TY  - JOUR
AU  - Dellorusso, Paul V
AU  - Proven, Melissa A
AU  - Calero-Nieto, Fernando J
AU  - Wang, Xiaonan
AU  - Mitchell, Carl A
AU  - Hartmann, Felix
AU  - Amouzgar, Meelad
AU  - Favaro, Patricia
AU  - DeVilbiss, Andrew
AU  - Swann, James W
AU  - Ho, Theodore T
AU  - Zhao, Zhiyu
AU  - Bendall, Sean C
AU  - Morrison, Sean
AU  - Göttgens, Berthold
AU  - Passegué, Emmanuelle
TI  - Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
JO  - Cell stem cell
VL  - 31
IS  - 7
SN  - 1934-5909
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - DKFZ-2024-02326
SP  - 1020 - 1037.e9
PY  - 2024
AB  - 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.
KW  - Animals
KW  - Autophagy
KW  - Hematopoietic Stem Cells: metabolism
KW  - Inflammation: pathology
KW  - Inflammation: metabolism
KW  - Glycolysis
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Aging: pathology
KW  - Aging: metabolism
KW  - Cellular Senescence
KW  - Signal Transduction
KW  - Suppressor of Cytokine Signaling 3 Protein: metabolism
KW  - Glucose: metabolism
KW  - aging (Other)
KW  - autophagy (Other)
KW  - hematopoietic stem cells (Other)
KW  - inflammation (Other)
KW  - metabolism (Other)
KW  - regeneration (Other)
KW  - Suppressor of Cytokine Signaling 3 Protein (NLM Chemicals)
KW  - Glucose (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38754428
C2  - pmc:PMC11350610
DO  - DOI:10.1016/j.stem.2024.04.020
UR  - https://inrepo02.dkfz.de/record/294551
ER  -