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 HSCs during aging. This work has exciting implications for elucidating the biology of HSC aging, which may lead to strategies to restore blood and immune homeostasis in the elderly.

Public Health Relevance

The goal of this project is to understand how autophagy is utilized by a subset of hematopoietic stem cells (HSCs) from old mice to maintain their metabolism and function. The current lack of knowledge regarding the causes of HSC functional decline with age is a major roadblock in designing anti-aging interventions aimed at maintaining the regenerative function of the hematopoietic system. The research described here will provide important new insights into molecular mechanisms that can be targeted to improve HSC function in aging and prevent or delay the onset of associated blood pathologies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Welniak, Lisbeth A
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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