Age-associated changes in the response of tendon explants to stress deprivation is sex-dependent

<b>Purpose of the Study:</b> The incidence of tendon injuries increases dramatically with age, which presents a major clinical burden. While previous studies have sought to identify age-related changes in extracellular matrix structure and function, few have been able to explain fully why aged tissues are more prone to degeneration and injury. In addition, recent studies have also demonstrated that age-related processes in humans may be sex-dependent, which could be responsible for muddled conclusions in changes with age. In this study, we investigate short-term responses through an ex vivo explant culture model of stress deprivation that specifically questions how age and sex differentially affect the ability of tendons to respond to altered mechanical stimulus. <b>Materials and Methods:</b> We subjected murine flexor explants from young (4 months of age) and aged (22–24 months of age) male and female mice to stress-deprived culture conditions for up to 1 week and investigated changes in viability, cell metabolism and proliferation, matrix biosynthesis and composition, gene expression, and inflammatory responses throughout the culture period. <b>Results and Conclusions</b>: We found that aging did have a significant influence on the response to stress deprivation, demonstrating that aged explants have a less robust response overall with reduced metabolic activity, viability, proliferation, and biosynthesis. However, age-related changes appeared to be sex-dependent. Together, this work demonstrates that the aging process and the subsequent effect of age on the ability of tendons to respond to stress-deprivation are inherently different based on sex, where male explants favor increased activity, apoptosis, and matrix remodeling while female explants favor reduced activity and tissue preservation.

<b>研究目的：</b>肌腱损伤的发病率随年龄增长显著升高，给临床诊疗带来了沉重负担。既往研究虽已尝试阐明细胞外基质结构与功能的增龄性改变，但鲜有研究能够完整阐释老年组织更易发生退变与损伤的内在机制。此外，近期研究证实，人类的增龄相关生理过程存在性别依赖性，这或许是导致年龄相关变化研究结论混淆不清的关键原因。本研究采用应力缺失（stress deprivation）离体外植体培养模型，探究短期应激响应，旨在明确年龄与性别如何差异性调控肌腱对机械刺激改变的应答能力。
<b>材料与方法：</b>本研究选取年轻（4月龄）与老年（22~24月龄）雌雄小鼠的屈肌腱外植体，将其置于应力缺失培养环境中培养长达1周，并在整个培养周期内检测细胞活力、细胞代谢与增殖、基质合成与组成、基因表达以及炎症应答的动态变化。
<b>结果与结论：</b>本研究发现，衰老确实会显著影响肌腱外植体对应力缺失的应答能力：老年外植体整体应答强度更低，代谢活性、细胞活力、增殖能力与基质合成能力均出现显著下降。不过，增龄相关的改变呈现出显著的性别依赖性。综上，本研究证实，衰老进程以及衰老对肌腱应力缺失应答能力的后续影响，因性别存在本质差异：雄性外植体表现为活性升高、细胞凋亡与基质重塑增强，而雌性外植体则表现为活性降低且组织得以有效保留。