The parasitic worm product ES-62 protects the osteoimmunology axis in a mouse model of obesity-accelerated ageing.
The parasitic worm product ES-62 protects the osteoimmunology axis in a mouse model of obesity-accelerated ageing.
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DOI：
10.3389/fimmu.2022.953053
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
尽管在上个世纪人类寿命显著增加，但高热量饮食（HCD）的采用已经推动了全球2型糖尿病、肥胖症和心血管疾病的增加，这些疾病阻碍了健康寿命的相应改善。反映出这种情况与慢性全身性炎症有关，有证据表明，寄生蠕虫感染可能会通过促进生存的抗炎分子的进化来防止肥胖加速衰老。事实上，ES-62是一种丝状线虫Acanthocheilonema viteae的抗炎分泌产物，通过对炎症、脂肪代谢和肠道微生物组老化参数产生积极影响，改善了经历肥胖加速老化的雄性和雌性C57 BL/6 J小鼠的健康寿命，并延长了雄性动物的中位寿命。因此，我们探讨了ES-62是否影响骨免疫学轴，该轴整合了环境信号，如饮食和肠道微生物组，以稳态调节造血和免疫反应的训练，这些免疫反应在（肥胖加速）衰老期间变得失调。值得注意的是，我们发现在肥胖加速衰老过程中，骨骼健康下降以及相关的造血功能失调和随之而来的外周免疫反应中存在性别二态性，这突出了制定性别特异性抗衰老策略的重要性。与此相关，ES-62保护骨小梁结构，维持骨髓（BM）小生境，对抗造血干细胞（HSC）功能的衰老相关下降，这一下降在雄性而非雌性的HCD喂养小鼠中突出表现为骨髓谱系。这通过ES-62抑制脂肪细胞和巨核细胞偏好性并相应地促进BM中B淋巴细胞增加的能力得到证明。此外，随后预防衰老相关的骨髓/淋巴偏斜与脂肪组织中炎性CD 11 c+巨噬细胞和IL-1β的积累减少有关，破坏了雄性HCD喂养小鼠在肥胖加速衰老期间炎症驱动的造血失调的持续存在。最后，我们报告了ES-62的小药物样分子类似物模仿其一些关键作用的能力，特别是在强烈保护骨小梁结构方面，突出了这些研究的转化潜力。
Despite significant increases in human lifespan over the last century, adoption of high calorie diets (HCD) has driven global increases in type-2 diabetes, obesity and cardiovascular disease, disorders precluding corresponding improvements in healthspan. Reflecting that such conditions are associated with chronic systemic inflammation, evidence is emerging that infection with parasitic helminths might protect against obesity-accelerated ageing, by virtue of their evolution of survival-promoting anti-inflammatory molecules. Indeed, ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, improves the healthspan of both male and female C57BL/6J mice undergoing obesity-accelerated ageing and also extends median lifespan in male animals, by positively impacting on inflammatory, adipose metabolic and gut microbiome parameters of ageing. We therefore explored whether ES-62 affects the osteoimmunology axis that integrates environmental signals, such as diet and the gut microbiome to homeostatically regulate haematopoiesis and training of immune responses, which become dysregulated during (obesity-accelerated) ageing. Of note, we find sexual dimorphisms in the decline in bone health, and associated dysregulation of haematopoiesis and consequent peripheral immune responses, during obesity-accelerated ageing, highlighting the importance of developing sex-specific anti-ageing strategies. Related to this, ES-62 protects trabecular bone structure, maintaining bone marrow (BM) niches that counter the ageing-associated decline in haematopoietic stem cell (HSC) functionality highlighted by a bias towards myeloid lineages, in male but not female, HCD-fed mice. This is evidenced by the ability of ES-62 to suppress the adipocyte and megakaryocyte bias and correspondingly promote increases in B lymphocytes in the BM. Furthermore, the consequent prevention of ageing-associated myeloid/lymphoid skewing is associated with reduced accumulation of inflammatory CD11c+ macrophages and IL-1β in adipose tissue, disrupting the perpetuation of inflammation-driven dysregulation of haematopoiesis during obesity-accelerated ageing in male HCD-fed mice. Finally, we report the ability of small drug-like molecule analogues of ES-62 to mimic some of its key actions, particularly in strongly protecting trabecular bone structure, highlighting the translational potential of these studies.
影响因子：
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作者：
Selman C;Sinclair A;Pedroni SM;Irvine EE;Michie AM;Withers DJ
通讯作者：
Withers DJ
影响因子：
3.4
作者：
Farkasdi S;Pammer D;Rácz R;Hriczó-Koperdák G;Szabó BT;Dobó-Nagy C;Kerémi B;Blazsek J;Cuisinier F;Wu G;Varga G
通讯作者：
Varga G