# Lifelong impact of PAE on stem cell dynamics and cellular aging

> **NIH NIH UH2** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2022 · $220,433

## Abstract

Project Summary:
Prenatal alcohol exposure (PAE) is common and can result in brain-based disabilities and growth deficits. The
impact of PAE is not just in early development, but also can lead to secondary health problems throughout the
lifespan. These secondary problems can include higher rate and earlier onset of aging-related diseases,
including cardiovascular disease, autoimmune disorders such as arthritis, and decreased bone density. The
early onset of these aging-related diseases indicates that a consequence of PAE is premature aging of tissues
and organs. There is an unmet need to better understand this PAE-induced premature aging and determine
the underlying mechanisms that could be leveraged to delay or prevent these secondary health conditions.
We know that PAE is a potent teratogen that reprograms stem cells. Our hypothesis is that this stem cell
reprogramming has lifelong consequences, including the premature aging of stem cells as a mechanism that
drives systemic aging. This hypothesis is supported by published literature that shows PAE can disrupt stem
cell self-renewal, due, in part, to premature or aberrant differentiation, and that these disrupted stem cell
behaviors persist into adulthood. Based on these data, we plan to address two questions: firstly, “does PAE in
human populations diminish stem cell function across the lifespan?”; secondly, “does PAE induce or
exacerbate human stem cell aging?”.
To address the above two questions, we plan to create human induced pluripotent stem cells (hiPSCs), as
early passages of these cells retain epigenetic markers of aging. These cells will be derived from regionally
and ethnically diverse neonatal, child/adolescent, and adult cohorts of individuals with PAE/fetal alcohol
spectrum disorders (FASDs) and from matched controls. In Aim 1 we plan to use a panel of cellular and
molecular assays to assess PAE/FASD-induced changes in stem cell growth, self-renewal, and trilineage
(ectoderm, mesoderm, endoderm) differentiation. In Aim 2 we plan to assess alterations to stem cell aging,
including exhaustion, senescence, and release of pro-inflammatory molecules as part of the senescence-
associated secretory phenotype.
Our overarching goal, to ultimately identify underlying mechanisms mediate the emergence of secondary
health conditions for individuals with FASDs, is consistent with the mission of the NIAAA (RFA-AA-21-014).
PAE is known to inhibit stem cell function. However, tissue stem cells may also be a novel target for the
prevention and treatment of PAE-induced premature aging. At the conclusion of these studies, we will have:
firstly, created a unique community resource, a panel of patient-derived hiPSC cells, that can be used to
assess the systemic impact of PAE across the lifespan; secondly, expanded our knowledge of the impact of
PAE on stem cell behavior; and thirdly, identified important cellular mechanisms of premature aging.

## Key facts

- **NIH application ID:** 10470507
- **Project number:** 1UH2AA030186-01
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Amanda H. Mahnke
- **Activity code:** UH2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $220,433
- **Award type:** 1
- **Project period:** 2022-08-10 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470507

## Citation

> US National Institutes of Health, RePORTER application 10470507, Lifelong impact of PAE on stem cell dynamics and cellular aging (1UH2AA030186-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10470507. Licensed CC0.

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