PDF(Pubmed)
Abstract：
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.
摘要：
尽管人类寿命在上个世纪显著增加，采用高热量饮食（HCD）推动了全球2型糖尿病的增加，肥胖和心血管疾病，阻碍健康相应改善的疾病。反映这种情况与慢性全身性炎症有关，有证据表明，寄生虫感染可以防止肥胖加速衰老，凭借其促进生存的抗炎分子的进化。的确,ES-62，一种丝状线虫刺五加的抗炎分泌产物，改善了经历肥胖加速衰老的雄性和雌性C57BL/6J小鼠的健康状况，并延长了雄性动物的中位寿命，通过对炎症产生积极影响，衰老的脂肪代谢和肠道微生物组参数。因此，我们探索了ES-62是否影响整合环境信号的骨免疫学轴，例如饮食和肠道微生物组来稳态调节造血和免疫反应的训练，在（肥胖加速）衰老过程中失调。值得注意的是，我们发现性二态在骨骼健康下降中，以及相关的造血功能失调和随之而来的外周免疫反应，在肥胖加速衰老期间，强调制定针对性别的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）生态位，以对抗造血干细胞（HSC）功能的衰老相关下降，这突出了对骨髓谱系的偏见，在男性，而不是女性，HCD喂养的小鼠。ES-62抑制脂肪细胞和巨核细胞偏向并相应地促进BM中B淋巴细胞增加的能力证明了这一点。此外，随后预防与衰老相关的骨髓/淋巴样偏斜与脂肪组织中炎症CD11c+巨噬细胞和IL-1β的积累减少有关，在HCD喂养的雄性小鼠肥胖加速衰老过程中，破坏了炎症驱动的造血功能失调的持续存在。最后,我们报告了ES-62的小药物样分子类似物模拟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，强调这些研究的转化潜力。
