# Cerebromicrovascular rejuvenation by heterochronic blood exchange

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $442,112

## Abstract

PROJECT SUMMARY/ ABSTRACT
 Aging-induced cerebromicrovascular endothelial dysfunction is the primary factor in impairment
of neurovascular coupling (NVC) responses and dysregulation of cerebral blood flow (CBF),
contributing to the genesis of vascular cognitive impairment and dementia (VCID). Heterochronic blood
exchange (HBE) in mice as well as bioassay experiments in cultured endothelial cells treated with sera
from human patients, non-human primates and rodent models of aging provide compelling evidence
that implicates non-cell autonomous mechanisms as key drivers of endothelial aging processes.
Guided by analysis of vascular transcriptomic changes in heterochronic parabiont mice the objective
of the proposal is to elucidate the mechanism of cerebromicrovascular rejuvenation activated by
specific circulating anti-geronic factors present in young blood. The central hypothesis is that young
blood rescues the age-related decline in signaling via the NAD+/SIRT1 axis and reverses circulating
IGF-1 deficiency, each of which can result in vascular mitochondrial rejuvenation, attenuation of
endothelial oxidative stress, improved endothelial vasodilator function and restoration of endothelial
angiogenic processes. The resulting increases in CBF and NVC responses reduce ischemic loci,
promoting brain health. The following aims are proposed: 1) Determine the role of the
cerebromicrovascular NAD+ /SIRT1 axis in rejuvenation by HBE. The working hypothesis is that HBE
rescues the age-related decline in NAD+, which rejuvenates cerebromicrovascular endothelial cells via
a SIRT1-dependent pathway. It is predicted that disruption of the NAD+ /SIRT1 axis will prevent
cerebrovascular rejuvenation by HBE in aged mice. 2) Determine the role of circulating IGF-1 in
cerebromicrovascular rejuvenation by HBE. The working hypothesis is that HBE reverses age-related
IGF-1 deficiency, which exerts multifaceted endothelial protective effects contributing to
cerebromicrovascular rejuvenation by young blood. It is predicted that HBE-mediated endothelial
functional and transcriptomic changes are partially prevented by disruption of IGF-1/IGFR1 signaling.
3) Determine how circulating NAD precursors and IGF-1 in young and old humans determine
cerebromicrovascular endothelial function and phenotype. This will be tested by bioassaying the effects
of circulating factors and integrating the results with existing endothelial function, NVC and CBF data
from the serum donors. To optimize cognitive status prediction with automated machine learning we
will perform association analyses of endothelial signatures with cerebrovascular and cognitive
measures using linear mixed effect models. Together, the proposed studies will elucidate the
involvement of two key mechanisms in the protective effects of HBE against cerebromicrovascular
aging and the pathogenesis of VCID.

## Key facts

- **NIH application ID:** 10891786
- **Project number:** 4R01AG072295-02
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Anna Csiszar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,112
- **Award type:** 4N
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891786

## Citation

> US National Institutes of Health, RePORTER application 10891786, Cerebromicrovascular rejuvenation by heterochronic blood exchange (4R01AG072295-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10891786. Licensed CC0.

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