» Articles » PMID: 38754428

Autophagy Counters Inflammation-driven Glycolytic Impairment in Aging Hematopoietic Stem Cells

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.

Citing Articles

Deciphering the Complexities of Adult Human Steady State and Stress-Induced Hematopoiesis: Progress and Challenges.

Watt S, Roubelakis M Int J Mol Sci. 2025; 26(2).

PMID: 39859383 PMC: 11766050. DOI: 10.3390/ijms26020671.


The dichotomic role of cytokines in aging.

Silva R Biogerontology. 2024; 26(1):17.

PMID: 39621124 DOI: 10.1007/s10522-024-10152-4.


Hematopoietic stem cell metabolism within the bone marrow niche - insights and opportunities.

Kemna K, van der Burg M, Lankester A, Giera M Bioessays. 2024; 47(2):e2400154.

PMID: 39506498 PMC: 11755706. DOI: 10.1002/bies.202400154.


CHIP: a clonal odyssey of the bone marrow niche.

Schleicher W, Hoag B, De Dominici M, DeGregori J, Pietras E J Clin Invest. 2024; 134(15).

PMID: 39087468 PMC: 11290965. DOI: 10.1172/JCI180068.

References
1.
Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

2.
Hopkins B, Goncalves M, Cantley L . Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol. 2020; 16(5):276-283. PMC: 7286536. DOI: 10.1038/s41574-020-0329-9. View

3.
Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

4.
Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D . IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol. 2003; 4(6):551-6. DOI: 10.1038/ni938. View

5.
Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H . Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med. 2004; 10(7):739-43. DOI: 10.1038/nm1071. View