Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells

Area of Science:

• Hematology
• Cellular Biology
• Aging Research

Background:

• Hematopoietic stem cell (HSC) dysfunction is a hallmark of aging, leading to various blood and immune disorders.
• Autophagy plays a critical role in HSC function, longevity, and response to metabolic stress.
• While some aged HSCs upregulate autophagy to maintain function, the signals and mechanisms remain unclear.

Approach:

• Investigated the role of chronic inflammation in the aging bone marrow niche on HSC function.
• Examined the impact of inflammation on glucose metabolism and AKT/FoxO signaling in aged HSCs.
• Assessed the effect of transient autophagy induction via fasting/refeeding on aged HSC metabolism and regenerative capacity.

Key Points:

• Chronic inflammation in aged bone marrow impairs HSC glucose metabolism and glycolysis via Socs3-mediated suppression of AKT/FoxO signaling.
• Autophagy activation serves as an adaptive survival response, preserving HSC quiescence by facilitating metabolic adaptation to impaired glycolysis.
• Transiently inducing autophagy through a fasting/refeeding regimen normalizes glucose uptake and glycolytic flux in aged HSCs.

Conclusions:

• Inflammation-induced glucose hypometabolism is a significant driver of HSC dysfunction during aging.
• Autophagy is a critical mediator of HSC adaptation to metabolic stress and inflammation.
• Targeting autophagy presents a promising strategy to restore the metabolic and regenerative capacity of aged HSCs.