# Heterochronic hepatocyte transplantation to rejuvenate the aged liver

> **NIH NIH R21** · DUKE UNIVERSITY · 2024 · $442,750

## Abstract

Abstract: Heterochronic parabiosis and serum transfer models have given evidence for the rejuvenating
properties of young blood in old mice and equally potent deleterious effects of old blood in young mice. The
critical factors or even tissues responsible for such effects remained elusive due, in part, to the complexity of
the parabiosis models. Taking an organ-specific approach may lead to better understanding of how individual
tissues contribute to the effects we have seen with parabiosis. Since the liver is a critical organ regulating
whole-body metabolism and is the primary source of secreted proteins in circulation, it is an intriguing target
to manipulate its biological age and determine resulting functional and molecular changes. To alter the
biological age of the liver, we will utilize the heterochronic hepatocyte transplantation technique to incorporate
young cells in the aged liver, and vice versa. Isochronic hepatocyte transplantation and non-surgical groups
will serve as controls. We have generated preliminary data showing successful transplantation into both
young and old livers and see whole-body effects on adiposity to validate efficacy of the model. We
hypothesize the donor cells will engraft and influence the host liver to take on either, a more youthful or
accelerated aging state based on the donor cell age. Moreover, we hypothesize that transplanted cells will
contribute to the liver secretome and mimic profiles of the young and old plasma proteome. We will test these
hypotheses through the following aims. Aim1 will test the hypothesis that transplanted cells will alter the host
liver function, cellular landscape and biological age. We will measure clinical markers of liver function,
including AST, ALT and BUN after heterochronic transplantation. In addition, we will use the recently
developed 10xGenomics Xenium Spatial transcriptomic platform to determine how this procedure affects the
cellular landscape of the liver, while using epigenetic clocks as an indices of biological age of the tissue.
Aim2 will test the hypothesis that donor hepatocytes will alter host liver secretome dependent on the donor
cell age. Hepatocytes-derived secreted proteins will be measured using the MetRS mouse model to label
proteins in the plasma and compare the plasma proteome across groups. The proposed studies will fully test
the hypothesis that donor cells will engraft into the host liver and influence tissue function, cellular phenotype
and secretome, which may mimic the effects of heterochronic blood sharing.

## Key facts

- **NIH application ID:** 10987403
- **Project number:** 1R21AG086701-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** James P. White
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,750
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987403

## Citation

> US National Institutes of Health, RePORTER application 10987403, Heterochronic hepatocyte transplantation to rejuvenate the aged liver (1R21AG086701-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10987403. Licensed CC0.

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