# Autophagy Engagement and Hematopoietic Stem Cell Maintenance During Aging

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $45,079

## Abstract

The hallmarks of an aging blood system, including chronic inflammatory disorders, anemia, and hematological
malignancies, result in large part from the loss of hematopoietic stem cell (HSC) function. Age-associated loss
of HSC function is strongly linked to metabolic deregulation, loss of epigenetic fidelity, and exposure to chronic
inflammation in the bone marrow (BM) niche. Autophagy plays important roles in maintaining cellular fitness in
the face of aging stress across several mammalian tissues. Our laboratory recently published that a subset of
HSCs from aged mice had increased basal levels of autophagy flux (AThi oHSCs) relative to HSCs from young
mice (yHSCs), maintained a quiescent metabolic state, and demonstrated improved regenerative potential. In
contrast, most old HSCs that did not engage autophagy (ATlo oHSCs) were metabolically overactive and
exhibited classical age-related functional decline. This project aims to elucidate the intrinsic molecular
mediators and extrinsic signals that drive increased autophagy engagement and associated metabolic
maintenance in a subset of old HSCs. Preliminary data was generated to characterize the molecular
architecture of AThi and ATlo oHSCs vs. yHSCs, analyzing the chromatin accessibility landscape by ATAC-seq
and the transcriptome by RNA-seq. ATAC-seq analyses indicated conserved epigenetic de-repression in both
old HSC subsets at loci that are suggested to promote metabolic activation and inflammatory responses by
pathway analysis. The similarity in chromatin profiles between AThi and ATlo oHSCs suggests a lack of
engrained differences and, instead, points to an environmental driver of autophagy engagement in aging. In
this context, transcriptome analyses reveal a strong metabolic activation signature unique to ATlo oHSCs.
Supplementary validation narrowed the focus to the most differentially expressed gene in ATlo oHSCs,
Ppargc1a, which encodes the master regulator of mitochondrial oxidative metabolism PGC-1. The first aim
will determine if the increase in oxidative metabolism observed in ATlo oHSCs is driven by aberrant PGC-1
activity, the consequences of inducible genetic ablation of PGC-1 for steady state and stress hematopoiesis,
and if PGC-1 can be targeted pharmacologically to restore the metabolic profile of oHSCs. Transcriptome
analyses also identified a unique inflammation response signature in AThi oHSCs. In fact, preliminary validation
showed that differential autophagy engagement could be modeled in yHSCs using an in vivo inflammatory
TNF challenge. The second aim will investigate how inflammatory cytokine exposure drives autophagy
engagement in a subset of old HSCs, as opposed to a default response resulting in metabolic activation, and
determine if autophagy is required for a productive response to chronic inflammation in the aging BM niche.
Together, these aims will dissect the relationship between autophagy engagement, inflammatory signaling, and
metabolic activation in HS...

## Key facts

- **NIH application ID:** 10086774
- **Project number:** 5F31HL151140-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Paul Vincent Dellorusso
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $45,079
- **Award type:** 5
- **Project period:** 2020-01-01 → 2021-12-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086774

## Citation

> US National Institutes of Health, RePORTER application 10086774, Autophagy Engagement and Hematopoietic Stem Cell Maintenance During Aging (5F31HL151140-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10086774. Licensed CC0.

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