Journal Article

DKFZ-2024-02326

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.

Dellorusso, P. V. ; Proven, M. A. ; Calero-Nieto, F. J. ; Wang, X. ; Mitchell, C. A. ; Hartmann, F.DKFZ* ; Amouzgar, M. ; Favaro, P. ; DeVilbiss, A. ; Swann, J. W. ; Ho, T. T. ; Zhao, Z. ; Bendall, S. C. ; Morrison, S. ; Göttgens, B. ; Passegué, E.

2024
Elsevier Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.stem.2024.04.020

Abstract: Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche. We find that inflammation impairs glucose uptake and suppresses glycolysis in oHSCs through Socs3-mediated inhibition of AKT/FoxO-dependent signaling, with inflammation-mediated autophagy engagement preserving functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we show that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glycolytic flux and significantly boosts oHSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset oHSC regenerative capacity.

Keyword(s): Animals (MeSH) ; Autophagy (MeSH) ; Hematopoietic Stem Cells: metabolism (MeSH) ; Inflammation: pathology (MeSH) ; Inflammation: metabolism (MeSH) ; Glycolysis (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Aging: pathology (MeSH) ; Aging: metabolism (MeSH) ; Cellular Senescence (MeSH) ; Signal Transduction (MeSH) ; Suppressor of Cytokine Signaling 3 Protein: metabolism (MeSH) ; Glucose: metabolism (MeSH) ; aging ; autophagy ; hematopoietic stem cells ; inflammation ; metabolism ; regeneration ; Suppressor of Cytokine Signaling 3 Protein ; Glucose

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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