

## Abstract

We propose to develop as sustainable aging research infrastructure, a new and unique genetically
heterogeneous laboratory rat model that can be used to evaluate putative life- and health-extending
interventions. The rat has numerous advantages over the mouse for interventional aging research including more
human-like physiology and pathophysiology, more cognitive sophistication, and greater genetic diversity
compared with standard mouse strains. Inspired by the UM-HET3 mice used by the Interventions testing
program, our rat model (OKC-HETb/w) will also be populations of genetically heterogeneous F2 descendants of 4
divergent, inbred strains. A significant difference from the UM-HET3 mice, our breeding scheme takes advantage
of the rat’s substantial mitochondrial genomic diversity compared with the mouse to create a population half of
which carries the BN strain mitochondria (OKC-HETb), the other half carries the WKY strain mitochondria (OKC-
HETw). These mitochondrial genomes mimic great human mitochondrial diversity in that they differ at 95
nucleotides involving 11 of 13 mitochondrial protein-coding genes, 5 tRNA’s and both ribosomal subunits. Our
preliminary data show that the OKC-HETb and OKC-HETw rats respond differently to exercise endurance, grip
strength, and responsiveness to 17α-estradiol. As a proof of principle, we will evaluate in the OKC-HETb/w rat an
anti-aging intervention (17α-estradiol) that was previously found to enhance the longevity of male mice only. An
intriguing outcome of our project will be to verify whether or not, this sex-specificity is also seen in our rat model.
In the R21 phase of this project we will produce the OKC-HETb/w rats and (1) characterize energetics-based
health assays at whole animal and cellular levels under standard and stressed (HFD) conditions in both sexes
in both mitochondrial genotypes, (2) determine the dose of 17α-estradiol that will yield blood levels comparable
to those found at effective life-extending doses in the ITP study and the short-term effects of 17α-estradiol on
metabolic parameters in diet-induced obese mice of both sexes, and (3) provide investigators with tissues as
well as young and old OKC-HETb/w. In the R33 phase, we will use the information gained in the R21 phase to:
(1) determine the effect of 17α-estradiol on the longevity and age-related pathology in both sexes and both
mitochondrial genotypes and (2) determine the long-term effects of 17α-estradiol on age-related changes in
metabolic and health parameters, again, in both sexes and both mitochondrial genotypes.

## Key facts

- **NIH application ID:** 11083189
- **Project number:** 4R33AG072137-03
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** STEVEN N. AUSTAD
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $728,662
- **Award type:** 4N
- **Project period:** 2022-07-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11083189

## Citation

> US National Institutes of Health, RePORTER application 11083189, A New Translational Rat Model for Evaluating Anti-Aging Interventions (4R33AG072137-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11083189. Licensed CC0.

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