Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom.
Blood Adv. 2023 Jan 24;7(2):256-268. doi: 10.1182/bloodadvances.2022007033.
Rapid and effective leukocyte response to infection is a fundamental function of the bone marrow (BM). However, with increasing age, this response becomes impaired, resulting in an increased burden of infectious diseases. Here, we investigate how aging changes the metabolism and function of hematopoietic progenitor cells (HPCs) and the impact of the BM niche on this phenotype. We found that, in response to lipopolysaccharide-induced stress, HPC mitochondrial function is impaired, and there is a failure to upregulate the TCA cycle in progenitor populations in aged animals compared with young animals. Furthermore, aged mesenchymal stromal cells (MSCs) of the BM niche, but not HPCs, exhibit a senescent phenotype, and selective depletion of senescent cells from the BM niche, as well as treatment with the senolytic drug ABT-263, improves mitochondrial function of HPCs when stressed with lipopolysaccharide. In summary, age-related HPC metabolic dysfunction occurs indirectly as a "bystander phenomenon" in the aging BM niche and can be restored by targeting senescent MSCs.
快速有效的白细胞对感染的反应是骨髓（BM）的基本功能。然而，随着年龄的增长，这种反应会受损，导致传染病的负担增加。在这里，我们研究了衰老如何改变造血祖细胞（HPC）的代谢和功能，以及 BM 龛对这种表型的影响。我们发现，在脂多糖诱导的应激下，HPC 的线粒体功能受损，与年轻动物相比，老年动物祖细胞群中 TCA 循环的上调失败。此外，衰老的 BM 龛间充质基质细胞（MSCs），而不是 HPCs，表现出衰老表型，并且选择性地从 BM 龛中耗尽衰老细胞，以及用 senolytic 药物 ABT-263 治疗，当用脂多糖应激时，可改善 HPC 的线粒体功能。总之，与年龄相关的 HPC 代谢功能障碍是衰老的 BM 龛中的一种“旁观者现象”，可以通过靶向衰老的 MSCs 来恢复。
